−Removed: 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.
−Removed: Magenta’s drug development pipeline includes multiple product candidates designed to improve stem cell transplants.
−Removed: 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.
−Removed: 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.
−Removed: Our mobilization program is intended to enable rapid, reliable, predictable and safe mobilization and collection of high numbers of functional stem cells for transplant.
−Removed: 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.
−Removed: 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.
+Added: Magenta Therapeutics, Inc.
+Added: is a clinical-stage biotechnology company developing novel medicines designed to bring the curative power of stem cell transplants to more patients with blood cancers, genetic diseases and autoimmune diseases.
+Added: Magenta’s drug development pipeline includes multiple clinical and preclinical product candidates designed to improve stem cell transplants.
+Added: We are 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.
+Added: Our 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.
+Added: Our first targeted conditioning program, MGTA-117,
+Added: has entered clinical development in a Phase 1/2 trial, and our second program, a CD45-antibody drug conjugate, or CD45-ADC,
+Added: is advancing in preclinical development.
+Added: In addition to our conditioning programs, we are also developing a product candidate, MGTA-145,
+Added: to improve the process by which stem cells are stimulated out of the bone marrow and into the bloodstream so they are available for collection for future reinfusion, known as mobilization, which is required for all transplants and gene therapy applications.
+Added: is a Phase 2 clinical stage program intended to enable rapid, reliable, predictable and safe mobilization and collection of high numbers of functional stem cells for transplant.
+Added: Stem cell transplant is a well-established and potentially 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.
+Added: Over 90,000 patients globally received a stem cell transplant in 2020.
Stem cell transplants involve a three-step process:
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Autoimmune diseases such as multiple sclerosis and systemic sclerosis may also benefit from resetting the immune system through stem cell transplant.
−Removed: 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.
−Removed: 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.
−Removed: Many patients require multiple collections, including approximately 40% of blood cancer patients and 75% of sickle cell disease patients.
−Removed: 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,
−Removed: 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.
−Removed: Similarly, HSC-based
−Removed: gene therapies could benefit from more efficient collection of stem cells which could potentially reduce gene therapy manufacturing timelines and costs.
−Removed: Additionally, there are no approved mobilization options for patients with sickle cell disease and autoimmune diseases, and the off-label
−Removed: use of currently available medicines is associated with significant safety risks including vaso-occlusive events in sickle cell disease patients.
−Removed: Magenta is developing MGTA-145
−Removed: for stem cell mobilization in a broad range of diseases, for both autologous and allogeneic transplants.
−Removed: 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.
−Removed: In 2020, we completed a Phase 1 clinical trial in healthy volunteers to evaluate the ability of MGTA-145,
−Removed: in combination with plerixafor, to mobilize stem cells.
−Removed: 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;
−Removed: 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;
−Removed: and lastly, a planned trial in partnership with bluebird bio, Inc.
−Removed: to mobilize and collect the stem cells of sickle cell disease patients.
−Removed: 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.
−Removed: 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.
−Removed: 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.
−Removed: Magenta’s lead conditioning program, MGTA-117,
−Removed: 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.
−Removed: 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.
−Removed: Our C100 program focuses on addressing opportunities in immune reset for autoimmune diseases.
−Removed: Our C300 program is being designed to provide for lymphodepletion prior to cell therapies such as chimeric antigen receptor T cells, or CAR-T.
−Removed: Our G100 program is being designed to provide prophylaxis of graft-versus-host disease, a common post-transplant complication following allogeneic stem cell transplant.
−Removed: Magenta is also evaluating two programs with potential in cell therapy.
−Removed: 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.
−Removed: 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.
−Removed: In June 2020, we announced that we discontinued enrollment in our Phase 2 trial of MGTA-456
−Removed: in inherited metabolic diseases.
−Removed: 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.
−Removed: Our second cell therapy program, E478, is a small molecule aryl hydrocarbon receptor, or AHR, antagonist which
−Removed: uses the same mechanism used to manufacture MGTA-456
−Removed: to expand gene-modified HSCs for stem cell-based gene therapy and genome editing.
+Added: In addition to our product candidates, Magenta’s research efforts are evaluating several early-stage targets that include a program for targeted lymphodepletion prior to therapies such as chimeric antigen receptor T-cells
+Added: We also have a cell therapy program, E478, which is a small molecule aryl hydrocarbon receptor, or AHR, antagonist designed to increase the numbers of 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.
−Removed: We are developing our product candidates to be used individually or, in some cases, in combination with each other.
+Added: We are developing our product candidates to be used individually or, in some cases, in combination with each other or together with other therapies.
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.
−Removed: We expect to continue to advance our portfolio and innovate through our productive research platform.
+Added: We expect to continue to advance our portfolio and innovate through our productive research programs.
Stem Cell Transplant:
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A stem cell transplant procedure involves three main steps:
−Removed: (i) stem cells from the patient’s or donor’s bone marrow are collected;
+Added: (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;
3 unchanged sentences
lymphoma and autoimmune diseases—the patient’s own stem cells are used.
−Removed: 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.
+Added: In the case of autologous stem cell gene therapy and genome editing in certain non-malignant
+Added: diseases such as sickle cell disease, beta-thalassemia, and severe combined immunodeficiencies, the cells are collected from the patient and are modified to insert a functioning gene or correct a defective gene within the cell.
+Added: Modified cells are then 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.
−Removed: For patients without a matched related donor, the second option is a matched unrelated donor identified through a bone marrow donor registry.
+Added: Patients without a matched related donor have the option of finding 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;
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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
−Removed: We believe we are the only company that is committed to
−Removed: addressing both mobilization and conditioning opportunities in stem cell transplant and HSC-based
+Added: We believe we are the only company that is committed to addressing both conditioning and mobilization opportunities in stem cell transplant and HSC-based
gene therapies.
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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.
−Removed: Leverage MGTA-145
−Removed: as our most advanced product candidate in the clinic and as a possible first commercial product for our portfolio
−Removed: In addition to the potential to bring meaningful clinical benefit to patients, MGTA-145
−Removed: provides strategic value to Magenta by allowing us to accelerate the build-out
−Removed: of our clinical development infrastructure and footprint and to establish key prescriber relationships that will be important for future commercialization of our products.
−Removed: Continue to integrate our innovative collaboration with National Marrow Donor Program/Be the Match with our science, medicine and business approaches
−Removed: 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.
−Removed: Because of our shared patient focus, we and Be the Match established a broad, first-of-its-kind
−Removed: collaboration in 2017.
−Removed: 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.
−Removed: 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.
−Removed: 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.
−Removed: 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,
−Removed: 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
−Removed: We own all product rights across our mobilization and conditioning programs, including MGTA-145
+Added: We own all product rights across our conditioning and mobilization programs, including MGTA-117
and MGTA-145.
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opportunistically bring in preclinical or clinical assets that fit with our integrated portfolio.
−Removed: Our Pipeline of Stem Cell Transplant Product Candidates
+Added: Our Pipeline of 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.
1 unchanged sentence
transformative blood and immune reset through stem cell transplant with better outcomes and reduced risk of toxicities and mortality.
−Removed: 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.
−Removed: 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:
+Added: Targeted Conditioning Programs
+Added: program is focused on selectively depleting stem cells from patients prior to transplant or HSC-based
+Added: 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.
+Added: Our second targeted conditioning program, CD45-ADC,
+Added: is focused on depleting both stem and immune cells to enable transplant as a single agent in autologous autoimmune disease and allogenic blood cancer transplants.
Stem Cell Mobilization
1 unchanged sentence
program is focused on enabling rapid, reliable, predictable and safe mobilization and collection of high numbers of functional blood stem cells for transplant.
−Removed: Targeted Conditioning Program
−Removed: program is focused on selectively depleting stem cells from patients prior to transplant or HSC-based
−Removed: 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.
−Removed: Conditioning Research Platform:
−Removed: 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
−Removed: gene therapy.
−Removed: 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.
−Removed: Initial applications of our research-stage programs include immune reset for autoimmune diseases;
−Removed: lymphodepletion prior to cell therapies such as CAR-T;
−Removed: and prophylaxis of graft-versus-host disease, or GvHD, a post-transplant complication following allogeneic stem cell transplant.
−Removed: Cell Therapy Programs
−Removed: 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.
−Removed: Our E478 program is designed to expand gene-modified HSCs for gene therapy and genome editing.
−Removed: Stem Cell Mobilization & Collection Program
−Removed: 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.
−Removed: 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.
−Removed: There are three methods of collecting stem cells from either patients or healthy donors for transplant:
−Removed: 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;
−Removed: 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;
−Removed: harvesting from umbilical cord blood units, which are stored in cord blood banks.
−Removed: 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.
−Removed: 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.
−Removed: Mobilizing stem cells from the bone marrow to the blood has been shown to be an effective way to collect stem cells for transplant.
−Removed: 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.
−Removed: The current standard of care for mobilization in most patients and donors is granulocyte colony-stimulating factor, or G-CSF,
−Removed: 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.
−Removed: The multi-day
−Removed: regimen requires at least five days of injections of G-CSF,
−Removed: 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.
−Removed: The current unreliable and inefficient mobilization and collection process can also pose a significant logistical burden on transplant and apheresis centers.
−Removed: 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.
