What changed in this filing

/stocks — the workspaceLOADING

Item 1. Business

2021-03-03 compared with 2020-03-03 · 1459 added, 1982 removed, 214 unchanged (94% of the section changed)

We are a clinical-stage

biotechnology company developing novel medicines to bring the curative power of immune reset to more patients with autoimmune diseases, blood cancers and genetic diseases.

Resetting the immune system through stem cell transplant is a well-established and often curative medical procedure involving a two-step process:

(i) removing the disease-causing cells and (ii) replacing them with healthy cells to rebuild the immune system.

As it exists today, stem cell transplant is a large market opportunity, but

currently only approximately 40 percent of eligible patients receive a curative immune reset because of the risks and toxicities associated with the transplant procedure.

New approaches are needed to extend immune reset to more patients,

including drugs to:

collect sufficient stem cells to rebuild a healthy immune system, remove disease-causing cells and prevent complications in rebuilding the new immune system.

At Magenta, we believe we are uniquely positioned to address these opportunities and to lead a new era in immune reset.

Our portfolio of

product candidates includes biologics, small molecules and a cell therapy designed as new approaches to extend the curative power of immune reset through transplant to more patients across many diseases.

Currently, only a fraction of eligible

patients with these diseases receive a transplant because the risks and challenges outweigh the potential for a cure.

These include diseases where transplant is a standard of care (e.g., blood cancers such as acute myelogenous leukemia,

myelodysplastic syndromes, multiple myeloma, and non-Hodgkin lymphoma), diseases where transplant is performed but limited in use (e.g., hemoglobinopathies such as sickle cell disease and beta-thalassemia) and

autoimmune diseases (e.g., multiple sclerosis and systemic sclerosis).

Emerging clinical data suggest that immune reset through stem cell transplant may represent a breakthrough approach with curative potential for patients with severe autoimmune

For example, recent results from multiple clinical trials show that patients with autoimmune diseases, including multiple sclerosis and systemic sclerosis, can be cured with a transplant.

However, based on our epidemiology analyses,

currently only approximately 1 to 2% of eligible patients with these autoimmune diseases in the U.S.

and Europe receive a stem cell transplant.

To harness the curative power of immune reset through stem cell transplant for more patients, we have created a new stem cell biology

discovery platform and are developing a comprehensive portfolio of novel therapeutics.

Our programs will allow more patients to benefit through a more precise stem cell transplant process.

This includes targeted conditioning medicines that remove

the disease-causing cells before transplant (conditioning program), a medicine for stem cell collection for donors and patients (mobilization program) and a cell therapy with a high stem cell dose to rebuild a healthy immune system (cell therapy

Our conditioning programs, including MGTA-117, are designed to selectively remove disease-causing stem and/or immune cells from a patient prior to transplant, and to be far less toxic than the decades-old radiation and chemotherapy-based approaches, which are still the only available options.

Within our mobilization program, MGTA-145 is our first-line stem cell

mobilization product candidate, and it is designed to enable physicians to more easily collect a greater number of blood stem cells, known as hematopoietic stem cells or HSCs, from patients and donors to improve patient outcomes and scale the

capacity of transplant and apheresis centers.

MGTA-456 is a cell therapy designed to provide a high dose of stem cells that are well matched to the patient, and it has the potential to allow more patients to

have a better chance for a successful stem cell transplant.

Our program to prevent post-transplant complications is designed to target the donor immune cells within the patient that cause Graft vs.

Host Disease, or GvHD, and allow safe rebuilding of

a healthy immune system (post-transplant complications program).

We intend to become a fully integrated discovery, development and commercial company that

will pioneer the field of immune reset.

We believe that our product portfolio will offer significant commercial synergies.

We are developing our products so that they can each be used individually or in combination with each other.

As a result, our

portfolio could be utilized in a manner tailored to the patients disease, such that a patient may receive more than one Magenta therapy as part of their individual immune reset journey.

Our goal is to advance our medicines through registration trials and commercialize them.

We expect to do this based on clinical results and a

dialogue with agencies and payers.

Our two most advanced product candidates, MGTA-145 and MGTA-456, are expected to be in multiple Phase 2 trials in 2020 and our first

targeted conditioning product candidate, MGTA-117, is anticipated to enter clinical development in 2021.

We expect to continue to advance our portfolio and innovate through our sustainable platform.

Background on Immune Reset through Stem Cell Transplant

Bone marrow is the tissue inside the bones where HSCs are located.

HSCs produce all of the cells in the blood and immune systems, including:

cells and B cells to fight infections;

red blood cells to carry oxygen;

and platelets to control bleeding.

Bone marrow is highly active and gives rise to billions of new cells every day.

However, abnormal functioning of bone marrow can lead to

serious and sometimes fatal blood and immune diseases.

The aim of stem cell transplant, also called HSC transplant or bone marrow transplant, is to replace the diseased blood and immune cells with new stem cells that will produce a healthy new blood

and immune system.

Stem cell transplant is a well-established procedure to reset the immune system with curative intent and is rooted in decades of clinical experience.

Starting from the first stem cell transplant in 1956, more than 1 million patients with blood cancers and genetic diseases worldwide have

undergone a stem cell transplant, and currently approximately 65,000 patients in the U.S.

and Europe undergo the procedure annually.

Stem cell transplant serves as the standard of care in many blood cancers, such as leukemias, lymphomas and multiple

myeloma, and for rare genetic diseases such as Hurler syndrome.

However, stem cell transplant is a procedure that carries significant

risks, including serious complications such as infection, infertility, secondary cancers and even death.

A majority of patients who could significantly benefit from or be cured by a transplant do not receive one, primarily because of the toxicity

and risks associated with the procedure.

For example, primarily because of these risks, approximately two out of three eligible patients suffering from acute myeloid leukemia do not receive a transplant despite it being the standard of care.

debilitating but non-life-threatening diseases, such as sickle cell disease and multiple sclerosis, even fewer patients are offered and receive a transplant because the risks of the current transplant

procedure often outweigh the potential benefits.

There is a clear opportunity to improve the safety and efficacy of transplant so that we can bring the curative power of immune reset to more patients.

Our mission and our culture

are centered around the goal of enabling more patients with severe or life-threatening diseases to have access to the transformative benefit of immune reset.

We intend to provide physicians with a tailored, multi-product treatment regimen based on

the disease setting and the individual needs of each patient.

Magenta Therapeutics is a clinical-stage biotechnology company developing novel medicines to bring the curative power of stem cell transplants to more patients with blood cancers, genetic diseases and autoimmune diseases.

Magenta’s drug development pipeline includes multiple product candidates designed to improve stem cell transplants.

Our lead clinical program is designed to more efficiently and reliably mobilize and collect sufficient functional stem cells for use in stem cell transplantation, a process known as mobilization.

We are also developing product candidates that are designed to deplete targeted cells in the bone marrow to make space for the bone marrow to receive newly transplanted stem cells, a process known as conditioning.

Our mobilization program is intended to enable rapid, reliable, predictable and safe mobilization and collection of high numbers of functional stem cells for transplant.

Magenta’s targeted conditioning programs are intended to enhance the efficacy of and/or reduce the dosing levels, intensity or, in some cases, even the need for chemotoxic agents.

Stem cell transplant is an established and, for certain patients, can be a curative medical procedure that can reset a patient’s blood and immune system after the patient has received treatment for certain blood cancers, genetic diseases or autoimmune diseases.

Stem cell transplants involve a three-step process:

(i) stem cells are mobilized out of the patient’s or donor’s bone marrow and collected from the blood (or, in rare cases, surgically extracted from their bone marrow);

(ii) the patient’s bone marrow is cleared of any remaining stem cells in order to make space to receive new transplanted stem cells;

and (iii) the stem cells are transplanted into the patient via infusion where they fasten to, or engraft in, the bone marrow and grow into the blood cells and platelets that form the basis of a reset and rebuilt blood and immune system.

All transplants are categorized as either autologous or allogeneic depending on the source of the new stem cells for the transplant.

In an autologous transplant, the patient’s own stem cells are used.

In an allogeneic transplant, patients receive cells from a stem cell donor.

Stem cell transplant, whether autologous or allogeneic, has broad applicability across disease settings, including blood cancers, gene therapies for genetic diseases and autoimmune diseases.

It is the current standard of care for certain blood cancers such as acute myeloid leukemia, or AML, myelodysplastic syndromes, or MDS, multiple myeloma and non-Hodgkin’s

Hematopoietic stem cell, or HSC, -based gene therapies also rely on the same steps of the stem cell transplant process with an additional step where collected stem cells are gene-corrected or modified to address the underlying disease prior to transplant.

Such gene therapy approaches that leverage the stem cell transplant procedure are being investigated by numerous companies in a variety of diseases, including sickle cell disease, beta-thalassemia and lysosomal storage disorders.

Autoimmune diseases such as multiple sclerosis and systemic sclerosis may also benefit from resetting the immune system through stem cell transplant.

Currently, the number of days required to mobilize and collect a patient’s or donor’s stem cells is a minimum of five days in blood cancer patients and healthy donors and as many as 30 days or more in patients with sickle cell disease.

When planning for a patient’s transplant, transplanting physicians cannot reliably predict at the outset how long it will take for patients to mobilize the number of cells required.

Many patients require multiple collections, including approximately 40% of blood cancer patients and 75% of sickle cell disease patients.

including personnel time, and the indirect costs associated with the need to block time in the limited number of chairs in transplant centers that are used to collect stem cells.

Similarly, HSC-based

gene therapies could benefit from more efficient collection of stem cells which could potentially reduce gene therapy manufacturing timelines and costs.

Additionally, there are no approved mobilization options for patients with sickle cell disease and autoimmune diseases, and the off-label

use of currently available medicines is associated with significant safety risks including vaso-occlusive events in sickle cell disease patients.

Magenta is developing MGTA-145

for stem cell mobilization in a broad range of diseases, for both autologous and allogeneic transplants.

is Magenta’s biologic stem cell mobilization product candidate designed to address these time and cost inefficiencies while enabling the rapid, reliable, predictable and safe collection of functional blood stem cells for transplant in a single day.

In 2020, we completed a Phase 1 clinical trial in healthy volunteers to evaluate the ability of MGTA-145,

in combination with plerixafor, to mobilize stem cells.

Based on the results of the study, we have advanced the program into three ongoing and planned Phase 2 clinical trials, including an autologous transplant trial in multiple myeloma patients;

an allogeneic transplant trial with healthy donor cells collected for transplant in patients with acute myeloid leukemia, myelodysplastic syndromes or acute lymphocytic leukemia, or ALL;

and lastly, a planned trial in partnership with bluebird bio, Inc.

to mobilize and collect the stem cells of sickle cell disease patients.

In addition to the opportunity to address the challenges in mobilization and collection of stem cells, Magenta also seeks to improve patient conditioning prior to transplant.

Conditioning is the process by which patients are treated with chemotherapy prior to transplant to ensure that the bone marrow has sufficient space to receive newly transplanted stem cells.

Currently, only approximately 50% of eligible patients receive a stem cell transplant, in part because of the risks and toxicities of the chemotherapeutic agents available today.

Magenta’s lead conditioning program, MGTA-117,

is designed to selectively deplete stem cells and reduce the need for high-dose or high-intensity chemotherapeutic agents in oncology applications and potentially eliminate the use of busulfan in gene therapy applications.

Our additional research-stage conditioning programs target stem and/or immune cells and are being designed to eliminate toxic chemotherapy conditioning regimens across multiple disease settings.

Our C100 program focuses on addressing opportunities in immune reset for autoimmune diseases.

Our C300 program is being designed to provide for lymphodepletion prior to cell therapies such as chimeric antigen receptor T cells, or CAR-T.

Our G100 program is being designed to provide prophylaxis of graft-versus-host disease, a common post-transplant complication following allogeneic stem cell transplant.

Magenta is also evaluating two programs with potential in cell therapy.

Each is a small molecule used to manufacture a high number of functional stem cells, from either a donor or gene-modified stem cells from a patient.

is a cell therapy designed to generate higher cell doses that are well matched to the patient, which has been shown to improve the speed and success of engraftment in stem cell transplant and improve disease outcomes.

In June 2020, we announced that we discontinued enrollment in our Phase 2 trial of MGTA-456

in inherited metabolic diseases.

Enrollment in an investigator-initiated trial in patients with blood cancers has been completed, and we plan to use these data, when available, to inform a decision regarding future program development in blood cancers.

Our second cell therapy program, E478, is a small molecule aryl hydrocarbon receptor, or AHR, antagonist which

uses the same mechanism used to manufacture MGTA-456

to expand gene-modified HSCs for stem cell-based gene therapy and genome editing.

Magenta intends to become a fully integrated discovery, development and commercial company in the field of stem cell transplant.

We are developing our product candidates to be used individually or, in some cases, in combination with each other.

As a result, our portfolio could be tailored to the patient’s disease, such that a patient may receive more than one Magenta therapy as part of his or her individual stem cell transplant.

Our goal is to advance our product candidates through regulatory approval and bring them to the commercial market based on the data from our clinical trials and communications with regulatory agencies and payer communities.

We expect to continue to advance our portfolio and innovate through our productive research platform.

Stem Cell Transplant:

The Process and Current Opportunities

A stem cell transplant procedure involves three main steps:

(i) stem cells from the patient’s or donor’s bone marrow are collected;

(ii) the patient’s bone marrow is cleared of any remaining stem cells in order to make space to receive new transplanted stem cells;

All transplants are categorized as either autologous or allogeneic, depending on the source of the new stem cells for the transplant.

In an autologous transplant—used for conditions such as multiple myeloma, non-Hodgkin’s

lymphoma and autoimmune diseases—the patient’s own stem cells are used.

In the case of stem cell gene therapy and genome editing, once the cells are collected from the patient, these cells are then modified to either insert a functioning gene into, or correct a defective gene within, the collected stem cells before they are transplanted into the patient via infusion.

In an allogeneic transplant—used for conditions such as acute leukemias and myelodysplastic syndromes—patients receive cells from a stem cell donor.

The preferred source of stem cells for an allogeneic transplant is a donor from a biological relative who has a well-matched immune system.

For patients without a matched related donor, the second option is a matched unrelated donor identified through a bone marrow donor registry.

For patients without a matched related or unrelated donor, other options include mismatched donors, who can either be unrelated or related;

however, transplant outcomes are not optimal with these donor types.

Magenta’s mission and culture are centered around the goal of enabling more patients with severe or life-threatening diseases to have access to the transformative benefit of stem cell transplant.

We intend to provide transplant physicians with a tailored, multi-product treatment regimen based on the disease setting and the individual needs of patients.

Our strategic priorities are as follows:

Bring the curative power of

immune reset through stem cell transplant to all patients who can benefit by advancing an integrated product portfolio :

We believe we are the only company that is committed to addressing the major opportunities in stem cell transplant

and transplant-based therapies, such as stem cell gene therapy, to revolutionize this entire field of medicine.

Our product engine is generating a comprehensive portfolio of therapies to optimize the immune reset process.

Our initial focus is on

autoimmune diseases, blood cancers and genetic diseases, and we also plan to address other diseases for which immune reset could represent a one-time, curative treatment.

Build on our deep expertise in stem cell biology to lead a new era in immune reset

through stem cell transplant :

We have assembled a group of world leaders and pioneers in the fields of stem cell biology, biotherapeutics and transplant medicine.

With this team, we are converting recent scientific

breakthroughs into a product engine for immune reset therapies.

Create a fully integrated patient-focused biotechnology

We are building a fully integrated biotechnology company with end-to-end capabilities in research, development and commercialization, and we

believe the broad and synergistic nature of our portfolio will allow us to address many of the significant limitations of immune reset through stem cell transplant and transplant-based therapies.

Commercialize our therapeutics to bring tailored immune reset solutions to physicians and patients :

We are developing our

portfolio of products so that they can be used individually or in combination with each other, such that a patient may receive more than one Magenta therapy as part of their individual patient journey.

Our commercial model centers around

hospital-based prescribers, and this is consistent across all of the products in our portfolio.

Stem cell transplants are performed in a few hundred accredited medical centers in the U.S.

Bring the curative power of blood and immune reset through stem cell transplant to all patients who can benefit by advancing an integrated product portfolio

We believe we are the only company that is committed to

addressing both mobilization and conditioning opportunities in stem cell transplant and HSC-based

gene therapies.

We are focused on creating a comprehensive portfolio of therapies to optimize the blood and immune reset process.

Our initial focus is on blood cancers, genetic diseases and autoimmune diseases, and we also plan to address other diseases for which blood and immune reset could represent a one-time,

curative treatment.

Build on our deep expertise in stem cell biology to lead a new era in blood and immune reset through stem cell transplant

We have assembled a group of experts in the fields of stem cell biology, biotherapeutics and transplant medicine.

With this team, we plan to convert recent scientific breakthroughs into a pipeline of product candidates for blood and immune reset therapies.

Create a fully integrated patient-focused biotechnology company

We are building a fully integrated biotechnology company with end-to-end

capabilities in research, development and commercialization, and we believe the broad and synergistic nature of our portfolio will allow us to address many of the significant limitations of stem cell transplant and transplant-based therapies.

Commercialize our drug products to bring tailored blood and immune reset solutions to patients and physicians

Our commercial planning centers around hospital-based prescribers, and this is consistent across all product candidates in our portfolio.

Stem cell transplants are performed in approximately 450 accredited medical centers in the U.S.

and Europe, with more than half of the U.S.

performed at 20% of transplant centers.

We believe the synergies among our programs and the well-defined structure of the current stem cell transplant provider network will allow us to commercialize all of our own therapeutics in the U.S.

through a focused, targeted commercial organization.

Leverage our two most advanced product candidates, MGTA-145 and MGTA-456, as clinical catalysts and commercial beachheads for our portfolio :

In addition to the potential to bring meaningful clinical benefit to

patients, MGTA-145 and MGTA-456 provide strategic value to Magenta by allowing us to accelerate the build-out of our clinical

development infrastructure and footprint and to establish key customer relationships that will be important for future commercialization of all of our products.

Continue to integrate our innovative collaboration with National Marrow Donor Program with our science, medicine and business

National Marrow Donor Program (as successor in interest to Be the Match Biotherapies, LLC), or NMDP, is a leading patient-focused stem cell transplant organization in the U.S.

Because of our shared patient focus, we and

NMDP have established a broad, first-of-its-kind collaboration.

This collaboration positions us as a partner with high-priority

access to many services that will continue to enable us to establish relationships across transplant centers and with key transplant physicians.

Through our partnership, we access clinical strategy support;

clinical development operational support,

including a unique cell supply platform that is very well established at NMDP and which will also enable our commercialization efforts across several programs.

We also have access to the NMDP payer and policy group to inform and support our pricing

and reimbursement plans across the portfolio.

Strategically collaborate to realize the full potential of our

We currently retain 100% of the commercial rights for our products, including all uses of MGTA-456 other than gene-modified stem cells.

We will evaluate additional collaborations to:

maximize the patient impact of our portfolio by partnering to enable gene and cell therapies, including stem

cell-based gene therapies, genome editing and CAR T therapy;

build relationships with partners to access complementary expertise and capabilities to bring our therapies as

quickly as possible to all patients who can benefit;

procedures performed at 20% of transplant centers.

We have established relationships with key stakeholders within many of these top transplant centers.

We believe the synergies among our programs and the well-defined structure of the current stem cell transplant provider network will allow us to commercialize our therapeutics through a focused, targeted commercial and medical affairs organization.

Leverage MGTA-145

as our most advanced product candidate in the clinic and as a possible first commercial product for our portfolio

In addition to the potential to bring meaningful clinical benefit to patients, MGTA-145

provides strategic value to Magenta by allowing us to accelerate the build-out

of our clinical development infrastructure and footprint and to establish key prescriber relationships that will be important for future commercialization of our products.

Continue to integrate our innovative collaboration with National Marrow Donor Program/Be the Match with our science, medicine and business approaches

National Marrow Donor Program (as successor in interest to Be the Match Biotherapies, LLC), or Be the Match, is a leading patient-focused stem cell transplant organization in the U.S.

Because of our shared patient focus, we and Be the Match established a broad, first-of-its-kind

collaboration in 2017.

This collaboration positions us as a partner with high-priority access to many services that will continue to enable us to establish relationships across transplant centers and with key transplant physicians.

Through our partnership, we access clinical strategy support and clinical development operational support, including a cell supply platform which will enable our commercialization efforts across several programs.

We also have access to the Be the Match payer and policy group to inform and support our pricing and reimbursement plans across the portfolio.

In June 2020, we announced a clinical collaboration agreement with Be the Match, as an extension of our existing strategic partnership, to evaluate the potential utility of MGTA-145,

in combination with plerixafor, for mobilizing and collecting HSCs from donors more efficiently and then using them for allogeneic transplants in patients.

Strategically collaborate to realize the full potential of our portfolio

We own all product rights across our mobilization and conditioning programs, including MGTA-145

and MGTA-117.

We will evaluate additional collaborations when available to:

maximize the patient impact of our portfolio by finding value-creating partnerships to enable gene and cell therapies, including stem cell-based gene therapies, genome editing and CAR-T

build relationships with partners to access complementary expertise and capabilities to bring our therapies as quickly as possible to all patients who can benefit;

opportunistically bring in preclinical or clinical assets that fit with our integrated portfolio.

Immune Reset through Stem Cell Transplant:

The Process and Current Opportunities

A stem cell transplant procedure involves two main steps:

(i) removing the disease-causing cells and (ii) replacing them with healthy

new stem cells to rebuild a new immune system.

All transplants are categorized as either autologous or allogeneic, depending on the source of the new stem cells for the transplant.

In an autologous transplantused for conditions such as autoimmune diseases, multiple

myeloma and non-Hodgkin lymphomathe patients own stem cells are used.

In the case of stem cell gene therapy and genome editing, once the cells are collected from the patient, they are then modified

to either insert a functioning gene or correct a defective gene.

In an allogeneic transplantused for conditions such as acute

leukemia and inherited genetic diseasespatients receive cells from a stem cell donor or umbilical cord blood.

Stem Cell Sourcing and

Once the patient and physician agree that stem cell transplant is the best treatment option, first the source of stem

cells must be identified and then the cells are collected.

There are three sources of stem cells for transplant:

mobilization into the peripheral blood, which currently requires several days of injections of a drug or

combination of drugs to mobilize the cells, or move them from the bone marrow into the bloodstream, where they are then collected through a process called apheresis;

extraction from the bone marrow, which requires a procedure performed under general anesthesia where cells are

withdrawn directly from the bone marrow with needle aspirates;

Our Pipeline of Stem Cell Transplant Product Candidates

We are developing a portfolio of novel product candidates that we believe have the potential to meaningfully improve stem cell transplant for patients with blood cancers, genetic diseases and autoimmune diseases.

Additionally, we believe our product candidates have the potential to allow more patients with debilitating or life-threatening diseases to access a one-time,

transformative blood and immune reset through stem cell transplant with better outcomes and reduced risk of toxicities and mortality.

We are developing our product candidates so that they can be used individually or in combination with each other, such that a patient may receive more than one Magenta therapy as part of his or her individual transplant journey.

In addition to our first set of clinical product candidates, we are in the process of identifying several other potential candidates from our conditioning research platform.

We are applying our expertise in stem cell biology and biotherapeutics discovery to bring innovative product candidates to the stem cell transplant field through our programs, specifically designed to address each of the key opportunities in the stem cell transplant journey for patients:

Stem Cell Mobilization

& Collection Program

program is focused on enabling rapid, reliable, predictable and safe mobilization and collection of high numbers of functional blood stem cells for transplant.

Targeted Conditioning Program

program is focused on selectively depleting stem cells from patients prior to transplant or HSC-based

gene therapy to lessen the need for high-dose or high-intensity chemotherapeutic agents or, in the case of gene therapy applications, to potentially eliminate the need for chemotherapeutic agents altogether.

Conditioning Research Platform:

Our targeted conditioning research platform is designed to identify future product candidates that selectively deplete stem cells and/or immune cells from a patient prior to transplant or HSC-based

gene therapy.

These programs focus on developing targeted products that remove specific cell types, with an approach that is tailored to the patient’s disease and transplant requirements.

Initial applications of our research-stage programs include immune reset for autoimmune diseases;

lymphodepletion prior to cell therapies such as CAR-T;

and prophylaxis of graft-versus-host disease, or GvHD, a post-transplant complication following allogeneic stem cell transplant.

Cell Therapy Programs

program is focused on generating higher cell doses that are well matched to the patient, which has been shown to improve the speed and success of engraftment in stem cell transplant and improve disease outcomes.

Our E478 program is designed to expand gene-modified HSCs for gene therapy and genome editing.

Stem Cell Mobilization & Collection Program

A CXCR2 agonist biologic combined with plerixafor, a CXCR4 antagonist small molecule, as the preferred first-line mobilization regimen for rapid, reliable, predictable and safe mobilization and collection of functional stem cells for use in stem cell transplantation.

Once the patient and physician agree that stem cell transplant is the best treatment option, the source of stem cells must be identified and then the cells are collected.

There are three methods of collecting stem cells from either patients or healthy donors for transplant:

mobilization into the peripheral blood, which typically requires several days of injections of a drug or combination of drugs to mobilize the cells, or move them from the bone marrow into the bloodstream, where they are then collected through a process called apheresis;

extraction from the bone marrow in a process known as bone marrow harvest, which requires a procedure performed under general anesthesia where cells are withdrawn directly from the bone marrow with needle aspirates;

harvesting from umbilical cord blood units, which are stored in cord blood banks.

Opportunities

a better matched donor for patients :

For patients undergoing autologous transplant, the patients own cells are used for the transplant.

For patients requiring an allogeneic transplant, the preferred source of stem cells is a donor

from their family who has a well-matched immune system.

For patients without a matched, related donor, the second option is a matched, unrelated donor identified through the bone marrow donor registry.

Although there are nearly 35 million

registered bone marrow donors worldwide, nearly half of all patients are unable to find a matched donor.

Of the matched donors identified for patients, almost half decline to donate, which reduces the chance for finding a well-matched donor for the

For patients without a matched donor, other options include mismatched donors, who can either be unrelated or related;

transplant outcomes are not optimal with these donor types.

For patients without a matched, related donor, umbilical cord blood also provides a potential source of stem cells that is readily available.

However, despite the utility of this approach,

there are significant challenges with umbilical cord blood transplant.

Even when patients find matched cord blood units, transplants are severely limited because there are often too few stem cells in the cord blood unit.

Although more than 712,000

units are available in the worldwide cord blood inventory, current cell dose requirements mean that fewer than approximately 4% of these units contain enough stem cells for use in adult patients.

Because so few units are suitable for use in adult

patients, the patient is less likely to find a closely matched cord blood unit, leading to less than optimal transplant outcomes.

Collecting more high-quality cells :

It is critical that physicians obtain enough stem cells for the transplant or gene therapy,

whether from the patient or a donor, as higher cell doses are closely correlated to better patient outcomes.

In some cases, multiple invasive bone marrow harvests are needed to obtain an adequate number of stem cells.

Mobilized peripheral blood is

used for the majority of the 65,000 stem cell transplants performed each year across the U.S.

and Europe, but the current standard of care, a drug known as granulocyte colony-stimulating factor, or G-CSF,

requires at least five days of injections and is associated with significant side effects, including bone pain that often requires narcotics.

Further, patients with autoimmune diseases or sickle cell disease can have severe side effects with G-CSF, including potentially fatal complications.

Additionally, mobilization failure rates for autologous transplants are as high as 40%.

Targeted Conditioning

Once sufficient cells have been obtained, the patient is then prepared, or conditioned, for transplant using systemic, toxic chemotherapy

and/or radiation.

This treatment is intended to remove the disease-causing cells and make room for the new stem cells that will rebuild the healthy immune system.

Opportunities

removing disease-causing cells :

Stem cell transplant and gene therapy conditioning is very burdensome and risky for both pediatric and adult patients.

Conditioning treatments today are typically

non-targeted and involve systemic, toxic chemotherapy and/or radiation.

Most of these genotoxic chemotherapy agents, including derivatives of mustard gas, were discovered more than 50 years ago and were never

intended for stem cell transplant conditioning.

The current treatments eradicate the stem cells, immune cells and diseased cells but also indiscriminately damage DNA and kill normal, healthy cells in the body, which can lead to severe infections,

organ failure, infertility, secondary cancers and even death.

Nearly all transplant patients experience complications as a result of current conditioning treatments, and conditioning toxicity is responsible for up to 35% of mortality following

allogeneic transplants.

The severe immediate and long-term side effects and mortality risk of conditioning are among the major barriers preventing stem cell transplants from being performed more widely to treat other diseases where they may be

Efforts to reduce chemotherapy doses have met with some success, but the most commonly used conditioning regimens all involve the use of genotoxic agents.

Stem Cell Infusion and Engraftment

Once the patient is prepared, the stem cells that were collected are infused into the patient via the bloodstream.

The cells travel to the bone

marrow and engraft there, meaning they lodge in the bone marrow and begin to make new blood and immune cells.

Once the bone marrow has made enough blood cells particularly white blood cells to fight infection which typically takes

several weeks, the patient can be discharged from the hospital.

There are instances where the stem cells do not engraft or are rejected by the patients body, leading to prolonged hospitalization and the need for an additional transplant.

Outcomes of additional transplants are typically very poor.

Opportunities

Improving rejection :

A major complication of stem cell transplant is when the infused stem cells are rejected by the patients

Rejection is a particular problem where stem cell doses are low, for example, with cord blood transplants.

engraftment :

Depending on the dose of stem cells infused, engraftment can take between two to six weeks.

During this period, patients are required to be in specialized isolation rooms at the hospital and are susceptible to infections.

Safer immune system rebuilding :

GvHD is a reaction that commonly develops after an allogeneic stem cell transplant and is a result of

the donor immune cells recognizing the patients cells as foreign and attacking them.

Acute GvHD typically occurs within weeks of a patient receiving a stem cell transplant and can severely damage the skin, liver, and gastrointestinal system.

GvHD accounts for approximately 10% of deaths following allogeneic transplant.

Immune Reset Patient Journey

Our Medicines

We are applying our expertise in stem cell biology and biotherapeutics discovery to bring innovative, modern medicines to the transplant field

through our programs, specifically designed to address each of the key opportunities in the stem cell transplant journey for patients:

Targeted conditioning programs :

Our targeted conditioning programs are designed to

selectively eliminate only the disease-causing cells from a patient prior to transplant or gene therapy, and to be far less toxic than the current radiation and chemotherapy-based treatments.

These programs focus on developing targeted products that

remove specific cell types, with an approach that is tailored to the patients disease and transplant requirements.

Mobilization program :

Our mobilization program,

MGTA-145, is focused on enabling physicians to more easily collect larger numbers of high-quality HSCs from patients and donors to yield higher cell doses and better outcomes for transplant, as well as gene

Cell therapy program :

Our cell therapy program,

MGTA-456, is focused on generating higher cell doses that are well matched to the patient, which has been shown to improve the speed and success of engraftment in stem cell transplant and improve disease

Our aryl hydrocarbon receptor, or AHR, antagonist, E478, uses the same mechanism used to manufacture MGTA-456 to expand gene-modified HSCs for gene therapy and genome editing.

Post-transplant complications program :

Our post-transplant complications

program is designed to target the donor immune cells within the patient that cause GvHD, potentially reducing the occurrence of GvHD without sacrificing the benefits of an allogeneic transplant, broadening access to the curative potential of immune

Summary of Our Current Programs

We are developing a pipeline of biologics, including antibody drug conjugates;

small molecules and a cell therapy, which we believe can

meaningfully improve and expand curative immune reset for many more patients with autoimmune diseases, blood cancers and genetic diseases.

Our portfolio of novel medicines for transplant has the potential to allow more patients with debilitating or

life-threatening diseases to access a one-time, transformative immune reset with better outcomes, less toxicity risk and less mortality risk.

We are developing our product candidates so that they can each be

used individually or in combination with each other, such that a patient may receive more than one Magenta therapy as part of their individual transplant journey.

In addition to our first set of clinical and preclinical product candidates, we are in

the process of identifying several other potential candidates from our discovery programs as shown in the below chart, which summarizes our pipeline by program.

Conditioning:

Targeted antibody-drug conjugates to remove disease-causing cells

We are developing a suite of novel antibody-drug conjugates, or ADCs, for conditioning, a step in the transplant process that is still

dominated by the use of systemic chemotherapy agents and radiation.

We are seeking to replace these non-targeted toxic conditioning agents with targeted ADCs.

These drugs are designed for immune reset and

specifically remove only the cell types required to be eliminated in order to perform a successful transplant.

All of our patient

conditioning programs share an ADC platform but differ in the targeted cell types.

The CD45-ADC program targets HSCs and disease-causing immune cells, the MGTA-117

product candidate targets disease-causing HSCs and genetically mutated cells and the C300 program targets only disease-causing immune cells.

This is achieved by tuning the antibodies to specific cellular markers or receptors that are expressed on

the particular cell types.

The first conditioning program in our portfolio is CD45-ADC, under

which we are developing ADCs that specifically deplete patient HSCs and immune cells.

Our lead target is CD45, an important cell surface molecule broadly expressed throughout the hematopoietic and immune systems.

We presented our first immune reset

results with CD45-ADC at the American College of Rheumatology, or ACR, annual meeting in November 2019.

These results showed that a single dose of CD45-ADC removed disease-causing cells and halted disease in animal models of multiple sclerosis, systemic sclerosis and inflammatory arthritis.

We plan to develop CD45-ADC

for use in patients with autoimmune diseases, such as multiple sclerosis and scleroderma, and patients with leukemias and lymphomas.

We have identified a lead antibody and progressed this program into investigational new drug, or IND, enabling

studies, which we plan to further advance in 2020.

Our most advanced conditioning product candidate,

MGTA-117, is designed to specifically remove disease-causing HSCs and genetically mutated cells.

MGTA-117 targets CD117, also known as

c-Kit, which is highly expressed on HSCs and leukemia cells, making it an ideal target for conditioning across broad sets of diseases.

This includes blood cancers as well as hemoglobinopathies like sickle cell

disease and beta-thalassemia, with potential applicability in both stem cell transplant and stem cell gene therapy.

At the American Society of Hematology, or ASH, annual meeting in December 2019, we presented data that showed, for the first time,

that a single dose of an experimental CD117-ADC selectively depleted HSCs in non-human primates, while sparing immune cells, which are important for recovery following

The single dose of this CD117-ADC in non-human primates enabled successful transplant and engraftment of HSCs modified with a lentiviral vector

encoding the ß-globin gene.

We have moved MGTA-117 into

IND-enabling studies.

We plan to advance this product candidate into the clinic with initial clinical data expected in 2021.

Our third ADC-based conditioning program, C300, targets T cells, a type of immune cell.

depletion is currently performed with highly toxic, non-specific drugs which can lead to immune deficiency, infections and other complications, including secondary autoimmune reactions.

We are pursuing targets

expressed on the surfaces of T cells with the goal of offering a safer and more optimized targeted conditioning approach through T cell depletion before CAR T therapy for blood cancers, prevention of stem cell rejection prior to allogeneic stem

cell transplant or achievement of immune system reset through autologous stem cell transplant in patients with autoimmune diseases.

CXCR2 agonist combined with plerixafor for first-line mobilization of large numbers of stem cells in a single day

Approximately 85% of stem cell transplants, or approximately 55,000 transplants per year in the U.S.

and Europe, use mobilized peripheral blood

from either donors or patients themselves as a source of stem cells to rebuild the new immune system.

Magenta is developing MGTA-145 as the new first-line standard of care for stem cell mobilization in a broad

range of diseases, including autoimmune diseases, genetic diseases and blood cancers.

MGTA-145, a CXCR2 agonist, works in combination with plerixafor, a CXCR4 antagonist, to harness the physiological mechanism

of stem cell mobilization.

The goal of MGTA-145 is to achieve high levels of stem cell mobilization in patients and donors in the first-line setting and replace the current standard of care for mobilization, a

drug known as G-CSF.

G-CSF is a glycoprotein that mobilizes stem cells indirectly and comes with limitations that include five or more days of injections, lack of

efficacy in some patients, and significant bone pain.

We have completed a Phase 1 trial of

MGTA-145 plus plerixafor in healthy subjects.

Successful stem cell transplant requires collection of HSCs in both sufficient number and functionality, whether from the patient or a donor, to allow for robust engraftment and rebuilding of the blood and immune systems.

Higher cell doses are associated with better outcomes and are especially important for gene therapy applications, which require processing of the stem cells following collection.

Mobilizing stem cells from the bone marrow to the blood has been shown to be an effective way to collect stem cells for transplant.

Approximately 85% of the approximately 90,000 stem cell transplants performed globally each year use mobilized peripheral blood from either donors or patients as a source of stem cells.

The current standard of care for mobilization in most patients and donors is granulocyte colony-stimulating factor, or G-CSF,

which mobilizes stem cells indirectly, requires repeated daily injections and is associated with significant side effects, including bone pain and, in some cases, splenic rupture and death.

The multi-day

regimen requires at least five days of injections of G-CSF,

and side effects can be disruptive for both patients having their cells collected for autologous transplants and for healthy volunteers donating their cells for allogeneic transplants.

The current unreliable and inefficient mobilization and collection process can also pose a significant logistical burden on transplant and apheresis centers.

When planning for a patient’s transplant, transplanting physicians cannot reliably predict at the outset how long it will take to collect the number of cells required.

In addition, each day scheduled for attempted mobilization and collection can cause an accumulation of both the direct costs associated with the repeated use of mobilization agents and other healthcare resources, including personnel time, and the indirect costs associated with the need to block time in the limited number of chairs in transplant centers that are used to collect stem cells.

It is difficult to predict whether mobilization with G-CSF

will be successful, especially in heavily treated blood cancer patients.

Many patients require multiple collections,

including approximately 40% of blood cancer patients.

Additionally, of the biologically unrelated donors identified for patients, approximately half decline to donate, in part due to the lengthy and cumbersome donation process, which reduces the chance for finding a well-matched donor for the patient.

Finally, patients with sickle cell disease can have severe side effects with G-CSF,

including potentially fatal complications, and therefore, this agent is not used in these patients, leaving few mobilization options.

For patients who are unable to mobilize a sufficient number of functional stem cells with G-CSF,

physicians may then be required to re-treat

and add another drug, known as plerixafor.

Plerixafor is a small molecule CXCR4 antagonist that blocks a pathway that otherwise plays an essential role in attracting and retaining HSCs in the bone marrow.

It is approved for use in combination with G-CSF

for patients who fail to achieve sufficient mobilization of stem cells with G-CSF

It can mobilize stem cells as a single agent but not to sufficient levels to be effective as a standalone agent in most disease settings.

However, because plerixafor is the only available mobilization option for sickle cell disease patients who, as stated, cannot use G-CSF

due to safety concerns, it is used as a single agent in this specific setting.

Because of its poor efficacy as a standalone agent and the high number of stem cells required for a transplant, multiple doses of plerixafor and collections are needed in approximately 75% of sickle cell disease patients.

Current state of stem cell mobilization:

an unreliable, inefficient, multi-day

Product Candidate

Magenta is developing MGTA-145

as a new first-line standard of care for stem cell mobilization in a broad range of diseases, for both autologous and allogeneic transplants.

a CXCR2 agonist, works in combination with plerixafor, a CXCR4 antagonist, to harness the physiological mechanism of stem cell mobilization.