−Removed: 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.
−Removed: It is difficult to predict whether mobilization with G-CSF
−Removed: will be successful, especially in heavily treated blood cancer patients.
−Removed: Many patients require multiple collections,
−Removed: including approximately 40% of blood cancer patients.
−Removed: 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.
−Removed: Finally, patients with sickle cell disease can have severe side effects with G-CSF,
−Removed: including potentially fatal complications, and therefore, this agent is not used in these patients, leaving few mobilization options.
−Removed: For patients who are unable to mobilize a sufficient number of functional stem cells with G-CSF,
−Removed: physicians may then be required to re-treat
−Removed: and add another drug, known as plerixafor.
−Removed: 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.
−Removed: It is approved for use in combination with G-CSF
−Removed: for patients who fail to achieve sufficient mobilization of stem cells with G-CSF
−Removed: 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.
−Removed: However, because plerixafor is the only available mobilization option for sickle cell disease patients who, as stated, cannot use G-CSF
−Removed: due to safety concerns, it is used as a single agent in this specific setting.
−Removed: 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.
−Removed: Current state of stem cell mobilization:
−Removed: an unreliable, inefficient, multi-day
−Removed: Product Candidate
−Removed: Magenta is developing MGTA-145
−Removed: as a new first-line standard of care for stem cell mobilization in a broad range of diseases, for both autologous and allogeneic transplants.
−Removed: a CXCR2 agonist, works in combination with plerixafor, a CXCR4 antagonist, to harness the physiological mechanism of stem cell mobilization.
−Removed: The goal of MGTA-145
−Removed: 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.
−Removed: In May 2020, we received Orphan Drug Designation from the U.S.
−Removed: Food and Drug Administration, or the FDA, for MGTA-145
−Removed: for the mobilization of HSCs to the peripheral blood for collection and subsequent transplant.
−Removed: Mechanism of action
−Removed: CXCR2 is a chemokine receptor expressed on the surface of neutrophils.
−Removed: Binding of MGTA-145
−Removed: to the receptor results in neutrophil activation.
−Removed: Published data from Magenta founders and scientists show that a key event for mobilization of stem cells is the MGTA-145-mediated
−Removed: 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.
−Removed: Blocking CXCR4 using plerixafor and activating neutrophils with MGTA-145
−Removed: 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.
−Removed: in combination with plerixafor harnesses the natural mechanism of stem cell mobilization.
−Removed: Clinical data
−Removed: We have completed a Phase 1 trial of MGTA-145
−Removed: plus plerixafor in healthy subjects.
−Removed: The trial met all primary and secondary endpoints.
−Removed: The Phase 1 trial was a dose-finding trial to evaluate safety and activity of MGTA-145
−Removed: and consisted of four parts:
−Removed: In Part A, healthy volunteers were dosed with MGTA-145
−Removed: (0.0075 – 0.3 mg/kg) or a placebo.
−Removed: In Part B, subjects received a single dose of MGTA-145
−Removed: (0.03 – 0.15 mg/kg) or a placebo in combination with a single dose of plerixafor (0.24 mg/kg).
−Removed: In Part C, subjects received MGTA-145
−Removed: or a placebo plus plerixafor administered on day one and day two.
−Removed: In Part D, subjects received a single dose of MGTA-145
−Removed: (0.03 or 0.015 mg/kg) plus plerixafor followed by a single apheresis collection of multiple blood volumes.
−Removed: Clinical endpoints included safety and tolerability, pharmacokinetics, target engagement and pharmacodynamic effects.
−Removed: Data from the trial presented at the American Society of Hematology, or ASH, in December 2020 showed that MGTA-145
−Removed: was safe and well tolerated as a single agent and in combination with plerixafor, and that MGTA-145
−Removed: in combination with plerixafor demonstrated rapid, single-day
−Removed: mobilization and collection of sufficient numbers of functional stem cells.
−Removed: 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.
−Removed: Six subjects who received a single dose of MGTA-145
−Removed: 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.
−Removed: 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
−Removed: dosing and collection is feasible.
−Removed: dosing and apheresis collection in eight subjects across two dose ranges in Part D yielded a median of four million CD34+ cells/kg.
−Removed: The clinically accepted threshold for a successful transplant is two million cells/kg.
−Removed: in combination with plerixafor enables safe, same-day
−Removed: dosing, mobilization and collection of sufficient numbers of functional stem cells for transplant.
−Removed: 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
−Removed: or plerixafor alone.
−Removed: in combination with plerixafor enables greater collection of HSCs after apheresis in a Phase 1 healthy volunteer study.
−Removed: A) CD34+ cell number, (B) CD34+CD90+CD45RA- cell frequency and
−Removed: (C) CD34+CD90+CD45RA- cell number collected from healthy subjects mobilized with a single dose of MGTA-145
−Removed: in combination with plerixafor (n=eight donors), a five-day
−Removed: regimen of G-CSF
−Removed: (n=three donors) or a single dose of plerixafor (n=six donors).
−Removed: Flow cytometric data shows that a median of 1.4x10 6
−Removed: ) CD34+CD90+CD45RA- cells/kg were collected from MGTA-145+plerixafor
−Removed: mobilized donors, compared to 0.40x10 6
−Removed: (0.36-0.48x10
−Removed: mobilized subjects (p<0.05) or 0.32x10 6
−Removed: (0.12-0.67x10
−Removed: ) for plerixafor mobilized subjects (p<0.01).
−Removed: Bars represent median, each symbol represents an individual subject.
−Removed: Statistics were calculated by one-way
−Removed: ANOVA with post-hoc
−Removed: Plerixafor control data were first presented at the Transplant and Cellular Therapy, or TCT, annual meeting in February 2021.
−Removed: Cells collected from four subjects dosed in Part D led to up to 23-fold
−Removed: higher multilineage engraftment in primary and secondary transplants in the immunodeficient NSG mouse model compared to cells mobilized by either G-CSF
−Removed: or plerixafor alone.
−Removed: These data demonstrate rapid and durable multilineage engraftment of MGTA-145
−Removed: + plerixafor mobilized cells relative to other graft sources.
−Removed: + plerixafor CD34+ cells from Phase 1 healthy volunteer study show higher multilineage engraftment compared to G-CSF
−Removed: and plerixafor mobilized CD34+ cells.
−Removed: (A) CD34+ cells collected from healthy subjects mobilized with a single injection of MGTA-145
−Removed: + plerixafor, five daily injections of G-CSF,
−Removed: or a single injection of plerixafor (n=3-4
−Removed: donors) were transplanted into sublethally irradiated (200 cGy) NSG mice at limit dilution (3 cell doses).
−Removed: 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.
−Removed: Data represent 7-8
−Removed: mice per cell dose and are expressed as SRC number per 1x10 6
−Removed: cells +/- 95% CI.
−Removed: Cells collected from healthy subjects mobilized with a single dose of MGTA-145
−Removed: in combination with plerixafor in Part D were capable of efficient gene-modification and engraftment in a pre-clinical
−Removed: NSG mouse transplant study.
−Removed: Knockout of beta-2
−Removed: microglobulin by CRISPR-Cas9 led to approximately 90% editing in vitro
−Removed: of CD34+CD90+CD45RA- cells and these cells engrafted in NSG mice, with maintenance of high levels of editing.
−Removed: + plerixafor CD34+ cells from Phase 1 healthy volunteer study can be efficiently gene modified and engraft in NSG mice.
−Removed: (A) CD34+ cells collected from healthy donors mobilized with a single injection of MGTA-145
−Removed: in combination with plerixafor were gene-modified with CRISPR/Cas9 to knockout beta-2
−Removed: microglobulin.
−Removed: (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).
−Removed: (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
−Removed: + plerixafor mobilized grafts resulted in significantly less GvHD than G-CSF
−Removed: (p<0.01) or plerixafor (p<0.001) grafts (n=3-6
−Removed: donors/source) in a xenogeneic mouse model.
−Removed: + plerixafor grafts from Phase 1 healthy volunteer study are immunosuppressive in a xenograft mouse model
−Removed: peripheral blood mononuclear cells, or PBMCs, collected from healthy
−Removed: subjects mobilized with a single injection of MGTA-145
−Removed: in combination with plerixafor, five daily injections of G-CSF,
−Removed: or a single injection of plerixafor (n=3-6
−Removed: donors) were transplanted into sublethally irradiated (200 cGy) NSG mice at limit dilution (n=6-8
−Removed: Graft sources were compared to unmobilized whole blood controls.
−Removed: (B) Kaplan-Meier survival curve of transplanted NSG mice.
−Removed: Pooled data from individual donors and mice show significantly enhanced survival after transplant with MGTA-145
−Removed: in combination with plerixafor.
−Removed: Statistics were determined by a log-rank
−Removed: data presented at ASH in December 2020 showed that MGTA-145
−Removed: plus plerixafor could be an efficient, single-dose mobilization regimen for in vivo
−Removed: HSC gene therapy.
−Removed: 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
−Removed: mobilization regimen with G-CSF
−Removed: plus plerixafor.
−Removed: plus plerixafor mobilized cells were capable of efficient in vivo
−Removed: transduction using a helper dependent adenovirus (HDAd5/35++)-based vector platform.
−Removed: After in vivo selection, stable long-term, multilineage engraftment of gene-modified cells was observed in primary and secondary recipients (>90% gene marking).
−Removed: In a mouse disease model for thalassemia, phenotypic disease correction was observed after MGTA-145
−Removed: plus plerixafor mobilization and in vivo
−Removed: transduction.
−Removed: + plerixafor can mobilize HSCs in mice prior to
−Removed: CD46-transgenic animals were mobilized with G-CSF
−Removed: + plerixafor (5 days) or MGTA-145
−Removed: + 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.
−Removed: Arrows indicate timing and dose of the in vivo
−Removed: selection agent, O 6
−Removed: By week 12 post-transduction, >90% of PBMCs expressed GFP.
−Removed: No significant differences in gene marking were observed with the different selection agents.
−Removed: Clinical development plan
−Removed: We plan to develop MGTA-145
−Removed: as a first-line therapy for stem cell mobilization in a broad range of diseases, for both autologous and allogeneic transplants.
−Removed: We have announced three ongoing and planned Phase 2 clinical trials to evaluate the potential utility of MGTA-145,
−Removed: in combination with plerixafor, for the mobilization and collection of stem cells in multiple autologous and allogeneic transplant settings:
−Removed: Autologous Stem Cell Transplant of Multiple Myeloma Patients.
−Removed: In December 2020, we announced the commencement of an investigator-initiated Phase 2 trial of MGTA-145,
−Removed: in combination with plerixafor, to mobilize and collect stem cells for autologous stem cell transplantation in multiple myeloma patients at Stanford University.
−Removed: This trial continues to enroll patients.
−Removed: 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.
−Removed: Initial data from the study are expected in mid-2021.
−Removed: Allogeneic Donor Stem Cell Mobilization and Collection for Stem Cell Transplant in AML, ALL and MDS Patients.
−Removed: In June 2020, we announced a clinical trial collaboration with Be the Match to evaluate the potential utility of MGTA-145,
−Removed: 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.
−Removed: 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.
−Removed: Initial data from this clinical trial are expected in the second half of 2021.
−Removed: Sickle Cell Disease – Stem Cell Mobilization and Collection in Patients;
−Removed: Cell Characterization;
−Removed: Gene Modification Model.
−Removed: In December 2020, we entered into a Phase 2 clinical collaboration with bluebird bio, Inc.
−Removed: to evaluate the safety and potential utility of MGTA-145,
−Removed: in combination with plerixafor, for the mobilization and collection of stem cells in patients with sickle cell disease.
−Removed: Under the agreement, the companies will co-fund
−Removed: the clinical trial, which is currently expected to initiate in the second half of 2021.
−Removed: Each party will characterize the collected cells and Magenta plans to gene-modify the cells and transplant them into established pre-clinical
−Removed: models to evaluate engraftment.
−Removed: Data from this clinical trial could provide proof-of-concept
−Removed: for MGTA-145,
−Removed: in combination with plerixafor, as the preferred mobilization regimen for patients with sickle cell disease and, more broadly, across all HSC gene therapy applications.
−Removed: Targeted Conditioning Program & Conditioning Research Platform
−Removed: Conditioning:
−Removed: Targeted agents to selectively remove stem and/or immune cells.
+Added: Research Programs
+Added: Our current research efforts are focused on expanding the utilization of targeted conditioning by targeting the removal of additional specific cell types with an approach that is tailored to a patient’s disease and transplant requirements.
+Added: Targeted Conditioning Programs
+Added: Targeted conditioning refers to agents that can selectively deplete 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.
−Removed: Once sufficient cells have been mobilized and collected, patients must be prepared, or conditioned, for transplant.
−Removed: 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.
+Added: After a sufficient number of stem cells have been mobilized and collected, patients must be prepared, or conditioned, for transplant.
+Added: Conditioning 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
−Removed: and involve high doses of systemic, toxic chemotherapy and/or radiation.
−Removed: 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.
+Added: and involve high doses of systemic, toxic chemotherapy and/or radiation, which are known carcinogens and cause cancer.
+Added: Most of 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 stem cells, immune cells, and diseased cells but also indiscriminately damage DNA and kill normal, healthy cells in the body.
1 unchanged sentence
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.
−Removed: 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.
−Removed: 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-
−Removed: transplant, an impressive survival rate in these high-risk patient populations.
+Added: 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,
−Removed: such as decreased organ function, recent efforts have focused on reducing chemotherapy doses in regimens known as reduced intensity conditioning, or RIC.
−Removed: While significantly better tolerated, these RIC regimens have significantly poorer disease outcomes at five years post-transplant.
+Added: such as decreased organ function, recent efforts have focused on reducing chemotherapy doses in
+Added: regimens known as reduced intensity conditioning, or RIC.
+Added: While significantly better tolerated, these RIC regimens, when used alone, lack the potency to adequately deplete a sufficient number of leukemic cells and therefore RIC regimens have significantly poorer disease outcomes (due to relapse) 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.
−Removed: 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.
+Added: Multiple clinical trials, including multi-center Phase 3 trials, have also shown that certain autoimmune diseases can be cured with an immune system reset through autologous stem cell transplant, with 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.
−Removed: 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.
−Removed: Our Conditioning Programs
+Added: Our Targeted 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.
−Removed: 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.
−Removed: We are seeking to replace these toxic, non-targeted
−Removed: conditioning agents with targeted ADCs.
+Added: We are developing a suite of novel ADCs for targeted conditioning.
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.
−Removed: 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.
−Removed: 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.
−Removed: 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.
−Removed: The ADC binds the receptor on the target cell, is internalized and degraded to release the drug into the target cell.
−Removed: 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.
+Added: ADCs are a technology developed over the past 20 years where a monoclonal antibody specific for a cell surface protein is coupled to a payload via a molecule known as a linker.
+Added: The ADC binds the receptor on the target cell, is internalized and degraded to release the payload into the target cell.
+Added: Coupling the payload to the antibody increases the specificity of payload delivery to the target cell, reducing systemic exposure and increasing the safety and efficacy compared to delivering the payload alone or the antibody without the payload 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.
−Removed: Targeted conditioning with ADCs is more specific compared to traditional conditioning.
−Removed: Traditional conditioning is performed with total body irradiation and chemotherapy which eliminates all HSCs and nonspecifically damages other organs.
−Removed: Targeted conditioning with an ADC specifically eliminates the disease-causing cells while avoiding systemic side effects.
−Removed: In our development of ADCs for use in conditioning, we are optimizing for several key parameters:
−Removed: First, the antibody must specifically target a receptor that is expressed on the cells of interest.
−Removed: 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.
−Removed: 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.
−Removed: 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.
−Removed: Finally, the drug must be able to remove non-dividing
−Removed: cells, as most HSCs and immune cells are not actively dividing.
−Removed: The ADC linker must be chosen to minimize damage to non-target
−Removed: 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.
+Added: In our development of ADCs for use in conditioning, we are seeking to optimize several key parameters:
+Added: First, the antibody component of the ADC must specifically target a receptor that is expressed on the cells of interest.
+Added: Second, to comply with typical stem cell transplant conditioning timelines, the ADC must have suitable potency to ensure that the agent is able to remove the target cells rapidly, in days rather than weeks or months.
+Added: Third, the ADC 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.
+Added: This requirement stems from the fact that the target receptor is expressed on cells present in the patient but also on the newly transplanted cells which should not be targeted for depletion in order for the transplant to be successful.
+Added: Finally, the drug must be well-tolerated for patients at dose levels where stem cells are effectively removed.
+Added: We designed the ADC with a stable linker-payload which is intended to ensure that the payload used for cell depletion is primarily released intracellularly following internalization by target cells.
+Added: 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-payload chemistry.
Our targeted conditioning programs include both our ADC programs and earlier-stage research programs that leverage alternate modalities for targeted cell depletion.
2 unchanged sentences
targets HSCs and genetically mutated stem cells that cause acute myeloid leukemia and myelodysplastic syndromes.
−Removed: targets HSCs and immune cells.
−Removed: Our lead target under the C100 program is CD45 and our lead product candidate is referred to as CD45-ADC.
−Removed: targets only immune cells.
−Removed: targets alloreactive T cells implicated in GvHD.
−Removed: product candidate
+Added: targets both HSCs and immune cells and is currently in Investigational New Drug application, or IND enabling studies for potential use as a single-agent in autoimmune diseases and hematology-oncology transplants.
+Added: Clinical Candidate
Our most advanced conditioning product candidate, MGTA-117,
−Removed: is designed to specifically remove disease-causing HSCs and genetically mutated cells.
−Removed: targets CD117, also known as c-Kit,
−Removed: which is highly expressed on HSCs and leukemia cells, making it an ideal target for conditioning across broad sets of diseases.
−Removed: 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
−Removed: gene therapies.
−Removed: We have declared a development candidate, MGTA-117,
−Removed: which is an anti-CD117 antibody conjugated to an amanitin payload.
+Added: has entered a Phase 1/2 clinical trial in patients with relapsed/refractory AML or MDS.
+Added: is an anti-CD117 antibody conjugated to an amanitin payload, and it targets CD117, also known as c-Kit,
+Added: which is highly expressed on HSCs and leukemia cells.