The goal of MGTA-145

is to be the preferred first-line mobilization option for all patients and donors through rapid, reliable, predictable and safe mobilization and collection of high numbers of functional stem cells.

In May 2020, we received Orphan Drug Designation from the U.S.

Food and Drug Administration, or the FDA, for MGTA-145

for the mobilization of HSCs to the peripheral blood for collection and subsequent transplant.

Mechanism of action

CXCR2 is a chemokine receptor expressed on the surface of neutrophils.

Binding of MGTA-145

to the receptor results in neutrophil activation.

Published data from Magenta founders and scientists show that a key event for mobilization of stem cells is the MGTA-145-mediated

release of proteases from activated neutrophils, which together with the actions of the CXCR4 antagonist, plerixafor, results in the rapid release of HSCs from the bone marrow into the blood.

Blocking CXCR4 using plerixafor and activating neutrophils with MGTA-145

has been shown to produce an effective and synergistic untethering and release of HSCs from bone marrow into the blood, resulting in rapid, reliable, predictable and safe mobilization of HSCs.

in combination with plerixafor harnesses the natural mechanism of stem cell mobilization.

Clinical data

We have completed a Phase 1 trial of MGTA-145

plus plerixafor in healthy subjects.

The trial met all primary and secondary endpoints.

Data from the trial presented at the Annual Meeting of Transplant and Cellular Therapy, or TCT, in February 2020

showed that MGTA-145 was safe and well tolerated as a single agent and in combination with plerixafor, and that MGTA-145 in combination with plerixafor demonstrated

rapid, single-day mobilization and collection of sufficient numbers of stem cells.

We intend to move this program into multiple Phase 2 trials in patients in 2020.

The Phase 2 trials will include both

allogeneic and autologous transplant settings and will evaluate mobilization and collection of high-quality stem cells and engraftment of the stem cells after transplant.

High-dose, well matched allogeneic cell therapy to

halt the progression of inherited metabolic disorders and blood cancers

MGTA-456 is a

novel proprietary allogeneic stem cell therapy that is designed to provide a high dose of stem cells that are well matched to the patient to safely rebuild the immune and blood system.

Larger stem cell doses and better matched transplants are both correlated with more successful transplant outcomes, reduced risk of transplant

failure, and faster time to engraftment and immune recovery.

The goal of MGTA-456 is to halt the progression of disease through higher doses of stem cells that are well matched to the patient.

We have initiated a Phase 2 trial of MGTA-456 in patients with inherited metabolic disorders and may

explore other debilitating diseases where we believe MGTA-456 could bring transformative benefit to patients.

Although transplant can be curative in these diseases, between approximately 20 to 30% of patients

with inherited metabolic disorders treated with transplant experience engraftment failure, resulting in severe complications, including death.

We believe the high number of HSCs present in MGTA-456 should

provide a rapid and durable resolution of disease.

Our initial trial results in patients with inherited metabolic disorders treated with MGTA-456 have shown early resolution of disease that persisted at one

year of follow-up.

In September 2019, the U.S.

Food and Drug Administration, or FDA, granted

Regenerative Medicine Advanced Therapy, or RMAT, designation for MGTA-456 for the treatment of multiple inherited metabolic disorders.

We intend to complete enrollment in the Phase 2 trial in inherited

metabolic disorders in 2020 and continue dialogue with the FDA under the RMAT designation, and to discuss the development path in Europe with the European Medicines Agency, or EMA.

AHR antagonist for expansion of gene-modified stem cells

E478 is a novel and proprietary small molecule AHR antagonist that was developed to increase the number of gene-modified HSCs ex vivo

for stem cell based-gene therapy.

Gene therapy, or stem cell transplant with gene-modified or genome-edited cells, is a promising treatment approach for several diseases.

However, this approach is significantly limited by the inability to

generate a sufficient dose of gene-modified HSCs that retain the ability to engraft in patients as well as the cost and complexity of manufacturing viral vectors for gene modification of cells.

These constraints could limit the commercial viability

of this approach.

E478 uses the same clinically validated mechanism as MGTA-456 to expand gene-modified HSCs.

In addition to addressing cell dose limitations, the ability to expand long-term repopulating HSCs

ex vivo has the potential to reduce manufacturing costs for these therapies by requiring less viral vector for gene modification of the stem cells.

At the American Society of Cell and Gene Therapy annual meeting in May 2019, we presented data

showing that culturing gene-corrected cells with E478 increased the dose of corrected cells.

We are developing E478 specifically to partner with gene therapy and genome editing companies.

E478 would be integrated into our potential partners

cell-based products, leading to a newly defined cell therapy.

ADC program for prevention of acute GvHD

We are developing a unique approach to preventing acute GvHD, a major complication and a leading cause of death in allogeneic transplantation.

GvHD occurs when alloreactive T cells in the donor stem cell graft recognize the patient as foreign and attack their tissues.

Current treatments for acute GvHD prevention include the prophylactic use of

non-specific immune suppressive agents.

The use of high doses of non-specific immune suppressive agents for GvHD treatment is correlated with an increased risk of

infection and poor immune function, and despite the use of these powerful immune suppressive agents, approximately 50 to 80% of allogeneic transplant patients will experience acute GvHD.

Our G100 program is designed to selectively eliminate only the

components of the graft that cause acute GvHD, specifically the alloreactive T cells.

This ADC therapy is intended to be dosed in vivo at the time of transplant.

By specifically targeting the alloreactive T cells that arise shortly after

transplant, this therapy should spare the remainder of the patients immune system to allow safe rebuilding of the immune system and protection from infections.

Targeted Conditioning Programs

undergoing immune reset through stem cell transplant, the toxicity and mortality associated with current conditioning protocols are significant challenges and prevent more patients from benefitting from a life-saving and potentially curative

In many diseases, physicians use the most aggressive conditioning regimens to generate the best efficacy outcomes for transplant and transplant-based therapies, such as stem cell gene therapy.

Conditioning treatments today are typically non-targeted and involve high doses of radiation and/or

toxic chemotherapy.

These chemotherapy agents, including derivatives of mustard gas, were discovered more than 50 years ago and were never intended for stem cell transplant conditioning.

The current treatments eradicate the disease-causing

cells but also indiscriminately damage the DNA and kill normal, healthy cells in the body.

These conditioning regimens can cause long-term lung injury and liver toxicity, serious infections, organ failure, infertility, secondary cancers and even

The Phase 1 trial was a dose-finding trial to evaluate safety and activity of MGTA-145

and consisted of four parts:

In Part A, healthy volunteers were dosed with MGTA-145

(0.0075 – 0.3 mg/kg) or a placebo.

In Part B, subjects received a single dose of MGTA-145

(0.03 – 0.15 mg/kg) or a placebo in combination with a single dose of plerixafor (0.24 mg/kg).

In Part C, subjects received MGTA-145

or a placebo plus plerixafor administered on day one and day two.

In Part D, subjects received a single dose of MGTA-145

(0.03 or 0.015 mg/kg) plus plerixafor followed by a single apheresis collection of multiple blood volumes.

Clinical endpoints included safety and tolerability, pharmacokinetics, target engagement and pharmacodynamic effects.

Data from the trial presented at the American Society of Hematology, or ASH, in December 2020 showed that MGTA-145

was safe and well tolerated as a single agent and in combination with plerixafor, and that MGTA-145

in combination with plerixafor demonstrated rapid, single-day

mobilization and collection of sufficient numbers of functional stem cells.

was shown to engage CXCR2 on neutrophils to mobilize CD34+ cells into peripheral blood with limited neutrophil activation, which may minimize risk of vaso-occlusive crises in patients with sickle cell disease.

Six subjects who received a single dose of MGTA-145

at the 0.03 mg/kg dose level and plerixafor in Part B mobilized a median of 40 CD34+ cells/microliter compared with a median of 26 CD34+ cells/microliter in subjects receiving plerixafor alone.

Subjects in Part C demonstrated reliable mobilization of CD34+ cells on day two with peak counts that were comparable to day one mobilization yields, which suggests that two-day

dosing and collection is feasible.

dosing and apheresis collection in eight subjects across two dose ranges in Part D yielded a median of four million CD34+ cells/kg.

The clinically accepted threshold for a successful transplant is two million cells/kg.

in combination with plerixafor enables safe, same-day

dosing, mobilization and collection of sufficient numbers of functional stem cells for transplant.

in combination with plerixafor mobilized a greater proportion and number (three- to four-fold higher) of CD34+CD90+CD45RA- cells (a cell type enriched for functional stem cells) compared to subjects mobilized with either G-CSF

or plerixafor alone.

in combination with plerixafor enables greater collection of HSCs after apheresis in a Phase 1 healthy volunteer study.

A) CD34+ cell number, (B) CD34+CD90+CD45RA- cell frequency and

in combination with plerixafor (n=eight donors), a five-day

regimen of G-CSF

(n=three donors) or a single dose of plerixafor (n=six donors).

Flow cytometric data shows that a median of 1.4x10 6

) CD34+CD90+CD45RA- cells/kg were collected from MGTA-145+plerixafor

mobilized donors, compared to 0.40x10 6

(0.36-0.48x10

mobilized subjects (p<0.05) or 0.32x10 6

(0.12-0.67x10

) for plerixafor mobilized subjects (p<0.01).

Bars represent median, each symbol represents an individual subject.

Statistics were calculated by one-way

ANOVA with post-hoc

Plerixafor control data were first presented at the Transplant and Cellular Therapy, or TCT, annual meeting in February 2021.

Cells collected from four subjects dosed in Part D led to up to 23-fold

higher multilineage engraftment in primary and secondary transplants in the immunodeficient NSG mouse model compared to cells mobilized by either G-CSF

or plerixafor alone.

These data demonstrate rapid and durable multilineage engraftment of MGTA-145

+ plerixafor mobilized cells relative to other graft sources.

+ plerixafor CD34+ cells from Phase 1 healthy volunteer study show higher multilineage engraftment compared to G-CSF

and plerixafor mobilized CD34+ cells.

(A) CD34+ cells collected from healthy subjects mobilized with a single injection of MGTA-145

+ plerixafor, five daily injections of G-CSF,

or a single injection of plerixafor (n=3-4

donors) were transplanted into sublethally irradiated (200 cGy) NSG mice at limit dilution (3 cell doses).

Engraftment of human CD45+ (hCD45+) cells in peripheral blood was measured at week 16 post-transplant by flow cytometry and SCID-repopulating cell (SRC) number was determined by ELDA in primary (B) and secondary (C) recipients.

Data represent 7-8

mice per cell dose and are expressed as SRC number per 1x10 6

cells +/- 95% CI.

Cells collected from healthy subjects mobilized with a single dose of MGTA-145

in combination with plerixafor in Part D were capable of efficient gene-modification and engraftment in a pre-clinical

NSG mouse transplant study.

Knockout of beta-2

microglobulin by CRISPR-Cas9 led to approximately 90% editing in vitro

of CD34+CD90+CD45RA- cells and these cells engrafted in NSG mice, with maintenance of high levels of editing.

+ plerixafor CD34+ cells from Phase 1 healthy volunteer study can be efficiently gene modified and engraft in NSG mice.

(A) CD34+ cells collected from healthy donors mobilized with a single injection of MGTA-145

in combination with plerixafor were gene-modified with CRISPR/Cas9 to knockout beta-2

microglobulin.

(B) Edited cells (electroporated in the presence of guide RNA and Cas9) were compared to mock edited cells (electroporated in the absence of guide RNA and Cas9) and CD34+CD90+CD45RA- cell number and editing rates were measured by flow cytometry (n=2).

(C) Mock edited or edited cells were transplanted into sublethally irradiated (200 cGy) NSG mice and engraftment of human CD45+ (hCD45+) cells and editing rates were measured at week 16 post-transplant in the peripheral blood by flow cytometry (n=7-8

+ plerixafor mobilized grafts resulted in significantly less GvHD than G-CSF

(p<0.01) or plerixafor (p<0.001) grafts (n=3-6

donors/source) in a xenogeneic mouse model.

+ plerixafor grafts from Phase 1 healthy volunteer study are immunosuppressive in a xenograft mouse model

peripheral blood mononuclear cells, or PBMCs, collected from healthy

subjects mobilized with a single injection of MGTA-145

in combination with plerixafor, five daily injections of G-CSF,

or a single injection of plerixafor (n=3-6

donors) were transplanted into sublethally irradiated (200 cGy) NSG mice at limit dilution (n=6-8

Graft sources were compared to unmobilized whole blood controls.

(B) Kaplan-Meier survival curve of transplanted NSG mice.

Pooled data from individual donors and mice show significantly enhanced survival after transplant with MGTA-145

in combination with plerixafor.

Statistics were determined by a log-rank

data presented at ASH in December 2020 showed that MGTA-145

plus plerixafor could be an efficient, single-dose mobilization regimen for in vivo

HSC gene therapy.

when administered with plerixafor to wild-type mice or a mouse model of thalassemia, led to robust HSC mobilization, with no significant elevation of cytokines and significantly less leukocytosis than that observed following a five-day

mobilization regimen with G-CSF

plus plerixafor.

plus plerixafor mobilized cells were capable of efficient in vivo

transduction using a helper dependent adenovirus (HDAd5/35++)-based vector platform.

After in vivo selection, stable long-term, multilineage engraftment of gene-modified cells was observed in primary and secondary recipients (>90% gene marking).

In a mouse disease model for thalassemia, phenotypic disease correction was observed after MGTA-145

plus plerixafor mobilization and in vivo

transduction.

+ plerixafor can mobilize HSCs in mice prior to

CD46-transgenic animals were mobilized with G-CSF

+ plerixafor (5 days) or MGTA-145

+ plerixafor (single dose) and then injected one hour later with an integrating HDAd5/35++ mgmt./GFP vector, GFP marking was measured at the various time points after transduction.

Arrows indicate timing and dose of the in vivo

selection agent, O 6

By week 12 post-transduction, >90% of PBMCs expressed GFP.

No significant differences in gene marking were observed with the different selection agents.

Clinical development plan

We plan to develop MGTA-145

as a first-line therapy for stem cell mobilization in a broad range of diseases, for both autologous and allogeneic transplants.

We have announced three ongoing and planned Phase 2 clinical trials to evaluate the potential utility of MGTA-145,

in combination with plerixafor, for the mobilization and collection of stem cells in multiple autologous and allogeneic transplant settings:

Autologous Stem Cell Transplant of Multiple Myeloma Patients.

In December 2020, we announced the commencement of an investigator-initiated Phase 2 trial of MGTA-145,

in combination with plerixafor, to mobilize and collect stem cells for autologous stem cell transplantation in multiple myeloma patients at Stanford University.

This trial continues to enroll patients.

We expect that this trial will provide data on stem cell mobilization and collection, durability of engraftment in transplanted patients and disease outcomes, including progression-free survival.

Initial data from the study are expected in mid-2021.

Allogeneic Donor Stem Cell Mobilization and Collection for Stem Cell Transplant in AML, ALL and MDS Patients.

In June 2020, we announced a clinical trial collaboration with Be the Match to evaluate the potential utility of MGTA-145,

in combination with plerixafor, to mobilize and collect stem cells from allogeneic donors for transplant in patients with acute myeloid leukemia, or AML, acute lymphocytic lymphoma, or ALL, and myelodysplastic syndromes, or MDS.

The clinical trial commenced in February 2021 and will evaluate stem cell mobilization, collection, cell quality, engraftment and disease outcomes, including GvHD, which is of particular importance in the allogeneic transplant setting, as patients receive donor cells.

Initial data from this clinical trial are expected in the second half of 2021.

Sickle Cell Disease – Stem Cell Mobilization and Collection in Patients;

Cell Characterization;

Gene Modification Model.

In December 2020, we entered into a Phase 2 clinical collaboration with bluebird bio, Inc.

to evaluate the safety and potential utility of MGTA-145,

in combination with plerixafor, for the mobilization and collection of stem cells in patients with sickle cell disease.

Under the agreement, the companies will co-fund

the clinical trial, which is currently expected to initiate in the second half of 2021.

Each party will characterize the collected cells and Magenta plans to gene-modify the cells and transplant them into established pre-clinical

models to evaluate engraftment.

Data from this clinical trial could provide proof-of-concept

for MGTA-145,

in combination with plerixafor, as the preferred mobilization regimen for patients with sickle cell disease and, more broadly, across all HSC gene therapy applications.

Targeted Conditioning Program & Conditioning Research Platform

Conditioning:

Targeted agents to selectively remove stem and/or immune cells.

These product candidates are designed to lessen the need for high-dose or high-intensity chemotherapeutic agents or, in the case of gene therapy applications, potentially eliminate the need for chemotherapeutic agents altogether, and make stem cell transplant more effective.

Once sufficient cells have been mobilized and collected, patients must be prepared, or conditioned, for transplant.

This treatment is intended to remove the disease-causing cells and make room for the new stem cells that will rebuild the healthy blood and immune system.

Conditioning for stem cell transplant and gene therapy is currently burdensome and risky for both pediatric and adult patients.

The agents used today are non-targeted

and involve high doses of systemic, toxic chemotherapy and/or radiation.

Most of these genotoxic chemotherapy agents, including derivatives of mustard gas, were discovered more than 50 years ago and were never intended for stem cell transplant conditioning.

The current treatments eradicate the stem cells, immune cells and diseased cells but also indiscriminately damage DNA and kill normal, healthy cells in the body.

These conditioning regimens can cause long-term lung injury and liver toxicity, serious infections, organ failure, infertility, secondary cancers and even death.

Nearly all transplant patients experience complications as a result of current conditioning treatments, and conditioning toxicity is responsible for up to 35% of mortality following allogeneic transplants.

Emerging clinical data have shown that we are now at a stage where autoimmune disease can be cured with an immune system reset through

autologous stem cell transplant, with recent data in multiple sclerosis and scleroderma.

However, the toxicity of the required conditioning regimens has historically led many physicians to conclude that the risks of transplant in these patient

populations far outweigh the benefits.

A pair of comprehensive reviews published in 2017 in Nature journals summarized the clinical transplant results in multiple sclerosis and broader rheumatic autoimmune diseases.

The main conclusions from

this combined experience in more than 3,000 patients during the past 20 years were that the therapeutic benefit of stem cell transplant is significant across multiple trials in severe autoimmune diseases:

Relapsing remitting multiple sclerosis, or

RRMS, (five Phase 2 trials) and systemic sclerosis (two Phase 2 trials and two randomized trials) have the most clinical evidence using stringent disease endpoints.

When compared to the standard of care in RRMS, certain trials have shown that the

proportion of patients with clinical benefit at two years appears to be double that of the next best treatment.

Another trial showed complete long-term suppression of all inflammatory activity in a cohort of patients with active and progressing

multiple sclerosis who received a stem cell transplant, and a third trial compared transplant to disease-modifying therapies and found that transplant resulted in prolonged time to disease progression.

Given a stem cell transplants ability to

durably eliminate relapses and disease activity in multiple sclerosis patients, we believe a safer transplant procedure would be a viable option for those patients with active disease beyond what therapeutics can manage.

However, currently only

approximately 1 to 2% of eligible patients with multiple sclerosis and scleroderma in the U.S.

and Europe receive a stem cell transplant to reset their immune systems, primarily because the risk of the procedure outweighs the benefits of a potential

We believe we can significantly expand the number of autoimmune patients who can benefit from immune reset.

Timeline of clinical relapses .

Each line represents a patient treated in the trial.

continue until the latest follow-up assessment, death (cross), or censoring because the patient received a conventional, experimental, or unproven treatment (star).

The lines begin at diagnosis of multiple

sclerosis, inverted triangles denote a clinical relapse.

In January 2018, a paper was published in the New England Journal of Medicine

demonstrating that HSC transplant with myeloablative conditioning for patients with scleroderma resulted in long-term benefit, including improved event-free and overall survival;

however, these benefits came with increased toxicity due to the non-targeted conditioning used in the trial.

Our medicines

We are developing a suite of novel, targeted ADCs to prepare patients for immune reset through stem cell transplant.

We are seeking to replace

the current non-targeted toxic conditioning agents with targeted ADCs to specifically remove only the disease-causing cells.

While ADCs are an established treatment for certain cancers, we believe this is the

first time that ADC technology has been harnessed for transplant medicine.

These programs have the potential to extend the curative power of immune reset to all of the currently eligible patients, and also to expand the number of patients who are

considered eligible.

Additional eligible patients would include more patients with autoimmune diseases, such as multiple sclerosis and systemic sclerosis, where the current risk-benefit of transplant is not considered favorable for many patients due

to the toxicity of the existing conditioning regimens.

ADCs are a technology developed over the past 20 years where a monoclonal antibody specific

for a cell surface protein is coupled to a drug.

These severe short- and long-term side effects and the mortality risk of conditioning are significant challenges for patients currently undergoing stem cell transplants and are also among the major barriers preventing stem cell transplants from being performed even more widely to enable more patients to benefit from a potentially curative treatment.

Whenever possible, physicians use the most aggressive conditioning regimens, known as myeloablative conditioning, or MAC, to generate optimal efficacy outcomes for oncology and gene therapy patients.

For oncology patients who can tolerate these high-intensity conditioning regimens to prepare them for stem cell transplant, over 50% are alive and without disease relapse, known as relapse-free survival, at five years post-

transplant, an impressive survival rate in these high-risk patient populations.

However, approximately 20% of patients receiving MAC regimens die from complications related to the transplant procedure, known as transplant-related mortality, and a significant majority experience serious short- and long-term side effects.

For the many patients that cannot tolerate such intense and toxic regimens due to advanced age or co-morbidities,

such as decreased organ function, recent efforts have focused on reducing chemotherapy doses in regimens known as reduced intensity conditioning, or RIC.

While significantly better tolerated, these RIC regimens have significantly poorer disease outcomes at five years post-transplant.

Over 50% of patients receiving RIC relapse and only approximately 30% of patients are alive without relapse at five years following stem cell transplant.

Therefore, physicians and patients must currently choose between either the superior long-term efficacy of MAC or the improved safety and tolerability of RIC.

Emerging clinical data have also shown that autoimmune disease can be cured with an immune system reset through autologous stem cell transplant, with recent data in multiple sclerosis and scleroderma.

When compared to the standard of care in relapsing remitting multiple sclerosis, clinical trials have shown that the proportion of patients with clinical benefit at two years appears to be double that of the next best treatment and that transplant prolongs the time to disease progression compared with disease modifying therapies.

However, the toxicity of the required conditioning regimens has historically led many physicians to conclude that the risks of transplant in these patient populations outweigh the benefits.

The current high-dose chemotherapeutic regimens that are used to condition patients can cause severe cardiac, lung, liver and gastrointestinal toxicities, serious infections, organ failure, infertility, secondary cancers and even death.

Currently only approximately 6% of eligible patients with multiple sclerosis and scleroderma receive a stem cell transplant, in part due to these significant risks.

Magenta believes we can significantly expand the number of autoimmune patients who can benefit from immune reset with effective and safe targeted conditioning.

Our Conditioning Programs

Our targeted conditioning programs are designed to selectively eliminate stem cells and/or immune cells from a patient prior to transplant or gene therapy, and to be far less toxic than the current radiation and chemotherapy-based treatments.

These programs focus on developing targeted products that remove specific cell types, with an approach that is tailored to the patient’s disease and transplant requirements.

We are developing a suite of novel ADCs for conditioning, a step in the transplant process that currently relies on the use of systemic chemotherapy agents and radiation.

We are seeking to replace these toxic, non-targeted

conditioning agents with targeted ADCs.

While ADCs are an established treatment for certain cancers, we believe this is the first time that ADC technology has been harnessed for transplant medicine.

These programs have the potential to extend the curative power of blood and immune reset to all of the currently eligible patients, and also to expand the number of patients who are considered eligible.

Additional eligible patients would include more patients with autoimmune diseases, such as multiple sclerosis and systemic sclerosis, where the current risk-benefit tradeoff of transplant is not considered favorable for many patients due to the toxicity of the existing conditioning regimens.

ADCs are a technology developed over the past 20 years where a monoclonal antibody specific for a cell surface protein is coupled to a drug via a molecule known as a linker.

The ADC binds the receptor on the target cell, is internalized and degraded to release the drug into the target cell.

Coupling the drug to the antibody increases the specificity of drug delivery to

the target cell, reducing systemic exposure and increasing the safety and efficacy compared to delivering the drug alone or the antibody without the drug attached.

Today most ADCs are directed toward treating cancer cells expressing specific target

receptors enriched on tumor cells.

Our programs build on this clinically validated modality and adapt it for preparing patients for immune reset through stem cell transplant.

Coupling the drug to the antibody increases the specificity of drug delivery to the target cell, reducing systemic exposure and increasing the safety and efficacy compared to delivering the drug alone or the antibody without the drug attached.

Today, most ADCs are directed toward treating cancer cells expressing specific target receptors enriched on tumor cells.

Our programs build on this clinically validated modality and adapt it for preparing patients for blood and immune reset through stem cell transplant.

Targeted conditioning with ADCs is more specific compared to traditional conditioning.

conditioning is performed with total body irradiation and chemotherapy which eliminates all HSCs and nonspecifically damages other organs.

Targeted conditioning with an antibody drug conjugate specifically eliminates the disease-causing cells while

avoiding systemic side effects.

Traditional conditioning is performed with total body irradiation and chemotherapy which eliminates all HSCs and nonspecifically damages other organs.

Targeted conditioning with an ADC specifically eliminates the disease-causing cells while avoiding systemic side effects.

In our development of ADCs for use in conditioning, we are optimizing for several key parameters:

First, the antibody must specifically target a receptor that is expressed on the cells of interest.

Second, to comply with typical stem cell transplant conditioning timelines, the antibody must have suitable

efficacy to ensure that the ADC is able to remove the target cells rapidly, in days rather than weeks or months.

Third, the antibody clearance needs to be accelerated so that it is eliminated by the time the transplanted cells

are infused into the patient, typically within a week of starting conditioning.

Second, to comply with typical stem cell transplant conditioning timelines, the antibody must have suitable efficacy to ensure that the ADC is able to remove the target cells rapidly, in days rather than weeks or months.

Third, the antibody clearance from the body needs to be accelerated so that it is eliminated by the time the transplanted cells are infused into the patient, typically within a week of starting conditioning.

This requirement stems from the fact that the target receptor is expressed on cells present in the patient but also on the similar cell types in the transplanted cells.

Finally, the linker-drug must be able to remove non-dividing cells, as

most HSC and immune cells are not actively dividing.

The ADC linker must be chosen to minimize damage to non-target cells.

We are addressing each of these requirements through careful selection of the appropriate target receptor as well as antibody properties,

including binding site, affinity, half-life and linker toxin.

We are developing three distinct programs for conditioning that

specifically remove the particular disease-causing cells that need to be removed to make room for the incoming cells.

All of our conditioning programs share an ADC platform but differ in the targeted cell types.

CD45-ADC program targets HSCs and disease-causing immune cells, MGTA-117 targets disease-causing HSCs and disease-causing cells, and the C300 program targets only

disease-causing immune cells.

CD45-ADC program

The first conditioning program in our portfolio is CD45-ADC, under which we are developing ADCs that

specifically remove HSCs and disease-causing immune cells.

Within our CD45-ADC program, our lead target is CD45, an important cell surface molecule broadly expressed throughout the hematopoietic and immune

We have identified a lead antibody and progressed this program into IND-enabling studies, which we plan to further advance in 2020.

CD45-ADC targeting HSC and immune cells

For many applications of HSC transplant, it is important to eliminate both immune cells and HSCs in the patient prior to transplant.

especially important in the allogeneic setting where host immune cells can elicit an immune-mediated rejection of the incoming foreign stem cells.

In addition, immune cell depletion is a key feature of the use of autologous transplant immune reset

in patients with severe autoimmune disease.

In this case, the goal is to eliminate the disease-causing auto-reactive immune cells that perpetuate the underlying autoimmune disease.

Lastly, for patients with tumors expressing CD45, there may also be

a direct anti-tumor effect providing additional therapeutic benefit.

For these reasons, we are developing therapeutics that simultaneously target both HSCs and immune cells.

Pioneering work from Magenta scientists presented at the ACR annual meeting in November 2019 demonstrated successful immune reset with a

single dose of its CD45-ADC in animal models of three autoimmune diseases:

multiple sclerosis, systemic sclerosis and inflammatory arthritis.

Multiple Sclerosis Results

presented at the ACR meeting in November 2019 showed that a single dose of CD45-ADC removed disease-causing reactive T cells, enabled successful immune reset and rebuild of the immune system and was well

tolerated in a reliable murine model of autoimmune disease, the EAE model.

Further, a single dose of CD45-ADC significantly reduced disease incidence and delayed disease onset in this model that has

successfully provided preclinical proof of concept for many clinically validated standard-of-care therapies.

Treatment with CD45-ADC and stem cell transplant (SCT) delays onset, reduces incidence, and reduces severity

of disease in a murine model of MS.

MS was induced in C57BL/6 (CD45.2+) mice, which were conditioned for CD45.1+ congenic transplant (B6.SJL donor) on day 5 and transplanted 48 hours after conditioning ( A ).

Disease onset was around 9-12

days post induction for vehicle treated animals, while treatment with CD45-ADC substantially delayed disease onset, reduced disease incidence, and limited disease severity ( B ).

Results presented at the ASH annual meeting in December 2019 showed that a single dose of CD45-ADC resulted in potent in vitro killing of human disease-causing cells from patients with multiple sclerosis.

Clinical development plans

We believe CD45-ADC has the potential to significantly increase the number of patients eligible to

receive an immune reset through stem cell transplant, particularly those patients with autoimmune diseases and acute leukemias.

sclerosis affects approximately 600,000 to 700,000 patients in the U.S.

and historically at least 650,000 patients in Europe.

Approximately 15,000 new patients in the U.S.

and 32,000 new patients in Europe are diagnosed annually.

eligibility in this population, we focused on the patients with active relapsing-remitting disease and relapsing secondary progressive multiple sclerosis patients who are not adequately treated by current therapies.

This population represents

approximately 45,000 multiple sclerosis patients who switch therapies each year in the U.S., and we believe that a greater population of patients switch therapies each year in Europe.

Many of these patients switch because their current therapy does

not adequately control disease activity that causes relapses.

Given stem cell transplants ability to durably eliminate relapses and disease activity in multiple sclerosis patients, we believe a safer transplant procedure would be a viable

option for those patients with highly active disease beyond what therapeutics offer.

Currently only approximately 1 to 2% of eligible multiple sclerosis patients in the U.S.

and Europe receive a stem cell transplant because the risk of the process

outweighs the benefits of a potential cure, and we believe we can significantly expand this number.

Scleroderma, a severe chronic

connective tissue disease that is characterized by thickening of the skin and fibrosis in multiple organs, is diagnosed in approximately 6,600 patients in the U.S.

and 10,900 patients in Europe annually.

Approximately 35% (2,300 patients in U.S.,

3,800 patients in Europe) of scleroderma patients suffer from the diffuse cutaneous form of the disease and are therefore eligible for stem cell transplant.

Currently, only approximately 1% or less of eligible scleroderma patients in the U.S.

Europe receive a stem cell transplant, though the recent inclusion of stem cell transplant in the European League Against Rheumatism, or EULAR, treatment guidelines for scleroderma may increase this number.

With this increased acceptance of stem

cell transplant as a treatment option for scleroderma and the opportunity for a safer transplant procedure through targeted conditioning, we believe transplant could become a new standard of care for patients with severe scleroderma, who have no

other therapeutic options available.

There are approximately 72,000 cases of non-Hodgkin lymphoma

diagnosed in the U.S.

each year, of which approximately 6,500 are eligible for transplant;

and in Europe there are approximately 95,000 new cases of non-Hodgkin lymphoma each year, with 8,500 eligible for

Of these patients, approximately 60 to 80% receive a transplant.

Additionally, approximately 47,000 patients in the U.S.

and Europe are diagnosed with acute myelogenous leukemia every year.

Of those patients, about 60% achieve

remission with chemotherapy agents and are eligible for transplant.

However, of these, only approximately 30 to 40% actually receive a transplant.

This is largely due to the toxicity risk associated with current conditioning protocols.

our targeted conditioning programs would allow more patients to become eligible for transplant.

MGTA-117 Product Candidate

Our most advanced conditioning product candidate, MGTA-117, is designed to specifically deplete disease-causing HSCs and genetically mutated cells.

MGTA-117 targets CD117, also known as

c-Kit, which is expressed on HSCs, making it an ideal target for conditioning across broad sets of diseases.

This includes certain blood cancers, hemoglobinopathies (sickle cell disease and beta-thalassemia),

and inherited metabolic disorders, with potential applicability in both stem cell transplant and HSC-based gene therapy.

Nobili et.al., Long non-coding RNAs in normal and malignant hematopoiesis.

Finally, the drug must be able to remove non-dividing

cells, as most HSCs and immune cells are not actively dividing.

The ADC linker must be chosen to minimize damage to non-target

We are addressing each of these requirements through careful selection of the appropriate target receptor as well as antibody properties, including binding site, affinity, half-life and linker-drug.

Our targeted conditioning programs include both our ADC programs and earlier-stage research programs that leverage alternate modalities for targeted cell depletion.

This is achieved by tuning the antibodies to specific cellular markers or receptors that are expressed on the particular cell types.

These drugs are designed to specifically remove only the cell types required for a successful transplant, with an approach that is tailored to the patient’s disease and transplant requirements:

targets HSCs and genetically mutated stem cells that cause acute myeloid leukemia and myelodysplastic syndromes.

targets HSCs and immune cells.

Our lead target under the C100 program is CD45 and our lead product candidate is referred to as CD45-ADC.

targets only immune cells.

targets alloreactive T cells implicated in GvHD.

product candidate

Our most advanced conditioning product candidate, MGTA-117,

is designed to specifically remove disease-causing HSCs and genetically mutated cells.

targets CD117, also known as c-Kit,

which is highly expressed on HSCs and leukemia cells, making it an ideal target for conditioning across broad sets of diseases.

This includes certain blood cancers, hemoglobinopathies (sickle cell disease and beta-thalassemia) and inherited metabolic disorders, with potential applicability in both stem cell transplant and HSC-based

gene therapies.

We have declared a development candidate, MGTA-117,

which is an anti-CD117 antibody conjugated to an amanitin payload.

Nobili et.al., Long non-coding

RNAs in normal and malignant hematopoiesis.

Oncotarget (2016).

Our experiments have validated the concept of using an ADC targeting CD117 in animal models of conditioning

and transplant We found that a single dose of an experimental CD117-ADC was able to successfully deplete HSCs in immunocompetent mice and allow successful transplant.

We then showed in non-human primate models that a single dose of a CD117-ADC was able to remove HSCs from the bone marrow.

In contrast, treatment with an unconjugated CD117 antibody did not

have a significant impact on HSCs.

The anti-CD117-ADC selectively depletes human stem and

progenitor cells, or CD34+, in humanized NSG mice.

The depletion is on target and payload dependent as the naked antibody and isotype ADC have no effect.

CD117-ADC or controls were dosed on day 0.

was collected on day 21 and analyzed by flow cytometry.

The percent CD34+ cells remaining in the bone marrow of CD117-ADC or control treated mice 21 days after a single administration is shown.

We subsequently partnered with the National Institutes of Health on a non-human primate transplant

study using HSCs modified with a lentiviral vector encoding the ß-globin gene, the gene that causes sickle cell disease and ß-thalassemia.

Our anti-human CD117 amanitin ADC has been shown in preclinical studies to deplete HSCs and leukemia cells, therefore we hypothesize it will improve conditioning in patients with acute myeloid leukemia and myelodysplastic syndromes where stem cell transplant is already the standard of care.

We believe that MGTA-117,

in combination with reduced-intensity conditioning, has the potential to demonstrate clinical outcomes that preserve the safety and tolerability of RIC while achieving the efficacy of MAC.

Likewise, gene therapy is a promising approach to treat a variety of non-malignant

diseases, including inherited metabolic disorders, sickle cell disease and beta-thalassemia, but the risks and toxicity associated with current chemotherapy-based conditioning approaches may limit the utility of this approach.

Through its targeted approach, MGTA-117

has the potential to provide a safe and effective approach to preparing patients for stem cell transplant or HSC-based

gene therapy.

Preclinical data

Our experiments have validated the concept of using an ADC targeting CD117 in animal models of conditioning and transplant.

We found that a single dose of an experimental anti-murine CD117-ADC

was able to successfully deplete HSCs in immunocompetent mice and allow successful transplant.

We then showed in humanized mice that a single dose of an anti-human CD117 amanitin ADC was able to remove CD34+ HSCs from the bone marrow.

In contrast, treatment with an unconjugated CD117 antibody did not have a significant impact on HSCs.

The anti-human CD117 amanitin ADC selectively depletes CD34+ human stem and progenitor cells in humanized NSG mice.

The depletion is on target and payload dependent as the naked antibody (Anti-CD117) has no effect.

CD117 amanitin ADC or controls were dosed on day 0.

Bone marrow was collected on day 21 and analyzed by flow cytometry.

The number of CD34+ cells remaining in the bone marrow of CD117 amanitin ADC or control treated mice 21 days after a single administration is shown.

* denotes p value < 0.05 vs PBS group.

We subsequently partnered with the National Institutes of Health, or NIH, to investigate an experimental non-amanitin

in a non-human

primate transplant study using HSCs modified with a lentiviral vector encoding the beta-globin gene, the gene that causes sickle cell disease and beta-thalassemia.

Results from the study were presented by Dr.

John Tisdale of the National Institutes of

Health at the ASH annual meeting in December 2019.

This study showed, for the first time, that a single dose of an experimental CD117-ADC selectively depleted HSCs in non-human primates, while sparing immune cells, which are important for recovery following transplant .

The single dose of this

CD117-ADC in non-human primates enabled successful transplant and engraftment of HSCs modified with a lentiviral vector encoding the ß-globin gene.

CD117 ADC enables engraftment of autologous gene-modified HSCs in a

non-human primate, or NHP, model.

CD34+ cells were harvested from two rhesus NHPs and transduced with lentiviral vector encoding ß-globin.

The transduced cells were transplanted into the same animals six

days after a single dose of CD117 ADC.

The neutrophils counts before and after transplantation of the transduced cells are shown for animal #1 (magenta line) and animal #2 (teal line).

The animals recovered their neutrophils on day eight (animal #1)

and day ten (animal #2).

The CD117-ADC was engineered to have a fast half-life to clear the

body quickly, and it enabled transplant of gene-modified HSCs within days of dosing in non-human primates.

The CD117 ADC is a full length human IgG1 that has been engineered to have fast clearance and allows

for safe graft infusion within five days after dosing.

The engineered half-life anti-CD117 ADC demonstrates rapid clearance (10 hour half-life) in non-human primates with a half-life suitable for patient

preparation for transplant (n=3/group).

John Tisdale of the NIH at the ASH annual meeting in December 2019.

The experimental CD117-ADC

was engineered to have a fast half-life to clear the body quickly, and it enabled transplant of gene-modified HSCs within days of dosing in non-human

The experimental CD117-ADC

is a full length human IgG1 that has been engineered to have fast clearance and allows for safe graft infusion within five days after dosing.

The engineered half-life experimental CD117-ADC

demonstrates rapid clearance (10 hour half-life) in non-human

primates with a half-life suitable for transplant (n=3/group).

The wild type CD117 antibody half-life is approximately three days.