+Added: If clinically proven to target and safely deplete these types of cells, MGTA-117
+Added: could improve conditioning across broad sets of diseases where stem cell transplant is either already the standard of care or could be expanded to benefit more patients.
+Added: For stem cell transplant in AML/MDS, we believe that MGTA-117,
+Added: in combination with RIC, has the potential to demonstrate clinical outcomes that preserve the safety and tolerability of RIC while achieving the efficacy of MAC.
+Added: Likewise, gene therapy is a promising approach to treat a variety of non-malignant
+Added: diseases, including inherited metabolic disorders, sickle cell disease and beta-thalassemia, but the risks and toxicity associated with current chemotherapy-based conditioning approaches (e.g.
+Added: busulfan) may limit the utility of this approach.
+Added: In gene-therapy stem cell transplant, MGTA-117
+Added: may enable single-agent conditioning and replace the use of busulfan.
+Added: Preclinical Data Supporting Clinical Development
+Added: We believe that it is critical for successful clinical development and commercialization of MGTA-117
+Added: that we demonstrate selective target engagement, robust cell depletion and rapid clearance from the body with an
+Added: acceptable safety profile.
+Added: Our preclinical experiments have supported each of these concepts and informed our clinical trial plans.
+Added: Selective Target Engagement and Cell Depletion
+Added: In the hematopoietic system, CD117 is primarily expressed on HSC/progenitor, or HSPC, cells and mast cells but not expressed on mature immune cells such as B cells or T cells.
+Added: We have demonstrated this selectivity in vitro by incubating cells with increasing concentrations of MGTA-117.
+Added: Cells expressing CD117 were dose-dependently depleted by MGTA-117,
+Added: while it had no depletion effect on cells lacking CD117, demonstrating the selectivity of MGTA-117.
Nobili et.al., Long non-coding
1 unchanged sentence
Oncotarget (2016)
−Removed: 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.
−Removed: We believe that MGTA-117,
−Removed: 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.
−Removed: Likewise, gene therapy is a promising approach to treat a variety of non-malignant
−Removed: 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.
−Removed: Through its targeted approach, MGTA-117
−Removed: has the potential to provide a safe and effective approach to preparing patients for stem cell transplant or HSC-based
−Removed: gene therapy.
−Removed: Preclinical data
−Removed: Our experiments have validated the concept of using an ADC targeting CD117 in animal models of conditioning and transplant.
−Removed: We found that a single dose of an experimental anti-murine CD117-ADC
−Removed: was able to successfully deplete HSCs in immunocompetent mice and allow successful transplant.
−Removed: 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.
−Removed: In contrast, treatment with an unconjugated CD117 antibody did not have a significant impact on HSCs.
−Removed: The anti-human CD117 amanitin ADC selectively depletes CD34+ human stem and progenitor cells in humanized NSG mice.
−Removed: The depletion is on target and payload dependent as the naked antibody (Anti-CD117) has no effect.
−Removed: CD117 amanitin ADC or controls were dosed on day 0.
−Removed: Bone marrow was collected on day 21 and analyzed by flow cytometry.
−Removed: 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.
−Removed: * denotes p value < 0.05 vs PBS group.
−Removed: We subsequently partnered with the National Institutes of Health, or NIH, to investigate an experimental non-amanitin
−Removed: in a non-human
−Removed: 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.
−Removed: Results from the study were presented by Dr.
−Removed: John Tisdale of the NIH at the ASH annual meeting in December 2019.
−Removed: The experimental CD117-ADC
−Removed: 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
−Removed: The experimental CD117-ADC
−Removed: 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.
−Removed: The engineered half-life experimental CD117-ADC
−Removed: demonstrates rapid clearance (10 hour half-life) in non-human
+Added: CD117 is expressed on stem cells and their progenitors and mast cells only within the hematopoetic system.
+Added: CD117-expressing cells are selectively depleted when cultured with increasing concentrations of MGTA-117,
+Added: while CD117-negative cells are unaffected.
+Added: Cell Depletion
+Added: In humanized mice, single dose administration of MGTA-117
+Added: engaged CD117-expressing cells with on-target
+Added: depletion of human stem and progenitor (CD34+) cells in the bone marrow.
+Added: Importantly, cells that did
+Added: not express CD117, for example T cells, were not depleted and functional immunity was preserved.
+Added: Additionally, cell depletion was payload dependent because the stand alone, or naked, antibody was shown to have no effect in the same experiment.
+Added: These data collectively demonstrate that MGTA-117
+Added: selectively engages the CD117 receptor on stem cells and their progenitors and once internalized the release of the amanitin payload results in effective potent targeted HSC depletion, while sparing non CD117 expressing cells of the immune system.
+Added: Administration of a single dose of MGTA-117
+Added: to humanized mice results in significant depletion of CD117-positive HSC/HSPC but is without effect on CD117-negative T-cells.
+Added: The monoclonal or naked antibody is ineffective in depleting stem cells.
+Added: In healthy primate studies, a single dose of MGTA-117
+Added: showed dose-dependent HSC depletion in the bone marrow at seven days post-dosing with doses ≥ 0.3 mg/kg achieving ≥ 90% HSC depletion as measured by CD34+CD90+CD45RA- cells.
+Added: These data demonstrate that in normal healthy primates, MGTA-117
+Added: selectively targeted and depleted bone marrow stem cells and their progenitors.
+Added: In the same studies, we observed dose-dependent depletion of peripheral blood reticulocytes.
+Added: Reticulocytes do not express CD117 and therefore this sensitive depletion of these red blood cell precursors indicates the sensitivity of bone marrow erythro-progenitor cells to MGTA-117.
+Added: Peripheral reticulocytes in the blood may therefore serve as a sensitive biomarker of MGTA-117
+Added: effectiveness in depleting HSC/HSPC in the bone marrow compartment.
+Added: has also been shown to be effective in killing human acute myeloid leukemia cells in vitro
+Added: To extend these data, we assessed the ability of MGTA-117
+Added: to reduce tumor burden and therefore extend survival in mice bearing two different human AML tumor types.
+Added: We selected patient-derived AML tumor cells from a patient prior to treatment and compared that with human tumor cells from a recurrent/relapsed AML that was resistant to multiple lines of therapy.
+Added: Tumor-bearing mice treated with a single dose of MGTA-117
+Added: showed improved survival regardless of tumor-type, compared to mice left untreated or those treated with isotype control ADC (which does not bind to CD117) or multiple doses of standard aracytidine chemotherapy.
+Added: Mice bearing human tumor explants from naïve patients (PDX1) or from recurrent/relapsed patients (PDX2) showed improved survival following treatment with MGTA-117
+Added: compared with either the isotype-control antibody or aracytidine.
+Added: Rapid Clearance
+Added: In preclinical studies, we utilized an experimental CD117-ADC
+Added: with a full length human IgG1 antibody that had been engineered to have rapid clearance from the body which enables safe graft infusion within five days after dosing.
+Added: As shown in the graphic below, the engineered half-life experimental CD117-ADC
+Added: (that has the
+Added: same engineered antibody as MGTA-117
+Added: with a different non-amanitin
+Added: payload) demonstrated rapid clearance in non-human
primates with a half-life suitable for transplant (n=3/group).
−Removed: The wild type CD117 antibody half-life is approximately three days.
+Added: The half-life of the wild type CD117 antibody is approximately three days.
The experimental CD117-ADC
−Removed: 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.
−Removed: This study showed, for the first time, that a single dose of an experimental CD117-ADC
−Removed: selectively depleted HSCs in non-human
−Removed: primates, while sparing immune cells, which are important for recovery following transplant .
−Removed: The single dose of this experimental CD117-ADC
−Removed: primates enabled successful transplant and engraftment of HSCs modified with a lentiviral vector encoding the beta-globin gene.
−Removed: Experimental CD117-ADC
−Removed: enables engraftment of autologous gene-modified HSCs in a non-human
+Added: drops below limit of detection for the assay after two days and modeled pharmacokinetics (gray line) predicts the ADC will be below cytotoxic concentrations after five days.
+Added: An Experimental CD117-ADC
+Added: Successfully Supports Transplant in a Gene Therapy Model
+Added: gene therapies also require conditioning of the transplant recipient prior to infusion with stem cells that have been gene-corrected or modified to address the underlying disease prior to transplant.
+Added: 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.
+Added: In a preclinical study, an experimental CD117-ADC
+Added: that has the same engineered antibody with a different non-amanitin
+Added: payload, enabled engraftment of autologous gene-modified HSCs in a non-human
primate, or NHP, model.
−Removed: CD34+ cells were harvested from two rhesus NHPs and transduced with lentiviral
−Removed: vector encoding beta-globin.
+Added: CD34+ cells were harvested from two rhesus NHPs and transduced with a 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).
−Removed: The animals recovered their neutrophils on day eight (animal #1) and day ten (animal #2).
−Removed: 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.
−Removed: This was comparable to historical data with multiple doses of busulfan conditioning.
−Removed: The vector copy number (VCN) of the transduced CD34+ cells used for the experimental CD117-ADC
−Removed: conditioned animal was lower compared to the VCN of the cells used in the busulfan conditioned animals.
−Removed: The peripheral granulocyte VCN is stable over time and in the same range as observed with busulfan conditioned animals shown in gray.