The CD117 ADC drops below limit of detection for the assay after 48 hours and modeled pharmacokinetics (gray line) predicts the ADC will be

below cytotoxic concentrations after five days.

Vector copy number was stable beyond three months, the longest time point in the study,

suggesting that the gene-modified cells persisted in the body.

The experimental CD117-ADC

drops below limit of detection for the assay after 48 hours and modeled pharmacokinetics (gray line) predicts the ADC will be below cytotoxic concentrations after five days.

This study showed, for the first time, that a single dose of an experimental CD117-ADC

selectively depleted HSCs in non-human

primates, while sparing immune cells, which are important for recovery following transplant .

The single dose of this experimental CD117-ADC

primates enabled successful transplant and engraftment of HSCs modified with a lentiviral vector encoding the beta-globin gene.

Experimental CD117-ADC

enables engraftment of autologous gene-modified HSCs in a non-human

primate, or NHP, model.

CD34+ cells were harvested from two rhesus NHPs and transduced with lentiviral

vector encoding beta-globin.

The transduced cells were transplanted into the same animals six days after a single dose of experimental CD117-ADC.

The neutrophil counts before and after transplantation of the transduced cells are shown for animal #1 (magenta line) and animal #2 (teal line).

The animals recovered their neutrophils on day eight (animal #1) and day ten (animal #2).

The vector copy number, or VCN, was stable beyond three months, the longest time point in the study, suggesting that the gene-modified cells persisted in the body.

This was comparable to historical data with multiple doses of busulfan conditioning.

The vector copy number, or VCN, of the transduced CD34+ cells used for the CD117-ADC conditioned animal was lower compared to the VCN of the cells used in the busulfan conditioned animals.

The peripheral granulocyte VCN is stable over time and in the same range as observed with busulfan

conditioned animals shown in gray.

This indicates the conditioning with CD117-ADC is sufficient to enable engraftment of gene modified HSCs.

The vector copy number (VCN) of the transduced CD34+ cells used for the experimental CD117-ADC

conditioned animal was lower compared to the VCN of the cells used in the busulfan conditioned animals.

The peripheral granulocyte VCN is stable over time and in the same range as observed with busulfan conditioned animals shown in gray.

This indicates the conditioning with experimental CD117-ADC

is sufficient to enable engraftment of gene modified HSCs.

The experimental CD117 ADC was well tolerated in non-human

primates with no evidence of the often severe side effects seen with busulfan conditioning, including veno-occlusive disease, weight loss, diarrhea, mucositis, vomiting, pulmonary fibrosis or seizures.

ADC-related blood chemistry changes outside normal range were observed.

We believe these proof-of-concept studies validate the use of CD117-ADC for targeted stem cell depletion prior to transplant and support its use as a

new conditioning agent for gene therapy and stem cell transplant without toxic chemotherapy or radiation.

Anti-tumor activity of CD117-ADC

In addition to its expressions on HSCs, CD117 is also frequently overexpressed on tumor

cells in patients with acute myeloid leukemia and myelodysplastic syndromes.

Thus, the CD117-ADC has the potential to reduce tumor burden in patients.

In data presented at the TCT conference in February 2019,

we showed that CD117-ADC was effective at killing human acute myeloid leukemia cells growing in vitro .

To extend these data, we also assessed the ability of

CD117-ADC to reduce tumor burden and confer a survival benefit in mice bearing a human acute myeloid leukemia cell line or patient-derived acute myeloid leukemias that were resistant to multiple lines of

therapy, including previous allogeneic transplant.

For these studies, mice were inoculated with a lethal dose of the acute myeloid leukemia and either left untreated or treated with CD117-ADC or unconjugated

CD117 antibody.

Tumor-bearing mice treated with a single dose of CD117-ADC showed significantly improved

survival compared to mice left untreated or those treated with unconjugated CD117 antibody.

These data suggest that CD117-ADC may have utility to treat

leukemias through a direct cytotoxic effect on tumors.

CD117-ADC effectively depletes human leukemic cells in NSG mice.

Schematic of in vivo leukemia model.

The human acute myeloid leukemia, or AML, cell line Kasumi-1 (left) or patient-derived acute myeloid leukemia cells (right) were injected into NSG mice to serve

as a pharmacology model of established acute myeloid leukemia.

A single injection of 0.3 mg/kg CD117 amanitin ADC or unconjugated anti-CD117 antibody or isotype amanitin occurred after tumors were established.

Survival curves of mice after tumor

injection and treatment are shown.

We have declared a development candidate, MGTA-117, which is

an anti-CD117 antibody conjugated to an amanitin payload and have moved into IND-enabling studies.

We plan to advance MGTA-117 into the clinic with initial clinical data

expected in 2021.

No experimental CD117 ADC-related

blood chemistry changes outside normal range were observed.

We believe these proof-of-concept

studies validate the use of a CD117-ADC

for targeted stem cell depletion prior to transplant and support its use as a new conditioning agent for gene therapy and stem cell transplant without toxic chemotherapy or radiation.

Anti-tumor activity of CD117 Amanitin ADC

In data presented at the ASH annual meeting in December 2020, we showed that an anti-human CD117 amanitin ADC was effective at killing human acute myeloid leukemia cells growing in vitro

To extend these data, we also assessed the ability of the CD117 amanitin ADC to reduce tumor burden and result in a survival benefit in mice bearing a human acute myeloid leukemia cell line or patient-derived recurrent/relapsed acute myeloid leukemia that was resistant to multiple lines of therapy, including previous allogeneic transplant.

Tumor-bearing mice treated with a single dose of CD117-ADC showed improved survival compared to mice left untreated or those treated with isotype ADC or multiple doses of ARA-C.

Clinical development plans

We currently intend to pursue the development of MGTA-117 for patients with certain blood cancers, such

as acute myeloid leukemia or myelodysplastic syndromes, and for patients with genetic diseases who may be eligible for allogeneic transplant or HSC-based gene therapy.

Because MGTA-117 has been shown in preclinical studies to deplete HSCs and leukemia cells, it could be

ideal for immune reset in patients with acute myeloid leukemia and myelodysplastic syndromes where stem cell transplant is already the standard of care.

Likewise, gene therapy is a promising approach to treat a variety of non-malignant diseases, including inherited metabolic disorders, sickle cell disease and beta-thalassemia, but the risks and toxicity associated with current chemotherapy-based conditioning approaches may limit the

utility of this approach.

Through its targeted approach, MGTA-117 has the potential to provide a safe and effective approach to preparing patients for immune and blood system reset through transplant or HSC-based gene therapy.

Our third ADC-based conditioning program, C300, targets T cells.

T cell depletion is currently

performed with highly toxic, non-specific drugs, which can lead to immune deficiency, infections and other complications, including secondary autoimmune reactions.

We are pursuing targets expressed on the

surfaces of T cells with the goal of offering a safer and more optimized targeted conditioning approach through T cell depletion before CAR T therapy for blood cancers, prevention of stem cell rejection prior to allogeneic stem cell

transplant or achievement of immune system reset through autologous stem cell transplant in patients with autoimmune disease.

MGTA-145 stem cell mobilization program

immune reset through stem cell transplant requires collection of HSCs in both sufficient number and quality to allow for robust engraftment and rebuilding of the blood and immune system.

Higher cell doses are associated with better outcomes.

Today there are 150,000 patients eligible for transplant each year.

Mobilizing stem cells from the bone marrow to the blood has been an

effective way to harvest stem cells for transplant.

Approximately 85% of stem cell transplants, or approximately 55,000 transplants per year in the U.S.

and Europe, use mobilized peripheral blood from either donors or patients themselves as a source

of stem cells.

The current standard of care for mobilization, G-CSF, mobilizes stem cells indirectly, requiring repeated daily injections, and is associated with significant side effects, including bone pain

that often requires narcotics.

The multi-day regimen requires five days of injections of G-CSF, and side effects can be disruptive for both patients having their cells

collected for autologous transplants and for healthy volunteers donating their cells for allogeneic transplants.

It is difficult to predict whether mobilization will be successful, especially in heavily treated blood cancer patients.

In fact, most

patients require multiple apheresis sessions and some patients require more than one stem cell collection procedure to obtain a sufficient number of cells for transplant.

Mobilization failure rates are as high as 35% in patients with multiple

myeloma or non-Hodgkin lymphoma.

Further, patients with autoimmune diseases or sickle cell disease can have severe side effects with G-CSF, including potentially fatal

complications.

For patients who are unable to mobilize sufficient numbers of stem cells with

G-CSF, physicians are then required to re-treat with G-CSF and add another drug, called plerixafor.

Plerixafor acts as a small

molecule CXCR4 antagonist, blocking a pathway that otherwise plays an essential role in attracting and retaining HSCs in the bone marrow.

It is approved for use in combination with G-CSF for patients who fail

to achieve sufficient mobilization of stem cells with G-CSF alone.

It can mobilize stem cells as a single agent but not to sufficient levels to be used as a standalone agent.

Current state of stem cell mobilization with G-CSF:

multi-day process

We are developing MGTA-145 as the new first-line standard of care for stem cell mobilization in a broad

range of diseases, for both autologous and allogeneic transplants.

MGTA-145, a CXCR2 agonist, works in combination with plerixafor to harness the physiological mechanism of stem cell mobilization.

The goal of MGTA-145 is to achieve high levels of stem cell mobilization in patients and donors in a

single day in the first-line setting and replace G-CSF.

dosing and collection of stem cells

Mechanism of action

CXCR2 is a chemokine receptor expressed on the surface of neutrophils.

Binding of MGTA-145 to the

receptor results in neutrophil activation.

Published data from Magenta founders and scientists show that a key event for mobilization of stem cells is the

MGTA-145-mediated release of proteases from activated neutrophils, which together with the actions of the CXCR4 antagonist, plerixafor, results in the rapid release of

HSCs from the bone marrow into the blood.

Blocking CXCR4 using plerixafor and activating neutrophils with MGTA-145 together produce an effective and synergistic untethering and release of HSCs from bone marrow

into the blood, resulting in rapid and robust mobilization of HSCs.

MGTA-145 in combination with plerixafor harnesses the natural

mechanism of stem cell mobilization.

We currently intend to pursue the development of MGTA-117

(an amanitin-based ADC) for patients with certain blood cancers, such as acute myeloid leukemia and myelodysplastic syndromes, and for patients with genetic diseases who are eligible for stem cell gene therapy.

We have declared a development candidate, MGTA-117, and have moved it into Investigational New Drug, or IND, -enabling studies.

We have recently completed GLP toxicology studies and our GMP manufacturing process, as well as completing our pre-IND communications with the FDA.

We expect to file an IND application with the FDA in mid-2021.

Upon acceptance of this IND, we plan to initiate a Phase 1/2 clinical trial evaluating MGTA-117 in patients with acute myeloid leukemia and myelodysplastic syndromes to generate initial safety and pharmacokinetic data in the fourth quarter of 2021.

These initial data are expected to be directional for our dose escalation plans.

In 2020, we also announced two non-exclusive

research and clinical collaborations to evaluate the potential utility of MGTA-117

for conditioning of patients prior to stem cell-based gene therapies:

Lysosomal Storage Disorders.

In May 2020, we entered into an agreement with AVROBIO, Inc.

to evaluate the potential utility of MGTA-117

for conditioning of patients receiving one or more of AVROBIO, Inc.’s investigational lentiviral gene therapies.

Hemoglobinopathies.

In June 2020, we entered into an agreement with Beam Therapeutics, Inc.

to evaluate the potential utility of MGTA-117

for conditioning of patients with sickle cell disease and beta-thalassemia receiving Beam Therapeutics, Inc.’s base editing gene therapies.

Our second ADC-based

conditioning program, C100, targets both patient HSCs and disease-causing immune cells.

For many stem cell transplant applications, it is important to eliminate both immune cells and HSCs in the patient prior to transplant.

This is especially important in the allogeneic setting where host immune cells can elicit an immune-mediated rejection of the incoming foreign stem cells.

In addition, immune cell depletion is a key feature of the use of autologous stem cell transplant in patients with severe autoimmune disease.

In this case, the goal is to eliminate the disease-causing auto-reactive immune cells that perpetuate the underlying autoimmune disease.

Lastly, for cancer patients with tumors expressing CD45, there may also be a direct anti-tumor effect providing additional therapeutic benefit.

For these reasons, we are developing product candidates that simultaneously target both HSCs and immune cells.

Our lead target for the C100 program is CD45, an important cell surface molecule broadly expressed throughout the hematopoietic and immune systems.

We believe CD45-ADC

has the potential to significantly increase the number of patients eligible to receive a stem cell transplant, particularly those patients with autoimmune diseases and acute leukemias.

Preclinical data

Mouse Models of Autoimmune Disease

Data presented at the Transplant and Cellular Therapy, or TCT, and the European League Against Rheumatism, or EULAR, annual meetings in 2020 showed that a single dose of CD45-ADC

removed disease-causing reactive T cells, enabled successful blood and immune reset and rebuild of the immune system and was well tolerated in a reliable murine model of autoimmune disease, proteoglycan-induced arthritis.

Further, a single dose of CD45-ADC

significantly reduced disease incidence and delayed disease onset in this model that has successfully provided preclinical proof of concept for many clinically validated standard-of-care

Therapeutic Treatment with CD45-ADC

Enables Immune Reset via Congenic Bone Marrow Transplant and results in halt of disease progression in a murine model of Rheumatoid Arthritis.

BALB/c mice (CD45.2 +

) were given three immunizations (study day 0, 21, and 42) with recombinant human core G1 aggrecan (60 m

g in 2 mg DDA) ( A

Animals were treated on day 11 post the final immunization (study day 53) and conditioned animals were transplanted with Balb/c CD45.1 +

congenic bone marrow 48 hours later.

Animals treated with a neutralizing monoclonal antibody to murine TNF a

received 500 m

g/mouse IP weekly starting on study day 53.

Treatment with 2 mg/kg of CD45-ADC,

but not Isotype-ADC,

enabled full congenic donor chimerism in peripheral blood ( B

) at three weeks post-transplant.

Representative paws from control and CD45-ADC

–treated animals are shown in ( C

Scores for the treatment groups over time are graphed in ( D

Mouse Models of Transplant

Data presented at the European Society for Blood and Marrow Transplantation, or EMBT, and ASH annual meetings in 2020 and at the TCT annual meeting in February 2021 showed that a single dose of CD45-ADC

is fully myeloablative and enables complete chimerism in a full mismatch allogeneic stem cell transplant model without the need for additional conditioning agents.

A single dose of 5 mg/kg CD45-ADC

is sufficient to enable allogeneic transplant of Balb/c CD45.1 donor cells into C57BL/6 recipients.

C57BL/six mice were conditioned with 5 mg/kg Isotype-ADC

95% donor chimerism (A) and peripheral donor engraftment is multilineage through week 20.

Terminal splenic (E) and thymic (F) chimerism in CD45-ADC

conditioned mice were similar to TBI.

*p<0.05 versus TBI;

#p<0.05 versus CD45-ADC;

ANOVA with post hoc Tukey’s multiple comparisons test.

Oncology Model Results

Data presented at the TCT annual meeting in 2020 demonstrated that a single dose administration of a short half-life CD45-ADC

is well tolerated and is capable of reducing tumor burden by potently targeting leukemia cells in xenograft models.

It significantly prolonged the median survival of established cell line and patient derived xenograft models as compared to both untreated controls and a multi-dose regimen of ARA-C,

a standard-of-care

chemotherapy.

A single dose of a short half-life CD45-ADC

increases survival (A)

and effectively decreases tumor burden (B)

of human acute myeloid leukemia cells in two patient derived xenograft models compared to vehicle (PBS) or isotype-ADC,

and comparable to a multi-dose regimen of ARA-C,

a standard-of-care

chemotherapy.

Treatment began when 2-16%

tumor blasts were detected in the periphery (n=3-5

mice/group/AML PDX model).

Mice were treated with a single intravenous dose of anti-human CD45-ADC,

or vehicle (PBS).

chemotherapy was administered intravenously once daily for five consecutive days.

(A) Survival of CD45+CD117+ PDX AML mice treated with a single intravenous dose of CD45-ADC

was significantly increased as compared to PBS or isotype-ADC

controls (B).

significantly delayed tumor burden (expressed as %hCD45) in the peripheral blood of treated mice compared to PBS, isotype-ADC

and standard of care controls.

Development plans

We plan to develop CD45-ADC

for use in patients with autoimmune diseases, such as multiple sclerosis and scleroderma, and patients with leukemias and myelodysplastic syndromes.

We have identified a lead antibody and progressed this program into IND enabling studies, which we plan to further advance in 2021.

Our third ADC-based

conditioning program, C300, targets T cells, a type of immune cell.

T cell depletion is currently performed with highly toxic, non-specific

drugs which can lead to immune deficiency, infections and other complications, including secondary autoimmune reactions.

We are pursuing targets expressed on the surfaces of T cells with the goal of offering a safer and more optimized targeted conditioning approach through T cell depletion before cell therapy such as CAR-T

for blood cancers, prevention of stem cell rejection prior to allogeneic stem cell transplant or achievement of immune system reset through autologous stem cell transplant in patients with autoimmune diseases.

We are developing our G100 product candidate as a targeted conditioning agent with the aim of preventing acute GvHD.

GvHD is a reaction that commonly develops after an allogeneic stem cell transplant and occurs when the transplanted cells see the recipient’s body as foreign.

The grafted cells then attack their new host.

It is the result of the donor T cells not matching the recipient’s, and this underscores the importance of matching between the donor and the recipient.

If they are not well matched, the donor’s T cells recognize the recipient’s cells as foreign and attack them.

Recipients who receive poorly matched stem cells are among those at the highest risk of developing this condition.

However, GvHD can occur even with proper matching.

Acute GvHD typically occurs within the first 100 days following transplant and can severely damage the skin, liver and gastrointestinal system.

It occurs in approximately 50% of patients receiving an allogenic stem cell transplant, depending on several factors including cell source and conditioning regimen, and accounts for approximately 10% of deaths following an allogeneic transplant.

Approximately 40% of all stem cell transplants are allogeneic.

Current treatments for acute GvHD prevention include the prophylactic use of immune suppressive agents that prevent T cell activation, such as cyclosporine or tacrolimus along with mycophenolic acid, which inhibits DNA base synthesis which is required by proliferating T cells or steroids.

Despite the use of these powerful immune suppressive agents, most allogeneic transplant patients will experience GvHD.

For severe cases, patients are treated with high doses of steroids, immune ablating antibodies or chemotherapy.

The use of high-dose non-specific

immune suppressive agents for GvHD treatment is correlated with an increased risk of opportunistic and viral infections, poor immune function and is a leading cause of death in allogenic transplant patients.

Our G100 product candidate is an ADC designed to selectively eliminate the cells that cause acute GvHD, specifically the alloreactive T cells.

This ADC product candidate is intended to be dosed in vivo

at the time of transplant and eliminate the activated alloreactive T cells.

By specifically targeting the alloreactive T cells that arise shortly after transplant, this product candidate has the potential to spare the remainder of the immune system to allow immune recovery and protection from opportunistic infections.

Cell Therapy Programs

High-dose, well-matched allogeneic investigational stem cell therapy for use in patients with high-risk hematologic malignancies

It is critical that patients receive a sufficiently high dose of well-matched HSCs in a stem cell transplant, as higher cell doses and better matched cells are closely correlated to improved patient outcomes.

In allogeneic transplant, up to half of patients will not find a suitable donor within their biological relatives or among registered bone marrow donors.

Long search times for unrelated, well-matched donors and their frequent unavailability represent a major challenge, particularly for patients with diseases that can progress rapidly, such as certain inherited metabolic disorders and high-risk acute leukemias.

Because of the urgency for these patients to undergo transplant, there is a need for improved options, and the ability to quickly find a well-matched stem cell donor with sufficient volume of cells remains one of the most significant hurdles in achieving successful stem cell transplant.

Cell dose and degree of graft matching are independent risk factors impacting risk of non-relapse

mortality in individuals undergoing cord blood transplant for acute leukemia.

Low numbers of CD34+ stem cells can result in prolonged periods of cytopenia and higher risk of graft failure.

The availability of MGTA-456

could reduce the barriers associated with cell dose and poor matching that currently limit the successful use of cord blood in transplant.

is currently being evaluated in a Phase 2 study in patients with high-risk blood cancers undergoing stem cell transplant.

Enrollment is this study has been completed and patients are currently in a follow-up

product candidate

is an investigational, novel, proprietary allogeneic stem cell therapy designed to provide a high dose of stem cells that are well matched to the patient.

Larger stem cell doses and better matched transplants are both correlated with more successful transplant outcomes, reduced risk of transplant failure and faster time to engraftment and immune recovery.

Clinical data:

We have completed a Phase 1 trial of MGTA-145 plus plerixafor in healthy subjects.

The trial met all

primary and secondary endpoints.

The Phase 1 trial was a dose-finding trial to evaluate safety and activity of MGTA-145 and consisted of four parts:

In Part A, healthy volunteers were dosed with MGTA-145 (0.0075 0.3

mg/kg) or placebo.

In Part B, subjects received a single dose of MGTA-145 (0.03 0.15

mg/kg) or placebo in combination with a single dose of plerixafor (0.24 mg/kg).

In Part C, subjects received MGTA-145 or placebo plus plerixafor

administered on day one and day two.

In Part D, subjects received a single dose of MGTA-145 (0.03 or 0.015

mg/kg) plus plerixafor followed by a single apheresis collection of multiple blood volumes.

Clinical endpoints include

safety and tolerability, pharmacokinetics, target engagement, and pharmacodynamic effects.

We presented results from the trial at TCT in

February 2020.

Results showed that MGTA-145 was safe and well-tolerated as a single agent and in

combination with plerixafor and showed the expected target pharmacology.

MGTA-145 was shown to engage CXCR2 on neutrophils to mobilize CD34+ cells into peripheral blood with limited neutrophil activation,

which may minimize risk of vaso-occlusive crises in patients with sickle cell disease and immune flares in patients with autoimmune disease.

Eleven of 12 subjects who received a single dose of the combination of MGTA-145 at the .03 dose level

and plerixafor mobilized more than 20 CD34+ cells/microliter, the clinically accepted threshold for successful mobilization, in a single day.

Subjects in Part C demonstrated reliable mobilization of CD34+ cells on day two with peak counts that were

comparable to day one mobilization yields, suggesting that two-day dosing and collection is feasible.

Single-day dosing and apheresis collection in eight subjects across two dose ranges in Part D yielded

a median of 4.1 million CD34+ cells/kg.

The clinically accepted threshold for a successful transplant is 2 million cells/kg.

The median percentage of CD34+CD90+ cells (functional stem cells) collected in Part D was 35% (range:

compared to approximately 10% with G-CSF-mobilized peripheral blood.

Cells collected from the first two subjects dosed in Part D transplanted into humanized mice engrafted more rapidly and at a ten-fold higher level than G-CSF-mobilized peripheral blood.

MGTA-145 in combination with plerixafor enables safe, same-day dosing, mobilization and collection of robust numbers of functional HSCs for transplant.

(A) CD34+ cells collected from healthy donors mobilized with a single injection of MGTA-145 + plerixafor (n=2) or five daily injections of G-CSF (n=3) were transplanted into sublethally irradiated (200 cGy) NSG mice at limit dilution (3 cell doses).

Engraftment of human CD45+ (hCD45+) in peripheral blood was measured at week 12 post-transplant by flow cytometry and SCID-repopulating cell (SRC) number per 1x106 cells was determined by ELDA.

Data represent

7-8 mice per cell dose and are expressed as SRC number +/- 95% CI.

Clinical development

We plan to develop MGTA-145 as a first-line therapy for stem cell mobilization in a broad

range of diseases, for both autologous and allogeneic transplant.

We have completed dosing in the Phase 1 trial in healthy subjects and plan to move this program into multiple Phase 2 trials in patients in 2020.

The Phase 2 trials may include

both allogeneic and autologous transplant settings and will evaluate mobilization and collection of high-quality stem cells and engraftment of the stem cells after transplant.

MGTA-456 cell therapy program

critical that patients receive a sufficiently high dose of well-matched HSCs in the transplant, as higher cell doses and better matched cells are closely correlated to more successful immune system rebuilding and better patient outcomes.

allogeneic transplant, up to half of the approximately 23,000 patients requiring donor cells will not find a suitable donor within their families or among the registered bone marrow donors.

Long search times for unrelated donors and their frequent

unavailability represent a major challenge, particularly for patients

with diseases that can progress rapidly, such as certain inherited metabolic disorders and high-risk acute leukemias.

Because of the urgency for these patients to undergo transplant, there is a

need for new options, and the ability to quickly find a well-matched stem cell donor with sufficient cells remains one of the most significant hurdles in stem cell transplant.

MGTA-456 is an allogeneic cell therapy that is designed to provide patients with a high dose of stem cells that are well matched to the patient.

MGTA-456 originally achieved

human proof-of-concept in a Phase 1/2 trial in patients with blood cancers.

Data from this trial showed that the median expansion of stem cells from the original cord

blood unit was 330-fold, and all 36 patients treated with MGTA-456 in the trial successfully achieved engraftment of this expanded stem cell dose.

We are adding to the

body of data for MGTA-456 in blood cancers through an investigator-initiated Phase 2 trial in blood cancers at the University of Minnesota, which was initiated in December 2018.

We anticipate that this trial

will triple the number of patients with blood cancers undergoing myeloablative conditioning who have been treated with MGTA-456, build experience with the cryopreserved formulation of MGTA-456 and help inform the design of further Magenta-sponsored trials.

We are the sponsor of the IND

for MGTA-456 in inherited metabolic disorders.

The IND was originally filed by Novartis International Pharmaceutical Ltd, or Novartis, on November 6, 2015 and formally transferred to us on July 25,

The IND is active and up to date with reporting requirements, such as annual reports.

We obtained the rights to MGTA-456 through an April 2017 license agreement with Novartis granting us the sole

worldwide rights to research, develop and commercialize certain AHR antagonist compounds specifically for the expansion of cord blood-derived non-gene-edited/-modified HSCs.

See Licenses and

Collaborations section.

Inherited Metabolic Disorders

We are currently studying MGTA-456 in a Phase 2 trial in patients with inherited metabolic disorders.

These rare genetic diseases, which include Hurler syndrome, cerebral adrenoleukodystrophy, or cALD;

metachromatic leukodystrophy, or MLD;

and globoid cell leukodystrophy, or GLD;

progress rapidly and are fatal if left untreated.

Stem cell transplant

is the only disease-modifying treatment option for Hurler syndrome, and the only treatment option for cALD, MLD and GLD.

We believe the high dose of HSCs present in MGTA-456 will speed engraftment, reduce or

eliminate engraftment failure and improve patient outcomes, with the potential to deliver transformative and durable disease benefit to these patients.

We estimate that approximately 7,000 patients worldwide suffer from one of these inherited

metabolic disorders.

At the TCT conference in February 2019, we reported early data from the first five patients treated in this Phase 2

All five patients with inherited metabolic disorders treated with MGTA-456 as of the data cut-off met the primary endpoint of successful engraftment.

with Hurler syndrome showed an increase in corrected enzyme and decrease in disease-related metabolites, and patients with cALD showed resolution of brain inflammation on MRI as early as one month post-treatment.

These early disease markers and

brain imaging evidence, respectively, are correlated with positive long-term disease outcomes.

Two treatment-related adverse events were observed:

one grade 1 vomiting and one grade 3 nausea, both of which were transient.

Normalization of enzyme activity in patients with Hurler syndrome within 42 days of receiving MGTA-456.

In December 2019, we presented updated results from the patients with cALD treated in

At one year of follow-up, both patients showed continued resolution of gadolinium enhancement by MRI.

The Loes score, a method for quantifying the severity of brain abnormalities and atrophy found

on MRI, also remained stable in both patients at one year.

Both patients had stable neurological function scores, which remained unchanged between baseline and one year of follow-up, suggesting progress of the

disease has been durably arrested.

Resolution of gadolinium enhancement persisted at one year of

follow-up in two patients with cALD, and Loes score and neurological function score remained stable.

blood cancers

MGTA-456 has also shown promise in patients with blood cancers.

In a Phase 1/2 trial conducted at the University of Minnesota beginning in 2014, nine patients underwent a myeloablative conditioning regimen

before receiving MGTA-456, and the other nine patients underwent non-myeloablative conditioning before receiving MGTA-456.

Data from this trial were presented at the ASH annual meeting in December 2017.

MGTA-456 successfully

engrafted in all 18 patients, with rapid time to neutrophil engraftment and immune recovery regardless of conditioning intensity.

Under the myeloablative protocol, all patients transplanted with MGTA-456

engrafted with a median time to neutrophil recovery of 14 days.

Overall survival at two years for patients treated with MGTA-456 was 67%.

Investigators at the University of Minnesota are now studying the cryopreserved formulation of

MGTA-456 in a Phase 2 clinical trial in patients with high-risk malignancies, which was initiated in December 2018.

Initial data presented at ASH in December 2019 showed that nine of nine patients treated with

MGTA-456 successfully engrafted.

No patients experienced chronic GvHD, and rates of acute GvHD were low.

Clinical Development Plan

complete enrollment in the Phase 2 trials in inherited metabolic disorders in 2020, continue dialogue with the FDA under the RMAT designation granted in February 2019 for the treatment of multiple inherited metabolic disorders, and discuss the

development path in Europe with the EMA.

There are approximately 400 patients diagnosed with inherited metabolic disorders each year in the U.S.

and Europe, and we estimate approximately 7,000 patients worldwide are living with one of these

inherited metabolic disorders.

We are adding to the body of data for MGTA-456 in blood cancers

through the investigator-initiated Phase 2 trial in blood cancers at the University of Minnesota.

We anticipate that this trial will triple the number of patients with blood cancers undergoing myeloablative conditioning treated with MGTA-456 as a stand-alone cell source, build experience with the cryopreserved formulation of MGTA-456 and help inform the design of further clinical trials in patients with

blood cancers.

Previously, in April 2018, we received orphan drug designation from the FDA for

MGTA-456 for the enhancement of cell engraftment in patients receiving stem cell transplant.

obtained the rights to MGTA-456 through an April 2017 license agreement with Novartis granting us the sole worldwide rights to research, develop and commercialize certain AHR antagonist compounds specifically

for the expansion of cord blood-derived non-gene-edited/-modified HSCs.

MGTA-456 manufacturing process

MGTA-456 is manufactured at a good manufacturing practice, or GMP, certified contract manufacturing

facility, which has produced all batches of MGTA-456 used for clinical trials.

The manufacturing process involves selection of CD34+ cells, which contain the stem cells, from an umbilical cord blood unit

matched to the patient to create a CD34-enriched cell fraction and a CD34-depleted cell fraction.

The CD34-depleted fraction is cryopreserved following selection and later thawed and infused at the time of transplant.

The CD34-depleted fraction

contains immune cells that are important for immune recovery and provide a source of donor T cells that can recognize and kill residual tumor cells in the patient when used in patients with blood cancers.

The CD34+ enriched cells are cultured for 15

days with growth factors that promote cell division and the low molecular weight AHR antagonist to produce MGTA-456.

While the cells are being cultured, the patient is

conditioned for transplant.

The MGTA-456 manufacturing process results in a median increase in the number of CD34+ cells of

327-fold (range:

67-fold to 848-fold) across all studies.

Summary of clinical manufacturing of MGTA-456, CD34+ cell

numbers before and after expansion in 36 clinical manufacturing batches.

After culture, the cells are washed, characterized, and re-suspended in human serum albumin solution.

The cells then undergo quality and release testing.

MGTA-456 can then be infused directly into the recipient (fresh

product) or can be mixed with cryopreservation medium, cryopreserved and infused to the patient after thawing.

The ability to cryopreserve MGTA-456 should allow for shipment of the product globally.

manufacturing process takes a total of 15 days from receipt of the cord blood unit to product release.

The shelf life of the fresh product is 24 hours after manufacturing.

The shelf life of the frozen product is up to 90 days.

We are currently

working with third-party GMP suppliers for our clinical manufacturing process and with commercial contract manufacturing organizations to develop a process for commercial supply.

Schematic of the MGTA-456 manufacturing process.

starting stem cell unit is thawed and the CD34 + cells are selected and expanded in the presence of an AHR antagonist.

Following expansion, the

CD34 + cells are frozen and shipped to the transplant center.

They are then thawed and infused in the patient.

The HSCs migrate to the bone marrow and rebuild the immune and blood system.

The manufacturing process for MGTA-456 does not

require genomic manipulation.

The small molecule AHR antagonist used in the MGTA-456 manufacturing process is manufactured under GMP conditions from readily available starting materials in reliable and

reproducible synthetic processes that do not require specialized equipment in the manufacturing process.

E478 Cell Therapy Program

transplant with gene-modified HSCs, which is referred to as stem cell gene therapy or genome editing, is a promising treatment approach for a number of inherited diseases but is currently limited by the inability to generate a sufficient dose of

gene-modified HSCs to achieve clinically meaningful results.

The ability to expand HSCs ex vivo has the potential to improve

outcomes with gene therapy or genome editing by increasing the dose of genetically modified stem cells.

This has been a long-term goal of the field and has the potential to reduce manufacturing costs for these therapies by requiring less viral

vector for gene modification of the stem cells.

Scaling up vector manufacturing in a cost-effective manner has been a significant challenge for HSC-based gene therapy companies and a significant cost driver.

Data were presented at the TCT annual meeting in February 2021 from 18 patients transplanted in a Phase 1/2 clinical trial in patients with blood cancers.

The trial showed that expansion of CD34+CD90+ cells in MGTA-456

results in rapid and sustained hematopoietic recovery, complete engraftment in all subjects, improved matching in adults weighing >59 kg and reduced incidence of GvHD.

In addition, neutrophil recovery occurred in 100% of patients at a median of 17 days versus 23 days in recipients of unmodified cord blood.

Similarly, platelet recovery was higher (94% vs.

74%) and faster (median 36 days vs.

59 days) for patients receiving MGTA-456

versus unmodified cord blood, respectively.

Both neutrophil and platelet recovery correlated to dose of CD34+CD90+ cells.

With all patients now out beyond day 100, only one patient had grade 3-4

acute GvHD and one had chronic GvHD limited to the oral mucosa (off immunosuppression 15 months after transplant).

Development plan

Previously, MGTA-456

was evaluated in patients with rare genetic inherited metabolic disorders.

In June 2020, we announced that we would discontinue enrollment in our Phase 2 trial of MGTA-456

in patients with inherited metabolic disorders undergoing stem cell transplant.

This decision was the result of several factors, including enrollment challenges common to rare disease populations, which were heightened as a result of the COVID-19

a growing understanding in the transplant field of the current challenges of allogeneic stem cell transplant in patients with non-malignant

diseases, including inherited metabolic diseases;

and feedback from the FDA on endpoints and clinical trial design for registration.

We will continue to evaluate the data for MGTA-456

in blood cancers through the investigator-initiated Phase 2 trial in blood cancers at the University of Minnesota to inform best next steps for the program.

AHR antagonist for expansion of gene-modified stem cells

Stem cell transplant with gene-modified HSCs, which is referred to as stem cell gene therapy or genome editing, is a promising treatment approach for many diseases.

However, this approach is significantly limited by (1) the inability to generate a sufficient dose of gene-modified HSCs that retain the ability to durably engraft in patients and (2) the cost and complexity of manufacturing viral vectors for gene modification of cells.

These constraints could limit the commercial viability of this approach.

The ability to expand HSCs ex vivo

has the potential to improve outcomes with gene therapy or genome editing by increasing the dose of genetically modified stem cells.

This has been a long-term goal of the field and

has the potential to reduce manufacturing costs for these therapies by requiring less viral vector for gene modification of the stem cells.

Scaling up vector manufacturing in a cost-effective manner has been a significant challenge for HSC-based

gene therapy companies and a significant cost driver.

Such cost and capacity issues could limit the commercial viability and widespread deployment of gene therapies.

This will only be a bigger challenge as more gene therapies enter the marketplace in the coming years.

developed the E478 program in response to an unmet technological need recognized in the field of gene therapy the challenge of achieving sufficiently high doses of transduced or gene-modified cells.

We believe that E478 could represent a key

component for unlocking the full value of gene therapy by providing each patient with an optimal dose of gene-modified HSCs for rapid and successful engraftment.

E478 uses the same clinically validated method used to produce MGTA-456, AHR antagonism, to expand

gene-modified HSCs.

We are developing E478 specifically to partner with gene therapy and/or genome editing companies to integrate into their manufacturing processes, leading to newly defined cell therapy products.

We have shown that E478 can

generate higher numbers of long-term engrafting cells compared to other expansion technologies.

We have presented in vitro and in vivo data demonstrating successful expansion of gene-modified HSCs from both bone marrow and mobilized

blood and in vivo engraftment of the expanded cells modified via lentiviral transduction, CRISPR/Cas9 and other gene-modifying approaches.

We performed experiments designed to evaluate the ability of E478 to increase HSC numbers for HSC based

gene therapy.

In these studies, human CD34 + cells isolated from G-CSF mobilized peripheral blood were cultured with cytokines in the presence or absence of

E478 and transduced with lentiviral vectors expressing a green fluorescent protein (GFP) to identify cells that were effectively transduced.

Inclusion of E478 increased the number of CD34 + cells

and improved the level of human cell engraftment while maintaining high levels of transduction.

At the American Society of Cell and Gene Therapy annual meeting in May 2019, we presented

in vitro data showing that culturing gene-corrected cells with E478 increased the dose of corrected cells.

E478 increases the dose of oligonucleotide donor corrected cells.

Our E478 product candidate

We developed the E478 program in response to an unmet technological need recognized in the field of stem cell gene therapy – the challenge of achieving sufficiently high doses of gene-modified stem cells.

E478 is a novel and proprietary small molecule AHR antagonist that was developed to increase the number of gene-modified HSCs ex vivo

for stem cell based-gene therapy.

E478 uses the same clinically validated method used to produce MGTA-456,

AHR antagonism, to expand gene-modified HSCs.

We believe that E478 could represent a key component for unlocking the full value of gene therapy by providing each patient with an optimal dose of gene-modified HSCs for rapid and successful engraftment.

In addition to addressing cell dose limitations, the ability to expand long-term repopulating HSCs ex vivo

has the potential to reduce manufacturing costs for these therapies by requiring less viral vector for gene modification of the stem cells.

Preclinical data

We have shown that E478 can generate higher numbers of long-term engrafting human HSCs compared to other expansion technologies.

We have presented in vitro

data demonstrating successful expansion of gene-modified HSCs from both bone marrow and mobilized blood cell sources with E478 and showed that ex vivo

expansion with E478 leads to higher and durable levels of engraftment in NSG mice compared to conventional culture approaches.

Our data demonstrate that HSCs modified via lentiviral transduction, CRISPR/Cas9 and other gene-modifying approaches can be expanded in vitro

by E478 and engraft in vivo

We performed experiments designed to evaluate the ability of E478 to increase HSC numbers for HSC based gene therapy.

In these studies, human CD34+ cells isolated from G-CSF

mobilized peripheral blood were cultured with cytokines in the presence or absence of E478 and transduced with lentiviral vectors expressing a green fluorescent protein to identify cells that were effectively transduced.

Inclusion of E478 increased the number of CD34+ cells and significantly improved the level of human cell engraftment in NSG mice while maintaining high levels of transduction.

Similar findings were observed using CRISPR-based approaches.

At the American Society of Cell and Gene Therapy annual meeting in May 2020, we presented in vivo

data showing that ex vivo

expansion with E478 led to significantly higher rate and number of NSG-engrafting

gene-corrected cells.

E478 increases the dose of gene-corrected NSG-engrafting

Mobilized blood CD34+ cells from healthy subjects were pre-stimulated

in cytokine-containing media followed by electroporation with CRISPR/Cas9 and AAV.GFP donor and expanded post-editing.

Four day pre-stimulation

followed by a four day expansion (called a 4+4 culture) compared to a conventional two day pre-stimulation

period followed by a one day expansion (called a 2+1 culture).

E478 was added to the 4+4 culture and compared to a conventional 2+1 culture with vehicle control.

Engraftment (frequency of human CD45+ cells);

rate of homology-directed repair, or HDR;

number of engraftable HDR+ cells was measured in the peripheral blood at week 16 post-transplant.

Bars represent median and each symbol represents an individual mouse (n=eight).

Statistics were determined by a one-tailed

Student’s t-test.

Development plan

developing E478 specifically to partner with gene therapy and/or genome editing companies to integrate into their manufacturing processes, leading to newly defined cell therapy products.

Post-transplant complications program

Approximately

40% of all stem cell transplants are allogeneic.

GvHD, a reaction that commonly develops after an allogeneic stem cell transplant, occurs when the transplanted cells see the recipients body as foreign.

The grafted cells then attack their

It is the result of the donor T cells not matching the recipients, and this underscores the importance of HLA matching between the donor and the recipient.

If they are not well matched, the donors T cells recognize the

recipients cells as foreign and attack them.

Recipients who receive poorly matched stem cells are among those at the highest risk of developing this condition.

However, GvHD can occur even with proper HLA matching.

Acute GvHD typically occurs

within the first 100 days following transplant and can severely damage the skin, liver, and gastrointestinal system.

It occurs in approximately 50 to 80% of patients receiving an allogenic stem cell transplant, depending on the specific indication,

and accounts for approximately 10% of deaths following an allogeneic transplant.

Current treatments for acute GvHD prevention include the prophylactic use of immune suppressive agents that prevent T cell activation, such as cyclosporine or

tacrolimus along with mycophenolic acid, first discovered in 1893, which inhibits DNA base synthesis which is required by proliferating T cells or steroids.

Despite the use of these powerful immune suppressive agents, most allogeneic transplant

patients will experience GvHD.

For severe cases, patients are treated with high doses of steroids, immune ablating antibodies or chemotherapy.

The use of high-dose non-specific immune suppressive agents for

GvHD treatment is correlated with an increased risk of opportunistic and viral infections, poor immune function and is a leading cause of death in allogenic transplant patients.

developing a unique approach to preventing acute GvHD.

Our ADC-based therapeutics are designed to selectively eliminate only the components of the graft that cause acute GvHD, specifically the alloreactive T

This ADC therapy is intended to be dosed in vivo at the time of transplant and eliminate the activated alloreactive T cells.

By specifically targeting the alloreactive T cells that arise shortly after transplant, this therapy should

spare the remainder of the immune system to allow immune recovery and protection from opportunistic infections.

We are developing E478 specifically to partner with gene therapy, genome editing and cell therapy companies.

E478 would be integrated into our potential partners’ cell-based products, leading to newly defined cell/gene therapies.

Commercialization Plan

We plan to establish sales, marketing and commercial product distribution capabilities.

Ahead of our first commercial launch, we are building

upon relationships with transplant centers and thought leaders, furthering our understanding of the influences on the transplant decision-making process, refining our market research into reimbursement and market access, and leveraging our

partnership with the NMDP.

Transplants are currently conducted in a small number of specialist sites in the U.S.

As our product candidates advance in clinical development, we are building upon our existing relationships with transplant centers and thought leaders, furthering our understanding of the influences on the transplant decision-making process, refining our market research into reimbursement and market access and leveraging our partnership with Be the Match.

Transplants are currently conducted in a small number of specialist sites worldwide.

There are approximately 180 transplant centers in the U.S.

that are accredited through the NMDP, of which 20% of these

transplant centers collectively account for over 50% of transplant volume.

In Europe, approximately 205 transplant centers are accredited through the Joint Accreditation Committee ISCT-Europe-EMBT and data show that 30% of transplants in Europe

between 2012 and 2015 were carried out by 20 centers in France and Spain.

that are accredited through Be the Match, of which 20% collectively account for over 50% of transplant volume.

In Europe, approximately 275 transplant centers are accredited through the Joint Accreditation Committee ISCT-Europe-EMBT.

All of our product candidates are focused on the transplant physician as the key prescriber and decision maker.

As we advance our development programs in the U.S.

and Europe, we will evaluate our sales and marketing resource needs.

In advance of approval

of our first product in the U.S.

and Europe, we plan to build out a dedicated transplant-center-focused sales and marketing organization.

We intend to leverage the infrastructure developed for MGTA-456 and MGTA-145 to support commercialization of any additional product candidates in our portfolio for which we gain approval.

In addition, we will build upon physicians familiarity with MGTA-456 and MGTA-145 to accelerate adoption of our other medicines.

As we advance our development programs, we will evaluate our sales and marketing resource needs and develop plans to build out a dedicated transplant center-focused medical affairs, sales and marketing

organization.

We intend to leverage any infrastructure developed for our lead product candidate, MGTA-145,

to support commercialization of any additional product candidates in our portfolio for which we gain approval.

In addition, we expect to build upon physicians’ familiarity with MGTA-145

to accelerate adoption of our other potential products.

As additional product candidates advance through our pipeline, our commercial plans may change.

particular, some of our pipeline assets target autoimmune disease indications, which could potentially require commercial reach that captures referring physicians outside of transplant centers and clinical trial sites.

Our commercial strategy may include the use of strategic partners, distributors, a contract sales force or the establishment of our own

commercial structure.

Immune Reset Market Opportunity

Despite the existing risks associated with stem cell transplant, today transplant is a large market opportunity with approximately 65,000

procedures performed annually in the U.S.

However, this number represents only 40% of the patient population that is eligible for transplant.

At Magenta, we believe our portfolio of product candidates could not only improve upon existing approaches but also extend the curative power

of immune reset to more patients.

Each of our product candidates contributes uniquely to addressing certain opportunities in stem cell transplant.

By using multiple Magenta products, physicians would be able to tailor the transplant procedure,

thereby improving patient outcomes and increasing the potential for every eligible patient to benefit from an immune reset.

diseases where transplant has been shown to result in improved patient outcomes, only a small fraction of eligible patients currently receive a transplant because the risks and challenges outweigh the potential for a cure.

Depending on the disease,

the barriers for treatment include finding a matched donor, obtaining an adequate cell dose and the morbidity and mortality associated with current conditioning regimens.

We believe that by removing the major barriers to transplant with

Magentas programs, we enable safe immune reset through stem cell transplant for all of the approximately 150,000 eligible patients in the U.S.

Further, by making the procedure less risky and toxic, we believe the eligible patient

populations could increase beyond the current numbers.

At Magenta, we are planning to develop our suite of medicines for immune reset across several indications.

These include diseases where stem

cell transplant is currently a standard of care (e.g., blood cancers such as acute myelogenous leukemia, myelodysplastic syndromes, multiple myeloma, and non-Hodgkin lymphoma), diseases where transplant is

performed but limited in use (e.g., hemoglobinopathies such as sickle cell disease and beta-thalassemia), and diseases where the clinical promise for immune reset is emerging (e.g., autoimmune diseases such as systemic sclerosis and multiple

The introduction of innovative medicines to the marketplace that address some of the primary barriers for treatment with transplant would therefore potentially enable all of the 150,000 currently eligible patients across these diseases

to receive a transplant.

In addition, we believe our medicines will increase the number of patients who are eligible for an immune reset.

We further assessed the existing eligible patient population on a

per-program basis to estimate the potential number of treatments that could be provided on a per patient basis.

This analysis, summarized in the table below, assumes demonstration of clinical outcomes that

address barriers to treatment with transplant.

Of the approximately 150,000 patients currently eligible for a stem cell transplant patients

and Europe, each will potentially need multiple treatments using products to be developed under our programs:

Autoimmune diseases:

emerging data support use of stem cell transplant as a clinically promising one-time therapy, however the high morbidity and mortality associated with current conditioning regimens limit the uptake of transplant as a therapeutic option.

Multiple sclerosis affects approximately 600,000 to 700,000 patients in the U.S.

and historically at least 650,000 patients in Europe.

Approximately 15,000 new patients in the U.S.

and 32,000 new patients in Europe are diagnosed annually.

To assess eligibility in this population.

we focused on the patients with active relapsing-remitting disease and relapsing secondary progressive

multiple sclerosis patients who are not adequately treated by current therapies.

This population represents approximately 45,000 multiple sclerosis patients who switch therapies each year in the U.S.

and we believe that a greater population of

patients switch therapies each year in Europe.

Many of these patients switch because their current therapy does not adequately control disease activity such as relapses.

Given stem cell transplants ability to durably eliminate relapses and

disease activity in multiple sclerosis patients, we believe a safe immune reset would be a viable option for those patients with highly active disease beyond what therapeutics can manage.

Currently approximately 1 to 2% of eligible multiple

sclerosis patients in the U.S.

and Europe receive a stem cell transplant because the risk of the process outweighs the benefits of a potential cure and we believe we can significantly expand this number.

Scleroderma, a chronic connective tissue disease that is characterized by thickening of the skin, is diagnosed in approximately 6,600 patients

and 10,900 patients in Europe annually.

Approximately 35% (2,300 patients in the U.S., 3,800 patients in Europe) of scleroderma patients suffer from diffuse cutaneous disease and are therefore eligible for stem cell transplant.

approximately 1% or less of eligible scleroderma patients in the U.S.

and Europe receive a stem cell transplant.

However, with the addition of stem cell transplant into the EULAR, treatment guidelines for scleroderma and with the opportunity for a

safer transplant procedure, we believe transplant would be a viable option for the severe scleroderma patient population who have no other therapeutic options available.

Our conditioning programs, such as CD45-ADC or a combination of MGTA-117 and C300, have the potential to provide safer, targeted conditioning for these autoimmune disease patients receiving autologous transplant.

We are developing these targeted conditioning approaches to grow

the use of transplant in autoimmune disease significantly.

In addition, our MGTA-145 product candidate may address the

difficult-to-mobilize patients who cannot receive G-CSF because of the risk of triggering autoimmune flares.

In particular, some of our discovery-stage pipeline assets target autoimmune disease indications, which could potentially require additional commercial resources in order to engage with referring physicians outside of transplant centers and clinical trial sites.

Our commercial strategy in the U.S., Europe, and Asia may include the use of strategic partners, distributors, a contract salesforce and/or the establishment of our own commercial structure.

Stem Cell Transplant Commercial Market Opportunity

Stem cell transplant is currently a large commercial market opportunity with approximately 90,000 procedures annually in the U.S., Europe and Asia.

This is a significant existing potential market for Magenta medicines.

However, this number represents only approximately 50% of the patient population that is eligible for stem cell transplant given the existing barriers and risks that can prevent eligible patients from proceeding to transplant.

At Magenta, we believe our portfolio of product candidates could not only improve upon existing approaches but also extend the curative power of stem cell transplant to more patients.

Each of our product candidates is designed to address distinct unmet needs in the stem cell transplant patient journey.

By using multiple Magenta products, physicians would be able to tailor the transplant procedure, thereby improving patient outcomes and increasing the potential for every eligible patient to benefit from stem cell transplant.

Across diseases where transplant has been shown to result in improved patient outcomes, only a fraction of eligible patients currently receives a transplant because the current risks and challenges associated with the drug products used to prepare patients often outweigh the potential for a cure.

Depending on the disease, the barriers for treatment currently include the risk of morbidity and mortality associated with current conditioning regimens, efficiently obtaining an adequate cell dose to complete the transplant and finding a matched donor.

We believe that by removing the major barriers to transplant with Magenta’s programs, we can potentially enable safe and effective stem cell transplant for more of the 175,000 eligible patients worldwide.

Further, by optimizing the benefit-risk tradeoff, we believe the eligible patient populations could increase beyond the current numbers.

We have assessed the existing stem cell transplant market and potential eligible patient population on a per-indication

basis to estimate the potential number of patients that could benefit from Magenta’s product candidates.

Blood Cancers:

Stem cell transplant is a standard of care, however a significant number of eligible patients do not receive a transplant

because of lack of a matched donor, poor mobilization, and the toxicity of conditioning:

Acute myeloid leukemia, a cancer arising from

myeloid cells, an immature white blood cell found in the bone marrow, is diagnosed in approximately 20,000 patients in the U.S.

and 27,000 patients in Europe annually.

Approximately 60% (12,500 patients in the U.S., 16,400 patients in Europe) of

newly diagnosed patients have a complete response to induction chemotherapy and become eligible for transplant for a more durable remission.

However, the current challenges of stem cell transplant and patient

co-morbidities limit transplant to approximately 30 to 40% of those patients who are otherwise eligible.

Myelodysplastic syndrome occurs when the blood-forming cells in the bone marrow become abnormal, leading to low numbers of one or more types

of blood cells.

It is diagnosed in approximately 21,000 patients in the U.S.

and 13,300 patients in Europe annually.

Approximately 30% (6,700 patients in the U.S., 4,600 patients in Europe) of newly diagnosed patients have high risk disease and

are eligible for stem cell transplant.

However, toxicities of stem cell transplant and patient co-morbidities limit transplant to approximately 16 to 40% of those patients who are otherwise eligible.

Non-Hodgkin lymphoma, a cancer arising from lymphocytes, a type of white blood cell, is diagnosed in

approximately 72,000 patients in the U.S.

and 95,000 patients in Europe annually.

Non-Hodgkin lymphoma, the most common blood cancer, can be treated by autologous stem cell transplant.

The largest Non-Hodgkin lymphoma subtype is Diffuse Large B-Cell Lymphoma, or DLBCL, comprising approximately 33% of Non-Hodgkin lymphoma.

First-line chemotherapy and targeted therapies like rituximab are effective for about two-thirds of DLBCL patients.

In the remaining one-third of patients with

relapsed/refractory disease, the National Comprehensive Cancer Network recommends autologous stem cell transplant as one therapeutic option.

Therefore, approximately 6,500 newly diagnosed patients in the U.S.

and 8,500 patients in Europe are

eligible for stem cell transplant.

Currently, approximately 60 to 80% of those eligible Non-Hodgkin lymphoma patients in the U.S.

and Europe receive a stem cell transplant.

Multiple myeloma a cancer arising from plasma cells, is diagnosed in approximately 30,000 patients in the U.S.

and 40,000 patients in Europe

Stem cell transplant is an existing standard of care for many diseases, however outcomes can be impacted by many factors, including lack of a matched donor or poor mobilization, and a significant number of eligible patients do not receive a transplant because of the toxicity of conditioning:

product candidate has the potential to address the challenges in mobilizing and collecting stem cells faced by patients and healthy donors for transplant in blood cancer patients.

Our conditioning programs, including our MGTA-117

product candidate, have the potential to provide safer and more effective targeted conditioning for blood cancer patients, particularly allogeneic transplant candidates, who currently weight the tradeoffs of long-term efficacy and toxicity with current conditioning regimens that impact patient outcomes.

Pending further development for the MGTA-456

program informed by ongoing data, MGTA-456

has the potential to offer allogeneic transplant recipients access to a well-matched cell therapy, with a high stem cell dose and the higher likelihood of durable clinical outcomes.

Multiple myeloma, a cancer arising from plasma cells, is diagnosed in approximately 64,000 patients annually in the major global markets:

U.S., Germany, France, U.K., Italy, Spain and Japan.

Multiple myeloma represents the second most common blood cancer treated by autologous stem cell transplant.

Approximately 50% (15,000 patients in the U.S., 20,000 patients in Europe) of newly diagnosed patients are eligible for stem

cell transplant.

The National Comprehensive Cancer Network recommends stem cell transplant for patients after primary therapeutic treatment, including novel orals, injectables, and chemotherapy.

This recommendation is founded on evidence that

autologous stem cell transplant consistently achieves higher response rates and survival rates than primary treatment alone.

However, toxicities of stem cell transplant and patient co-morbidities limit

transplant to approximately 55 to 60% of those patients who are otherwise eligible.

Our conditioning programs, such as CD45-ADC and MGTA-117, have the potential to provide safer, targeted conditioning for these blood cancer patients who are too frail to tolerate the current conditioning

Our MGTA-145 product candidate has the potential to address the difficult-to-mobilize patients who are suffering from

blood cancers as well so that patients can access a robust single-day mobilization regimen.

For allogeneic transplant recipients, MGTA-456 offers access to a

well-matched cell therapy, with a high stem cell dose and the higher likelihood of durable clinical outcomes.

Hemoglobinopathies:

Stem cell transplant is clinically accepted but still limited in use

due to challenges identifying well-matched donors and conditioning-associated morbidity and mortality.

Gene therapy is a promising treatment option but is limited by the same conditioning challenges as well as the ability to obtain a sufficient dose

of gene-modified cells.

Sickle cell disease is diagnosed in approximately 1,700 patients in the U.S.

and 720 patients in Europe

Approximately 25% (400 patients in the U.S., 180 patients in Europe) of patients with sickle cell disease have severe disease and are therefore eligible for stem cell transplant.

Currently, only approximately 36 to 58% of eligible patients

with sickle cell disease in the U.S.

and Europe receive a stem cell transplant because it is particularly difficult to find a matched donor and the risk of the procedure often outweighs the benefits of a potential cure.

Beta-thalassemia is diagnosed in approximately 500 patients in the U.S.

and 1,500 patients in Europe annually.

Approximately 60% (340 patients

in the U.S., 1,020 patients in Europe) of patients with beta-thalassemia patients have severe disease, or beta-thalassemia major, and are therefore eligible for stem cell transplant.

Currently, only approximately 27% of eligible beta-thalassemia

patients in the U.S.

and Europe receive a stem cell transplant because they are unable to find a matched donor and/or the risk of the process outweighs the benefits of a potential cure.

Our conditioning programs, such as MGTA-117, have the potential to provide safer, targeted

conditioning for these hemoglobinopathy patients receiving autologous gene therapy or an allogeneic transplant.

Our MGTA-145 product candidate has the potential to address patients with sickle cell disease who

cannot receive G-CSF because of the risk of triggering sickle cell crises.

E478 uses the same clinically-validated mechanism as MGTA-456 to generate higher doses of

gene-modified stem cells.

Our portfolio of products is designed to address several opportunities in transplant, providing the potential

opportunity for our products to be used in combination to create disease-tailored solutions for patients.

Based on the 150,000 patients who are currently eligible for transplant in the U.S.

and Europe and who could benefit from our medicines, we

estimate the potential for up to 375,000 aggregate treatments per year in the future.

This estimate includes approximately 150,000 treatments under our conditioning programs, 150,000 treatments under our mobilization program, 15,000 treatments

under our expansion programs, and 60,000 treatments under our post-transplant complications program, each on an annual basis.

Following diagnosis, patients typically undergo treatment with one or more therapeutic classes which may include chemotherapy, immunotherapy, targeted agents, and/or corticosteroids.

After one or more courses of initial treatment, patients may proceed to a stem cell transplant depending on whether they are considered an appropriate candidate depending on several patient- and disease-related factors.

Currently, approximately 15,300 multiple myeloma patients receive a stem cell transplant annually in the major global markets.

Non-Hodgkin’s

and Hodgkin’s lymphomas, cancers arising from lymphocytes or white blood cells, are diagnosed in approximately 180,000 patients annually in the major global markets.

Non-Hodgkin’s

lymphoma, or NHL is the most common group of blood cancers, the largest of which is Diffuse Large B-Cell

Lymphoma, comprising approximately 33% of cases.

Both major types of lymphomas can be treated by autologous stem cell transplant.

Following diagnosis, patients typically undergo treatment with one or more therapeutic classes which may include chemotherapy, immunotherapy, cell therapy, targeted agents, and/or corticosteroids.

Currently, approximately 10,500 lymphoma patients receive a stem cell transplant annually in the major global markets.

Acute myeloid leukemia, or AML, a cancer arising from myeloid cells, an immature white blood cell found in the bone marrow, is diagnosed in approximately 36,000 patients annually in the major global markets:

U.S., Germany, France, U.K., Italy, Spain and Japan.

Eligibility for a stem cell transplant is determined by several criteria including patient fitness (including age and comorbidities), cytogenetic risk status and response to induction therapy.

Approximately 40% of newly diagnosed AML patients become eligible for transplant to achieve a more durable remission based on the criteria outlined.

However, the current challenges of stem cell transplant, including highly toxic chemotherapy conditioning regimens, limit transplant to approximately 60% of those patients who are otherwise eligible.

Currently, approximately 8,400 patients with AML receive a stem cell transplant annually in the major global markets.

Myelodysplastic syndrome, or MDS, occurs when the blood-forming cells in the bone marrow become abnormal, leading to low numbers of one or more types of blood cells.

It is diagnosed in approximately 46,000 patients annually in the major global markets.

Approximately 35% of newly diagnosed MDS patients have intermediate- to high-risk disease and one-third

of those are eligible for stem cell transplant based on patient fitness (including age and comorbidities) and blast count.

However, the current challenges of stem cell transplant, including highly toxic chemotherapy conditioning regimens, limit transplant to approximately 60% of those

MDS patients who are otherwise eligible.

Currently, approximately 2,900 patients with MDS receive a stem cell transplant annually in the major global markets.

Acute lymphocytic leukemia, or ALL, is a cancer that develops from immature white blood cells and is common in children.

It is diagnosed in approximately 11,000 patients annually in the major global markets.

Currently, approximately 3,800 patients with ALL receive a stem cell transplant annually in the major global markets.

Hematopoietic Stem Cell-Based Gene Therapies:

Stem cell gene therapy is a promising treatment option but is limited by the same conditioning challenges as standard stem cell transplant, as the current standard of care, busulfan, has many risks including long-term infertility and secondary cancers.

Additionally, all HSC-based

gene therapy patients require a high dose of stem cells for gene modification, and sickle cell patients specifically have limited options and experience significant safety risks with current mobilization regimens.

product candidate has the potential to address patients with sickle cell disease who cannot receive G-CSF

because of the risk of triggering sickle cell crises, as well as other patients requiring collection of stem cells prior to HSC-based

gene therapy.

conditioning program has the potential to provide safer, targeted conditioning for patients who are eligible to receive autologous stem cell gene therapies, including but not limited to patients with sickle cell disease, beta thalassemia, and lysosomal storage disorders.

may also further expand the number of patients who are eligible for these currently investigational gene therapy product candidates.

E478 uses the same clinically validated mechanism as MGTA-456

to generate higher doses of gene-modified stem cells.

Sickle cell disease affects over 100,000 patients in the U.S.

and 50,000 patients in Germany, France, U.K., Italy and Spain.

Approximately 50,000 of these patients have severe disease (based on annualized sickle cell crises) and are therefore eligible for stem cell transplant or gene therapy.

Beta-thalassemia affects approximately 7,500 patients in the U.S., 7,000 patients in Italy, and 2,600 patients in Germany, France, U.K., Spain and Japan annually.

Approximately 70% of these patients, or 12,500 patients, have severe disease, or beta-thalassemia major, and are therefore eligible for stem cell transplant.

Autoimmune Diseases:

emerging data support use of stem cell transplant as a one-time

therapy, however the high morbidity and mortality associated with current conditioning regimens limit the uptake of transplant as a therapeutic option.

product candidate has the potential to be the first product specifically indicated for the mobilization of autoimmune disease patients, without the risks associated with G-CSF.

In addition, our C100 conditioning program has the potential to provide safer, targeted conditioning for autoimmune disease patients eligible to receive autologous transplant.

We are developing targeted conditioning approaches to grow the use of transplant in autoimmune disease significantly.

Multiple sclerosis affects over 1 million patients worldwide and approximately 62,000 new patients are diagnosed annually in the major global markets.

To assess current eligibility in this population, we focused on the patients with active relapsing-remitting disease and relapsing secondary progressive multiple sclerosis patients who are not adequately treated by current therapies.

We believe this population represents more than 6,000 diagnosed severe multiple sclerosis patients annually who are eligible for stem cell transplant under current guidelines.

Given stem cell transplant’s proven ability to durably eliminate relapses and disease activity in multiple sclerosis patients, we believe a safe blood and immune reset would be a viable option for those patients with highly active disease beyond what therapeutics can manage.

Currently fewer than 10% of eligible multiple sclerosis patients receive a stem cell transplant because the risk of the process outweighs the benefits of a potential cure, and we believe we can significantly expand this number.

Systemic sclerosis, or scleroderma, is a chronic connective tissue disease that is characterized by thickening of the skin.

It affects over 245,000 patients and approximately 21,000 new patients are diagnosed annually in the

major global markets.

Although 35% of scleroderma patients suffer from diffuse cutaneous disease and are therefore eligible for stem cell transplant today, currently fewer than 10% of eligible scleroderma patients receive a stem cell transplant.

However, with the recent addition of stem cell transplant into the EULAR treatment guidelines for scleroderma and with the opportunity for a safer transplant procedure, we believe transplant would be a viable option for the severe scleroderma patient population who have no other therapeutic options available.

Manufacturing

We do not own or operate, and currently have no plans to establish, any manufacturing facilities.

We currently depend on third-party contract

manufacturing organizations, or CMOs, for all of our requirements of raw materials, drug substance and drug product for our preclinical research and our ongoing clinical trials of MGTA-456 and MGTA-145.

We currently depend on third-party contract manufacturing organizations, or CMOs, for all of our requirements of raw materials, drug substance and drug product for our preclinical research and our ongoing clinical trials of MGTA-145

and MGTA-456.

We have not entered into long-term agreements with our current CMOs.

We intend to continue to rely on CMOs for later-stage development and commercialization of

MGTA-456 and MGTA-145, as well as the development and commercialization of MGTA-117 and other product candidates that we may

We intend to continue to rely on CMOs for later-stage development and commercialization of MGTA-145,

as well as the development and commercialization of MGTA-117

and other product candidates that we may identify.

Although we rely on CMOs, we have personnel and consultants with extensive manufacturing experience to oversee the relationships with our contract manufacturers.

We believe the synthesis of the AHR antagonist that we use to manufacture MGTA-456 is reliable and

reproducible from readily available starting materials, and the synthetic routes are amenable to large-scale production and do not require unusual equipment or handling in the manufacturing process.

We acquired data from Novartis related to the

chemical synthesis of the AHR antagonist, which has been manufactured by Novartis to satisfy our immediate and near term clinical and preclinical needs.

We also acquired data from Novartis related to manufacturing of

MGTA-456, which is currently manufactured by a single CMO to satisfy our immediate and near term clinical and pre-commercial needs.

We have begun working with a second

drug product manufacturer for our development and commercial supply needs for MGTA-456.

We believe the synthesis of the MGTA-145 drug

substance used to manufacture drug product is reliable and reproducible from readily available starting materials, amenable to commercial-scale production, and does not require unusual equipment or handling in the manufacturing process.

manufactured and released for early clinical use drug product which has been manufactured by our CMO to satisfy our immediate and near term clinical and preclinical needs.

We expect to refine, scale, and optimize the process, including the final

product formulation, for our development and commercial supply needs.

Our manufacturing strategy enables us to more efficiently direct

financial resources to the research, development, and commercialization of product candidates rather than diverting resources to internally develop manufacturing facilities.

As our product candidates advance through development and

commercialization, we expect to enter into longer-term commercial supply agreements with key suppliers and manufacturers to fulfill and secure the ongoing and planned preclinical, clinical, and, if our product candidates are approved for marketing,

commercial supply needs for ourselves and our collaborators.

Manufacturing of any product candidate is subject to extensive regulations

that impose various procedural and documentation requirements, which govern recordkeeping, manufacturing processes and controls, personnel, quality control and quality assurance, among others.

We expect that all of our CMOs will manufacture MGTA-456, MGTA-145 and MGTA-117 under current Good Manufacturing Practice, or cGMP, conditions.

cGMP is a regulatory standard for the

production of pharmaceuticals to be used in humans.

We believe the synthesis of the MGTA-145

drug substance used to manufacture drug product is reliable and reproducible from readily available starting materials, amenable to commercial-scale production, and does not require unusual equipment or handling in the manufacturing process.

We have manufactured, and released for early clinical use, drug products which have been manufactured by our CMO to satisfy our immediate and near term clinical and preclinical needs.

We expect to refine, scale, and optimize the process, including the final product formulation, for our development and commercial supply needs.

Our external manufacturing strategy enables us to more efficiently direct financial resources to the research, development, and commercialization of product candidates rather than diverting resources to internally develop manufacturing facilities.

As our product candidates advance through development and commercialization, we expect to enter into longer-term commercial supply agreements with key suppliers and manufacturers to fulfill and secure the ongoing and planned preclinical, clinical, and, if our product candidates are approved for marketing, commercial supply needs for ourselves and our collaborators.

Manufacturing of any product candidate is subject to extensive regulations that impose various procedural and documentation requirements, which govern recordkeeping, manufacturing processes and controls, personnel, quality control and quality assurance, among others.

We expect that all of our CMOs will manufacture MGTA-145

under current Good Manufacturing Practice, or cGMP, conditions.

cGMP is a regulatory standard for the production of pharmaceuticals to be used in humans.

The biotechnology industry is extremely competitive in the race to develop new products and treatment modalities.

While we believe we have

significant competitive advantages with our industry-leading expertise in transplant medicine, preclinical and clinical development expertise, our comprehensive approach to patient care and intellectual property position, we may face competition for

our development programs from companies focused on traditional therapeutic modalities, such as small molecules and antibodies, as well as companies developing next-generation cell therapies.

Competition is likely to come from multiple sources,

including larger pharmaceutical companies, biotechnology companies and academia.

For any products that we may ultimately commercialize, not only will we compete with any existing therapies and those therapies currently in development, we will have

to compete with new therapies that may become available in the future.

We believe we are the only company that is committed to addressing all of the major opportunities in stem cell transplant to revolutionize an entire field of medicine.

building a comprehensive portfolio of novel therapeutic development programs to address all major unmet medical needs inherent to the existing stem cell transplant process, which distinguishes us from our competition.

Many of our competitors may have significantly greater financial resources and expertise in research and development, manufacturing,

preclinical testing, clinical trials, regulatory approvals and product marketing than we currently do.

These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial

sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

Mergers and acquisitions in the pharmaceutical and biotechnology industries may result in even more resources

being concentrated among a smaller number of our competitors.

While we believe we have significant competitive advantages with our expertise in transplant medicine, preclinical and clinical development expertise, our comprehensive approach to patient care and intellectual property position, we may face competition for our development programs from companies focused on traditional therapeutic modalities, such as small molecules and antibodies, as well as companies developing next-generation cell therapies.

Competition is likely to come from multiple sources, including larger pharmaceutical companies, biotechnology companies and academia.

For any products that we may ultimately commercialize, not only will we compete with any existing therapies and those therapies currently in development, we will have to compete with new therapies that may become available in the future.

We believe we are the only company that is committed to addressing multiple major opportunities in stem cell transplant to revolutionize an entire field of medicine.

We are building a comprehensive portfolio of novel therapeutic development programs to address multiple major unmet medical needs inherent to the existing stem cell transplant process, which distinguishes us from our competition.

Many of our competitors may have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, clinical trials, regulatory approvals and product marketing than we currently do.

These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

Mergers and acquisitions in the pharmaceutical and biotechnology industries may result in even more resources being concentrated among a smaller number of our competitors.

Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.

Stem cell transplant is used to treat a number of diseases and indications.

We are aware of a number of companies that are developing

therapeutics, including biologics, small molecules and CAR T therapies that are directed to the treatment of autoimmunity, blood cancers, and genetic diseases that overlap with certain current stem cell transplant indications.

The following

competitive overview is focused on companies that are developing technologies to improve the distinct steps of stem cell transplant.

Competitors in our stem cell expansion programs include the following:

Gamida Cell Ltd., which is developing a UCB-derived cell product that

uses a small molecule to inhibit differentiation and enhance functionality of ex vivo- expanded HSCs;

ExCellThera Inc., which is focused on ex vivo expansion of stem cells using a pyrimidoindole-derivative

small molecule;

Angiocrine Bioscience, Inc., which is expanding cord blood and gene-modified HSCs using an endothelial cell

feeder layer;

Intellia Therapeutics, Inc., which has exclusively licensed from Novartis the AHR antagonist that we use to

manufacture MGTA-456 for expansion of gene-modified HSCs only.

Competitors in

our conditioning programs include the following:

Actinium Pharmaceuticals, Inc., which is developing an antibody to CD45 that is linked to radioisotope iodine-131;

Stem cell transplant is used to treat a range of diseases and indications.

We are aware of many companies that are developing therapeutics, including biologics, small molecules and CAR-T

therapies that are directed to the treatment of blood cancers, genetic diseases and autoimmune diseases that overlap with current stem cell transplant indications.

The following competitive overview is focused on companies that are developing technologies to improve the distinct steps of stem cell transplant.

Competitors for our mobilization program include the following:

BioLineRx Ltd., which is developing BL-8040,

a peptide that functions as a high-affinity antagonist for CXCR4;

Yifan Pharmaceutical Co., Ltd., which is developing YF-H-2015005,

a peptide that functions as a high-affinity antagonist for CXCR4.

Competitors for our conditioning programs include the following:

targeted conditioning program:

Jasper Therapeutics, Inc., which is developing an antibody to CD117 that is not conjugated to any toxin;

Forty Seven, Inc., which is developing an antibody to CD117 that is not conjugated to any toxin and is used in

combination with an antibody to CD47;

Gilead Sciences, Inc., which is developing an antibody to CD117 that is not conjugated to any toxin and is used in combination with an antibody to CD47.

C100 program (CD45-ADC):

Actinium Pharmaceuticals, Inc., which is developing an antibody to CD45 that is linked to radioisotope iodine-131;

Molecular Templates Inc., which is developing an antibody to CD45 that is conjugated to engineered Shiga-toxin.

Competitors in our post-transplant complications programs (acute GvHD) include the following:

Bellicum Pharmaceuticals, Inc., which is developing a combination of genetically modified T cells and activator

agent rimiducid;

Abbvie Inc., which has a Brutons tyrosine kinase inhibitor that is approved for use in chronic GvHD;

Incyte Corporation, which is developing Janus kinase inhibitors, ruxolitinib and itacitinib, for both the

treatment and prevention of acute and chronic GvHD.

Competitors in our mobilization programs include the following:

BioLineRx Ltd., which is developing BL-8040, a peptide that functions as

a high-affinity antagonist for CXCR4.

C300 program:

Allogene Therapeutics, Inc., which is developing an antibody to CD52 that is not conjugated to any toxin.

G100 program:

Incyte Corporation, which has a Janus kinase inhibitor, ruxolitinib, that is approved for the treatment of steroid-refractory acute GvHD, and is developing two Janus kinase inhibitors, ruxolitinib and itacitinib, for the treatment of chronic GvHD;

Bristol Myers Squibb Company, which is developing a selective T-cell

co-stimulation

inhibitor, abatacept, for the prevention of acute GvHD;

Sanofi S.A., which is developing an antibody to CD52, alemtuzumab, for the prevention of acute GvHD;

Mesoblast Ltd., which is developing a cellular therapy, remestemcel-L,

composed of ex vivo

-expanded mesenchymal stromal cells, for the treatment of acute GvHD;

Abbvie Inc., which has a Bruton’s tyrosine kinase inhibitor, ibrutinib, that is approved for use in steroid-refractory chronic GvHD;

Kadmon Holdings, Inc., which is developing a Rho-associated

kinase 2 (ROCK2) inhibitor, belumosudil, for the treatment of steroid-refractory chronic GvHD;

Bellicum Pharmaceuticals, Inc., which is developing a cellular therapy composed of genetically modified allogeneic T-cells

with the activator agent rimiducid, for the prevention of GvHD.

Competitors for our cell therapy programs include the following:

Intellia Therapeutics, Inc., which has exclusively licensed from Novartis the AHR antagonist that we use to manufacture MGTA-456

for expansion of gene-modified HSCs only;

Gamida Cell Ltd., which is developing a UCB-derived

cell product that uses a small molecule to inhibit differentiation and enhance functionality of ex vivo-

expanded HSCs;

ExCellThera Inc., which is focused on ex vivo

expansion of stem cells using a pyrimidoindole-derivative small molecule;

Angiocrine Bioscience, Inc., which is expanding cord blood and gene-modified HSCs using an endothelial cell feeder layer.

Licenses and Collaborations

Alliance with Novartis

April 2017, we entered into a license agreement with Novartis pursuant to which Novartis granted us an exclusive, worldwide, sublicensable license to research, develop and commercialize certain licensed products that contain Novartis compounds for

the expansion of cord blood derived non-Gene-Edited/-Modified HSCs.

In April 2017, we entered into a license agreement with Novartis pursuant to which Novartis granted us an exclusive, worldwide, sublicensable license to research, develop and commercialize certain licensed products that contain Novartis compounds for the expansion of cord blood derived non-Gene-Edited/-Modified

We refer to this agreement as the Novartis Agreement.

The license granted to us under the Novartis Agreement is subject to certain rights

retained by Novartis for internal research purposes and certain third parties for research and educational purposes.

The license granted to us under the Novartis Agreement is subject to certain rights retained by Novartis for internal research purposes and certain third parties for research and educational purposes.

Certain of the rights licensed to us under the Novartis Agreement are also subject to any retained rights of the U.S.

government in

the licensed patents.

The Novartis Agreement led to the establishment of MGTA-456 as one of our programs.

Under the terms of the Novartis Agreement, we are responsible for all research, development, regulatory

and commercialization activities related to licensed products.

government in the licensed patents.

The Novartis Agreement led to the establishment of MGTA-456

as one of our programs.

Under the terms of the Novartis Agreement, we are responsible for all research, development, regulatory and commercialization activities related to licensed products.

We are required to use commercially reasonable efforts to develop and commercialize licensed products in the U.S., United Kingdom, France, Germany, Spain, Italy and Japan.

Pursuant to the Novartis Agreement, we issued to Novartis 2,500,000 shares of Series A

preferred stock and 643,550 shares of Series B preferred stock.

We will be required to make milestone payments to Novartis upon dosing the first patient in Biologic Licensing Application, or BLA, enabling clinical trials and upon regulatory

approvals of licensed products across ultra-orphan, hemoglobinopathies and other indications.

For ultra-orphan indications, we may be required to pay development and regulatory milestones of up to $13.0 million for each of the first two

indications, and up to $5.0 million for a third indication.

Pursuant to the Novartis Agreement, we issued to Novartis 2,500,000 shares of Series A preferred stock and 643,550 shares of Series B preferred stock.

We will be required to make milestone payments to Novartis upon dosing the first patient in Biologic Licensing Application, or BLA, enabling clinical trials and upon regulatory approvals of licensed products across ultra-orphan, hemoglobinopathies and other indications.

For ultra-orphan indications, we may be required to pay development and regulatory milestones of up to $13.0 million for each of the first two indications, and up to $5.0 million for a third indication.

For hemoglobinopathies, we may be required to pay development and regulatory milestones of up to $13.0 million per indication, for the first two indications.