−Removed: This indicates the conditioning with experimental CD117-ADC
+Added: The animals recovered their neutrophils on day eight (animal #1) and day ten (animal #2) demonstrating that (1) the conditioning regiment was successful in depleting stem cells reflected by the severe depletion of neutrophils and (2) that the neutrophil count recovered demonstrating recovery from the conditioning and transplant.
+Added: The success of the transplants in both animals were confirmed by measurement of vector copy number, or VCN, in the immune cells which are derived from the infused gene modified stem cells.
+Added: The VCN was stable beyond three months, the longest time point in the study, demonstrating that the gene-modified cells persisted in the body indicating the gold-standard of a durable transplant.
+Added: This was comparable to historical data with four doses of busulfan conditioning, but without observation of the side effects associated with busulfan such as veno-occlusive disease, weight loss, diarrhea, mucositis, vomiting, pulmonary fibrosis or seizures.
+Added: The graphic above shows that the VCN in the peripheral neutrophils (granulocytes) was equivalent with conditioning with one dose of the experimental CD117-ADC
+Added: versus four doses of toxic busulfan even though the transduced CD34+ cell dose and VCN infused for the experimental CD117-ADC
+Added: conditioned animals was lower compared to the busulfan conditioned animals .
+Added: This indicates the conditioning with the experimental CD117-ADC
is sufficient to enable engraftment of gene modified HSCs.
−Removed: The experimental CD117 ADC was well tolerated in non-human
−Removed: 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.
−Removed: No experimental CD117 ADC-related
−Removed: blood chemistry changes outside normal range were observed.
−Removed: We believe these proof-of-concept
−Removed: studies validate the use of a CD117-ADC
−Removed: 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.
−Removed: Anti-tumor activity of CD117 Amanitin ADC
−Removed: 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
−Removed: 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.
−Removed: 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.
−Removed: Clinical development plans
−Removed: We currently intend to pursue the development of MGTA-117
−Removed: (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.
−Removed: We have declared a development candidate, MGTA-117, and have moved it into Investigational New Drug, or IND, -enabling studies.
−Removed: We have recently completed GLP toxicology studies and our GMP manufacturing process, as well as completing our pre-IND communications with the FDA.
−Removed: We expect to file an IND application with the FDA in mid-2021.
−Removed: 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.
−Removed: These initial data are expected to be directional for our dose escalation plans.
−Removed: In 2020, we also announced two non-exclusive
−Removed: research and clinical collaborations to evaluate the potential utility of MGTA-117
+Added: Well-Tolerated
+Added: A critical characteristic of our next generation conditioning agent MGTA-117
+Added: is that it demonstrates safety and tolerability that supports advancement into human testing.
+Added: We determined the safety of MGTA-117
+Added: by conducting a four-week good laboratory practices, or GLP, toxicology study in primates where a no observable adverse event level dose level was identified.
+Added: There were only two target organs identified.
+Added: At lower doses the target organ identified was the bone marrow with the intended pharmacological effect of stem cell depletion.
+Added: At higher doses the target organ identified was the liver with transient enzyme elevations and transient histopathological changes observed.
+Added: No histopathological changes were observed in kidney, reproductive organs and any other major organ.
+Added: The GLP toxicology study enabled the advancement of MGTA-117
+Added: into a Phase 1/2 clinical trial.
+Added: Clinical development of MGTA-117
+Added: We have an ongoing Phase 1/2 clinical trial to evaluate MGTA-117
+Added: in a multi-center, open-label, single-ascending-dose trial with patients with relapsed/refractory AML and MDS-excess
+Added: blasts, or MDS-EB
+Added: Dose escalation in the trial will be determined in accordance with a modified Fibonacci sequence.
+Added: The primary outcomes for the clinical trial will be the evaluation of the safety profile, pharmacokinetics and pharmacodynamics of MGTA-117
+Added: as a single dose.
+Added: The dosing cohorts expected to enroll in 2022 will allow for evaluation of MGTA-117’s
+Added: selectively target CD117 as measured by receptor occupancy;
+Added: potently deplete CD117-expressing cells such as stem cells, progenitors, and tumor cells;
+Added: rapidly clear from the body with a well-tolerated profile as determined by pharmacokinetic analysis and clinical chemistry tests, respectively.
+Added: Magenta will assess data from each cohort and, after collection of adequate safety, pharmacokinetic and pharmacodynamic data, Magenta intends to engage with the U.S.
+Added: Food and Drug Administration, or FDA, to transition to the primary target population of patients eligible for stem cell transplantation.
+Added: In addition, Magenta plans to explore MGTA-117
+Added: as a targeted conditioning agent for stem cell gene therapies.
+Added: We have entered into two 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.
−Removed: In May 2020, we entered into an agreement with AVROBIO, Inc.
+Added: We entered into an agreement with AVROBIO, Inc.
to evaluate the potential utility of MGTA-117
1 unchanged sentence
Hemoglobinopathies.
−Removed: In June 2020, we entered into an agreement with Beam Therapeutics, Inc.
+Added: We entered into an agreement with Beam Therapeutics, Inc.
to evaluate the potential utility of MGTA-117
1 unchanged sentence
Our second ADC-based
−Removed: conditioning program, C100, targets both patient HSCs and disease-causing immune cells.
−Removed: For many stem cell transplant applications, it is important to eliminate both immune cells and HSCs in the patient prior to transplant.
−Removed: This is especially important in the allogeneic setting where host immune cells can elicit an immune-mediated rejection of the incoming foreign stem cells.
−Removed: In addition, immune cell depletion is a key feature of the use of autologous stem cell transplant in patients with severe autoimmune disease.
−Removed: In this case, the goal is to eliminate the disease-causing auto-reactive immune cells that perpetuate the underlying autoimmune disease.
+Added: conditioning program is CD45-ADC,
+Added: which targets the CD45 receptor that is expressed on both HSCs and disease-causing immune cells.
+Added: For many stem cell transplant applications, it is
+Added: important to eliminate both HSCs and immune cells in the patient prior to transplant.
+Added: This is especially important as immune cell depletion is a key feature of the use of autologous stem cell transplant in patients with severe autoimmune disease.
+Added: In this case, our goal is to eliminate the disease-causing auto-reactive immune cells that perpetuate the underlying autoimmune disease.
+Added: Similarly, in the allogeneic blood cancer transplant setting, host immune cells must be depleted because they can elicit an immune-mediated rejection of the incoming foreign stem cells.
Lastly, for cancer patients with tumors expressing CD45, there may also be a direct anti-tumor effect providing additional therapeutic benefit.
−Removed: For these reasons, we are developing product candidates that simultaneously target both HSCs and immune cells.
−Removed: Our lead target for the C100 program is CD45, an important cell surface molecule broadly expressed throughout the hematopoietic and immune systems.
−Removed: We believe CD45-ADC
−Removed: 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.
−Removed: Preclinical data
+Added: For these reasons, we are developing a CD45-ADC
+Added: product candidate that simultaneously targets both HSCs and immune cells.
+Added: Preclinical Data Supporting Development
Mouse Models of Autoimmune Disease
−Removed: 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
+Added: 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 an experimental 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.
−Removed: Further, a single dose of CD45-ADC
+Added: Further, a single dose of the 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
−Removed: Therapeutic Treatment with CD45-ADC
−Removed: Enables Immune Reset via Congenic Bone Marrow Transplant and results in halt of disease progression in a murine model of Rheumatoid Arthritis.
+Added: Conditioning with CD45-ADC
+Added: Enables Immune Reset via Bone Marrow Transplant and results in halt of disease progression in a murine model of Rheumatoid Arthritis.
BALB/c mice (CD45.2 +
−Removed: ) were given three immunizations (study day 0, 21, and 42) with recombinant human core G1 aggrecan (60 m
−Removed: g in 2 mg DDA) ( A
+Added: ) were given three immunizations (study day 0, 21, and 42) with recombinant human core G1 aggrecan (60 µg in 2 mg DDA) to trigger rheumatoid arthritis ( A
Animals were treated on day 11 post the final immunization (study day 53) and conditioned animals were transplanted with Balb/c CD45.1 +
−Removed: congenic bone marrow 48 hours later.
−Removed: Animals treated with a neutralizing monoclonal antibody to murine TNF a
−Removed: received 500 m
−Removed: g/mouse IP weekly starting on study day 53.
+Added: congenic bone marrow 48 hours later (study day 55).
+Added: Animals treated with a neutralizing monoclonal antibody to murine TNF α received 500 µg/mouse IP weekly starting on study day 53.
Treatment with 2 mg/kg of CD45-ADC,
5 unchanged sentences
Scores for the treatment groups over time are graphed in ( D
−Removed: Mouse Models of Transplant
−Removed: 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
+Added: Mouse Models of Allogeneic Transplant
+Added: Data presented at the European Society for Blood and Marrow Transplantation, or EMBT, and American Society of Hematology, or 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.
2 unchanged sentences
C57BL/six mice were conditioned with 5 mg/kg Isotype-ADC
−Removed: 95% donor chimerism (A) and peripheral donor engraftment is multilineage through week 20.
−Removed: Terminal splenic (E) and thymic (F) chimerism in CD45-ADC
+Added: enables ≥ 95% donor chimerism (A)
+Added: and peripheral donor engraftment is multilineage through week 20.