For all other

indications that are not an ultra-orphan or hemoglobinopathy, we may be required to pay development and regulatory milestones of up to $75.0 million for the first indication and up to $45.0 million for the second indication.

licensed products, we may be required to pay Novartis up to $125.0 million in sales milestones, based on the first achievement of certain aggregate worldwide annual net sales thresholds.

We are also required to pay tiered royalties to Novartis

on worldwide net sales of licensed products by us, ranging from low single-digit percentages to up to 20% for higher net sales, which royalties are potentially subject to reduction and offset during the royalty term.

Royalties are payable on a

licensed product-by-licensed product and country-by-country basis until the later of

(i) expiration of the last valid claim of a licensed patent right that covers the manufacture, use or sale of such licensed product, or the licensed compound used in the manufacture of such licensed product, in such country and (ii) ten

years following the first commercial sale of such licensed product in such country.

Novartis controls the filing, prosecution,

maintenance and enforcement of the licensed patent rights at its expense.

For all other indications that are not an ultra-orphan or hemoglobinopathy, we may be required to pay development and regulatory milestones of up to $75.0 million for the first indication and up to $45.0 million for the second indication.

Across all licensed products, we may be required to pay Novartis up to $125.0 million in sales milestones, based on the first achievement of certain aggregate worldwide annual net sales thresholds.

We are also required to pay tiered royalties to Novartis on worldwide net sales of licensed products by us, ranging from low single-digit percentages to up to 20% for higher net sales, which royalties are potentially subject to reduction and offset during the royalty term.

Royalties are payable on a licensed product-by-licensed

product and country-by-country

basis until the later of (i) expiration of the last valid claim of a licensed patent right that covers the manufacture, use or sale of such licensed product, or the licensed compound used in the manufacture of such licensed product, in such country and (ii) ten years following the first commercial sale of such licensed product in such country.

Novartis controls the filing, prosecution, maintenance and enforcement of the licensed patent rights at its expense.

We have the right to assume these responsibilities should Novartis not wish to pursue them.

We own all rights in any intellectual property related to the licensed compound or

licensed products that we solely develop under the Novartis Agreement.

We own all rights in any intellectual property related to the licensed compound or licensed products that we solely develop under the Novartis Agreement.

The Novartis Agreement does not otherwise allocate ownership of improvements developed thereunder;

however, Novartis grants us a

non-exclusive, royalty-free license to practice any improvements that Novartis owns under the Novartis Agreement in connection with non-gene-edited/-modified HSCs, and

we grant a non-exclusive, royalty-free license to Novartis to practice any improvements that we own under the agreement outside of such field.

however, Novartis grants us a non-exclusive,

royalty-free license to practice any improvements that Novartis owns under the Novartis Agreement in connection with non-gene-edited/-modified

HSCs, and we grant a non-exclusive,

royalty-free license to Novartis to practice any improvements that we own under the agreement outside of such field.

The Novartis Agreement will continue until the last-to-expire

1 unchanged sentence

Each party may terminate the Novartis Agreement due to the other party’s insolvency or uncured breach of a material obligation.

We have the right to terminate the

Novartis Agreement in its entirety or on a product-by-product or country-by-country basis

for convenience upon 90 days prior written notice to Novartis.

Upon termination of the Novartis Agreement by us for convenience or by Novartis for cause, the license granted to us by Novartis will terminate and we will grant a worldwide,

perpetual, non-exclusive license to Novartis to develop and commercialize the licensed products under any intellectual property that we (i) control and used in the development, manufacture or

commercialization of licensed products or (ii) developed under the agreement to develop and commercialize the licensed products.

We have the right to terminate the Novartis Agreement in its entirety or on a product-by-product

or country-by-country

basis for convenience upon 90 days’ prior written notice to Novartis.

Upon termination of the Novartis Agreement by us for convenience or by Novartis for cause, the license granted to us by Novartis will terminate and we will grant a worldwide, perpetual, non-exclusive

license to Novartis to develop and commercialize the licensed products under any intellectual property that we (i) control and used in the development, manufacture or commercialization of licensed products or (ii) developed under the agreement to develop and commercialize the licensed products.

Collaboration with National Marrow Donor Program (as successor in interest to Be The Match Biotherapies, LLC)

In November 2017, we entered into a collaboration agreement with Be The Match BioTherapies, LLC, then a subsidiary of National Marrow Donor

Program, or NMDP.

In November 2017, we entered into a collaboration agreement with Be The Match BioTherapies, LLC, then a subsidiary of National Marrow Donor Program, or NMDP.

We refer to this agreement, as amended, as the NMDP Agreement.

Pursuant to the NMDP Agreement, the NMDP grants us priority access to subject matter experts at the NMDP and the CIBMTR, which is an affiliation between the Medical

College of Wisconsin and NMDP, for consultation on our clinical development and commercialization needs.

We believe that, through this

priority access, the partnership enables us to establish relationships across transplant centers and with transplant physicians, giving us access to clinical strategy and development operational support, and potentially supporting our eventual

commercialization efforts across several programs.

Pursuant to the NMDP Agreement, the NMDP grants us priority access to subject matter experts at the NMDP and the CIBMTR, which is an affiliation between the Medical College of Wisconsin and NMDP, for consultation on our clinical development and commercialization needs.

We believe that, through this priority access, the partnership enables us to establish relationships across transplant centers and with transplant physicians, giving us access to clinical strategy and development operational support, and potentially supporting our eventual commercialization efforts across several programs.

Under the NMDP Agreement, we will make quarterly payments to NMDP of $17,500.

of the NMDP Agreement will continue until December 31, 2020 unless terminated earlier by either party.

may terminate the NMDP Agreement in whole or in part (i) for convenience upon 60 days notice, (ii) for the other partys uncured material breach upon ten days notice or

(iii) upon the other partys insolvency.

The term of the NMDP Agreement will continue until December 31, 2021 unless terminated earlier by either party.

Either party may terminate the NMDP Agreement in whole or in part (i) for convenience upon 60 days’ notice, (ii) for the other party’s uncured material breach upon ten days’ notice or (iii) upon the other party’s insolvency.

Harvard University License Agreement

In November 2016, we entered into a license agreement with Harvard University, or Harvard, pursuant to which Harvard granted us the worldwide

exclusive, subject to Harvards retained right solely for research and educational purposes, sublicensable, right, to research, develop and commercialize licensed products under certain conditioning-related and mobilization-related patents.

license granted to us under the Harvard Agreement is also subject to any retained rights of the U.S.

In November 2016, we entered into a license agreement with Harvard University, or Harvard, pursuant to which Harvard granted us the worldwide exclusive, subject to Harvard’s retained right solely for research and educational purposes, sublicensable, right, to research, develop and commercialize licensed products under certain conditioning-related and mobilization-related patents.

The license granted to us under the Harvard Agreement is also subject to any retained rights of the U.S.

government in the licensed patents.

Under the terms of the agreement, which we refer to as the Harvard Agreement, we will be responsible for all

research, development, regulatory and commercialization activities related to licensed products.

We are obligated to use commercially reasonable efforts to commercialize at least two licensed products under the Harvard Agreement, including one for

conditioning and one for mobilization.

Under the terms of the agreement, which we refer to as the Harvard Agreement, we will be responsible for all research, development, regulatory and commercialization activities related to licensed products.

We are obligated to use commercially reasonable efforts to commercialize at least two licensed products under the Harvard Agreement, including one for conditioning and one for mobilization.

The license from the Harvard Agreement relates to our conditioning and mobilization programs.

Pursuant to the Harvard Agreement, we made an upfront payment to Harvard of $85,000 and issued to Harvard and the other co-owners of the licensed patent rights (The General Hospital Corporation d/b/a Massachusetts General Hospital, and Childrens Medical Center Corporation) 385,063 shares of our common stock.

In addition, we

reimbursed Harvard for approximately $300,000 in expenses incurred by Harvard in connection with the licensed patent rights.

Harvard is also entitled to receive an annual license maintenance fee of $25,000 for each calendar year through 2019 and

$50,000 for each calendar year thereafter until expiration or termination of the Harvard Agreement.

Harvard is entitled to payments upon

certain development and regulatory milestones for the first two licensed products of up to $7.4 million per licensed product.

In addition, we must pay Harvard low-single digit royalties on net sales of

licensed products.

pendency of such proceeding and will remain double thereafter if such action is determined in Harvards favor.

Depending on the type of licensed product, royalties are payable on a

product-by-product and country-by-country basis until the later of (i) the last to

expire valid claim in the applicable country covering or claiming the composition, manufacture, sale or use of such licensed product and (ii) 12 years from the date of the first commercial sale of such licensed product in such country.

Pursuant to the Harvard Agreement, we made an upfront payment to Harvard of $85,000 and issued to Harvard and the other co-owners

of the licensed patent rights (The General Hospital Corporation d/b/a

Massachusetts General Hospital, and Children’s Medical Center Corporation) 385,063 shares of our common stock.

In addition, we reimbursed Harvard for approximately $300,000 in expenses incurred by Harvard in connection with the licensed patent rights.

Harvard is also entitled to receive an annual license maintenance fee of $25,000 for each calendar year through 2019 and $50,000 for each calendar year thereafter until expiration or termination of the Harvard Agreement.

Harvard is entitled to payments upon certain development and regulatory milestones for the first two licensed products of up to $7.4 million per licensed product.

In addition, we must pay Harvard low-single

digit royalties on net sales of licensed products.

If we or our affiliates or sublicensees under the Harvard Agreement commence a legal action to challenge the validity, enforceability or scope of any licensed patents, the royalty rate payable to Harvard will double during the pendency of such proceeding and will remain double thereafter if such action is determined in Harvard’s favor.

Depending on the type of licensed product, royalties are payable on a product-by-product

and country-by-country

basis until the later of (i) the last to expire valid claim in the applicable country covering or claiming the composition, manufacture, sale or use of such licensed product and (ii) 12 years from the date of the first commercial sale of such licensed product in such country.

Harvard controls the filing, prosecution and maintenance of the licensed patent rights at our expense.

We have the first right, but not the

obligation, to enforce licensed patent rights against third-party infringement.

The term of the Harvard Agreement will continue until the

later of (i) the expiration of the last to expire valid claim under a licensed patent, and (ii) the expiration of the last royalty period Each party has the right to terminate the Harvard Agreement due to the other partys uncured

material breach or insolvency.

We have the first right, but not the obligation, to enforce licensed patent rights against third-party infringement.

The term of the Harvard Agreement will continue until the later of (i) the expiration of the last to expire valid claim under a licensed patent, and (ii) the expiration of the last royalty period Each party has the right to terminate the Harvard Agreement due to the other party’s uncured material breach or insolvency.

In particular, Harvard may terminate the Harvard Agreement upon our uncured failure to meet certain development and regulatory milestone deadlines set forth therein.

We have the right to terminate the Harvard Agreement

for convenience upon 60 days prior written notice to Harvard.

We have the right to terminate the Harvard Agreement for convenience upon 60 days’ prior written notice to Harvard.

Upon termination of the Harvard Agreement for any reason, the license granted to us by Harvard will terminate.

Research, Development Option and License Agreement with Heidelberg Pharma Research GmbH

In March 2018, we entered into an exclusive research, development option and license agreement with Heidelberg Pharma Research GmbH, or

Heidelberg Pharma.

In March 2018, we entered into an exclusive research, development option and license agreement with Heidelberg Pharma Research GmbH, or Heidelberg Pharma.

We refer to this agreement, as amended, as the Heidelberg Agreement.

Heidelberg Pharma has developed a proprietary antibody targeted amanitin conjugates platform.

This collaboration enables our research and development efforts

across several targeted conditioning programs through the combination of our proprietary antibodies and Heidelberg Pharmas antibody targeted amanitin conjugates platform.

Under the terms of the Heidelberg Agreement, Heidelberg Pharma has granted to us a

worldwide, non-exclusive research license for a one-year period with respect to certain targets set forth in an agreed-to

This collaboration enables our research and development efforts across several targeted conditioning programs through the combination of our proprietary antibodies and Heidelberg Pharma’s antibody targeted amanitin conjugates platform.

Under the terms of the Heidelberg Agreement, Heidelberg Pharma has granted to us a worldwide, non-exclusive

research license for a one-year

period with respect to certain targets set forth in an agreed-to

research plan.

1 unchanged sentence

We also have an option to obtain an exclusive target-specific research license, which would expire two years after the exercise of such option.

addition, we will have an option to obtain a target-specific exclusive license for global development and commercialization rights to each of the product candidates resulting from the research collaboration.

We may obtain such exclusive

target-specific rights to up to four targets.

We are required to use commercially reasonable efforts to perform our research activities under the Heidelberg Agreement and, if we exercise our right to obtain a development and commercialization

license, we are required to use commercially reasonable efforts to pursue development and commercialization of a product directed to the applicable target.

Under the terms of the Heidelberg Agreement, we granted Heidelberg Pharma a worldwide, non-exclusive

license under all of our patents and know-how, and any improvements of the foregoing developed under the Heidelberg Agreement, that are reasonably necessary or useful for Heidelberg Pharma to perform its

research activities under the Heidelberg Agreement.

In addition, we grant Heidelberg Pharma a worldwide, royalty-free, non-exclusive license under all joint improvements developed under the Heidelberg

Agreement for non-clinical research purposes only.

Payment terms to Heidelberg Pharma include an

upfront technology access fee, research exclusivity fees with respect to the two initial targets, and payments for research support.

Heidelberg Pharma is entitled to additional fees of between $50,000 and $1.1 million in the aggregate if we

extend the initial research license or if we exercise our research exclusivity options with respect to additional targets.

Upon our exercise of an option for an exclusive development and commercialization license, with respect to a target, we are

required to make a low single digit million-dollar payment to Heidelberg Pharma for each exercised option.

In addition, on a per target basis, we may be required to pay development, regulatory and commercial milestones totaling up to approximately

$83.5 million per target.

We will pay Heidelberg Pharma mid-single digit royalties on a country-by-country and product-by-product basis, on worldwide net product sales of licensed products.

Royalties are payable on a licensed product-by-licensed product and country-by-country basis until the later of (i) expiration of the last valid claim of a

licensed patent right that covers the use, import, offering for sale, or sale of such licensed product in such country, and (ii) ten years following the first commercial sale of such licensed product in such country.

We have the option to buy-down royalties at certain points during the development path of each product.

Heidelberg Pharma

will own all improvements solely related to the intellectual property rights Heidelberg Pharma licensed to us under the Heidelberg Agreement.

We will own all improvements solely related to the intellectual property rights that we licensed to

Heidelberg Pharma and all other intellectual property rights developed under the Heidelberg Agreement for which ownership is not otherwise allocated.

Heidelberg Pharma controls the filing, prosecution, maintenance and enforcement of the intellectual property that it licenses to us under the

Heidelberg Agreement.

In addition, we will have an option to obtain a target-specific exclusive license for global development and commercialization rights to each of the product candidates resulting from the research collaboration.

We may obtain such exclusive target-specific rights to up to four targets.

We are required to use commercially reasonable efforts to perform our research activities under the Heidelberg Agreement and, if we exercise our right to obtain a development and commercialization license, we are required to use commercially reasonable efforts to pursue development and commercialization of a product directed to the applicable target.

In addition, we granted Heidelberg Pharma a worldwide, non-exclusive

license under all of our patents and know-how,

and any improvements of the foregoing developed under the Heidelberg Agreement, that are reasonably necessary or useful for Heidelberg Pharma to perform its research activities under the Heidelberg Agreement.

In addition, we grant Heidelberg Pharma a worldwide, royalty-free, non-exclusive

license under all joint improvements developed under the Heidelberg Agreement for non-clinical

research purposes only.

Payment terms to Heidelberg Pharma include an upfront technology access fee, research exclusivity fees with respect to the two initial targets, and payments for research support.

Heidelberg Pharma is entitled to additional fees of between $50,000 and $1.1 million in the aggregate if we extend the initial research license or if we exercise our research exclusivity options with respect to additional targets.

Upon our exercise of an option for an exclusive development and commercialization license, with respect to a target, we are required to make a low single digit million-dollar payment to Heidelberg Pharma for each exercised option.

In addition, we may be required to pay development, regulatory and commercial milestones totaling up to approximately $83.5 million per target.

We will pay Heidelberg Pharma mid-single

digit royalties on a country-by-country

and product-by-product

basis, on worldwide net product sales of licensed products.

Royalties are payable on a licensed product-by-licensed

product and country-by-country

basis until the later of (i) expiration of the last valid claim of a licensed patent right that covers the use, import, offering for sale, or sale of such licensed product in such country, and (ii) ten years following the first commercial sale of such licensed product in such country.

We have the option to buy-down

royalties at certain points during the development path of each product.

Heidelberg Pharma will own all improvements solely related to the intellectual property rights Heidelberg Pharma licensed to us under the Heidelberg Agreement.

We will own all improvements solely related to the intellectual property rights that we licensed to Heidelberg Pharma and all other intellectual property rights developed under the Heidelberg Agreement for which ownership is not otherwise allocated.

Heidelberg Pharma controls the filing, prosecution, maintenance and enforcement of the intellectual property that it licenses to us under the Heidelberg Agreement.

We have the right to enforce such licensed intellectual property against infringement if the infringement is competitive with our licensed products and Heidelberg Pharma does not pursue enforcement.

We control the filing,

prosecution, maintenance and enforcement of the intellectual property we license to Heidelberg Pharma under the Heidelberg Agreement.

term of the Heidelberg Agreement will continue until the last to expire royalty term unless terminated earlier by either party.

Each party has the right to terminate the Heidelberg Pharma Agreement due to the other partys uncured material

breach or insolvency on a product-by-product or target-by-target basis.

We have the right

to terminate the Heidelberg Agreement for convenience in its entirety or on a product-by-product,

target-by-target or country-by-country basis upon 60 days prior written notice to

Heidelberg Pharma if terminating before the first commercial sale of a product in a country or upon six months prior written notice to Heidelberg Pharma if terminating after the first commercial sale of any product directed to such target in

such country.

Upon termination of the Heidelberg Agreement in its entirety or with respect to a product or

target, all applicable licenses granted to us will terminate immediately.

We control the filing, prosecution, maintenance and enforcement of the intellectual property we license to Heidelberg Pharma under the Heidelberg Agreement.

The term of the Heidelberg Agreement will continue until the last to expire royalty term unless terminated earlier by either party.

Each party has the right to terminate the Heidelberg Pharma Agreement due to the other party’s uncured material breach or insolvency on a product-by-product

or target-by-target

We have the right to terminate the Heidelberg Agreement for convenience in its entirety or on a product-by-product,

target-by-target

or country-by-country

basis upon 60 days’ prior written notice to Heidelberg Pharma if terminating before the first commercial sale of a product in a country or upon six months’ prior written notice to Heidelberg Pharma if terminating after the first commercial sale of any product directed to such target in such country.

Upon termination of the Heidelberg Agreement in its entirety or with respect to a product or target, all applicable licenses granted to us will terminate immediately.

Bachem Master Development and Manufacturing Agreement

In February 2018, we entered into a Master Development and Manufacturing Agreement with Bachem Americas, Inc., or Bachem.

agreement, which we refer to as the Bachem Agreement, governs several projects related to the development and manufacture of CXCR2 agonists, including MGTA-145, each pursuant to a separate project plan.

active pharmaceutical ingredient of MGTA-145 is a 69 amino acid protein.

We selected Bachem as our contract manufacturer for this program based on their deep expertise in the synthesis and production of

Financial terms related to this agreement will be determined on a project-by-project basis.

In April 2018, we entered into an initial one-year project plan pursuant to which Bachem will be responsible for producing batches of MGTA-145 for GLP toxicology studies completed in 2018, as well as GMP material for

the Phase 1 trial of MGTA-145, which commenced in the second quarter of 2019.

The term of the

Bachem Agreement is initially five years and will be automatically renewed for one-year periods unless either party provides the other with written notice of nonrenewal at least three months prior to expiry.

This agreement, which we refer to as the Bachem Agreement, governs several projects related to the development and manufacture of CXCR2 agonists, including MGTA-145,

each pursuant to a separate project plan.

The active pharmaceutical ingredient of MGTA-145

is a 69 amino acid protein.

We selected Bachem as our contract manufacturer for this program based on their deep expertise in the synthesis and production of proteins.

Financial terms related to this agreement will be determined on a project-by-project

In April 2018, we entered into an initial one-year

project plan pursuant to which Bachem will be responsible for producing batches of MGTA-145

for GLP toxicology studies completed in 2018, as well as GMP material for the Phase 1 trial of MGTA-145,

which commenced in the second quarter of 2019.

The term of the Bachem Agreement is initially five years and will be automatically renewed for one-year

periods unless either party provides the other with written notice of nonrenewal at least three months prior to expiry.

Each party may terminate the agreement upon a material uncured breach of the other party.

During the term, Bachem will be restricted from producing a pre-defined set of agonists, including MGTA-145, for clinical or commercial use by any third party without our prior written consent, as long as Bachem remains our primary supplier of CXCR2 agonists.

Each project plan may be terminated independently of

the agreement as a whole.

term, Bachem will be restricted from producing a pre-defined

set of agonists, including MGTA-145,

for clinical or commercial use by any third party without our prior written consent, as long as Bachem remains our primary supplier of CXCR2 agonists.

Each project plan may be terminated independently of the agreement as a whole.

Clinical Trial Agreement with University of Minnesota

In January 2018, we entered into a Clinical Trial Agreement with the Regents of the University of Minnesota, or UMinn, pursuant to which UMinn

will undertake a Phase 2 clinical trial with MGTA-456 for the treatment of inherited metabolic disorders.

Under this agreement, UMinn is also responsible for the manufacture and supply of the required

quantities of MGTA-456 for the trial, subject to specified quality assurance provisions.

of the agreement will run through the course of the trial, unless earlier terminated.

Each party may terminate the agreement immediately upon the other partys material failure to follow the specified protocol for the trial or upon a material

uncured breach by the other party.

In January 2018, we entered into a Clinical Trial Agreement with the Regents of the University of Minnesota, or UMinn, pursuant to which UMinn will undertake a Phase 2 clinical trial with MGTA-456

for the treatment of inherited metabolic disorders.

Under this agreement, UMinn is also responsible for the manufacture and supply of the required quantities of MGTA-456

for the trial, subject to specified quality assurance provisions.

The term of the agreement will run through the course of the trial, unless earlier terminated.

Each party may terminate the agreement immediately upon the other party’s material failure to follow the specified protocol for the trial or upon a material uncured breach by the other party.

Intellectual Property

protect the proprietary product candidates and technologies that we believe are important to our business, including seeking and maintaining patent protection intended to cover the composition of matter of our product candidates, their methods of

use, related technologies, diagnostics and other inventions.

As of December 31, 2019, our owned patent portfolio is composed of seven issued patents and more than 130 pending patent applications in the U.S.

We strive to protect the proprietary product candidates and technologies that we believe are important to our business, including seeking and maintaining patent protection intended to cover the composition of matter of our product candidates, their methods of use, related technologies, diagnostics and other inventions.

As of December 31, 2020, our owned patent portfolio is composed of more than 10 issued patents and more than 200 pending patent applications in the U.S.

and foreign jurisdictions.

addition, we have licensed more than 200 issued patents and pending patent applications in the U.S.

In addition, we have licensed more than 200 issued patents and pending patent applications in the U.S.

and foreign jurisdictions.

Company-Owned Patent Rights Relating to Our Targeted Conditioning and Post-Transplant Complications Programs

With regard to our targeted conditioning and post-transplant complications programs, our owned patent portfolio includes two issued U.S.

patents, two issued foreign patents, and more than 100 pending patent applications in the U.S.

With regard to our targeted conditioning and post-transplant complications programs, our owned patent portfolio includes approximately five issued U.S.

patents, approximately four issued foreign patents, and more than 140 pending patent applications in the U.S.

and foreign jurisdictions.

Our targeted conditioning and post-transplant complications patent portfolio includes, for example, composition of matter and

methods of use claims directed to program-

specific ADCs and antibodies, as well as claims directed more generally to our targeted conditioning and post-transplant complications programs that provide coverage for multiple programs.

Our MGTA-117 patent portfolio contains patent families directed to compositions and methods for the

depletion of CD117+ cells.

As of December 31, 2019, we owned one issued U.S.

patent, three pending U.S.

patent applications, one issued Australian patent, more than fifteen pending patent applications in foreign jurisdictions, four families of

provisional patent applications, and four pending PCT applications.

The issued U.S.

patent and the issued Australian patent would be expected to expire in 2037, absent any applicable patent term extensions.

Any other patents that issue

from the pending patent applications would be expected to expire between 2037 and 2040, absent any applicable patent term extensions.

CD45-ADC patent portfolio contains patent families directed to compositions and methods for the depletion of CD45+ cells.

As of December 31, 2019, we owned two pending U.S.

patent applications, one issued Australian patent, more than ten

pending patent applications in foreign jurisdictions, four families of pending U.S.

provisional patent applications, and one pending PCT application.

The issued Australian patent would be expected to expire in 2037, absent any applicable patent term

Any other patents that issue from the pending patent applications would be expected to expire between 2037 and 2040, absent any applicable patent term extensions.

Our C300 patent portfolio, as of December 31, 2019, includes four pending PCT patent applications and one pending U.S.

provisional patent

application that we own.

Any patents that issue from the pending patent applications would be expected to expire between 2038 and 2040, absent any applicable patent term extensions.

Our G100 patent portfolio, as of December 31, 2019, includes one issued U.S.

patent, one pending U.S.

patent application, more than ten

pending patent applications in foreign jurisdictions, and three pending PCT patent applications that we own.

Our targeted conditioning and post-transplant complications patent portfolio includes, for example, composition of matter and methods of use claims directed to program-specific ADCs and antibodies, as well as claims directed more generally to our targeted conditioning and post-transplant complications programs that provide coverage for multiple programs.

Our CD117 patent portfolio contains patent families that we own covering compositions and methods for the depletion of CD117+ cells and includes patent families that cover the MGTA-117

composition of matter and methods of use.

As of December 31, 2020, our CD117 patent portfolio includes one issued U.S.

patent, approximately eight pending U.S.

patent applications, two issued Australian patents, more than 40 pending patent applications in foreign jurisdictions, approximately three families of pending U.S.

provisional patent applications, and approximately seven pending PCT applications.

The issued U.S.

patent would be expected to expire in 2038, absent any applicable patent term extensions.

Any other patents that issue from

the pending patent applications would be expected to expire between 2038 and 2039, absent any applicable patent term extensions.

patent and the issued Australian patents would be expected to expire in 2037, absent any applicable patent term extensions.

Any other patents that issue from the pending patent applications in this portfolio would be expected to expire between 2037 and 2041, absent any applicable patent term extensions.

Company-Owned Patent Rights Relating to Our Mobilization Program

Our MGTA-145 patent portfolio contains patent families directed to methods of mobilizing HSCs.

of December 31, 2019, we owned one issued U.S.

patent, three pending U.S.

patent applications, one pending PCT patent application, and three families of provisional patent applications.

patent portfolio contains patent families directed to methods of mobilizing HSCs.

As of December 31, 2020, we owned one issued U.S.

patent, approximately three pending U.S.

patent applications, more than 15 pending foreign patent applications, and one pending PCT patent application.

The issued U.S.

patent would be expected to expire in

2037, absent any applicable patent term extensions.

patent would be expected to expire in 2037, absent any applicable patent term extensions.

Any other patents that issue from the pending patent applications would be expected to expire between 2037 and 2040, absent any applicable patent term extensions.

Company-Owned Patent Rights Relating to Our Cell Therapy Programs

Our cell therapy patent portfolio contains patent families directed to compositions of matter for AHR antagonists, including E478, methods of

using these compounds, and methods of treatment using expanded HSCs.

Our cell therapy patent portfolio contains patent families directed to compositions of matter for AHR antagonists, including E478, methods of using these compounds, and methods of treatment using expanded HSCs.

As of December 31, 2020, we owned two issued U.S.

patents, three pending U.S.

patent applications, more than fifteen pending patent applications in foreign jurisdictions, and

six pending PCT patent applications.

patents, approximately five pending U.S.

patent applications, more than 30 pending patent applications in foreign jurisdictions, and approximately three pending PCT patent applications.

The issued U.S.

patents would be expected to expire in 2038, absent any applicable patent term extensions.

Any patents that issue from the pending patent applications would be expected to expire between 2038 and

2039, absent any applicable patent term extensions.

In-Licensed Harvard Portfolio

We have exclusively licensed a patent portfolio from Harvard applicable to our targeted conditioning and mobilization programs that contains

patent families directed to compositions and methods

for non-myeloablative conditioning, compositions and methods for mobilizing HSCs, and highly engraftable hematopoietic stem cells and their uses.

As of December 31, 2019, this patent portfolio includes one issued U.S.

patent, five pending U.S.

patent applications, and more than twenty pending patent applications in foreign jurisdictions.

Any patents that issue from the pending patent applications would be expected to expire between 2038 and 2039, absent any applicable patent term extensions.

Harvard Portfolio

We have exclusively licensed a patent portfolio from Harvard applicable to our targeted conditioning and mobilization programs that contains patent families directed to compositions and methods for non-myeloablative conditioning,

compositions and methods for mobilizing HSCs, and highly engraftable hematopoietic stem cells and their uses.

As of December 31, 2020, this patent portfolio includes two issued U.S.

patents, approximately six pending U.S.

patent applications, and more than 20 pending patent applications in foreign jurisdictions.

The issued U.S.

patent would be expected to expire

in 2036, absent any applicable patent term extensions.

patents would be expected to expire in 2036, absent any applicable patent term extensions.

Any patents that issue from the pending patent applications in this patent portfolio would be expected to expire between 2034 and 2037, absent any applicable patent term extensions.

In-Licensed Heidelberg Portfolio

We have licensed a patent portfolio from Heidelberg Pharma applicable to our targeted conditioning and post-transplant complications programs

that contains patent families directed to amatoxin conjugates, methods of treatment, and methods of synthesizing amatoxins.

As of December 31, 2019, these families include more than 90 issued patents and pending patent applications in

jurisdictions worldwide.

Heidelberg Portfolio

We have licensed a patent portfolio from Heidelberg Pharma applicable to our targeted conditioning and post-transplant complications programs that contains patent families directed to amatoxin conjugates, methods of treatment, and methods of synthesizing amatoxins.

As of December 31, 2020, these families include more than 90 issued patents and pending patent applications in jurisdictions worldwide.

The issued patents and any other patents that issue from these families would be expected to expire between 2030 and 2040, absent any applicable patent term extensions.

In-Licensed Novartis Portfolio

We have licensed a patent family from Novartis applicable to our MGTA-456 program that is directed to

AHR antagonists and their use in the expansion of HSCs.

Novartis Portfolio

We have licensed a patent family from Novartis applicable to our MGTA-456

program that is directed to AHR antagonists and their use in the expansion of HSCs.

As of December 31, 2020, this family includes two issued U.S.

patents, one with method claims covering the use of AHR antagonists in the expansion of HSCs and one with composition of

matter claims covering AHR antagonists, one pending U.S.

patent application, and more than 80 issued patents and pending patent applications in jurisdictions worldwide.

patents, one with method claims covering the use of AHR antagonists in the expansion of HSCs and one with composition of matter claims covering AHR antagonists, two pending U.S.

patent applications, and more than 80 issued patents and pending patent applications in jurisdictions worldwide.

The issued U.S.

patents are expected to expire in 2032 and 2031, respectively,

absent any applicable patent term extensions.

patents are expected to expire in 2032 and 2031, respectively, absent any applicable patent term extensions.

The issued foreign patents and any patents that may issue from U.S.

and foreign pending patent applications in this family would be expected to expire in 2029, absent any applicable patent term

and foreign pending patent applications in this family would be expected to expire in 2029, absent any applicable patent term extensions.

The term of individual patents depends upon the legal term for patents in the countries in which they are obtained.

countries in which we have filed, including the U.S., the patent term is 20 years from the earliest filing date of a non-provisional patent application.

In the U.S., a patents term may be

lengthened by patent term adjustment, which compensates a patentee for administrative delays by the U.S.

Patent and Trademark Office in examining and granting a patent, or may be shortened if a patent is terminally disclaimed over an earlier filed

The term of a patent that covers a drug or biological product may also be eligible for patent term extension when FDA approval is granted for a portion of the term effectively lost as a result of the FDA regulatory review period, subject to

certain limitations and provided statutory and regulatory requirements are met.

Any such patent term extension can be for no more than five years, only one patent per approved product can be extended, the extension cannot extend the total patent

term beyond 14 years from approval, and only those claims covering the approved drug, a method for using it or a method for manufacturing it may be extended.

We may not receive an extension if we fail to exercise due diligence during the testing

phase or regulatory review process, fail to apply within applicable deadlines, fail to apply prior to expiration of relevant patents or otherwise fail to satisfy applicable requirements.

Moreover, the length of the extension could be less than we

In the future, if and when our product candidates receive approval from the FDA or foreign regulatory authorities, we expect to apply for patent term extensions on issued patents we may obtain in the future covering those products,

depending upon the length of the clinical trials for each product and other factors.

There can be no assurance that any of our pending patent applications will issue or that we will benefit from any patent term extension or favorable adjustment to

the term of any of our patents.

As with other biotechnology and pharmaceutical companies, our ability to maintain and solidify our

proprietary and intellectual property position for our product candidates will depend on our success in obtaining effective patent claims and enforcing those claims if granted.

However, our owned and licensed pending patent applications, and any

patent applications that we may in the future file or license from third parties may not result in the issuance of patents.

We also cannot predict the breadth of claims that may be allowed or enforced in our

In most countries in which we have filed, including the U.S., the patent term is 20 years from the earliest filing date of a non-provisional patent

In the U.S., a patent’s term may be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the U.S.

Patent and Trademark Office in examining and granting a patent, or may be shortened if a patent is terminally disclaimed over an earlier filed patent.

The term of a patent that covers a drug or biological product may also be eligible for patent term extension when FDA approval is granted for a portion of the term effectively lost as a result of the

FDA regulatory review period, subject to certain limitations and provided statutory and regulatory requirements are met.

Any such patent term extension can be for no more than five years, only one patent per approved product can be extended, the extension cannot extend the total patent term beyond 14 years from approval, and only those claims covering the approved drug, a method for using it or a method for manufacturing it may be extended.

We may not receive an extension if we fail to exercise due diligence during the testing phase or regulatory review process, fail to apply within applicable deadlines, fail to apply prior to expiration of relevant patents or otherwise fail to satisfy applicable requirements.

Moreover, the length of the extension could be less than we request.

There can be no assurance that any of our pending patent applications will issue or that we will benefit from any patent term extension or favorable adjustment to the term of any of our patents.

As with other biotechnology and pharmaceutical companies, our ability to maintain and solidify our proprietary and intellectual property position for our product candidates will depend on our success in obtaining effective patent claims and enforcing those claims if granted.

However, our owned and licensed pending patent applications, and any patent applications that we may in the future file or license from third parties may not result in the issuance of patents.

We also cannot predict the breadth of claims that may be allowed or enforced in our patents.

Any issued patents that we may receive in the future may be challenged, invalidated, infringed or circumvented.

In addition, because of the extensive time required for clinical

development and regulatory review of a product candidate we may develop, it is possible that, before any of our product candidates can be commercialized, any related patent may expire or remain in force for only a short period following

commercialization, thereby limiting the protection such patent would afford the respective product and any competitive advantage such patent may provide.

For more information, see the section entitled Risk FactorsRisks Related to

Intellectual Property.

In addition, because of the extensive time required for clinical development and regulatory review of a product candidate we may develop, it is possible that, before any of our product candidates can be commercialized, any related patent may expire or remain in force for only a short period following commercialization, thereby limiting the protection such patent would afford the respective product and any competitive advantage such patent may provide.

For more information, see the section entitled “Risk Factors—Risks Related to Intellectual Property”.

Other IP Rights

In addition to patents, we rely upon unpatented trade secrets and know-how and continuing

technological innovation to develop and maintain our competitive position.

However, trade secrets and know-how can be difficult to protect.

We seek to protect our proprietary information, in part, by

executing confidentiality agreements with our collaborators and scientific advisors, and non-competition, non-solicitation, confidentiality, and invention

assignment agreements with our employees and consultants.

In addition to patents, we rely upon unpatented trade secrets and know-how and

continuing technological innovation to develop and maintain our competitive position.

However, trade secrets and know-how can

be difficult to protect.

We seek to protect our proprietary information, in part, by executing confidentiality agreements with our collaborators and scientific advisors, and non-competition, non-solicitation, confidentiality,

and invention assignment agreements with our employees and consultants.

We have also executed agreements requiring assignment of inventions with selected scientific advisors and collaborators.

The confidentiality agreements we enter into are designed to protect

our proprietary information and the agreements or clauses requiring assignment of inventions to us are designed to grant us ownership of technologies that are developed through our relationship with the respective counterparty.

We cannot guarantee,

however, that we have executed such agreements with all applicable counterparties, such agreements will not be breached, or that these agreements will afford us adequate protection of our intellectual property and proprietary rights.

information, see the section entitled Risk FactorsRisks Related to Intellectual Property.

We have filed and obtained trademark protection for the MAGENTA THERAPEUTICS character mark and service mark logo for pharmaceutical research

and development services and biochemical research and development services.

We have also filed for trademark protection for the #THECOLOROFCURE character mark for promoting public awareness of medical disorders and their treatment, promoting public

awareness of bone marrow diseases, cancer, tumors, infectious diseases, autoimmune diseases and related diseases and disorders, providing a website featuring medical information, and providing medical information.

We plan to register trademarks in

connection with our future products.

Government Regulation

The confidentiality agreements we enter into are designed to protect our proprietary information and the agreements or clauses requiring assignment of inventions to us are designed to grant us ownership of technologies that are developed through our relationship with the respective counterparty.

We cannot guarantee, however, that we have executed such agreements with all applicable counterparties, such agreements will not be breached, or that these agreements will afford us adequate protection of our intellectual property and proprietary rights.

For more information, see the section entitled “Risk Factors—Risks Related to Intellectual Property”.

We have filed and obtained trademark protection for the MAGENTA THERAPEUTICS character mark and service mark logo for pharmaceutical research and development services and biochemical research and development services.

We have also filed for trademark protection for the #THECOLOROFCURE character mark for promoting public awareness of medical disorders and their treatment, promoting public awareness of bone marrow diseases, cancer, tumors, infectious diseases, autoimmune diseases and related diseases and disorders, providing a website featuring medical information, and providing medical information.

We plan to register trademarks in connection with our future products.

Governmental Regulation

Compliance with various governmental regulations has an impact on our business, including our capital expenditures and competitive position, which can be material.

We incur costs to monitor and take actions to comply with governmental regulations that are applicable to our business, which include, among others, federal securities laws and regulations, applicable stock exchange requirements, tax laws and regulations, environmental and health and safety laws and regulations and the regulations that govern our products and drug discovery efforts.

Government authorities in the U.S.

at the federal, state and local level and in other countries regulate, among other things, the research,

development, testing, manufacture, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, post-approval monitoring and reporting, marketing and export and import of drug and biological

products, such as MGTA-456, MGTA-145 and any future product candidates.

Generally, before a new drug or biologic can be marketed, considerable data demonstrating its

quality, safety and efficacy must be obtained, organized into a format specific for each regulatory authority, submitted for review and approved by the regulatory authority.

at the federal, state and local level and in other countries extensively regulate, among other things, the research, development, testing, manufacture, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, post-approval monitoring and reporting, marketing and export and import of drug and biological products, such as MGTA-145

and any other current or future product candidates.