+Added: Terminal splenic (E)
+Added: and thymic (F)
+Added: chimerism in CD45-ADC
conditioned mice were similar to TBI.
5 unchanged sentences
is well tolerated and is capable of reducing tumor burden by potently targeting leukemia cells in xenograft models.
−Removed: 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,
+Added: It significantly prolonged the median survival of animals harboring an established AML cell line and patient derived tumor cells as compared to both untreated controls and a multi-dose regimen of aracytidine, or ARA-C,
a standard-of-care
21 unchanged sentences
for use in patients with autoimmune diseases, such as multiple sclerosis and scleroderma, and patients with leukemias and myelodysplastic syndromes.
−Removed: We have identified a lead antibody and progressed this program into IND enabling studies, which we plan to further advance in 2021.
−Removed: Our third ADC-based
−Removed: conditioning program, C300, targets T cells, a type of immune cell.
−Removed: T cell depletion is currently performed with highly toxic, non-specific
+Added: We have identified a lead antibody and progressed this program into IND-enabling
+Added: Magenta expects to have preclinical data from a dose ranging toxicology study in the second half of 2022.
+Added: Stem Cell Mobilization & Collection Program
+Added: Stem cell mobilization is a process by which stem cells are stimulated out of the bone marrow and into the bloodstream so they are available for collection for future reinfusion.
+Added: The cells are then preserved, frozen, and stored until the time of transplant.
+Added: We are developing MGTA-145
+Added: as a new medicine intended to transform the process of mobilization and collection of stem cells.
+Added: 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.
+Added: There are three methods of collecting stem cells from either patients or healthy donors for transplant:
+Added: 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;
+Added: 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;
+Added: harvesting from umbilical cord blood units, which are stored in cord blood banks.
+Added: 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.
+Added: 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.
+Added: Mobilizing stem cells from the bone marrow to the blood has been shown to be an effective way to collect stem cells for transplant.
+Added: 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.
+Added: Current approaches for stem cell mobilization include granulocyte colony-stimulating factor, or G-CSF,
+Added: 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.
+Added: The multi-day
+Added: regimen requires at least five days of injections of G-CSF,
+Added: 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.
+Added: For patients who are unable to mobilize a sufficient number of functional stem cells with G-CSF,
+Added: physicians may add another drug, known as plerixafor.
+Added: 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.
+Added: It is approved for use in combination with G-CSF
+Added: for multiple myeloma, and non-Hodgkin’s
+Added: lymphoma patients who fail to achieve sufficient mobilization of stem cells with G-CSF
+Added: can mobilize stem cells as a single agent but not to sufficient levels to be effective as a standalone agent in most disease settings.
+Added: The current unpredictability and inefficiency of stem cell mobilization and collection can also pose a significant logistical burden on transplant and apheresis centers.
+Added: 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.
+Added: 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.
+Added: It is difficult to predict whether mobilization with G-CSF
+Added: will be successful, especially in heavily treated blood cancer patients.
+Added: Many patients require multiple collections, including approximately 40% of blood cancer patients.
+Added: Finally, patients with sickle cell disease can have severe side effects with G-CSF,
+Added: including potentially fatal complications, and therefore, plerixafor is the only available mobilization option for sickle cell disease patients.
+Added: However, because of its poor efficacy as a standalone agent and the high number of stem cells required for a transplant in sickle cell disease, multiple doses of plerixafor and collections are needed in approximately 75% of sickle cell disease patients.
+Added: Product Candidate
+Added: Magenta is developing MGTA-145
+Added: as a potential first-line standard of care for stem cell mobilization in a broad range of diseases, for both autologous and allogeneic transplants.
+Added: a CXCR2 agonist, works in combination with plerixafor, a CXCR4 antagonist, to harness the physiological mechanism of stem cell mobilization.
+Added: Our goal is for MGTA-145
+Added: 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.
+Added: We received Orphan Drug Designation from the FDA, for MGTA-145
+Added: for the mobilization of HSCs to the peripheral blood for collection and subsequent transplant.
+Added: Mechanism of action
+Added: CXCR2 is a chemokine receptor expressed on the surface of neutrophils.
+Added: Binding of MGTA-145
+Added: to the receptor results in neutrophil activation.
+Added: Published data from Magenta founders and scientists show that a key event for mobilization of stem cells is the MGTA-145-mediated
+Added: 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.
+Added: Blocking CXCR4 using plerixafor and activating neutrophils with MGTA-145
+Added: has been shown clinically to produce an effective and synergistic untethering and release of HSCs from bone marrow into the blood, resulting in rapid, reliable, predictable and well-tolerated mobilization of HSCs.
+Added: in combination with plerixafor harnesses the natural mechanism of stem cell mobilization.
+Added: Phase 1 Clinical Data – Healthy Subjects
+Added: We have completed a Phase 1 clinical trial of MGTA-145
+Added: plus plerixafor in healthy subjects.
+Added: The trial met all primary and secondary endpoints.
+Added: Clinical endpoints included safety and tolerability, pharmacokinetics, target engagement and pharmacodynamic effects.
+Added: Data from the trial presented at the ASH annual meeting in December 2020 showed that MGTA-145
+Added: was safe and well tolerated as a single agent and in combination with plerixafor, and that MGTA-145
+Added: in combination with plerixafor demonstrated rapid, single-day
+Added: mobilization and collection of sufficient numbers of functional stem cells.
+Added: was shown to engage CXCR2 on neutrophils to mobilize CD34+ stem cells into peripheral blood with limited neutrophil activation, which may minimize risk of vaso-occlusive crises in patients with sickle cell disease.
+Added: Phase 2 Clinical Data – Phase 2 Investigator-Initiated Trial in Multiple Myeloma
+Added: A Magenta supported Phase 2 investigator-initiated clinical trial at Stanford University with 25 multiple myeloma patients showed that MGTA-145,
+Added: in combination with plerixafor, mobilized a sufficient number of stem cells for transplantation and met the trial’s primary endpoint in 88% of patients (22/25).
+Added: In addition, all patients transplanted with cells mobilized by MGTA-145
+Added: plus plerixafor as of the data cut-off
+Added: date had successful engraftment (18/18 patients) with prolonged durability through the 100-day
+Added: period (13/13 patients) which were two key exploratory endpoints.
+Added: The regimen was generally well-tolerated.
+Added: Clinical Data Confirms Potential Clinical Benefit, as Demonstrated in Multiple Myeloma from Single-Center Phase 2 Investigator-Initiated Trial (n=25 patients)
+Added: Next Steps in MGTA-145
+Added: Clinical Development
+Added: Phase 2 Dosing and Administration Optimization Clinical Trial.
+Added: Building upon the encouraging cell collection data from the Phase 2 investigator-initiated clinical trial in multiple myeloma patients, Magenta plans to pursue a company-sponsored Phase 2 clinical trial to evaluate identified possible adjustments in the dosing and administration regimen that are expected to further increase the number of stem cells mobilized for collection.
+Added: This evaluation will be performed in healthy subjects which we believe will enable expedited enrollment and reduced patient variability.
+Added: This clinical trial approach is intended to inform our clinical development plans in autologous transplant, including multiple myeloma, and allogeneic stem cell transplant.
+Added: Phase 2 Sickle Cell Disease Stem Cell Mobilization and Collection (Cell Characterization;
+Added: Gene Modification Model).
+Added: We entered into a Phase 2 clinical collaboration with bluebird bio, Inc.
+Added: to evaluate the safety and potential utility of MGTA-145,
+Added: in combination with plerixafor, for the mobilization and collection of stem cells in patients with sickle cell disease.
+Added: Under the agreement, the companies will co-fund
+Added: the clinical trial.
+Added: Each party will characterize the collected cells and Magenta plans to gene- modify the cells and transplant them into established pre-clinical
+Added: models to evaluate engraftment.
+Added: Data from this clinical trial could provide proof-of-concept
+Added: for MGTA-145,
+Added: in combination with plerixafor, as the preferred mobilization regimen for patients with sickle cell disease and, more broadly, across all HSC gene therapy applications.
+Added: Phase 2 Allogeneic Donor Stem Cell Mobilization and Collection for Stem Cell Transplant in AML, ALL and MDS Patients.
+Added: We entered into a clinical trial collaboration with National Marrow Donor Program (as successor in interest to Be the Match Biotherapies, LLC, or Be the Match, to evaluate the potential utility of MGTA-145,
+Added: in combination with plerixafor, to mobilize and collect stem cells from allogeneic donors for transplant in patients with AML, acute lymphocytic leukemia, or ALL, and MDS.
+Added: The clinical trial commenced in 2021 and, after review of initial clinical data from the trial in parallel with the review of the multiple myeloma clinical data, we decided to close the allogeneic donor clinical trial in favor of exploring the dosing and administration adjustments described above.
+Added: We decided that the dosing and administration optimization clinical trial would be more beneficial to the overall MGTA-145
+Added: program due to its applicability to both allogeneic and autologous mobilization.
+Added: Research Programs
+Added: Our research efforts currently focus on future ADC-based
+Added: conditioning programs.
+Added: Our most advanced research program targets a receptor that is expressed on T cells, a type of immune cell.
+Added: T cell depletion is
+Added: currently performed with highly toxic, non-specific
drugs which can lead to immune deficiency, infections and other complications, including secondary autoimmune reactions.
1 unchanged sentence
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.
−Removed: We are developing our G100 product candidate as a targeted conditioning agent with the aim of preventing acute GvHD.
−Removed: 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.
−Removed: The grafted cells then attack their new host.
−Removed: 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.
−Removed: If they are not well matched, the donor’s T cells recognize the recipient’s cells as foreign and attack them.
−Removed: Recipients who receive poorly matched stem cells are among those at the highest risk of developing this condition.
−Removed: However, GvHD can occur even with proper matching.
−Removed: Acute GvHD typically occurs within the first 100 days following transplant and can severely damage the skin, liver and gastrointestinal system.
−Removed: 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.
−Removed: Approximately 40% of all stem cell transplants are allogeneic.
−Removed: 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.
−Removed: Despite the use of these powerful immune suppressive agents, most allogeneic transplant patients will experience GvHD.
−Removed: For severe cases, patients are treated with high doses of steroids, immune ablating antibodies or chemotherapy.
−Removed: The use of high-dose non-specific
−Removed: 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.
−Removed: Our G100 product candidate is an ADC designed to selectively eliminate the cells that cause acute GvHD, specifically the alloreactive T cells.
−Removed: This ADC product candidate is intended to be dosed in vivo
−Removed: at the time of transplant and eliminate the activated alloreactive T cells.
−Removed: 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.
−Removed: Cell Therapy Programs
−Removed: High-dose, well-matched allogeneic investigational stem cell therapy for use in patients with high-risk hematologic malignancies
−Removed: 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.
−Removed: In allogeneic transplant, up to half of patients will not find a suitable donor within their biological relatives or among registered bone marrow donors.
−Removed: 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.
−Removed: 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.
−Removed: Cell dose and degree of graft matching are independent risk factors impacting risk of non-relapse
−Removed: mortality in individuals undergoing cord blood transplant for acute leukemia.
−Removed: Low numbers of CD34+ stem cells can result in prolonged periods of cytopenia and higher risk of graft failure.
−Removed: The availability of MGTA-456
−Removed: could reduce the barriers associated with cell dose and poor matching that currently limit the successful use of cord blood in transplant.
−Removed: is currently being evaluated in a Phase 2 study in patients with high-risk blood cancers undergoing stem cell transplant.
−Removed: Enrollment is this study has been completed and patients are currently in a follow-up
−Removed: product candidate
−Removed: 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.
−Removed: 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.
−Removed: Clinical data:
−Removed: blood cancers
−Removed: 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.
−Removed: The trial showed that expansion of CD34+CD90+ cells in MGTA-456
−Removed: results in rapid and sustained hematopoietic recovery, complete engraftment in all subjects, improved matching in adults weighing >59 kg and reduced incidence of GvHD.
−Removed: In addition, neutrophil recovery occurred in 100% of patients at a median of 17 days versus 23 days in recipients of unmodified cord blood.
−Removed: Similarly, platelet recovery was higher (94% vs.
−Removed: 74%) and faster (median 36 days vs.
−Removed: 59 days) for patients receiving MGTA-456
−Removed: versus unmodified cord blood, respectively.
−Removed: Both neutrophil and platelet recovery correlated to dose of CD34+CD90+ cells.
−Removed: With all patients now out beyond day 100, only one patient had grade 3-4
−Removed: acute GvHD and one had chronic GvHD limited to the oral mucosa (off immunosuppression 15 months after transplant).
−Removed: Development plan
−Removed: Previously, MGTA-456
−Removed: was evaluated in patients with rare genetic inherited metabolic disorders.
−Removed: In June 2020, we announced that we would discontinue enrollment in our Phase 2 trial of MGTA-456
−Removed: in patients with inherited metabolic disorders undergoing stem cell transplant.
−Removed: 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
−Removed: a growing understanding in the transplant field of the current challenges of allogeneic stem cell transplant in patients with non-malignant
−Removed: diseases, including inherited metabolic diseases;
−Removed: and feedback from the FDA on endpoints and clinical trial design for registration.
−Removed: We will continue to evaluate the data for MGTA-456
−Removed: 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
−Removed: 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.
−Removed: 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.
−Removed: These constraints could limit the commercial viability of this approach.
−Removed: The ability to expand HSCs ex vivo
−Removed: has the potential to improve outcomes with gene therapy or genome editing by increasing the dose of genetically modified stem cells.
−Removed: This has been a long-term goal of the field and
−Removed: has the potential to reduce manufacturing costs for these therapies by requiring less viral vector for gene modification of the stem cells.
−Removed: Scaling up vector manufacturing in a cost-effective manner has been a significant challenge for HSC-based
−Removed: gene therapy companies and a significant cost driver.
−Removed: Such cost and capacity issues could limit the commercial viability and widespread deployment of gene therapies.
−Removed: Our E478 product candidate
−Removed: 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.
+Added: Stem cell transplant with gene-modified HSCs, which is referred to as gene therapy, stem cell gene therapy or genome editing, is a promising treatment approach for many diseases.
+Added: We believe this approach can be enhanced by (1) increasing the number of gene-modified HSCs that retain the ability to durably engraft in patients and (2) reducing the cost and complexity of manufacturing viral vectors for gene modification of cells.
+Added: These constraints could increase the commercial viability of stem cell gene therapy.
+Added: E478 product candidate
+Added: We developed the E478 program in response to the 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.
−Removed: E478 uses the same clinically validated method used to produce MGTA-456,
−Removed: AHR antagonism, to expand gene-modified HSCs.
+Added: AHR antagonism is a clinically validated mechanism to increase the number of HSCs, most recently having been studied in patients with hematologic malignancies and inherited metabolic diseases.
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.
2 unchanged sentences
Preclinical data
−Removed: We have shown that E478 can generate higher numbers of long-term engrafting human HSCs compared to other expansion technologies.
+Added: We have shown that E478 can generate higher numbers of long-term engrafting human HSCs compared to other technologies.
We have presented in vitro
−Removed: data demonstrating successful expansion of gene-modified HSCs from both bone marrow and mobilized blood cell sources with E478 and showed that ex vivo
−Removed: expansion with E478 leads to higher and durable levels of engraftment in NSG mice compared to conventional culture approaches.
+Added: data demonstrating successful increases in the number of gene-modified HSCs from both bone marrow and mobilized blood cell sources with E478 and showed that ex vivo
+Added: incubation 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
−Removed: We performed experiments designed to evaluate the ability of E478 to increase HSC numbers for HSC based gene therapy.
−Removed: In these studies, human CD34+ cells isolated from G-CSF
−Removed: 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.
−Removed: 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.
−Removed: Similar findings were observed using CRISPR-based approaches.
−Removed: At the American Society of Cell and Gene Therapy annual meeting in May 2020, we presented in vivo
−Removed: data showing that ex vivo
−Removed: expansion with E478 led to significantly higher rate and number of NSG-engrafting
−Removed: gene-corrected cells.
−Removed: E478 increases the dose of gene-corrected NSG-engrafting
−Removed: Mobilized blood CD34+ cells from healthy subjects were pre-stimulated
−Removed: in cytokine-containing media followed by electroporation with CRISPR/Cas9 and AAV.GFP donor and expanded post-editing.
−Removed: Four day pre-stimulation
−Removed: followed by a four day expansion (called a 4+4 culture) compared to a conventional two day pre-stimulation
−Removed: period followed by a one day expansion (called a 2+1 culture).
−Removed: E478 was added to the 4+4 culture and compared to a conventional 2+1 culture with vehicle control.
−Removed: Engraftment (frequency of human CD45+ cells);
−Removed: rate of homology-directed repair, or HDR;
−Removed: number of engraftable HDR+ cells was measured in the peripheral blood at week 16 post-transplant.
−Removed: Bars represent median and each symbol represents an individual mouse (n=eight).
−Removed: Statistics were determined by a one-tailed
−Removed: Student’s t-test.
Development plan
−Removed: We are developing E478 specifically to partner with gene therapy, genome editing and cell therapy companies.
+Added: We are developing E478 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.
−Removed: Commercialization Plan
+Added: Commercialization Plans
We plan to establish sales, marketing and commercial product distribution capabilities.
−Removed: 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.
+Added: 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
+Added: 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.
−Removed: that are accredited through Be the Match, of which 20% collectively account for over 50% of transplant volume.
+Added: that are accredited, of which approximately 36 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.
−Removed: 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
−Removed: organization.
−Removed: We intend to leverage any infrastructure developed for our lead product candidate, MGTA-145,
+Added: 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.
+Added: We intend to leverage any infrastructure developed for our most advanced product candidate, MGTA-145,
to support commercialization of any additional product candidates in our portfolio for which we gain approval.
5 unchanged sentences
Stem Cell Transplant Commercial Market Opportunity
−Removed: Stem cell transplant is currently a large commercial market opportunity with approximately 90,000 procedures annually in the U.S., Europe and Asia.
+Added: Stem cell transplant is currently a large commercial market opportunity and approximately 90,000 patients annually have a stem cell transplant 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.
−Removed: 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.
+Added: 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.
2 unchanged sentences
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.