Generally, before a new drug or biologic can be marketed, considerable data demonstrating its quality, safety and efficacy must be obtained, organized into a format specific for each regulatory authority, submitted for review and approved by the regulatory authority.

In addition to the discussion below, see “Item 1A—Risk Factors” for a discussion of material risks to us, including, to the extent material, to our competitive position, relating to governmental regulations, and see “Item 7.

Management’s Discussion and Analysis of Financial Condition and Results of Operation” together with our consolidated financial statements, including the related notes included therein, for a discussion of material information relevant to an assessment of our financial condition and results of operations, including, to the extent material, the effects that compliance with governmental regulations may have upon our capital expenditures.

drug development

U.S., the FDA regulates drugs under the Federal Food, Drug, and Cosmetic Act, or FDCA, and its implementing regulations and biologics under the FDCA, the Public Health Service Act, or PHSA, and their implementing regulations.

Both drugs and

biologics also are subject to other federal, state and local statutes and regulations.

The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, and local statutes and regulations requires the

expenditure of substantial time and financial resources.

In the U.S., the FDA regulates drugs under the Federal Food, Drug, and Cosmetic Act, or FDCA, and its implementing regulations and biologics under the FDCA, the Public Health Service Act, or PHSA, and their implementing regulations.

Both drugs and biologics also are subject to other federal, state and local statutes and regulations.

The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, and local statutes and regulations requires the expenditure of substantial time and financial resources.

Failure to comply with the applicable U.S.

requirements at any time during the product development process, approval process or post-market may subject an applicant to administrative or

judicial sanctions.

sanctions could include, among other actions, the FDAs refusal to approve pending applications, withdrawal of an approval, a clinical hold, untitled or warning letters, product recalls or

market withdrawals, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement and civil or criminal penalties.

Any agency or judicial enforcement

action could have a material adverse effect on us.

MGTA-145 and any future product candidates must be approved by the FDA through either a New Drug Application, or NDA, or a Biologics License Application, or BLA, process before they may be legally marketed in

requirements at any time during the product development process, approval process or post-market may subject an applicant to administrative or judicial sanctions.

These sanctions could include, among other actions, the FDA’s refusal to approve pending applications, withdrawal of an approval, a clinical hold, untitled or warning letters, product recalls or market withdrawals, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement and civil or criminal penalties.

Any agency or judicial enforcement action could have a material adverse effect on us.

and any other current or future product candidates must be approved by the FDA through either a New Drug Application, or NDA, or a Biologics License Application, or BLA, process before they may be legally marketed in the U.S.

The process generally involves the following:

completion of extensive preclinical studies in accordance with applicable regulations, including studies

conducted in accordance with good laboratory practice, or GLP, requirements;

submission to the FDA of an application for an IND application, which must become effective before human clinical

trials may begin;

approval by an institutional review board, or IRB, or independent ethics committee at each clinical trial site

before each trial may be initiated;

performance of adequate and well-controlled human clinical trials in accordance with applicable IND regulations,

good clinical practice, or GCP, requirements and other clinical trial-related regulations to establish the safety and efficacy of the investigational product for each proposed indication;

completion of extensive preclinical studies in accordance with applicable regulations, including studies conducted in accordance with good laboratory practice, or GLP, requirements;

submission to the FDA of an application for an IND application, which must become effective before human clinical trials may begin;

approval by an institutional review board, or IRB, or independent ethics committee at each clinical trial site before each trial may be initiated;

performance of adequate and well-controlled human clinical trials in accordance with applicable IND regulations, good clinical practice, or GCP, requirements and other clinical trial-related regulations to establish the safety and efficacy of the investigational product for each proposed indication;

submission to the FDA of an NDA or BLA;

a determination by the FDA within 60 days of its receipt of an NDA or BLA to accept the filing for review;

satisfactory completion of an FDA pre-approval inspection of the

manufacturing facility or facilities where the drug or biologic will be produced to assess compliance with current good manufacturing processes, or cGMP, requirements to assure that the facilities, methods and controls are adequate to preserve the

drug or biologics identity, strength, quality and purity;

satisfactory completion of an FDA pre-approval

inspection of the manufacturing facility or facilities where the drug or biologic will be produced to assess compliance with current good manufacturing processes, or cGMP, requirements to assure that the facilities, methods and controls are adequate to preserve the drug or biologic’s identity, strength, quality and purity;

potential FDA audit of the clinical trial sites that generated the data in support of the NDA or BLA;

FDA review and approval of the NDA or BLA, including consideration of the views of any FDA advisory committee,

prior to any commercial marketing or sale of the drug or biologic in the U.S.

The preclinical and clinical testing and

approval process requires substantial time, effort and financial resources, and we cannot be certain that any approvals for MGTA-456, MGTA-145 and any future product

candidates will be granted on a timely basis, or at all.

FDA review and approval of the NDA or BLA, including consideration of the views of any FDA advisory committee, prior to any commercial marketing or sale of the drug or biologic in the U.S.

The preclinical and clinical testing and approval process requires substantial time, effort and financial resources, and we cannot be certain that any approvals for MGTA-145

and any other current or future product candidates will be granted on a timely basis, or at all.

Preclinical studies and IND

Preclinical studies include laboratory evaluation of product chemistry and formulation, as well as in vitro and animal studies to assess

safety and, in some cases, to establish a rationale for therapeutic use.

Preclinical studies include laboratory evaluation of product chemistry and formulation, as well as in vitro

and animal studies to assess safety and, in some cases, to establish a rationale for therapeutic use.

The conduct of preclinical studies is subject to federal regulations and requirements, including GLP regulations for safety/toxicology studies.

An IND sponsor must submit the results of the preclinical tests, together with manufacturing information, analytical data, any available

clinical data or literature and plans for clinical trials, among other things, to the FDA as part of an IND.

An IND is a request for authorization from the FDA to administer an investigational product to humans and must become effective before human

clinical trials may begin.

Some long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity, may continue after

the IND is submitted.

An IND automatically becomes effective 30 days after receipt by the FDA, unless before that time, the FDA raises concerns or questions related to one or more proposed

clinical trials and places the trial on clinical hold.

An IND sponsor must submit the results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and plans for clinical trials, among other things, to the FDA as part of an IND.

An IND is a request for authorization from the FDA to administer an investigational product to humans and must become effective before human clinical trials may begin.

Some long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity, may continue after the IND is submitted.

An IND automatically becomes effective 30 days after receipt by the FDA, unless before that time, the FDA raises concerns or questions related to one or more proposed clinical trials and places the trial on clinical hold.

In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin.

As a result, submission of an IND may not result in the FDA allowing

clinical trials to commence.

As a result, submission of an IND may not result in the FDA allowing clinical trials to commence.

Clinical trials

The clinical stage of development involves the administration of the investigational product to healthy volunteers or patients under the

supervision of qualified investigators, generally physicians not employed by or under the trial sponsors control, in accordance with GCP requirements, which include the requirement that all research subjects provide their informed consent for

their participation in any clinical trial.

Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria, and the parameters to be used

to monitor subject safety and assess efficacy.

The clinical stage of development involves the administration of the investigational product to healthy volunteers or patients under the supervision of qualified investigators, generally physicians not employed by or under the trial sponsor’s control, in accordance with GCP requirements, which include the requirement that all research subjects provide their informed consent for their participation in any clinical trial.

Each protocol, and any subsequent amendments to the protocol, must be submitted to the FDA as part of the IND.

Furthermore, each clinical trial must be reviewed and approved by an IRB for each

institution at which the clinical trial will be conducted to ensure that the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits.

The IRB also approves the informed consent

form that must be provided to each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed.

There also are requirements governing the reporting of ongoing clinical trials and completed clinical

trial results to public registries.

Furthermore, each clinical trial must be reviewed and approved by an IRB for each institution at which the clinical trial will be conducted to ensure that the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits.

The IRB also approves the informed consent form that must be provided to each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed.

There also are requirements governing the reporting of ongoing clinical trials and completed clinical trial results to public registries.

A sponsor who wishes to conduct a clinical trial outside of the U.S.

may, but often need not, obtain

FDA authorization to conduct the clinical trial under an IND.

may, but often need not, obtain FDA authorization to conduct the clinical trial under an IND.

If a foreign clinical trial is not conducted under an IND, the sponsor may submit data from the clinical trial to the FDA in support of an NDA or BLA.

The FDA will accept a well-designed

and well-conducted foreign clinical trial not conducted under an IND if the trial was conducted in accordance with GCP requirements, and the FDA is able to validate the data through an onsite inspection if deemed necessary.

The FDA will accept a well-designed and well-conducted foreign clinical trial not conducted under an IND if the trial was conducted in accordance with GCP requirements, and the FDA is able to validate the data through an onsite inspection if deemed necessary.

Clinical trials are generally conducted in three sequential phases, known as Phase 1, Phase 2 and Phase 3, and may overlap.

Phase 1 clinical trials generally involve a small number of healthy volunteers or disease-affected patients who

are initially exposed to a single dose and then multiple doses of the product candidate.

Phase 1 clinical trials generally involve a small number of healthy volunteers or disease-affected patients who are initially exposed to a single dose and then multiple doses of the product candidate.

The primary purpose of these clinical trials is to assess the metabolism, pharmacologic action, side effect tolerability and safety of the drug.

Phase 2 clinical trials involve studies in disease-affected patients to determine the dose required to produce

the desired benefits.

Phase 2 clinical trials involve studies in disease-affected patients to determine the dose required to produce the desired benefits.

At the same time, safety and further pharmacokinetic and pharmacodynamic information is collected, possible adverse effects and safety risks are identified, and a preliminary evaluation of efficacy is conducted.

Phase 3 clinical trials generally involve a large number of patients at multiple sites and are designed to

provide the data necessary to demonstrate the product candidates safety and effectiveness for its intended use, and to establish the overall benefit/risk relationship of the product and provide an adequate basis for product labeling.

Post-approval trials, sometimes referred to as Phase 4 clinical trials, may be conducted after initial marketing

Phase 3 clinical trials generally involve a large number of patients at multiple sites and are designed to provide the data necessary to demonstrate the product candidate’s safety and effectiveness for its intended use, and to establish the overall benefit/risk relationship of the product and provide an adequate basis for product labeling.

Post-approval trials, sometimes referred to as Phase 4 clinical trials, may be conducted after initial marketing approval.

These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication.

In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of

an NDA or BLA.

Progress reports detailing the results of the clinical trials, among other information, must be submitted at least

annually to the FDA and written IND safety reports must be submitted to the FDA and the investigators for

serious and unexpected suspected adverse events, findings from other studies, animal or in vitro testing that suggest a significant risk for human subjects and any clinically important

increase in the rate of a serious suspected adverse reaction compared to that listed in the protocol or investigator brochure.

Phase 2 and Phase 3 clinical trials may not be completed successfully within any specified period, if at all.

The FDA or the sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research

subjects or patients are being exposed to an unacceptable health risk.

Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRBs

requirements or if the drug or biologic has been associated with unexpected serious harm to patients.

Additionally, some clinical trials are overseen by an independent group of qualified experts organized by the clinical trial sponsor, known as a

data safety monitoring board or committee.

In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of an NDA or BLA.

Progress reports detailing the results of the clinical trials, among other information, must be submitted at least annually to the FDA and written IND safety reports must be submitted to the FDA and the investigators for serious and unexpected suspected adverse events, findings from other studies, animal or in vitro

testing that suggest a significant risk for human subjects and any clinically important increase in the rate of a serious suspected adverse reaction compared to that listed in the protocol or investigator brochure.

Phase 1, Phase 2 and Phase 3 clinical trials may not be completed successfully within any specified period, if at all.

The FDA or the sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable health risk.

Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug or biologic has been associated with unexpected serious harm to patients.

Additionally, some clinical trials are overseen by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board or committee.

This group provides authorization for whether a trial may move forward at designated check points based on access to certain data from the trial.

Concurrent with clinical trials, companies usually complete

additional animal studies, must develop additional information about the chemistry and physical characteristics of the drug or biologic and finalize a process for manufacturing the product in commercial quantities in accordance with cGMP

requirements.

Concurrent with clinical trials, companies usually complete additional animal studies, must develop additional information about the chemistry and physical characteristics of the drug or biologic and finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.

The manufacturing process must be capable of consistently producing quality batches of the product and, among other things, companies must develop methods for testing the identity, strength, quality and purity of the final product.

1 unchanged sentence

NDA/BLA and FDA review process

Following completion of the clinical trials, data are analyzed to assess whether the investigational product is safe and effective for the

proposed indicated use or uses.

The results of preclinical studies and clinical trials are then submitted to the FDA as part of an NDA or BLA, along with proposed labeling, chemistry and manufacturing information to ensure product quality and other

relevant data.

Following completion of the clinical trials, data are analyzed to assess whether the investigational product is safe and effective for the proposed indicated use or uses.

The NDA or BLA is a request for approval to market the drug or biologic for one or more specified indications and must contain proof of safety and efficacy for a drug or safety, purity and potency for a biologic.

The application may

include both negative and ambiguous results of preclinical studies and clinical trials, as well as positive findings.

Data may come from company-sponsored clinical trials intended to test the safety and efficacy of a products use or from a

number of alternative sources, including studies initiated by investigators.

To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety and efficacy of the investigational product to the

satisfaction of the FDA.

The application may include both negative and ambiguous results of preclinical studies and clinical trials, as well as positive findings.

Data may come from company-sponsored clinical trials intended to test the safety and efficacy of a product’s use or from a number of alternative sources, including studies initiated by investigators.

To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety and efficacy of the investigational product to the satisfaction of the FDA.

FDA approval of an NDA or BLA must be obtained before a drug or biologic may be marketed in the U.S.

Prescription Drug User Fee Act, or PDUFA, as amended, each NDA or BLA must be accompanied by a user fee.

Under the Prescription Drug User Fee Act, or PDUFA, as amended, each NDA or BLA must be accompanied by a user fee.

The FDA adjusts the PDUFA user fees on an annual basis.

According to the FDAs fee schedule, effective through September 30, 2020, the

user fee for an application requiring clinical data, such as an NDA or BLA, is $2,942,965.

According to the FDA’s fee schedule, effective through September 30, 2021, the user fee for an application requiring clinical data, such as an NDA or BLA, is $2,875,842.

The sponsor of an approved NDA or BLA is also subject to an annual prescription drug program fee, which for fiscal year 2021 is $336,432.

Fee waivers or

reductions are available in certain circumstances, including a waiver of the application fee for the first application filed by a small business.

Additionally, no user fees are assessed on NDAs or BLAs for products designated as orphan drugs, unless

the product also includes a non-orphan indication.

The FDA reviews all submitted NDAs and BLAs

before it accepts them for filing and may request additional information rather than accepting the NDA or BLA for filing.

Fee waivers or reductions are available in certain circumstances, including a waiver of the application fee for the first application filed by a small business.

Additionally, no user fees are assessed on NDAs or BLAs for products designated as orphan drugs, unless the product also includes a non-orphan

The FDA reviews all submitted NDAs and BLAs before it accepts them for filing and may request additional information rather than accepting the NDA or BLA for filing.

The FDA generally makes a decision on accepting an NDA or BLA for filing within 60 days of receipt.

Once the submission is

accepted for filing, the FDA begins an in-depth review of the NDA or BLA.

Under the goals and policies agreed to by the FDA under PDUFA, the FDA has ten months from the filing date to complete its initial

review of a new molecular-entity NDA or original BLA and respond to the applicant, and six months from the filing date of a new molecular-entity NDA or original BLA designated for priority review.

The FDA does not always meet its PDUFA goal dates

for standard and priority NDAs or BLAs, and the review process is often extended by FDA requests for additional information or clarification.

Before approving an NDA or BLA, the FDA will conduct a

pre-approval inspection of the manufacturing facilities for the new product to determine whether they comply with cGMP requirements.

The FDA will not approve the product unless it determines that the

manufacturing processes and facilities are in compliance with cGMP requirements and are adequate to assure consistent production of the product within required specifications.

The FDA also may audit data from clinical trials to ensure compliance

with GCP requirements.

experts, for review, evaluation, and a recommendation as to whether the application should be approved and under what conditions, if any.

The FDA is not bound by recommendations of an advisory committee, but it considers such recommendations when

making decisions on approval.

Once the submission is accepted for filing, the FDA begins an in-depth

review of the NDA or BLA.

Under the goals and policies agreed to by the FDA under PDUFA, the FDA has ten months from the filing date to complete its initial review of a new molecular-entity NDA or original BLA and respond to the applicant, and six months from the filing date of a new molecular-entity NDA or original BLA designated for priority review.

The FDA does not always meet its PDUFA goal dates for standard and priority NDAs or BLAs, and the review process is often extended by FDA requests for additional information or clarification.

Before approving an NDA or BLA, the FDA will conduct a pre-approval

inspection of the manufacturing facilities for the new product to determine whether they comply with cGMP requirements.

The FDA will not approve the product unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and are adequate to assure consistent production of the product within required specifications.

The FDA also may audit data from clinical trials to ensure compliance with GCP requirements.

Additionally, the FDA may refer applications for novel drug products or drug products which present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation, and a recommendation as to whether the application should be approved and under what conditions, if any.

The FDA is not bound by recommendations of an advisory committee, but it considers such recommendations when making decisions on approval.

The FDA likely will reanalyze the clinical trial data, which could result in extensive discussions between the FDA and the applicant during the review process.

After the FDA evaluates an NDA or BLA, it will issue an

approval letter or a Complete Response Letter.

After the FDA evaluates an NDA or BLA, it will issue an approval letter or a Complete Response Letter.

An approval letter authorizes commercial marketing of the drug or biologic with specific prescribing information for specific indications.

A Complete Response Letter indicates that the review cycle of

the application is complete, and the application will not be approved in its present form.

A Complete Response Letter indicates that the review cycle of the application is complete, and the application will not be approved in its present form.

A Complete Response Letter usually describes all of the specific deficiencies in the NDA or BLA identified by the FDA.

The Complete Response Letter may

require additional clinical data, additional pivotal Phase 3 clinical trial(s) and/or other significant and time-consuming requirements related to clinical trials, preclinical studies or manufacturing.

If a Complete Response Letter is issued, the

applicant may either resubmit the NDA or BLA, addressing all of the deficiencies identified in the letter, or withdraw the application.

Even if such data and information are submitted, the FDA may decide that the NDA or BLA does not satisfy the

criteria for approval.

The Complete Response Letter may require additional clinical data, additional pivotal Phase 3 clinical trial(s) and/or other significant and time-consuming requirements related to clinical trials, preclinical studies or manufacturing.

If a Complete Response Letter is issued, the applicant may either resubmit the NDA or BLA, addressing all of the deficiencies

identified in the letter, or withdraw the application.

Even if such data and information are submitted, the FDA may decide that the NDA or BLA does not satisfy the criteria for approval.

Data obtained from clinical trials are not always conclusive and the FDA may interpret data differently than we interpret the same data.

Orphan drug designation

Orphan Drug Act, the FDA may grant orphan designation to a drug or biological product intended to treat a rare disease or condition, which is generally a disease or condition that affects fewer than 200,000 individuals in the U.S., or more than

200,000 individuals in the U.S.

Under the Orphan Drug Act, the FDA may grant orphan designation to a drug or biological product intended to treat a rare disease or condition, which is generally a disease or condition that affects fewer than 200,000 individuals in the U.S., or 200,000 or more individuals in the U.S.

and for which there is no reasonable expectation that the cost of developing and making the product available in the U.S.

1 unchanged sentence

Orphan drug designation must be requested before submitting an NDA or BLA.

After the FDA grants orphan drug designation, the identity of the

therapeutic agent and its potential orphan use are disclosed publicly by the FDA.

After the FDA grants orphan drug designation, the identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA.

Orphan drug designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.

If a product that has orphan designation subsequently receives the first FDA approval for the disease or condition for which it has such

designation, the product is entitled to orphan drug exclusivity, which means that the FDA may not approve any other applications to market the same drug for the same indication for seven years from the date of such approval, except in limited

circumstances, such as a showing of clinical superiority to the product with orphan exclusivity by means of greater effectiveness, greater safety, provision of a major contribution to patient care, or in instances of drug supply issues.

however, may receive approval of either a different product for the same indication or the same product for a different indication but that could be used off-label in the orphan indication.

exclusivity could also block the approval of one of our products for seven years if a competitor obtains approval before we do for the same product, as defined by the FDA, for the same indication we are seeking approval, or if our product is

determined to be contained within the scope of the competitors product for the same indication or disease.

If one of our products designated as an orphan drug receives marketing approval for an indication broader than that which is designated,

it may not be entitled to orphan drug exclusivity.

If a product that has orphan designation subsequently receives the first FDA approval for the disease or condition for which it has such designation, the product is entitled to orphan drug exclusivity, which means that the FDA may not approve any other applications to market the same drug for the same indication for seven years from the date of such approval, except in limited circumstances, such as a showing of clinical superiority to the product with orphan exclusivity by means of greater effectiveness, greater safety, provision of a major contribution to patient care, or in instances of drug supply issues.

Competitors, however, may receive approval of either a different product for the same indication or the same product for a different indication but that could be used off-label

in the orphan indication.

Orphan drug exclusivity could also block the approval of one of our products for seven years if a competitor obtains approval before we do for the same product, as defined by the FDA, for the same indication we are seeking approval, or if our product is determined to be contained within the scope of the competitor’s product for the same indication or disease.

If one of our products designated as an orphan drug receives marketing approval for an indication broader than that which is designated, it may not be entitled to orphan drug exclusivity.

Orphan drug status in the European Union has similar, but not identical, requirements and benefits.

Expedited development and review programs

The FDA has a fast track program that is intended to expedite or facilitate the process for reviewing new drugs and biologics that meet certain

Specifically, new drugs and biologics are eligible for fast track designation if they are intended to treat a serious or life-threatening condition and preclinical or clinical data demonstrate the potential to address unmet medical needs

for the condition.

The FDA has a fast track program that is intended to expedite or facilitate the process for reviewing new drugs and biologics that meet certain criteria.

Fast track designation applies to both the product and the specific indication for which it is being studied.

The sponsor can request the that FDA designate the product for fast track status any time before receiving NDA or BLA

approval, but ideally no later than the pre-NDA or pre-BLA meeting.

Any product submitted to the FDA for marketing, including under a fast track program, may be eligible for other types of FDA programs intended

to expedite development and review, such as priority review and accelerated approval.

Any product is eligible for priority review if it treats a serious or life-threatening condition and, if approved, would provide a significant improvement in

safety and effectiveness compared to available therapies.

The sponsor can request that the FDA designate the product for fast track status any time before receiving NDA or BLA approval, but ideally no later than the pre-NDA

Any product submitted to the FDA for marketing, including under a fast track program, may be eligible for other types of FDA programs intended to expedite development and review, such as priority review and accelerated approval.

Any product is eligible for priority review if it treats a serious or life-threatening condition and, if approved, would provide a significant improvement in safety and effectiveness compared to available therapies.

The FDA will attempt to direct additional resources to the evaluation of an application for a new drug or biologic designated for priority review in an effort to facilitate the review.

A product may also be eligible for accelerated approval if it treats a serious or life-threatening condition and generally provides a

meaningful advantage over available therapies.

In addition, it must demonstrate an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on a clinical endpoint that can be measured earlier than irreversible

morbidity or mortality, or IMM, that is reasonably likely to predict an effect on IMM or other clinical benefit.

As a condition of approval, the FDA may require that a sponsor of a drug or biologic receiving accelerated approval perform adequate and

well-controlled post-marketing clinical trials.

If the FDA concludes that a drug or biologic shown to be effective can be safely used only if distribution or use is restricted, it will require such post-marketing restrictions as it deems necessary

to assure safe use of the product.

Additionally, a drug or biologic may be eligible for designation as a breakthrough therapy if the

product is intended, alone or in combination with one or more other drugs or biologics, to treat a serious or life-threatening condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over

currently approved therapies on one or more clinically significant endpoints.

The benefits of breakthrough therapy designation include the same benefits as fast track designation plus intensive guidance from the FDA to ensure an efficient drug

development program.

As part of the 21 st Century Cures Act, Congress amended the

FDCA to facilitate an efficient development program for, and expedite review of RMATs which include cell and gene therapies, therapeutic tissue engineering products, human cell and tissue products, and combination products using any such therapies

A product may also be eligible for accelerated approval if it treats a serious or life-threatening condition and generally provides a meaningful advantage over available therapies.

In addition, it must demonstrate an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on a clinical endpoint that can be

measured earlier than irreversible morbidity or mortality, or IMM, that is reasonably likely to predict an effect on IMM or other clinical benefit.

As a condition of approval, the FDA may require that a sponsor of a drug or biologic receiving accelerated approval perform adequate and well-controlled post-marketing clinical trials.

If the FDA concludes that a drug or biologic shown to be effective can be safely used only if distribution or use is restricted, it will require such post-marketing restrictions as it deems necessary to assure safe use of the product.

Additionally, a drug or biologic may be eligible for designation as a breakthrough therapy if the product is intended, alone or in combination with one or more other drugs or biologics, to treat a serious or life-threatening condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over currently approved therapies on one or more clinically significant endpoints.

The benefits of breakthrough therapy designation include the same benefits as fast track designation plus intensive guidance from the FDA to ensure an efficient drug development program.

As part of the 21 st

Century Cures Act, Congress amended the FDCA to facilitate an efficient development program for, and expedite review of, RMATs which include cell and gene therapies, therapeutic tissue engineering products, human cell and tissue products, and combination products using any such therapies or products.

RMATs do not include those human cells, tissues, and cellular and tissue based products regulated solely under section 361 of the PHSA and 21 CFR Part 1271.

This program is intended to facilitate efficient development and expedite

review of RMATs, which are intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition and for which preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs for such

disease or condition.

A drug sponsor may request that FDA designate a drug as a RMAT concurrently with, or at any time after, submission of an IND.

FDA has 60 calendar days to determine whether the drug meets the criteria, including whether there is

preliminary clinical evidence indicating that the drug has the potential to address unmet medical needs for a serious or life-threatening disease or condition.

A BLA for a regenerative medicine therapy that has received RMAT designation may be

eligible for priority review or accelerated approval through use of surrogate or intermediate endpoints reasonably likely to predict long-term clinical benefit, or reliance upon data obtained from a meaningful number of sites.

Benefits of RMAT

designation also include early interactions with the FDA to discuss any potential surrogate or intermediate endpoint to be used to support accelerated approval.

A regenerative medicine therapy with RMAT designation that is granted accelerated

approval and is subject to post-approval requirements may fulfill such requirements through the submission of clinical evidence from clinical studies, patient registries, or other sources of real world evidence, such as electronic health records;

This program is intended to facilitate efficient development and expedite review of RMATs, which are intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition and for which preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs for such disease or condition.

A drug sponsor may request that the FDA designate a drug as a RMAT concurrently with, or at any time after, submission of an IND.

The FDA has 60 calendar days to determine whether the drug meets the criteria, including whether there is preliminary clinical evidence indicating that the drug has the potential to address unmet medical needs for a serious or life-threatening disease or condition.

A BLA for a regenerative medicine therapy that has received RMAT designation may be eligible for priority review or accelerated approval through use of surrogate or intermediate endpoints reasonably likely to predict long-term clinical benefit, or reliance upon data obtained from a meaningful number of sites.

Benefits of RMAT designation also include early interactions with the FDA to discuss any potential surrogate or intermediate endpoint to be used to support accelerated approval.

A regenerative medicine therapy with RMAT designation that is granted accelerated approval and is subject to post-approval requirements may fulfill such requirements through the submission of clinical evidence from clinical studies, patient registries, or other sources of real world evidence, such as electronic health records;

the collection of larger confirmatory data sets;

or post-approval monitoring of all patients treated with such therapy prior to its approval.

Fast track designation, priority review, accelerated approval, breakthrough therapy

designation, and RMAT designation do not change the standards for approval, but may expedite the development or approval process.

Under the Pediatric Research Equity Act, or PREA, certain NDAs and BLAs and certain supplements to an NDA or BLA must

contain data to assess the safety and efficacy of the drug for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

Fast track designation, priority review, accelerated approval, breakthrough therapy designation, and RMAT designation do not change the standards for approval, but may expedite the development or approval process.

Pediatric information

Under the Pediatric Research Equity Act, or PREA, certain NDAs and BLAs and certain supplements to an NDA or BLA must contain data to assess the safety and efficacy of the drug for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

The FDA may grant deferrals for submission of pediatric data or full or partial waivers.

The Food and Drug Administration Safety and Innovation Act amended the FDCA to require that a sponsor who is planning to submit a marketing application for a

drug that includes a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration submit an initial Pediatric Study Plan, or PSP, within 60 days of an end-of-Phase 2 meeting or, if there is no such meeting, as early as practicable before the initiation of the Phase 3 or Phase 2/3 trial.

The initial PSP must include an outline of the pediatric trial or

trials that the sponsor plans to conduct, including study objectives and design, age groups, relevant endpoints and statistical approach, or a justification for not including such detailed information, and any request for a deferral of pediatric

assessments or a full or partial waiver of the requirement to provide data from pediatric trials along with supporting information.

The FDCA, as amended, requires that a sponsor who is planning to submit a marketing application for a drug that includes a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration submit an initial Pediatric Study Plan, or PSP, within 60 days of an end-of-Phase

2 meeting or, if there is no such meeting, as early as practicable before the initiation of the Phase 3 or Phase 2/3 trial.

The initial PSP must include an outline of the pediatric trial or trials that the sponsor plans to conduct, including study objectives and design, age groups, relevant endpoints and statistical approach, or a justification for not including such detailed information, and any request for a deferral of pediatric assessments or a full or partial waiver of the requirement to provide data from pediatric trials along with supporting information.

The FDA and the sponsor must reach an agreement on the PSP.

A sponsor can submit amendments to an agreed-upon initial

PSP at any time if changes to the pediatric plan need to be considered based on data collected from preclinical studies, early phase clinical trials, and/or other clinical development programs.

A sponsor can submit amendments to an agreed-upon initial PSP at any time if changes to the pediatric plan need to be considered based on data collected from preclinical studies, early phase clinical trials, and/or other clinical development programs.

Post-marketing requirements

Following approval of a new product, the manufacturer and the approved product are subject to continuing regulation by the FDA, including,

among other things, monitoring and record-keeping activities, reporting of adverse experiences, complying with promotion and advertising requirements, which include restrictions on promoting drugs for unapproved uses or patient populations, or off-label use, and limitations on industry-sponsored scientific and educational activities.

Although physicians may prescribe legally available drugs for off-label uses,

manufacturers may not market or promote such uses.

Following approval of a new product, the manufacturer and the approved product are subject to continuing regulation by the FDA, including, among other things, monitoring and record-keeping activities, reporting of adverse experiences, complying with promotion and advertising requirements, which include restrictions on promoting drugs for unapproved uses or patient populations, or off-label

use, and limitations on industry-sponsored scientific and educational activities.

Although physicians may prescribe legally available drugs for off-label

uses, manufacturers may not market or promote such uses.

Prescription drug promotional materials must be submitted to the FDA in conjunction with their first use.

Further, if there are any modifications to the drug or biologic, including changes in

indications, labeling or manufacturing processes or facilities, the applicant may be required to submit and obtain FDA approval of a new NDA/BLA or NDA/BLA supplement, which may require the development of additional data or preclinical studies and

clinical trials.

The FDA may also place other conditions on approvals including the requirement for a Risk Evaluation and Mitigation

Strategy, or REMS, to assure the safe use of the product.

Further, if there are any modifications to the drug or biologic, including changes in indications, labeling or manufacturing processes or facilities, the applicant may be required to submit and obtain FDA approval of a new NDA/BLA or NDA/BLA supplement, which may require the development of additional data or preclinical studies and clinical trials.

The FDA may also place other conditions on approvals including the requirement for a Risk Evaluation and Mitigation Strategy, or REMS, to assure the safe use of the product.

If the FDA concludes a REMS is needed, the sponsor of the NDA or BLA must submit a proposed REMS.

The FDA will not approve the NDA or BLA without an approved REMS, if required.

include medication guides, physician communication plans or elements to assure safe use, such as restricted distribution methods, patient registries and other risk minimization tools.

Any of these limitations on approval or marketing could restrict

the commercial promotion, distribution, prescription or dispensing of products.

Product approvals may be withdrawn for non-compliance with regulatory standards or if problems occur following initial marketing.

A REMS could include medication guides, physician communication plans or elements to assure safe use, such as restricted distribution methods, patient registries and other risk minimization tools.

Any of these limitations on approval or marketing could restrict the commercial promotion, distribution, prescription or dispensing of products.

Product approvals may be withdrawn for non-compliance

with regulatory standards or if problems occur following initial marketing.

FDA regulations require that products be manufactured in specific approved facilities and in accordance with cGMP regulations.

and expect to continue to rely, on third parties for the production of clinical and commercial quantities of our products in accordance with cGMP regulations.

These manufacturers must comply with cGMP regulations that require, among other things,

quality control and quality assurance, the maintenance of records and documentation and the obligation to investigate and correct any deviations from cGMP.

Manufacturers and other entities involved in the manufacture and distribution of approved drugs or biologics are required to register their establishments with the FDA and certain state agencies

and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP requirements and other laws.

Accordingly, manufacturers must continue to expend time, money and effort in the area of production and

quality control to maintain cGMP compliance.

The discovery of violative conditions, including failure to conform to cGMP regulations, could result in enforcement actions, and the discovery of problems with a product after approval may result in

restrictions on a product, manufacturer or holder of an approved NDA or BLA, including recall.

We rely, and expect to continue to rely, on third parties for the production of clinical and commercial quantities of our products in accordance with cGMP regulations.

These manufacturers must comply with cGMP regulations that require, among other things, quality control and quality assurance, the maintenance of records and documentation and the obligation to investigate and correct any deviations from cGMP.

Manufacturers and other entities involved in the manufacture and distribution of approved drugs or biologics are required to register their establishments with the FDA and certain state agencies and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP requirements and other laws.

Accordingly, manufacturers must continue to expend time, money and effort in the area of production and quality control to maintain cGMP compliance.

The discovery of violative conditions, including failure to conform to cGMP regulations, could result in enforcement actions, and the discovery of problems with a product after approval may result in restrictions on a product, manufacturer or holder of an approved NDA or BLA, including recall.

Companion diagnostics and complementary diagnostics

We believe that the success of our product candidates may depend, in part, on the development and commercialization of either a

companion diagnostic or complementary diagnostic.

We believe that the success of our product candidates may depend, in part, on the development and commercialization of either a companion diagnostic or complementary diagnostic.

Companion diagnostics and complementary diagnostics can identify patients who are most likely to benefit from a particular therapeutic product;

identify patients likely to be at increased risk for

serious side effects as a result of treatment with a particular therapeutic product;

identify patients likely to be at increased risk for serious side effects as a result of treatment with a particular therapeutic product;

or monitor response to treatment with a particular therapeutic product for the purpose of adjusting treatment to achieve improved safety or effectiveness.

diagnostics and complementary diagnostics are regulated as medical devices by the FDA and, as such, require either clearance or approval prior to commercialization.

The level of risk combined with available controls to mitigate risk determines

whether a companion diagnostic device requires Premarket Approval Application approval or is cleared through the 510(k) premarket notification process.

For a novel therapeutic product for which a companion diagnostic device is essential for the safe

and effective use of the product, the companion diagnostic device should be developed and approved or 510(k)-cleared contemporaneously with the therapeutic.

The use of the companion diagnostic device will be stipulated in the labeling of the

therapeutic product.

Companion diagnostics and complementary diagnostics are regulated as medical devices by the FDA and, as such, require either clearance or approval prior to commercialization.

The level of risk combined with available controls to mitigate risk determines whether a companion diagnostic device requires Premarket Approval Application approval or is cleared through the 510(k) premarket notification process.

For a novel therapeutic product for which a

companion diagnostic device is essential for the safe and effective use of the product, the companion diagnostic device should be developed and approved or 510(k)-cleared contemporaneously with the therapeutic.

The use of the companion diagnostic device will be stipulated in the labeling of the therapeutic product.

This is also true for a complementary diagnostic, although it is not a prerequisite for receiving the therapeutic.

regulatory matters

Manufacturing, sales, promotion and other activities following product approval are also subject to regulation

by numerous regulatory authorities in the U.S.

in addition to the FDA, including the Centers for Medicare & Medicaid Services, or CMS, other divisions of the Department of Health and Human Services, the Department of Justice, the Drug

Enforcement Administration, the Consumer Product Safety Commission, the Federal Trade Commission, the Occupational Safety & Health Administration, the Environmental Protection Agency and state and local governments.

Healthcare providers, physicians, and third-party payors will play a primary role in the recommendation and prescription of any products for

which we obtain marketing approval.

financial arrangements and relationships through which we market, sell and distribute any drugs for which we obtain marketing approval.

Other regulatory matters

Manufacturing, sales, promotion and other activities following product approval are also subject to regulation by numerous regulatory authorities in the U.S.

in addition to the FDA, including the Centers for Medicare & Medicaid Services, or CMS, other divisions of the Department of Health and Human Services, or HHS, the Department of Justice, the Drug Enforcement Administration, the Consumer Product Safety Commission, the Federal Trade Commission, the Occupational Safety & Health Administration, the Environmental Protection Agency and state and local governments.

Healthcare providers, physicians, and third-party payors will play a primary role in the recommendation and prescription of any products for which we obtain marketing approval.

Our future arrangements with third party payors, healthcare providers and physicians may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations that may constrain the business or financial arrangements and relationships through which we market, sell and distribute any drugs for which we obtain marketing approval.

In the U.S., these laws include:

the federal Anti-Kickback Statute, the False Claims Act, laws and regulations

related to the reporting of payments to physicians and teaching hospitals, and the Health Insurance Portability and Accountability Act of 1996, or HIPAA.

The Anti-Kickback Statute makes it illegal for any person, including a prescription drug manufacturer (or a party acting on its behalf), to

knowingly and willfully solicit, receive, offer, pay or provide any remuneration, directly or indirectly, in cash or in kind, that is intended to induce or reward referrals, including the purchase, recommendation, order or prescription of a

particular drug, for which payment may be made under a federal healthcare program, such as Medicare or Medicaid.

Violations of this law are punishable by up to five years in prison, criminal fines, administrative civil money penalties for each

violation, plus up to three times the renumeration involved, and exclusion from participation in federal healthcare programs.

the federal Anti-Kickback Statute, the False Claims Act, laws and regulations related to the reporting of payments to physicians and teaching hospitals, and the Health Insurance Portability and Accountability Act of 1996, or HIPAA.

The Anti-Kickback Statute makes it illegal for any person, including a prescription drug manufacturer (or a party acting on its behalf), to knowingly and willfully solicit, receive, offer, pay or provide any remuneration, directly or indirectly, in cash or in kind, that is intended to induce or reward referrals, including the purchase, recommendation, order or prescription of a particular drug, for which payment may be made under a federal healthcare program, such as Medicare or Medicaid.

Violations of this law are punishable by up to five years in prison, criminal fines, administrative civil money penalties for each violation, plus up to three times the renumeration involved, and exclusion from participation in federal healthcare programs.

In addition, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it.

The federal civil and criminal false claims laws, including the civil False Claims Act, and

civil monetary penalty laws impose civil penalties, including through civil whistleblower or qui tam actions, against individuals or entities (including manufacturers) for, among other things, knowingly presenting or causing to be presented false or

fraudulent claims for payment by a federal healthcare program or making a false statement or record material to payment of a false claim or avoiding, decreasing or concealing an obligation to pay money to the federal government.

Penalties for a

False Claims Act violation include three times the actual damages sustained by the government, plus mandatory civil penalties for each separate false claim, the potential for exclusion from participation in federal healthcare programs, and the

potential implication of various federal criminal statutes.

Manufacturers can be held liable under the federal False Claims Act even when they do not submit claims directly to government payors if they are deemed to cause the submission

of false or fraudulent claims.

The federal civil and criminal false claims laws, including the civil False Claims Act, and civil monetary penalty laws impose civil penalties, including through civil whistleblower or qui tam actions, against individuals or entities (including manufacturers) for, among other things, knowingly presenting or causing to be presented false or fraudulent claims for payment by a federal healthcare program or making a false statement or record material to payment of a false claim or avoiding, decreasing or concealing an obligation to pay money to the federal government.

Penalties for a False Claims Act violation include three times the actual damages sustained by the government, plus mandatory civil penalties for each separate false claim, the potential for exclusion from participation in federal healthcare programs, and the potential implication of various federal criminal statutes.

Manufacturers can be held liable under the federal False Claims Act even when they do not submit claims directly to government payors if they are deemed to “cause” the submission of false or fraudulent claims.

The government may deem manufacturers to have “caused” the submission of false or fraudulent claims by, for example, providing inaccurate billing or coding information to customers or promoting a product off-label.

Claims which include items or services resulting from a violation of the federal Anti-Kickback Statute are false or fraudulent claims for purposes of the False Claims Act.

The federal False Claims Act

also permits a private individual acting as a whistleblower to bring actions on behalf of the federal government alleging violations of the False Claims Act and to share in any monetary recovery.

Our future marketing and activities

relating to the reporting of wholesaler or estimated retail prices for our products, the reporting of prices used to calculate Medicaid rebate information and other information affecting federal, state and third-party reimbursement for our products,

as well as the sale and marketing of our product and any future product candidates, are subject to scrutiny under this law.

HIPAA imposes

criminal and civil liability for knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program or knowingly and willfully making false statements, and concealing or covering up by any trick or device

a material fact or making any materially false statement relating to healthcare matters.

Similar to the federal Anti-Kickback Statute, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order

to have committed a violation.

HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009, or

HITECH, and their implementing regulations, also imposes obligations, including mandatory contractual terms and technical safeguards, with respect to maintaining the privacy, security and transmission of individually identifiable health information

held by covered entities and their business associates.

HITECH also created new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business associates, and gave state attorneys general new

authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys fees and costs associated with pursuing federal civil actions;

The Physician Payments Sunshine Act of 2010, as amended by the Health Care and Education Reconciliation Act, which requires applicable

manufacturers of covered drugs, biologics, and medical supplies (those paid for by a federal healthcare program) to report annually to CMS information related to any payments and other transfers of value made to physicians (defined to include

doctors, dentists, optometrists, podiatrists and chiropractors) and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members.

Effective January 1, 2022, these reporting obligations

will extend to include transfers of value made to certain non-physician providers such as physician assistants and nurse practitioners.

Analogous state and foreign fraud and abuse laws and regulations, such as state anti-kickback and false claims laws, may apply to sales or

marketing arrangements and claims involving healthcare items or services.

The federal False Claims Act also permits a private individual acting as a “whistleblower” to bring actions on behalf of the federal government alleging violations of the False Claims Act and to share in any monetary recovery.

Our future marketing and activities relating to the reporting of wholesaler or estimated retail prices for our products, the reporting of prices used to calculate Medicaid rebate information and other information affecting federal, state and third-party reimbursement for our products, as well as the sale and marketing of our product and any future product candidates, are subject to scrutiny under this law.

HIPAA imposes criminal and civil liability for knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program or knowingly and willfully making false statements, and concealing or covering up by any trick or device a material fact or making any materially false statement relating to healthcare matters.

Similar to the federal Anti-Kickback Statute, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009, or HITECH, and their implementing regulations, also imposes obligations, including mandatory contractual terms and technical safeguards, with respect to maintaining the privacy, security and transmission of individually identifiable health information held by covered entities and their business associates.

HITECH also created new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business associates, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions.

The Physician Payments Sunshine Act of 2010, as amended by the Health Care and Education Reconciliation Act, which requires applicable manufacturers of covered drugs, biologics, and medical supplies (those paid for by a federal healthcare program) to report annually to CMS information related to any payments and other transfers of value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors) and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members.

Effective January 1, 2022, these reporting obligations will extend to include transfers of value made to certain non-physician

providers such as physician assistants and nurse practitioners.

Analogous state and foreign fraud and abuse laws and regulations, such as state anti-kickback and false claims laws, may apply to sales or marketing arrangements and claims involving healthcare items or services.

Such laws are generally broad and are enforced by various state agencies and private actions.

Some state laws require pharmaceutical companies to comply with the

pharmaceutical industrys voluntary compliance guidelines and the relevant federal government compliance guidance and require drug manufacturers to report information related to payments and other transfers of value to physicians and other

healthcare providers or marketing expenditures.

Some state laws require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant federal government compliance guidance and require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers or marketing expenditures.

Certain state and local laws require the registration of pharmaceutical sales representatives.

State and foreign laws also govern the privacy and security of health information in some

circumstances, many of which differ from each other in significant ways and often are not pre-empted by HIPAA, thus complicating compliance efforts.

For example, in California, the California Consumer

Protection Act, or CCPA, which went into effect on January 1, 2020, establishes a new privacy framework for covered businesses by creating an expanded definition of personal information, establishing new data privacy rights for consumers in the

State of California, imposing special rules on the collection of consumer data from minors, and creating a new and potentially severe statutory damages framework for violations of the CCPA and for businesses that fail to implement reasonable

security procedures and practices to prevent data breaches.

While clinical trial data and information governed by HIPAA are currently exempt from the current version of the CCPA, other personal information may be applicable and possible changes to

the CCPA may broaden its scope.

The scope and enforcement of each of these laws is uncertain and subject to rapid change in the current

environment of healthcare reform, especially in light of the lack of applicable precedent and regulations.

Federal and state enforcement bodies have recently increased their scrutiny of interactions between healthcare companies and healthcare

providers, which has led to a number of investigations, prosecutions, convictions and settlements in the healthcare industry.

It is possible that governmental authorities will conclude that our business practices may not comply with current or

future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws and regulations.

If our operations are found to be in violation of any of these laws or any other governmental regulations that may apply to us,

we may be subject to significant civil, criminal and administrative penalties, damages, fines, imprisonment, exclusion of drugs from government funded healthcare programs, such as Medicare and Medicaid, and the curtailment or restructuring of our

If any of the physicians or other healthcare providers or entities with whom we expect to do business is found to not be in compliance with applicable laws, they may be subject to criminal, civil or administrative sanctions, including

exclusions from government funded healthcare programs.

Ensuring business arrangements comply with applicable healthcare laws, as well as responding to possible investigations by government authorities, can be time- and resource-consuming and can

divert a companys attention away from the business.

State and foreign laws also govern the privacy and security of health information in some circumstances, many of which differ from each other in significant ways and often are not pre-empted

by HIPAA, thus complicating compliance efforts.

For example, in California, the California Consumer Protection Act, or CCPA, which went into effect on January 1, 2020, establishes a new privacy framework for covered businesses by creating an expanded definition of personal information, establishing new data privacy rights for consumers in the State of California, imposing special rules on the collection of consumer data from minors, and creating a new and potentially severe statutory damages framework for violations of the CCPA and for businesses that fail to implement reasonable security procedures and practices to prevent data breaches.

While clinical trial data and information governed by HIPAA are currently exempt from the current version of the CCPA, other personal information may be applicable and possible changes to the CCPA may broaden its scope.

In addition, a new California ballot initiative, the California Privacy Rights Act, or CPRA, was passed in November 2020.

Effective starting on January 1, 2023, the CPRA imposes additional obligations on companies covered by the legislation and will significantly modify the CCPA, including by expanding consumers’ rights with respect to certain sensitive personal information.

The scope and enforcement of each of these laws is uncertain and subject to rapid change in the current environment of healthcare reform, especially in light of the lack of applicable precedent and regulations.

Federal and state enforcement bodies have recently increased their scrutiny of interactions between healthcare companies and healthcare providers, which has led to a number of investigations, prosecutions, convictions and settlements in the healthcare industry.

It is possible that governmental authorities will conclude that our business practices may not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or

other healthcare laws and regulations.

If our operations are found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant civil, criminal and administrative penalties, damages, fines, imprisonment, exclusion of drugs from government funded healthcare programs, such as Medicare and Medicaid, and the curtailment or restructuring of our operations.

Ensuring business arrangements comply with applicable healthcare laws, as well as responding to possible investigations by government authorities, can be time- and resource-consuming and can divert a company’s attention away from the business.

Current and Future Legislation

and foreign jurisdictions, there have been a number of legislative and regulatory changes and proposed changes regarding the

healthcare system that could prevent or delay marketing approval of our product candidates, restrict or regulate post-approval activities and affect our ability to profitably sell any product candidates for which we obtain marketing approval.

expect that current laws, as well as other healthcare reform measures that may be adopted in the future, may result in more rigorous coverage criteria and in additional downward pressure on the price that we, or any collaborators, may receive for

any approved products.

In March 2010, the Congress enacted the Affordable Care Act, as amended by the Health Care and Education

Reconciliation Act of 2010, or collectively the ACA, which, among other things:

created an annual, nondeductible fee on any entity that manufactures or imports specified branded prescription

drugs and biologic products, apportioned among these entities according to their market share in certain government healthcare programs;

expanded eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid

coverage to certain individuals with income at or below 133% of the federal poverty level, thereby potentially increasing a manufacturers Medicaid rebate liability;

expanded manufacturers rebate liability under the Medicaid Drug Rebate Program by increasing the minimum

rebate for both branded and generic drugs and revising the definition of average manufacturer price, or AMP, for calculating and reporting Medicaid drug rebates on outpatient prescription drug prices;

addressed a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are

calculated for drugs that are inhaled, infused, instilled, implanted or injected;

and foreign jurisdictions, there have been a number of legislative and regulatory changes and proposed changes regarding the healthcare system that could prevent or delay marketing approval of our product candidates, restrict or regulate post-approval activities and affect our ability to profitably sell any product candidates for which we obtain marketing approval.

We expect that current laws, as well as other healthcare reform measures that may be adopted in the future, may result in more rigorous coverage criteria and in additional downward pressure on the price that we, or any collaborators, may receive for any approved products.

In March 2010, the Congress enacted the Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, or collectively the ACA, which, among other things:

created an annual, nondeductible fee on any entity that manufactures or imports specified branded prescription drugs and biologic products, apportioned among these entities according to their market share in certain government healthcare programs;

expanded eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to certain individuals with income at or below 133% of the federal poverty level, thereby potentially increasing a manufacturer’s Medicaid rebate liability;

expanded manufacturers’ rebate liability under the Medicaid Drug Rebate Program by increasing the minimum rebate for both branded and generic drugs and revising the definition of “average manufacturer price,” or AMP, for calculating and reporting Medicaid drug rebates on outpatient prescription drug prices;

addressed a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected;

expanded the types of entities eligible for the 340B drug discount program;

established the Medicare Part D coverage gap discount program by requiring manufacturers to provide a 50% point-of-sale-discount, which was increased to 70% by the Bipartisan Budget Act of 2018 (as of January 1, 2019), off the negotiated price of applicable brand drugs to

eligible beneficiaries during their coverage gap period as a condition for the manufacturers outpatient drugs to be covered under Medicare Part D;

created a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct

comparative clinical effectiveness research, along with funding for such research.

With the new administration and

Congress, there will likely be additional administrative or legislative changes, including modification, repeal, or replacement of all, or certain provisions of the ACA which may impact reimbursement for drugs and biologics.

For example the Tax Cuts

and Jobs Act of 2017, or TCJA, includes a provision that decreased, effective January 1, 2019, the tax-based shared responsibility payment imposed by the ACA on certain individuals who fail to maintain

qualifying health coverage for all or part of a year that is commonly referred to as the individual mandate, to $0.

established the Medicare Part D coverage gap discount program by requiring manufacturers to provide a 50% point-of-sale-discount,

which was increased to 70% by the Bipartisan Budget Act of 2018 (as of January 1, 2019), off the negotiated price of applicable brand drugs to eligible beneficiaries during their coverage gap period as a condition for the manufacturers’ outpatient drugs to be covered under Medicare Part D;

created a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research.

With the new administration and Congress, there will likely be additional administrative or legislative changes, including modification, repeal, or replacement of all, or certain provisions of the ACA which may impact reimbursement for drugs and biologics.

For example the Tax Cuts and Jobs Act of 2017, or TCJA, includes a provision that decreased, effective January 1, 2019, the tax-based

shared responsibility payment imposed by the ACA on certain individuals who fail to maintain qualifying health coverage for all or part of a year that is commonly referred to as the “individual mandate,” to $0.

On December 14, 2018, a U.S.

District Court Judge in the Northern District of Texas, ruled that the individual

mandate is a critical and inseverable feature of the ACA, and therefore, because it was repealed as part of the TCJA, the remaining provisions of the ACA are invalid as well.

The current administration and CMS have both stated that the ruling will

have no immediate effect, and on December 18, 2019, the Fifth Circuit U.S.

Court Judge in the Northern District of Texas, ruled that the individual mandate is a critical and inseverable feature of the ACA, and therefore, because the Trump administration and CMS have both stated that the ruling will have no immediate effect, and on December 18, 2019, the Fifth Circuit U.S.

Court of Appeals held the individual mandate unconstitutional, and remanded the case to the lower court to reconsider its earlier invalidation of the full ACA.

review, the ACA remains in effect, but it is unclear at this time what effect the latest ruling will have on the status of the ACA.

On March 2, 2020, the U.S.

Supreme Court granted the petitions for writs of certiorari to review this case, and held oral arguments on November 10, 2020.

It is unclear what effect this will have on the status of the ACA.

Congress may also consider other legislation to repeal or replace certain elements of the ACA.

In addition, since

January 2017, President Trump has signed two Executive Orders designed to delay the implementation of certain provisions of the ACA or otherwise circumvent some of the requirements for health insurance mandated by the ACA.

On January 20, 2017,

President Trump signed an Executive Order directing federal agencies with authorities and responsibilities under the ACA to waive, defer, grant exemptions from, or delay the implementation of any provision of the ACA that would impose a fiscal

burden on states or a cost, fee, tax, penalty or regulatory burden on individuals, healthcare providers, health insurers, or manufacturers of pharmaceuticals or medical devices.

Further, on October 13, 2017, President Trump signed an Executive

Order terminating the cost-sharing subsidies that reimburse insurers under the ACA.

The Trump administration has concluded that cost-sharing reduction, or CSR, payments to insurance companies required under the ACA have not received necessary

appropriations from Congress and announced that it will discontinue these payments immediately until such appropriations are made.

The loss of the CSR payments is expected to increase premiums on certain policies issued by qualified health plans

under the ACA.

Several state attorneys general filed suit to stop the administration from terminating the subsidies, but their request for a restraining order was denied by a federal judge in California on October 25, 2017.

In addition, CMS has

published a final rule that would give states greater flexibility, starting in 2020, in setting benchmarks for insurers in the individual and small group market places, which may have the effect of relaxing the essential health benefits required

under the ACA for plans sold through such marketplaces.

In addition, since January 2017, President Trump has signed two Executive Orders designed to delay the implementation of certain provisions of the ACA or otherwise circumvent some of the requirements for health insurance mandated by the ACA.

On January 20, 2017, President Trump signed an Executive Order directing federal agencies with authorities and responsibilities under the ACA to waive, defer, grant exemptions from, or delay the implementation of any provision of the ACA that would impose a fiscal burden on states or a cost, fee, tax, penalty or regulatory burden on individuals, healthcare providers, health insurers, or manufacturers of pharmaceuticals or medical devices.

Further, on October 13, 2017, President Trump signed an Executive Order terminating the cost-sharing subsidies that reimburse insurers under the ACA.

The Trump administration has concluded that cost-sharing reduction, or CSR, payments to insurance companies required under the ACA have not received necessary appropriations from Congress and announced that it would discontinue these payments immediately until such appropriations are made.

Several state attorneys general filed suit to stop the Trump administration from terminating the subsidies, but their request for a restraining order was denied by a federal judge in California on October 25, 2017.

On August 14, 2020, the U.S.

Court of Appeals for the Federal Circuit ruled in two separate cases that the federal government is liable for the full amount of unpaid CSRs for the years preceding and including 2017.

For CSR claims made by health insurance companies for years 2018 and later, further litigation will be required to determine the amounts due, if any.

Further, on June 14, 2018, the U.S.

Court of Appeals for the Federal Circuit ruled that the federal government was not required to pay more than $12 billion in ACA risk corridor payments to third-party payors who argued they were owed to them.

On April 27, 2020, the U.S.

Supreme Court reversed the U.S.

Court of Appeals for the Federal Circuit decision and remanded the case to the U.S.

Court of Federal Claims, concluding the government has an obligation to pay these risk corridor payments under the relevant formula.

It is unclear what impact these rulings will have on our business.

In addition, CMS has published a final rule that gives states greater flexibility, starting in 2020, in setting benchmarks for insurers in the individual and small group market places, which may have the effect of relaxing the essential health benefits required under the ACA for plans sold through such marketplaces.

Litigation and legislation over the ACA are likely to continue, with unpredictable and uncertain results.

Packaging and Distribution in the U.S.

If our products are made available to authorized users of the Federal Supply Schedule of the General Services Administration, additional laws

and requirements apply.

If our products are made available to authorized users of the Federal Supply Schedule of the General Services Administration, additional laws and requirements apply.

Products must meet applicable child-resistant packaging requirements under the U.S.

Poison Prevention Packaging Act.

Manufacturing, sales, promotion and other activities also are potentially subject to federal and state

consumer protection and unfair competition laws.

The distribution of pharmaceutical products is subject to additional requirements and

regulations, including extensive record-keeping, licensing, storage and security requirements intended to prevent the unauthorized sale of pharmaceutical products.

The failure to comply with any of these laws or regulatory requirements subjects firms to

possible legal or regulatory action.

for recall, seizure of products, total or partial suspension of production, denial or withdrawal of product approvals, or refusal to allow a firm to enter into supply contracts, including government contracts.

Any action against us for violation of

these laws, even if we successfully defend against it, could cause us to incur significant legal expenses and divert our managements attention from the operation of our business.

Prohibitions or restrictions on sales or withdrawal of future

products marketed by us could materially affect our business in an adverse way.

Changes in regulations, statutes or the interpretation of

existing regulations could impact our business in the future by requiring, for example:

Manufacturing, sales, promotion and other activities also are potentially subject to federal and state consumer protection and unfair competition laws.

The distribution of pharmaceutical products is subject to additional requirements and regulations, including extensive record-keeping, licensing, storage and security requirements intended to prevent the unauthorized sale of pharmaceutical products.

The failure to comply with any of these laws or regulatory requirements subjects firms to possible legal or regulatory action.

Depending on the circumstances, failure to meet applicable regulatory requirements can result in criminal prosecution, fines or other penalties, injunctions, exclusion from federal healthcare programs, requests for recall, seizure of products, total or partial suspension of production, denial or withdrawal of product approvals, or refusal to allow a firm to enter into supply contracts, including government contracts.

Any action against us for violation of these laws, even if we successfully defend against it, could cause us to incur significant legal expenses and divert our management’s attention from the operation of our business.

Prohibitions or restrictions on sales or withdrawal of future products marketed by us could materially affect our business in an adverse way.

Changes in regulations, statutes or the interpretation of existing regulations could impact our business in the future by requiring, for example:

(i) changes to our manufacturing arrangements;

(ii) additions or modifications to product labeling;

(iii) the recall or discontinuation of our

(iii) the recall or discontinuation of our products;

or (iv) additional record-keeping requirements.

1 unchanged sentence

environmental, health and safety laws and regulations

We may be subject to numerous environmental, health and safety laws and regulations, including those governing laboratory procedures and the

handling, use, storage, treatment and disposal of hazardous materials and wastes.

From time to time and in the future, our operations may involve the use of hazardous and flammable materials, including chemicals and biological materials, and may

also produce hazardous waste products.

We may be subject to numerous environmental, health and safety laws and regulations, including those governing laboratory procedures and the handling, use, storage, treatment and disposal of hazardous materials and wastes.

From time to time and in the future, our operations may involve the use of hazardous and flammable materials, including chemicals and biological materials, and may also produce hazardous waste products.

Even if we contract with third parties for the disposal of these materials and waste products, we cannot completely eliminate the risk of contamination or injury resulting from these materials.

In the event of

contamination or injury resulting from the use or disposal of our hazardous materials, we could be held liable for any resulting damages, and any liability could exceed our resources.

We also could incur significant costs associated with civil or

criminal fines and penalties for failure to comply with such laws and regulations.

We maintain workers compensation insurance to

cover us for costs and expenses we may incur due to injuries to our employees, but this insurance may not provide adequate coverage against potential liabilities.

However, we do not maintain insurance for environmental liability or toxic tort claims

that may be asserted against us.

In addition, we may incur substantial costs in order to comply with current or future environmental,

health and safety laws and regulations.

In the event of contamination or injury resulting from the use or disposal of our hazardous materials, we could be held liable for any resulting damages, and any liability could exceed our resources.

We also could incur significant costs associated with civil or criminal fines and penalties for failure to comply with such laws and regulations.

We maintain workers’ compensation insurance to cover us for costs and expenses we may incur due to injuries to our employees, but this insurance may not provide adequate coverage against potential liabilities.

However, we do not maintain insurance for environmental liability or toxic tort claims that may be asserted against us.

In addition, we may incur substantial costs in order to comply with current or future environmental, health and safety laws and regulations.

Current or future environmental laws and regulations may impair our research, development or production efforts.

In addition, failure to comply with these laws and regulations may result in substantial fines,

penalties or other sanctions.

In addition, failure to comply with these laws and regulations may result in substantial fines, penalties or other sanctions.

patent term restoration and marketing exclusivity

Depending upon the timing, duration and specifics of FDA approval of MGTA-456, MGTA-145 and any future product candidates, some of our U.S.

patents may be eligible for limited patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984, commonly referred to

as the Hatch-Waxman Amendments.

Depending upon the timing, duration and specifics of FDA approval of MGTA-145

and any other current or future product candidates, some of our U.S.

patents may be eligible for limited patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984, commonly referred to as the Hatch-Waxman Amendments.

The Hatch-Waxman Amendments permit restoration of the patent term of up to five years as compensation for patent term lost during product development and FDA regulatory review process.

Patent-term restoration,

however, cannot extend the remaining term of a patent beyond a total of 14 years from the products approval date.

The patent-term restoration period is generally one-half the time between the effective

date of an IND and the submission date of an NDA or BLA plus the time between the submission date of an NDA or BLA and the approval of that application, except that the review period is reduced by any time during which the applicant failed to

exercise due diligence.

Patent-term restoration, however, cannot extend the remaining term of a patent beyond a total of 14 years from the product’s approval date.

The patent-term restoration period is generally one-half

the time between the effective date of an IND and the submission date of an NDA or BLA plus the time between the submission date of an NDA or BLA and the approval of that application, except that the review period is reduced by any time during which the applicant failed to exercise due diligence.

Only one patent applicable to an approved drug is eligible for the extension and the application for the extension must be submitted prior to the expiration of the patent.

Patent and Trademark Office, in consultation

with the FDA, reviews and approves the application for any patent term extension or restoration.

In the future, we may apply for restoration of patent term for our currently owned or licensed patents to add patent life beyond its current expiration

date, depending on the expected length of the clinical trials and other factors involved in the filing of the relevant NDA or BLA.

Market exclusivity provisions under the FDCA also can delay the submission or the approval

of certain applications.

The FDCA provides a five-year period of non-patent marketing exclusivity within the U.S.

Patent and Trademark Office, in consultation with the FDA, reviews and approves the application for any patent term extension or restoration.

In the future, we may apply for restoration of patent term for our currently owned or licensed patents to add patent life beyond its current expiration date, depending on the expected length of the clinical trials and other factors involved in the filing of the relevant NDA or BLA.

Market exclusivity provisions under the FDCA also can delay the submission or the approval of certain applications.

The FDCA provides a five-year period of non-patent

marketing exclusivity within the U.S.

to the first applicant to gain approval of an NDA for a new chemical entity.

A drug is a new

chemical entity if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the action of the drug substance.

During the exclusivity period, the FDA may not accept for

review an abbreviated new drug application, or ANDA, or a 505(b)(2) NDA submitted by another company for another version of such drug where the applicant does not own or have a legal right of reference to all the data required for approval.

an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement.

The FDCA also provides three years of marketing exclusivity for an NDA, 505(b)(2) NDA

or supplement to an existing NDA if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant are deemed by the FDA to be essential to the approval of the application, for example, new

indications, dosages or strengths of an existing drug.

This three-year exclusivity covers only the conditions of use associated with the new clinical investigations and does not prohibit the FDA from approving ANDAs for drugs containing the original

active agent.

A drug is a new chemical entity if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the action of the drug substance.

During the exclusivity period, the FDA may not accept for review an abbreviated new drug application, or ANDA, or a 505(b)(2) NDA submitted by another company for another version of such drug where the applicant does not own or have a legal right of reference to all the data

required for approval.

However, an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement.

The FDCA also provides three years of marketing exclusivity for an NDA, 505(b)(2) NDA or supplement to an existing NDA if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant are deemed by the FDA to be essential to the approval of the application, for example, new indications, dosages or strengths of an existing drug.

This three-year exclusivity covers only the conditions of use associated with the new clinical investigations and does not prohibit the FDA from approving ANDAs for drugs containing the original active agent.

Five-year and three-year exclusivity will not delay the submission or approval of a full NDA.

However, an applicant submitting a full NDA would be required to conduct or obtain a right of reference to all of the preclinical studies and

adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.

An abbreviated approval pathway for

biological products shown to be similar to, or interchangeable with, an FDA-licensed reference biological product was created by the Biologics Price Competition and Innovation Act of 2009 as part of the ACA.

However, an applicant submitting a full NDA would be required to conduct or obtain a right of reference to all of the preclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.

An abbreviated approval pathway for biological products shown to be similar to, or interchangeable with, an FDA-licensed

reference biological product was created by the Biologics Price Competition and Innovation Act of 2009 as part of the ACA.

This amendment to the PHSA, in part, attempts to minimize duplicative testing.

Biosimilarity, which requires that the biological product be highly similar to the reference product notwithstanding minor differences in clinically inactive components

and that there be no clinically meaningful differences between the product and the reference product in terms of safety, purity and potency, can be shown through analytical studies, animal studies and a clinical trial or trials.

Interchangeability

requires that a biological product be biosimilar to the reference product and that the product can be expected to produce the same clinical results as the reference product in any given patient and, for products administered multiple times to an

individual, that the product and the reference product may be alternated or switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biological

product without such alternation or switch.

Complexities associated with the larger, and often more complex, structure of biological products as compared to small molecule drugs, as well as the processes by which such products are manufactured, pose

significant hurdles to implementation that are still being worked out by the FDA.

A reference biological product is granted four- and

twelve-year exclusivity periods from the time of first licensure of the product.

The FDA will not accept an application for a biosimilar or interchangeable product based on the reference biological product until four years after the date of first

licensure of the reference product, and the FDA will not approve an application for a biosimilar or interchangeable product based on the reference biological product until twelve years after the date of first licensure of the reference product.

Biosimilarity, which requires that the biological product be highly similar to the reference product notwithstanding minor differences in clinically inactive components and that there be no clinically meaningful differences between the product and the reference product in terms of safety, purity and potency, can be shown through analytical studies, animal studies and a clinical trial or trials.

Interchangeability requires that a biological product be biosimilar to the reference product and that the product can be expected to produce the same clinical results as the reference product in any given patient and, for products administered multiple times to an individual, that the product and the reference product may be alternated or switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biological product without such alternation or switch.

A reference biological product is granted four- and twelve-year exclusivity periods from the time of first licensure of the product.

The FDA will not accept an application for a biosimilar or interchangeable product based on the reference biological product until four years after the date of first licensure of the reference product, and the FDA will not approve an application for a biosimilar or interchangeable product based on the reference biological product until twelve years after the date of first licensure of the reference product.

“First licensure” typically means the initial date the particular product at issue was licensed in the U.S.

Date of first licensure does not include the date of licensure of (and a new period of exclusivity is not available for) a

biological product if the licensure is for a supplement for the biological product or for a subsequent application by the same sponsor or manufacturer of the biological product (or licensor, predecessor in interest, or other related entity) for a

change (not including a modification to the structure of the biological product) that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device or strength, or for a modification to the

structure of the biological product that does not result in a change in safety, purity, or potency.

Therefore, one must determine whether a new product includes a modification to the structure of a previously licensed product that results in a

change in safety, purity, or potency to assess whether the licensure of the new product is a first licensure that triggers its own period of exclusivity.

Whether a subsequent application, if approved, warrants exclusivity as the first

licensure of a biological product is determined on a case-by-case basis with data submitted by the sponsor.

Date of first licensure does not include the date of licensure of (and a new period of exclusivity is not available for) a biological product if the licensure is for a supplement for the biological product or for a subsequent application by the same sponsor or manufacturer of the biological product (or licensor, predecessor in interest, or other related entity) for a change (not including a modification to the structure of the biological product) that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device or strength, or for a modification to the structure of the biological product that does not result in a change in safety, purity, or potency.

Therefore, one must determine whether a new product includes a modification to the structure of a previously licensed product that results in a change in safety, purity, or potency to assess whether the licensure of the new product is a first licensure that triggers its own period of exclusivity.

Whether a subsequent application, if approved, warrants exclusivity as the “first licensure” of a biological product is determined on a case-by-case

basis with data submitted by the sponsor.

Pediatric exclusivity is another type of regulatory market exclusivity in the U.S.

exclusivity, if granted, adds six months to existing regulatory exclusivity periods.

This six-month exclusivity may be granted based on the voluntary completion of a pediatric trial in accordance with an FDA-issued Written Request for such a trial.

Pediatric exclusivity, if granted, adds six months to existing regulatory exclusivity periods.

This six-month

exclusivity may be granted based on the voluntary completion of a pediatric trial in accordance with an FDA-issued

“Written Request” for such a trial.

European Union drug development

In the European Union, our future products also may be subject to extensive regulatory requirements.

As in the U.S., medicinal products can be

marketed only if a marketing authorization from the competent regulatory agencies has been obtained.

Similar to the U.S., the various

phases of preclinical and clinical research in the European Union are subject to significant regulatory controls.

Although the European Union Clinical Trials Directive 2001/20/EC, or Directive, has sought to harmonize the European Union clinical

trials regulatory framework, setting out common rules for the control and authorization of clinical trials in the European Union, the European Union Member States have transposed and applied the provisions of the Directive differently.

to significant variations in the member state regimes.

As in the U.S., medicinal products can be marketed only if a marketing authorization from the competent regulatory agencies has been obtained.

Similar to the U.S., the various phases of preclinical and clinical research in the European Union are subject to significant regulatory controls.

Although the European Union Clinical Trials Directive 2001/20/EC, or Directive, has sought to harmonize the European Union clinical trials regulatory framework, setting out common rules for the control and authorization of clinical trials in the European Union, the European Union Member States have transposed and applied the provisions of the Directive differently.

This has led to significant variations in the member state regimes.

Under the current regime, before a clinical trial can be initiated it must be approved in each of the European Union countries where the trial is to be conducted by two distinct bodies:

National Competent Authority, or NCA, and one or more Ethics Committees, or ECs.

Under the current regime all suspected unexpected serious adverse reactions to the investigated drug that occur during the clinical trial have to be reported to the NCA

and ECs of the European Union Member State where they occurred.

The European Union clinical trials legislation currently is undergoing a

transition process mainly aimed at harmonizing and streamlining clinical-trial authorization, simplifying adverse-event reporting procedures, improving the supervision of clinical trials and increasing their transparency.

Recently enacted Clinical

Trials Regulation EU No.

536/2014 ensures that the rules for conducting clinical trials in the European Union will be identical.

Union drug marketing

Much like the Anti-Kickback Statue prohibition in the U.S., the provision of benefits or advantages to

physicians to induce or encourage the prescription, recommendation, endorsement, purchase, supply, order or use of medicinal products is also prohibited in the European Union.

The provision of benefits or advantages to physicians is governed by the

national anti-bribery laws of European Union Member States, such as the UK Bribery Act 2010.

the National Competent Authority, or NCA, and one or more Ethics Committees, or ECs.

Under the current regime all suspected unexpected serious adverse reactions to the investigated drug that occur during the clinical trial have to be reported to the NCA and ECs of the European Union Member State where they occurred.

In April 2014, the European Union adopted a new Clinical Trials Regulation (EU) No 536/2014, which is set to replace the current Clinical Trials Directive 2001/20/EC.

It will overhaul the current system of approvals for clinical trials in the European Union, and is aimed at harmonizing and streamlining clinical-trial authorization (for example, by providing for a streamlined application procedure via a single entry point and strictly defined deadlines for the assessment of clinical trial applications), simplifying adverse-event reporting procedures, improving the supervision of clinical trials and increasing their transparency.

The new Clinical Trials Regulation ensures that the rules for conducting clinical trials in the European Union will be identical, as no national implementing legislation in each European Union Member State will be required.

It is expected that the new Clinical Trials Regulation will come into effect following confirmation of full functionality of the Clinical Trials Information System, the centralized European Union portal and database for clinical trials foreseen by the new Clinical Trials Regulation, through an independent audit, which is currently anticipated to occur in December 2021.

European Union drug marketing

Much like the Anti-Kickback Statue prohibition in the U.S., the provision of benefits or advantages to physicians to induce or encourage the prescription, recommendation, endorsement, purchase, supply, order or use of medicinal products is also prohibited in the European Union and the U.K.

The provision of benefits or advantages to induce or reward improper performance generally is governed by the national anti-bribery laws of European Union Member States, and the Bribery Act 2010 in the U.K.

Infringement of these laws could result in substantial fines and imprisonment.

European Union Directive 2001/83/EC, which is the European Union Directive governing medicinal products for human use, further provides that, where medicinal products are being promoted to persons qualified to prescribe or supply them, no gifts, pecuniary advantages or benefits in kind may be supplied, offered or promised to such persons unless they are inexpensive and relevant to the practice of medicine or pharmacy.

This provision has been transposed into the Human Medicines Regulations 2012 and so remains applicable in the U.K.

despite its departure from the European Union.

Payments made to physicians in certain European Union Member States must be publicly disclosed.

Moreover, agreements with physicians often

must be the subject of prior notification and approval by the physicians employer, his or her competent professional organization and/or the regulatory authorities of the individual European Union Member States.

These requirements are provided

in the national laws, industry codes or professional codes of conduct, applicable in the European Union Member States.

Failure to comply with these requirements could result in reputational risk, public reprimands, administrative penalties, fines or

imprisonment.

Moreover, agreements with physicians often must be the subject of prior notification and approval by the physician’s employer, his or her competent professional organization and/or the regulatory authorities of the individual European Union Member States.

These requirements are provided in the national laws, industry codes or professional codes of conduct, applicable in the European Union Member States.

Failure to comply with these requirements could result in reputational risk, public reprimands, administrative penalties, fines or imprisonment.

European Union drug review and approval

In the European Economic Area, or EEA, which is comprised of the 27 Member States of the European Union (including Norway and excluding

Croatia), Iceland and Liechtenstein, medicinal products can only be commercialized after obtaining a Marketing Authorization, or MA.

In the European Economic Area, or EEA, which is comprised of the Member States of the European Union (plus Norway, Iceland and Liechtenstein), medicinal products can only be commercialized after obtaining a Marketing Authorization, or MA.

There are two types of marketing authorizations.

The Community MA is issued by the European Commission through the Centralized Procedure, based on the opinion of

the Committee for Medicinal Products for Human Use of the EMA and is valid

throughout the entire territory of the EEA.

The Centralized Procedure is mandatory for certain types of products, such as biotechnology medicinal products, orphan medicinal products,

advanced-therapy medicines such as gene-therapy, somatic cell-therapy or tissue-engineered medicines and medicinal products containing a new active substance indicated for the treatment of HIV, AIDS, cancer, neurodegenerative disorders, diabetes,

auto-immune and other immune dysfunctions and viral diseases.

The Centralized Procedure is optional for products containing a new active substance not yet authorized in the EEA, or for products that constitute a significant therapeutic, scientific

or technical innovation or which are in the interest of public health in the European Union.

National MAs, which are issued by the competent authorities of the Member States of the EEA and only cover their

respective territory, are available for products not falling within the mandatory scope of the Centralized Procedure.

Where a product has already been authorized for marketing in a Member State of the EEA, this National MA can be recognized in

another Member State of the EEA through the Mutual Recognition Procedure.

If the product has not received a National MA in any Member State of the EEA at the time of application, it can be approved simultaneously in various Member States of the EEA

through the Decentralized Procedure.

Under the Decentralized Procedure an identical dossier is submitted to the competent authorities of each of the Member States of the EEA in which the MA is sought, one of which is selected by the applicant as the

Reference Member State, or RMS.

The competent authority of the RMS prepares a draft assessment report, a draft summary of the product characteristics, or SPC, and a draft of the labeling and package leaflet, which are sent to the other Member States

of the EEA (referred to as the Member States Concerned) for their approval.

If the Member States Concerned raise no objections, based on a potential serious risk to public health, to the assessment, SPC, labeling, or packaging proposed by the RMS,

the product is subsequently granted a national MA in all the Member States (i.e., in the RMS and the Member States Concerned).

Under the above described procedures, before granting the MA, the EMA or the competent authorities of the Member States of the EEA make an

assessment of the risk-benefit balance of the product on the basis of scientific criteria concerning its quality, safety and efficacy.

Union new chemical entity exclusivity

In the European Union, new chemical entities, sometimes referred to as new active

substances, qualify for eight years of data exclusivity upon marketing authorization and an additional two years of market exclusivity.

The data exclusivity, if granted, prevents regulatory authorities in the European Union from referencing the

innovators data to assess a generic application for eight years, after which generic marketing authorization can be submitted, and the innovators data may be referenced, but not approved for two years.

The overall ten-year period will be extended to a maximum of 11 years if, during the first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications

which, during the scientific evaluation prior to their authorization, are determined to bring a significant clinical benefit in comparison with currently approved therapies.

The Centralized MA is issued by the European Commission through the Centralized Procedure, based on the opinion of the Committee for Medicinal Products for Human Use, or CHMP, of the EMA and is valid throughout the entire territory of the EEA.

The Centralized Procedure is mandatory for certain types of products, such as biotechnology medicinal products, orphan medicinal products, advanced-therapy medicines (gene-therapy, somatic cell-therapy or tissue-engineered medicines) and medicinal products containing a new active substance indicated for the treatment of HIV, AIDS, cancer, neurodegenerative disorders, diabetes, auto-immune and other immune dysfunctions and viral diseases.

The Centralized Procedure is optional for products containing a new active substance not yet authorized in the EEA, or for products that constitute a significant therapeutic, scientific or technical innovation or which are in the interest of public health in the European Union.

Under the Centralized Procedure the maximum timeframe for the evaluation of a Marketing Authorization Application, or MAA, by the EMA is 210 days, excluding clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the CHMP.

Clock stops may extend the timeframe of evaluation of a MAA considerably beyond 210 days.

Where the CHMP gives a positive opinion, it provides the opinion together with supporting documentation to the European Commission, who make the final decision to grant a marketing authorization, which is issued within 67 days of receipt of the EMA’s recommendation.

Accelerated assessment might be granted by the CHMP in exceptional cases, when a medicinal product is expected to be of major public health interest, particularly from the point of view of therapeutic innovation.

The timeframe for the evaluation of a MAA under the accelerated assessment procedure is 150 days, excluding clock stops, but it is possible that the CHMP may revert to the standard time limit for the centralized procedure if it determines that the application is no longer appropriate to conduct an accelerated assessment.

National MAs, which are issued by the competent authorities of the Member States of the EEA and only cover their respective territory, are available for products not falling within the mandatory scope of the Centralized Procedure.

Where a product has already been authorized for marketing in a Member State of the EEA, this National MA can be recognized in other Member States of the EEA through the Mutual Recognition Procedure.

If the product has not received a National MA in any Member State of the EEA at the time of application, it can be approved simultaneously in various Member States of the EEA through the Decentralized Procedure.

Under the Decentralized Procedure an identical dossier is submitted to the competent authorities of each of the Member States of the EEA in which a MA is sought, one of which is selected by the applicant as the Reference Member State, or RMS.

The competent authority of the RMS prepares a draft assessment report, a draft summary of the product characteristics, or SmPC, and a draft of the labeling and package leaflet, which are sent to the other Member States of the EEA (referred to as the Concerned Member States) for their approval.

If the Concerned Member States raise no objections, based on a potential serious risk to public health, to the assessment, SmPC, labeling, or packaging proposed by the RMS, the product is subsequently granted a National MA in all the Member States (i.e., in the RMS and the Concerned Member States).

Under the above described procedures, before granting a MA, the EMA or the competent authorities of the Member States of the EEA make an assessment of the risk-benefit balance of the product on the basis of scientific criteria concerning its quality, safety and efficacy.

Now that the U.K.

(which comprises Great Britain and Northern Ireland) has left the European Union, Great Britain will no longer be covered by Centralized MAs (under the Northern Irish Protocol, Centralized MAs will continue to be recognized in Northern Ireland).

All medicinal products with a current Centralized MA were automatically converted to Great Britain MAs on January 1, 2021.

For a period of two years from January 1,

2021, the Medicines and Healthcare products Regulatory Agency, or MHRA, the U.K.

medicines regulator, may rely on a decision taken by the European Commission on the approval of a new MA in the Centralized Procedure, in order to more quickly grant a new Great Britain MA.

A separate application will, however, still be required.

The MHRA also has the power to have regard to MAs approved in the Member States of the EEA through Decentralized or Mutual Recognition Procedures with a view to more quickly granting a MA in the U.K.

or Great Britain.

European Union market and data exclusivity

In the EEA, innovative medicinal products qualify for eight years of data exclusivity upon marketing authorization and an additional two years of market exclusivity.

The data exclusivity, if granted, prevents generic or biosimilar applicants from referencing the innovator’s pre-clinical

and clinical trial data contained in the dossier of the reference product when applying for a generic or biosimilar marketing authorization in the EAA.

During the additional two-year

period of market exclusivity, a generic or biosimilar marketing authorization application can be submitted, and the innovator’s data may be referenced, but no generic or biosimilar product can be marketed until the expiration of the market exclusivity.

The overall ten-year

period will be extended to a maximum of 11 years if, during the first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are determined to bring a significant clinical benefit in comparison with currently approved therapies.

Even if a compound is considered to be a new chemical entity so that the innovator gains the prescribed period of data exclusivity, another company may market another version of the product if such company obtained marketing authorization based on an marketing authorization application with a complete independent data package of pharmaceutical tests, preclinical tests and clinical trials.

European Union orphan designation and exclusivity

In the European Union, the EMAs Committee for Orphan Medicinal Products grants orphan drug designation to promote the development of

products that are intended for the diagnosis, prevention or treatment of life-threatening or chronically debilitating conditions affecting not more than 5 in 10,000 persons in the European Union community (or where it is unlikely that the

development of the medicine would generate sufficient return to justify the investment) and for which no satisfactory method of diagnosis, prevention or treatment has been authorized (or, if a method exists, the product would be a significant

benefit to those affected).

In the European Union, orphan drug designation entitles a party to financial incentives such as reduction of

fees or fee waivers and ten years of market exclusivity is granted following medicinal product approval.

period may be reduced to six years if the orphan drug designation criteria are no longer met, including where it is shown that the product is sufficiently profitable not to justify maintenance of

market exclusivity.

In the EEA, the EMA’s Committee for Orphan Medicinal Products grants orphan drug designation to promote the development of products that are intended for the diagnosis, prevention or treatment of life-threatening or chronically debilitating conditions and either (i) such condition affects not more than 5 in 10,000 persons in the EEA or (ii) it is unlikely that the development of the medicine would generate sufficient return to justify the necessary investment in its development.

In either case, the applicant must also demonstrate that no satisfactory method of diagnosis, prevention or treatment for the condition has been authorized (or, if a method exists, the product would be a significant benefit to those affected compared to the product available).

In the European Union, orphan drug designation entitles a party to financial incentives such as reduction of fees or fee waivers and ten years of market exclusivity is granted following medicinal product approval.

During this market exclusivity period, neither the EMA nor the European Commission nor any of the competent authorities in the EEA Members States can accept an application or grant a marketing authorization for a “similar medicinal product.” A “similar medicinal product” is defined as a medicinal product containing a similar active substance or substances as contained in an authorized orphan medicinal product, and which is intended for the same therapeutic indication.

This period may be reduced to six years if the orphan drug designation criteria are no longer met, including where it is shown that the product is sufficiently profitable not to justify maintenance of market exclusivity.

Market exclusivity may also be revoked in very select cases, such as if (i) it is established that a similar medicinal product is safer, more effective or otherwise clinically superior;

(ii) the marketing authorization holder consents to such revocation;

or (iii) the marketing authorization holder cannot supply enough orphan medicinal product.

Orphan drug designation must be requested before submitting an application for marketing approval.

Orphan drug designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.

European Data Collection

collection and use of personal health data in the European Union is governed, as of May 2018, by the General Data Protection Regulation, or GDPR.

The GDPR imposes several requirements on companies that process personal data, including requirements

relating to the processing of health and other sensitive data, the consent of the individuals to whom the personal data relates, the information provided to the individuals regarding data processing activities, the notification of data processing

obligations to the competent national data protection authorities and certain measures to be taken when engaging third-party processors.

The GDPR also imposes strict rules on the transfer of personal data out of the European Economic Area, including

Failure to comply with the requirements of the GDPR, and the related national data protection laws of the European Union Member States, may result in fines and other administrative penalties, including potential fines of up to

20 million or 4% of annual global revenues, whichever is greater.

The GDPR also confers a private right of action on data subjects and consumer associations to lodge complaints with supervisory authorities, seek judicial remedies, and

obtain compensation for damages resulting from violations of the GDPR.

The GDPR regulations may impose additional responsibility and liability in relation to personal data that we process, and we may be required to put in place additional mechanisms

ensuring compliance with the new data protection rules, including as implemented by individual countries.

From January 1, 2021, a separate process for orphan drug designation will apply in Great Britain.

There will be no pre-marketing

authorization orphan designation (as there is in the EEA) and the application for orphan designation will be reviewed by the MHRA, at the time of the marketing authorization application.

are the same as in the EEA, save that they apply to Great Britain only (e.g., there must be no satisfactory method of diagnosis, prevention or treatment of the condition concerned in Great Britain).

Brexit and the Regulatory Framework in the U.K.

On June 23, 2016, the electorate in the U.K.

voted in favor of leaving the European Union (commonly referred to as Brexit).

Thereafter, on March 29, 2017, the country formally notified the European Union of its intention to withdraw pursuant to Article 50 of the Lisbon Treaty.

formally left the European Union on January 31, 2020.

A transition period began on February 1, 2020, during which European Union pharmaceutical law remained applicable to the U.K.

and ended on December 31, 2020.

Since the regulatory framework for pharmaceutical products in the U.K.

covering quality, safety, and efficacy of pharmaceutical products, clinical trials, marketing authorization, commercial sales, and distribution of pharmaceutical products is derived from European Union directives and regulations, Brexit could materially impact the future regulatory regime which applies to products and the approval of product candidates in the U.K., as the U.K.

legislation now has the potential to diverge from European Union legislation.

It remains to be seen how Brexit will impact regulatory requirements for medicinal products and devices in the U.K.

in the long-term.

The MHRA has recently published detailed guidance for industry and organizations to follow now the transition period is over, which will be updated as the U.K.’s regulatory position on medicinal products and medical devices evolves over time.

European and United Kingdom Data Collection

The collection and use of personal health data in the European Union is governed, as of May 2018, by the General Data Protection Regulation, or GDPR.

The GDPR imposes several requirements on companies that process personal data, including requirements relating to the processing of health and other sensitive data, the consent of the individuals to whom the personal data relates, the information provided to the individuals regarding data processing activities, the notification of data processing obligations to the competent national data protection authorities and certain measures to be taken when engaging third-party processors.

The GDPR also imposes strict rules on the transfer of personal data out of the European Economic Area, including to the U.S.

The GDPR also confers a private right of action on data subjects and consumer associations to lodge complaints with supervisory authorities, seek judicial remedies, and obtain compensation for damages resulting from violations of the GDPR.

The GDPR regulations may impose additional responsibility and liability in relation to personal data that we process, and we may be required to put in place additional mechanisms ensuring compliance with the new data protection rules, including as implemented by individual countries.

This may be onerous and adversely affect our business, financial condition, results of operations and prospects.

Compliance with the GDPR is a

rigorous and time-intensive process that may increase our cost of doing business or require us to change our business practices, and despite those efforts, there is a risk that we may be subject to fines and penalties, litigation, and reputational

harm in connection with any future European activities.

Further, the United Kingdoms vote in favor of exiting the European Union, often referred to as Brexit, has created uncertainty with regard to data protection regulation in the United

In particular, it is unclear how data transfers to and from the United Kingdom will be regulated.

In addition, further to the U.K.’s exit from the European Union on January 31, 2020, the GDPR ceased to apply in the U.K.

at the end of the transition period on December 31, 2020.

However, as of January 1, 2021, the U.K.’s European Union (Withdrawal) Act 2018 incorporated the GDPR (as it existed on December 31, 2020 but subject to certain U.K.

specific amendments) into U.K.

law (referred to as the U.K.

GDPR and the U.K.

Data Protection Act 2018 set out the U.K.’s data protection regime, which is independent from but aligned to the European Union’s data protection regime.

Non-compliance

with the U.K.

GDPR may result in monetary penalties of up to £17.5 million or 4% of worldwide revenue, whichever is higher.

The U.K., however, is now regarded as a third country under the European Union’s GDPR which means that transfers of personal data from the EEA to the U.K.

will be restricted unless an appropriate safeguard, as recognized by the European Union’s GDPR, has been put in place.

Although, under the EU-U.K.

Trade Cooperation Agreement it is lawful to transfer personal data between the U.K.

and the EEA for a 6 month period following the end of the transition period, with a view to achieving an adequacy decision from the European Commission during that period.

Like the European Union GDPR, the U.K.

GDPR restricts personal data transfers outside the U.K.

to countries not regarded by the U.K.

as providing adequate protection (this means that personal data transfers from the U.K.

to the EEA remain free flowing).

Compliance with the GDPR and the U.K.

GDPR is a rigorous and time-intensive process that may increase our cost of doing business or require us to change our business practices, and

despite those efforts, there is a risk that we may be subject to fines and penalties, litigation, and reputational harm in connection with any future European or U.K.

Rest of the world regulation

For other countries outside of the European Union and the U.S., such as countries in Eastern Europe, Latin America or Asia, the

requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary from country to country.

Additionally, the clinical trials must be conducted in accordance with GCP requirements and the applicable regulatory

requirements and the ethical principles that have their origin in the Declaration of Helsinki.

If we fail to comply with applicable

foreign regulatory requirements, we may be subject to, among other things, fines, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.

For other countries outside of the European Union and the U.S., such as countries in Eastern Europe, Latin America or Asia, the requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary from country to country.

Additionally, the clinical trials must be conducted in accordance with GCP requirements and the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.

If we fail to comply with applicable foreign regulatory requirements, we may be subject to, among other things, fines, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.

Additional laws and regulations governing international operations

If we further expand our operations outside of the U.S., we must dedicate additional resources to comply with numerous laws and regulations in

each jurisdiction in which we plan to operate.

If we further expand our operations outside of the U.S., we must dedicate additional resources to comply with numerous laws and regulations in each jurisdiction in which we plan to operate.

The Foreign Corrupt Practices Act, or FCPA, prohibits any U.S.

individual or business from paying, offering, authorizing payment or offering of anything of value, directly or indirectly, to any foreign

official, political party or candidate for the purpose of influencing any act or decision of the foreign entity in order to assist the individual or business in obtaining or retaining business.

The FCPA also obligates companies whose securities are

listed in the U.S.

to comply with certain accounting provisions requiring the company to maintain books and records that accurately and fairly reflect all transactions of the corporation, including international subsidiaries, and to devise and

maintain an adequate system of internal accounting controls for international operations.

Compliance with the FCPA is expensive and difficult, particularly in countries in which

corruption is a recognized problem.

In addition, the FCPA presents particular challenges in the pharmaceutical industry, because, in many countries, hospitals are operated by the government, and doctors and other hospital employees are considered

foreign officials.

individual or business from paying, offering, authorizing payment or offering of anything of value, directly or indirectly, to any foreign official, political party or candidate for the purpose of influencing any act or decision of the foreign entity in order to assist the individual or business in obtaining or retaining business.

The FCPA also obligates companies whose securities are listed in the U.S.

Compliance with the FCPA is expensive and difficult, particularly in countries in which corruption is a recognized problem.

Certain payments to hospitals in connection with clinical trials and other work have been deemed to be improper payments to government officials and have led to FCPA enforcement actions.

1 unchanged sentence

nationals, of information classified for national security purposes, as well as certain products and technical data relating to those products.

If we expand our presence outside of the U.S., it will require

us to dedicate additional resources to comply with these laws, and these laws may preclude us from developing, manufacturing, or selling certain products and product candidates outside of the U.S., which could limit our growth potential and increase

our development costs.

The failure to comply with laws governing international business practices may result in substantial civil and

criminal penalties and suspension or debarment from government contracting.

If we expand our presence outside of the U.S., it will require us to dedicate additional resources to comply with these laws, and these laws may preclude us from developing, manufacturing, or selling certain products and product candidates outside of the U.S., which could limit our growth potential and increase our development costs.

The failure to comply with laws governing international business practices may result in substantial civil and criminal penalties and suspension or debarment from government contracting.

The SEC also may suspend or bar issuers from trading securities on U.S.

1 unchanged sentence

Reimbursement

Sales of our products will

depend, in part, on the extent to which our products will be covered by third-party payors, such as government health programs, commercial insurance and managed healthcare organizations.

In the U.S., no uniform policy of coverage and reimbursement

for drug or biological products exists.

Accordingly, decisions regarding the extent of coverage and amount of reimbursement to be provided for any of our products will be made on a

payor-by-payor basis.

The process for determining whether a third-party payor will provide coverage for a product may be separate from the process for setting the price

or reimbursement rate that the payor will pay for the product once coverage is approved.

Third-party payors are increasingly challenging the prices charged, examining the medical necessity, and reviewing the cost-effectiveness of medical products

and services and imposing controls to manage costs.

Sales of our products will depend, in part, on the extent to which our products will be covered by third-party payors, such as government health programs, commercial insurance and managed healthcare organizations.

In the U.S., no uniform policy of coverage and reimbursement for drug or biological products exists.

Accordingly, decisions regarding the extent of coverage and amount of reimbursement to be provided for any of our products will be made on a payor-by-payor

The process for determining whether a third-party payor will provide coverage for a product may be separate from the process for setting the price or reimbursement rate that the

payor will pay for the product once coverage is approved.

Third-party payors are increasingly challenging the prices charged, examining the medical necessity, and reviewing the cost-effectiveness of medical products and services and imposing controls to manage costs.

Third-party payors may limit coverage to specific products on an approved list, also known as a formulary, which might not include all of the approved products for a particular indication.

result, the coverage determination process is often a time-consuming and costly process that will require us to provide scientific and clinical support for the use of our products to each payor separately, with no assurance that coverage and

adequate reimbursement will be obtained.

government, state legislatures and foreign governments have shown significant interest

in implementing cost containment programs to limit the growth of government-paid health care costs, including price-controls, restrictions on reimbursement and requirements for substitution of generic products for branded prescription drugs.

As a result, the coverage determination process is often a time-consuming and costly process that will require us to provide scientific and clinical support for the use of our products to each payor separately, with no assurance that coverage and adequate reimbursement will be obtained.

government, state legislatures and foreign governments have shown significant interest in implementing cost containment programs to limit the growth of government-paid health care costs, including price-controls, restrictions on reimbursement and requirements for substitution of generic products for branded prescription drugs.

Adoption of price controls and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures, could further limit a company’s revenue generated from the sale of any approved products.

extension of Medicaid rebates to Medicaid managed care plans, mandatory discounts for certain Medicare Part D beneficiaries and annual fees based on pharmaceutical companies share of sales to federal health care programs.

Adoption of general

controls and measures, coupled with the tightening of restrictive policies in jurisdictions with existing controls and measures, could limit payments for pharmaceutical drugs.

The Medicaid Drug Rebate Program requires pharmaceutical manufacturers to enter into and have in effect a national rebate agreement with the

Secretary of the Department of Health and Human Services as a condition for states to receive federal matching funds for the manufacturers outpatient drugs furnished to Medicaid patients.

The ACA made several changes to the Medicaid Drug

Rebate Program, including increasing pharmaceutical manufacturers rebate liability by raising the minimum basic Medicaid rebate on most branded prescription drugs of AMP and adding a new rebate calculation for line extensions

(i.e., new formulations,

such as extended release formulations) of solid oral dosage forms of branded products, creating a new methodology by which rebates owed are calculated for drugs that are inhaled, infused,

instilled, implanted or injected, as well as potentially impacting their rebate liability by modifying the statutory definition of AMP.

The ACA also expanded the universe of Medicaid utilization subject to drug rebates by requiring pharmaceutical

manufacturers to pay rebates on Medicaid managed care utilization and by enlarging the population potentially eligible for Medicaid drug benefits.

For example, the ACA contains provisions that subject biological products to potential competition by lower-cost biosimilars and may reduce the profitability of drug products through increased rebates for drugs reimbursed by Medicaid programs, extension of Medicaid rebates to Medicaid managed care plans, mandatory discounts for certain Medicare Part D beneficiaries and annual fees based on pharmaceutical companies’ share of sales to federal health care programs.

Adoption of general controls and measures, coupled with the tightening of restrictive policies in jurisdictions with existing controls and measures, could limit payments for pharmaceutical drugs.

The Medicaid Drug Rebate Program requires pharmaceutical manufacturers to enter into and have in effect a national rebate agreement with the Secretary of the Department of Health and Human Services as a condition for states to receive federal matching funds for the manufacturer’s outpatient drugs furnished to Medicaid patients.

The ACA made several changes to the Medicaid Drug Rebate Program, including increasing pharmaceutical manufacturers’ rebate liability by raising the minimum basic Medicaid rebate on most branded prescription drugs of AMP and adding a new rebate calculation for “line extensions” (i.e., new formulations, such as extended release formulations) of solid oral dosage forms of branded products, creating a new methodology by which rebates owed are calculated for drugs that are inhaled, infused, instilled, implanted or injected, as well as potentially impacting their rebate liability by modifying the statutory definition of AMP.

The ACA also expanded the universe of Medicaid utilization subject to drug rebates by requiring pharmaceutical manufacturers to pay rebates on Medicaid managed care utilization and by enlarging the population potentially eligible for Medicaid drug benefits.

Pricing and rebate programs must also comply with the Medicaid rebate requirements of the U.S.

Budget Reconciliation Act of 1990.

The Medicare Prescription Drug, Improvement, and Modernization Act of 2003, or the MMA, established

the Medicare Part D program to provide a voluntary prescription drug benefit to Medicare beneficiaries.

Under Part D, Medicare beneficiaries may enroll in prescription drug plans offered by private entities that provide coverage of outpatient

prescription drugs.

Omnibus Budget Reconciliation Act of 1990.

The Medicare Prescription Drug, Improvement, and Modernization Act of 2003, or the MMA, established the Medicare Part D program to provide a voluntary prescription drug benefit to Medicare beneficiaries.

Under Part D, Medicare beneficiaries may enroll in prescription drug plans offered by private entities that provide coverage of outpatient prescription drugs.

Unlike Medicare Part A and B, Part D coverage is not standardized.

While all Medicare drug plans must give at least a standard level of coverage set by Medicare, Part D prescription drug plan sponsors are not required to pay for

all covered Part D drugs, and each drug plan can develop its own drug formulary that identifies which drugs it will cover and at what tier or level.

However, Part D prescription drug formularies must include drugs within each therapeutic category

and class of covered Part D drugs, though not necessarily all the drugs in each category or class.

While all Medicare drug plans must give at least a standard level of coverage set by Medicare, Part D prescription drug plan sponsors are not required to pay for all covered Part D drugs, and each drug plan can develop its own drug formulary that identifies which drugs it will cover and at what tier or level.

However, Part D prescription drug formularies must include drugs within each therapeutic category and class of covered Part D drugs, though not necessarily all the drugs in each category or class.

Any formulary used by a Part D prescription drug plan must be developed and reviewed by a pharmacy and therapeutic committee.

Government payment for

some of the costs of prescription drugs may increase demand for products for which we receive marketing approval.

However, any negotiated prices for our products covered by a Part D prescription drug plan likely will be lower than the prices we

might otherwise obtain.

Government payment for some of the costs of prescription drugs may increase demand for products for which we receive marketing approval.

However, any negotiated prices for our products covered by a Part D prescription drug plan likely will be lower than the prices we might otherwise obtain.

Moreover, while the MMA applies only to drug benefits for Medicare beneficiaries, private payors often follow Medicare coverage policy and payment limitations in setting their own payment rates.

Any reduction in payment that

results from the MMA may result in a similar reduction in payments from non-governmental payors.

Any reduction in payment that results from the MMA may result in a similar reduction in payments from non-governmental

For a drug product to receive federal reimbursement under the Medicaid or Medicare Part B programs or to be sold directly to U.S.

agencies, the manufacturer must extend discounts to entities eligible to participate in the 340B drug pricing program.

The required 340B discount on a given product is calculated based on the AMP and Medicaid rebate amounts reported by the

manufacturer.

As of 2010, the ACA expanded the types of entities eligible to receive discounted 340B pricing, although, under the current state of the law, with the exception of childrens hospitals, these newly eligible entities will not be

eligible to receive discounted 340B pricing on orphan drugs.

In addition, as 340B drug pricing is determined based on AMP and Medicaid rebate data, the revisions to the Medicaid rebate formula and AMP definition described above could cause the

required 340B discount to increase.

As noted above, the marketability of any products for which we receive regulatory approval for

commercial sale may suffer if the government and third-party payors fail to provide adequate coverage and reimbursement.

government agencies, the manufacturer must extend discounts to entities eligible to participate in the 340B drug pricing program.

The required 340B discount on a given product is calculated based on the AMP and Medicaid rebate amounts reported by the manufacturer.

As of 2010, the ACA expanded the types of entities eligible to receive discounted 340B pricing, although, under the current state of the law, with the exception of children’s hospitals, these newly eligible entities will not be eligible to receive discounted 340B pricing on orphan drugs.

In addition, as 340B drug pricing is determined based on AMP and Medicaid rebate data, the revisions to the Medicaid rebate formula and AMP definition described above could cause the required 340B discount to increase.

As noted above, the marketability of any products for which we receive regulatory approval for commercial sale may suffer if the government and third-party payors fail to provide adequate coverage and reimbursement.

An increasing emphasis on cost containment measures in the U.S.

has increased and we expect will continue to increase the

pressure on pharmaceutical pricing.

has increased and we expect will continue to increase the pressure on pharmaceutical pricing.

Coverage policies and third-party reimbursement rates may change at any time.

Even if favorable coverage and reimbursement status is attained for one or more products for which we receive regulatory approval, less

favorable coverage policies and reimbursement rates may be implemented in the future.

In recent years, additional laws have resulted in

direct or indirect reimbursement reductions for certain Medicare providers.

Even if favorable coverage and reimbursement status is attained for one or more products for which we receive regulatory approval, less favorable coverage policies and reimbursement rates may be implemented in the future.

In recent years, additional laws have resulted in direct or indirect reimbursement reductions for certain Medicare providers.

The Budget Control Act of 2011, among other things, created measures for spending reductions by Congress.

Select Committee on Deficit Reduction, tasked with recommending a targeted deficit reduction of at least $1.2 trillion for the years 2013 through 2021, was unable to reach required goals, thereby triggering the legislations automatic reduction

to several government programs.

These changes included aggregate reductions to Medicare payments to providers of up to 2% per fiscal year, which went into effect in April 2013 and will remain in effect through 2029 unless additional Congressional

action is taken.

The American Taxpayer Relief Act of 2012, among other things, reduced Medicare payments to several providers, and

increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

The Middle Class Tax Relief and Job Creation Act of 2012 required that the Centers for Medicare &

Medicaid Services reduce the Medicare clinical laboratory fee schedule by 2% in 2013, which served as a base for 2014 and subsequent years.

In addition, effective January 1, 2014, CMS also began bundling the Medicare payments for certain

laboratory tests ordered while a patient received services in a hospital outpatient setting.

In addition, the current

administration released a Blueprint to reduce the cost of drugs.

The Trump administrations Blueprint contains certain measures that the U.S.

Department of Health and Human Services is already working to implement.

For example, on

October 25, 2018, CMS issued an Advanced Notice of Proposed Rulemaking, or ANPRM, indicating it was considering issuing a proposed rule in the spring of 2019 on a model called the International Pricing Index.

This model would utilize a basket

of other countries prices as a reference for the Medicare program to use in reimbursing for drugs covered under Part B.

The ANPRM also included an updated version of the Competitive Acquisition Program as an alternative to current buy

and bill payment methods for Part B drugs.

As of this time, the proposed rule has been delayed.

However, the model has been incorporated in the Medicare Prescription Drug Savings and Choice Act of 2019, a bill introduced in the House of

Representatives on October 21, 2019.

While any proposed measures will require authorization through additional legislation to become effective, Congress and the Trump administration have each indicated that it will continue to seek new

legislative and/or administrative measures to control drug costs.

For example, on September 25, 2019, the Senate Finance Committee introduced the Prescription Drug Pricing Reduction Action of 2019, a bill intended to reduce Medicare and

Medicaid prescription drug prices.

The proposed legislation would restructure the Part D benefit, modify payment methodologies for certain drugs, and impose an inflation cap on drug price increases.

An even more restrictive bill, the Lower Drug

Costs Now Act of 2019, was introduced in the House of Representatives on September 19, 2019, and would require the Department of Health and Human Services to directly negotiate drug prices with manufacturers.

The Lower Drugs Costs Now Act of

2019 has passed out of the House and was delivered to the Senate on December 16, 2019.

However, it is unclear whether either of these bills will make it through both chambers and be signed into law, and if either is enacted, what effect it

would have on our business.

Individual states in the U.S.

have also increasingly passed legislation and implemented regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts,

restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

At the state level, legislatures have become increasingly aggressive in passing legislation and implementing regulations designed to control

pharmaceutical and biological product pricing.

Some of these measures include price or patient reimbursement constraints, discounts, restrictions on certain product access, marketing cost disclosure and transparency measures, and, in some cases,

measures designed to encourage importation from other countries and bulk purchasing.

In addition, regional health care authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which

suppliers will be included in their prescription drug and other health care programs.

These laws, and future state and federal healthcare

reform measures may be adopted in the future, any of which may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for any of our product candidates for which we may obtain

regulatory approval or the frequency with which any such product candidate is prescribed or used.

In addition, in most foreign countries,

the proposed pricing for a drug must be approved before it may be lawfully marketed.

A Joint Select Committee on Deficit Reduction, tasked with recommending a targeted deficit reduction of at least $1.2 trillion for the years 2013 through 2021, was unable to reach required goals, thereby triggering the legislation’s automatic reduction to several government programs.

However, pursuant to the Coronavirus Aid, Relief and Economic Security Act, or CARES Act, and subsequent legislation, these Medicare sequester reductions are suspended from May 1, 2020 through March 31, 2020 due to the COVID-19

The American Taxpayer Relief Act of 2012, among other things, reduced Medicare payments to several providers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

The Middle Class Tax Relief and Job Creation Act of 2012 required that the Centers for Medicare & Medicaid Services reduce the Medicare clinical laboratory fee schedule by 2% in 2013, which served as a base for 2014 and subsequent years.

In addition, effective January 1, 2014, CMS also began bundling the Medicare payments for certain laboratory tests ordered while a patient received services in a hospital outpatient setting.

In addition, the Trump administration’s budget proposal for fiscal year 2021 includes a $135 billion allowance to support legislative proposals seeking to reduce drug prices, increase competition, lower out-of-pocket

drug costs for patients, and increase patient access to lower-cost generic and biosimilar drugs.

On March 10, 2020, the Trump administration sent “principles” for drug pricing to Congress, calling for legislation that would, among other things, cap Medicare Part D beneficiary out-of-pocket

pharmacy expenses, provide an option to cap Medicare Part D beneficiary monthly out-of-pocket

expenses, and place limits on pharmaceutical price increases.

Additionally, the Trump administration previously released a “Blueprint” to reduce the cost of drugs.

HHS has solicited feedback on some measures and has implemented others under its existing authority.

For example, in May 2019, CMS issued a final rule that would allow Medicare Advantage Plans the option of using step therapy, a type of prior authorization, for Part B drugs beginning January 1, 2020.

This final rule codified CMS’s policy change that was effective January 1, 2019.

At the state level, legislatures have become increasingly aggressive in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing.

Some of these measures include price or patient reimbursement constraints, discounts, restrictions on certain product access, marketing cost disclosure and transparency measures, and, in some cases, measures designed to encourage importation from other countries and bulk purchasing.

In addition, regional health care authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other health care programs.

These laws, and future state and federal healthcare reform measures may be adopted in the future, any of which may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for any of our product candidates for which we may obtain regulatory approval or the frequency with which any such product candidate is prescribed or used.

In addition, in most foreign countries, the proposed pricing for a drug must be approved before it may be lawfully marketed.

The requirements governing drug pricing and reimbursement vary widely from country to country.

For example, the European Union provides options for its member

states to restrict the range of

medicinal products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use.

Reference pricing used by various

European Union member states and parallel distribution, or arbitrage between low-priced and high-priced member states, can further reduce prices.

A member state may approve a specific price for the medicinal

product, or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product on the market.

In some countries, we may be required to conduct a clinical trial or other trials that compare

the cost-effectiveness of any of our product candidates to other available therapies in order to obtain or maintain reimbursement or pricing approval.

There can be no assurance that any country that has price controls or reimbursement limitations

for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any of our products.

For example, the European Union provides options for its member states to restrict the range of medicinal products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use.

Reference pricing used by various European Union member states and parallel distribution, or arbitrage between low-priced

and high-priced member states, can further reduce prices.

A member state may approve a specific price for the medicinal product, or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product on the market.

In some countries, we may be required to conduct a clinical trial or other trials that compare the cost-effectiveness of any of our product candidates to other available therapies in order to obtain or maintain reimbursement or pricing approval.

There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any of our products.

Historically, products launched in the European Union do not follow price structures of the U.S.

and generally prices tend to be

significantly lower.

and generally prices tend to be significantly lower.

Publication of discounts by third-party payors or authorities may lead to further pressure on the prices or reimbursement levels within the country of publication and other countries.

If pricing is set at unsatisfactory levels

or if reimbursement of our products is unavailable or limited in scope or amount, our revenues from sales by us or our strategic partners and the potential profitability of any of our product candidates in those countries would be negatively

December 31, 2019, we had 72 full-time employees, 32 of our employees have Ph.D.

If pricing is set at unsatisfactory levels or if reimbursement of our products is unavailable or limited in scope or amount, our revenues from sales by us or our strategic partners and the potential profitability of any of our product candidates in those countries would be negatively affected.

Employees and Human Capital

As of December 31, 2020, we had 69 full-time employees, 28 of our employees have Ph.D.

degrees and 45 of our employees are engaged in research and development activities.

Our human capital resource objectives include, as applicable, identifying, recruiting, retaining, incentivizing and integrating our employees with the common purpose of helping more patients live free from disease.

At Magenta, we celebrate our differences and value the power of a diverse array of people who bring all of themselves to their work.

We embrace cultural, racial, gender, cognitive, social and professional diversity because we know that the only way we are going to make new cures possible is by working together.

We prioritize employee development and seek to align employees’ goals with Magenta’s overall strategic direction.

We use our equity incentive plan to attract, retain and motivate selected employees, consultants and directors through the granting of stock-based compensation awards to achieve short- and long-term results that are in the best interests of investors, Magenta’s mission and our patients.

For additional information on the impact of COVID-19

on our employees, see “Management’s Discussion and Analysis of Financial Condition and Results of Operations—Impact of the COVID-19

Our Corporate Information

incorporated under the laws of the State of Delaware on June 17, 2015 under the name HSCTCo Therapeutics, Inc.

We were incorporated under the laws of the State of Delaware on June 17, 2015 under the name HSCTCo Therapeutics, Inc.

In February 2016, we changed our name to Magenta Therapeutics, Inc.

On June 25, 2018, we completed the initial public offering, or IPO, pursuant to which we issued and sold 6,666,667 shares of common stock

at a public offering price of $15.00 per share, resulting in net proceeds of $89.9 million, after deducting underwriting discounts and commissions and other offering expenses.

Upon the closing of the IPO, our outstanding redeemable convertible

preferred stock automatically converted into shares of common stock.

See Part IIItem 7Managements Discussion and

Analysis of Financial Condition and Results of Operations and Note 1 to the consolidated financial statements included in Part IIItem 8 for more information about the above-mentioned transactions.

On June 25, 2018, we completed the initial public offering, or IPO, pursuant to which we issued and sold 6,666,667 shares of common stock at a public offering price of $15.00 per share, resulting in net proceeds of $89.9 million, after deducting underwriting discounts and commissions and other offering expenses.

Upon the closing of the IPO, our outstanding redeemable convertible preferred stock automatically converted into shares of common stock.

See Part II—Item 7—Management’s Discussion and Analysis of Financial Condition and Results of Operations and Note 1 to the consolidated financial statements included in Part II—Item 8 for more information about the above-mentioned transactions.

We are an “emerging growth company” as defined in the Jumpstart Our Business Startups Act of 2012.

We will remain an emerging growth

company until the earlier of:

(i) the last day of the fiscal year (a) following the fifth anniversary of the completion of the IPO, (b) in which we have total annual gross revenue of at least $1.07 billion, or (c) in which

we are deemed to be a large accelerated filer, which means the market value of our common stock that is held by non-affiliates exceeds $700.0 million as of the prior June 30th, and (ii) the date

on which we have issued more than $1.0 billion in non-convertible debt during the prior three-year period.

We will remain an emerging growth company until the earlier of:

(i) the last day of the fiscal year (a) following the fifth anniversary of the completion of the IPO, (b) in which we have total annual gross revenue of at least $1.07 billion, or (c) in which we are deemed to be a large accelerated filer, which means the market value of our common stock that is held by non-affiliates

exceeds $700.0 million as of the prior June 30th, and (ii) the date on which we have issued more than $1.0 billion in non-convertible

debt during the prior three-year period.

We are also a “smaller reporting company” as defined in the Securities and Exchange Act of 1934, as amended, or the Exchange Act.

may continue to be a smaller reporting company even after we are no longer an emerging growth company.

We may take advantage of certain of the scaled disclosures available to smaller reporting companies until the fiscal year following the

determination that our voting and non-voting common stock held by non-affiliates is more than $250 million measured on the last business day of our second fiscal

quarter, or our annual revenues are more than $100 million during the most recently completed fiscal year and our voting and non-voting common stock held by

non-affiliates is more than $700 million measured on the last business day of our second fiscal quarter.

Our principal executive offices are located at 100 Technology Square, Cambridge, MA 02139,

and our telephone number is (857) 242-0170.

Our website address is www.magentatx.com .

Our website and the information contained on, or that can be accessed through, the website will not be

deemed to be incorporated by reference in, and are not considered part of, this Annual Report on Form 10-K.

We may continue to be a smaller reporting company even after we are no longer an emerging growth company.

We may take advantage of certain of the scaled disclosures available to smaller reporting companies until the fiscal year following the determination that our voting and non-voting

common stock held by non-affiliates

is more than $250 million measured on the last business day of our second fiscal quarter, or our annual revenues are more than $100 million during the most recently completed fiscal year and our voting and non-voting

common stock held by non-affiliates

is more than $700 million measured on the last business day of our second fiscal quarter.

Our principal executive offices are located at 100 Technology Square, Cambridge, MA 02139, and our telephone number is (857) 242-0170.

website address is www.magentatx.com

Our website and the information contained on, or that can be accessed through, the website will not be deemed to be incorporated by reference in, and are not considered part of, this Annual Report on Form 10-K.

Available Information

address is www.magentatx.com .

Our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on

Form 8-K, including exhibits, proxy and information statements and amendments to those reports filed or furnished pursuant to Sections 13(a) and 15(d) of the Exchange Act are available through the

Investors portion of our website free of charge as soon as reasonably practicable after we electronically file such material with, or furnish it to, the SEC.

Information on our website is not part of this Annual Report on Form 10-K or any of our other securities filings unless specifically incorporated herein by reference.

In addition, our filings with the SEC may be accessed through the SECs Interactive Data Electronic

Applications system at http://www.sec.gov .

All statements made in any of our securities filings, including all forward-looking statements or information, are made as of the date of the document in which the statement is included, and we do

not assume or undertake any obligation to update any of those statements or documents unless we are required to do so by law.

Our Internet address is www.magentatx.com

Our Annual Reports on Form 10-K,

Quarterly Reports on Form 10-Q,

Current Reports on Form 8-K,

including exhibits, proxy and information statements and amendments to those reports filed or furnished pursuant to Sections 13(a) and 15(d) of the Exchange Act are available through the “Investors” portion of our website free of charge as soon as reasonably practicable after we electronically file such material with, or furnish it to, the SEC.

Information on our website is not part of this Annual Report on Form 10-K

or any of our other securities filings unless specifically incorporated herein by reference.

In addition, our filings with the SEC may be accessed through the SEC’s Electronic Data Gathering, Analysis and Retrieval system at http://www.sec.gov

All statements made in any of our securities filings, including all forward-looking statements or information, are made as of the date of the document in which the statement is included, and we do not assume or undertake any obligation to update any of those statements or documents unless we are required to do so by law.

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business