−Removed: 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.
−Removed: Further, by optimizing the benefit-risk tradeoff, we believe the eligible patient populations could increase beyond the current numbers.
−Removed: We have assessed the existing stem cell transplant market and potential eligible patient population on a per-indication
+Added: We believe that by removing some of 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.
+Added: Today 90,000, or approximately 50%, of eligible patients worldwide undergo stem cell transplant.
+Added: Further, by optimizing the benefit versus risk tradeoff, we believe the eligible patient populations could increase beyond the current numbers.
+Added: We have assessed the existing stem cell transplant market and potential eligible patient population in major global markets:
+Added: U.S., Germany, France, U.K., Italy, Spain and Japan on a per-indication
basis to estimate the potential number of patients that could benefit from Magenta’s product candidates.
1 unchanged sentence
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:
−Removed: 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.
−Removed: Our conditioning programs, including our MGTA-117
−Removed: 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.
−Removed: Pending further development for the MGTA-456
−Removed: program informed by ongoing data, MGTA-456
−Removed: 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.
+Added: Our targeted conditioning programs, including our MGTA-117
+Added: product candidate, have the potential to provide more effective targeted conditioning for blood cancer patients, particularly allogeneic transplant candidates, who currently weigh the tradeoffs of long-term efficacy and toxicity with current conditioning regimens that impact patient outcomes.
+Added: product candidate has the potential to address the challenges in mobilizing and collecting stem cells faced by patients and healthy donors for autologous and allogeneic transplant in blood cancer patients.
Multiple myeloma, a cancer arising from plasma cells, is diagnosed in approximately 64,000 patients annually in the major global markets.
−Removed: 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.
9 unchanged sentences
Following diagnosis, patients typically undergo treatment with one or more therapeutic classes which may include chemotherapy, immunotherapy, cell therapy, targeted agents, and/or corticosteroids.
−Removed: 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.
+Added: After one or more courses of initial treatment, patients may proceed to a stem cell transplant depending on whether they are
+Added: considered an appropriate candidate depending on several patient- and disease-related factors.
Currently, approximately 10,500 lymphoma patients receive a stem cell transplant annually in the major global markets.
−Removed: 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:
−Removed: U.S., Germany, France, U.K., Italy, Spain and Japan.
+Added: AML is 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.
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.
2 unchanged sentences
Currently, approximately 8,400 patients with AML receive a stem cell transplant annually in the major global markets.
−Removed: 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.
+Added: 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.
1 unchanged sentence
of those are eligible for stem cell transplant based on patient fitness (including age and comorbidities) and blast count.
−Removed: However, the current challenges of stem cell transplant, including highly toxic chemotherapy conditioning regimens, limit transplant to approximately 60% of those
−Removed: MDS patients who are otherwise eligible.
+Added: 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.
−Removed: Acute lymphocytic leukemia, or ALL, is a cancer that develops from immature white blood cells and is common in children.
+Added: 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.
4 unchanged sentences
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.
+Added: 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.
+Added: may also further expand the number of patients who are eligible for these currently investigational gene therapy product candidates.
product candidate has the potential to address patients with sickle cell disease who cannot receive G-CSF
1 unchanged sentence
gene therapy.
−Removed: 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.
−Removed: may also further expand the number of patients who are eligible for these currently investigational gene therapy product candidates.
−Removed: E478 uses the same clinically validated mechanism as MGTA-456
−Removed: to generate higher doses of gene-modified stem cells.
−Removed: Sickle cell disease affects over 100,000 patients in the U.S.
−Removed: and 50,000 patients in Germany, France, U.K., Italy and Spain.
−Removed: 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.
+Added: Sickle cell disease affects over 150,000 patients in major global markets.
+Added: Approximately 20%, or 30,000, of these patients have severe disease (based on annualized sickle cell crises) and are therefore eligible for stem cell transplant or gene therapy once the current risks of the transplant are factored in.
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.
4 unchanged sentences
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.
−Removed: In addition, our C100 conditioning program has the potential to provide safer, targeted conditioning for autoimmune disease patients eligible to receive autologous transplant.
+Added: In addition, our CD45
+Added: 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.
5 unchanged sentences
Systemic sclerosis, or scleroderma, is a chronic connective tissue disease that is characterized by thickening of the skin.
−Removed: It affects over 245,000 patients and approximately 21,000 new patients are diagnosed annually in the
−Removed: major global markets.
+Added: 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.
1 unchanged sentence
Manufacturing
−Removed: We do not own or operate, and currently have no plans to establish, any manufacturing facilities.
−Removed: 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
−Removed: and MGTA-456.
−Removed: We have not entered into long-term agreements with our current CMOs.
−Removed: We intend to continue to rely on CMOs for later-stage development and commercialization of MGTA-145,
+Added: We do not own or operate, and have no plans to establish, any manufacturing facilities.
+Added: We currently depend on third-party contract development and manufacturing organizations, or CDMOs, 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,
+Added: and CD45-ADC.
+Added: We have not entered into long-term agreements with our current CDMOs.
+Added: We intend to continue to rely on CDMOs for later-stage development and commercialization of MGTA-145,
as well as the development and commercialization of MGTA-117,
+Added: and CD45-ADC,
and other product candidates that we may identify.
−Removed: Although we rely on CMOs, we have personnel and consultants with extensive manufacturing experience to oversee the relationships with our contract manufacturers.
−Removed: We believe the synthesis of the MGTA-145
−Removed: 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.
−Removed: 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.
+Added: Although we rely on CDMOs, we have personnel and consultants with extensive process, product development and manufacturing experience to oversee the development, manufacturing and overall relationships with our CDMOs.
+Added: In the case of MGTA-145,
+Added: we have manufactured, and released for clinical use, drug substance and drug products which have been manufactured by our CDMOs 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.
−Removed: 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.
+Added: The late-stage development efforts are underway for MGTA-145
+Added: and our ability to manufacture phase appropriate product quality and purity at a favorable yield is still to be determined.
+Added: In the case of MGTA-117,
+Added: we have developed, manufactured, and released for early clinical use, drug substance and drug product which have been manufactured by our CDMOs to satisfy our immediate and near term clinical and preclinical needs.
+Added: We expect to refine, scale, and optimize the process, including the final product formulation, for our development and commercial supply needs.
+Added: In the case of CD45-ADC,
+Added: we are developing a process to produce preclinical and early clinical trial material manufactured by our CDMOs to satisfy our immediate and near term clinical and preclinical needs.
+Added: We expect to refine, scale, and optimize the process, including the final product formulation, for our development and commercial supply needs.
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.
−Removed: We expect that all of our CMOs will manufacture MGTA-145
+Added: We expect that all of our CDMOs will manufacture MGTA-145,
under current Good Manufacturing Practice, or cGMP, conditions.
3 unchanged sentences
Competition is likely to come from multiple sources, including larger pharmaceutical companies, biotechnology companies and academia.
−Removed: 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.
+Added: 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 also 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.
−Removed: 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.
+Added: We are building a 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.
3 unchanged sentences
Stem cell transplant is used to treat a range of diseases and indications.
−Removed: We are aware of many companies that are developing therapeutics, including biologics, small molecules and CAR-T
−Removed: therapies that are directed to the treatment of blood cancers, genetic diseases and autoimmune diseases that overlap with current stem cell transplant indications.
−Removed: The following competitive overview is focused on companies that are developing technologies to improve the distinct steps of stem cell transplant.
−Removed: Competitors for our mobilization program include the following:
+Added: We are aware of many companies that are developing therapeutics, including biologics, small molecules, and cell and gene therapies that are directed to the treatment of blood cancers, genetic diseases and autoimmune diseases that overlap with current stem cell transplant indications.
+Added: The following overview is focused on companies that are developing technologies to improve the distinct steps of stem cell transplant.
+Added: Competitors for our targeted conditioning programs include the following:
+Added: Medexus Pharmaceuticals, Inc., which is developing treosulfan (reduced intensity conditioning alkylating agent used in allogeneic stem cell transplant) to replace busulfan;
+Added: Jasper Therapeutics, Inc., which is developing an antibody to CD117 that is not conjugated to a payload.
+Added: Actinium Pharmaceuticals, Inc., which is developing an antibody to CD45 that is linked to radioisotope iodine-131;
+Added: Molecular Templates Inc., which is developing an antibody to CD45 that is conjugated to engineered Shiga-toxin.
+Added: Competitors for our stem cell mobilization and collection program include the following:
BioLineRx Ltd., which is developing BL-8040,
a peptide that functions as a high-affinity antagonist for CXCR4.
+Added: They have Phase 3 data in multiple myeloma patients;
Yifan Pharmaceutical Co., Ltd., which is developing YF-H-2015005,
−Removed: a peptide that functions as a high-affinity antagonist for CXCR4.
−Removed: Competitors for our conditioning programs include the following:
−Removed: targeted conditioning program:
−Removed: Jasper Therapeutics, Inc., which is developing an antibody to CD117 that is not conjugated to any toxin;
−Removed: 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.
−Removed: C100 program (CD45-ADC):
−Removed: Actinium Pharmaceuticals, Inc., which is developing an antibody to CD45 that is linked to radioisotope iodine-131;
−Removed: Molecular Templates Inc., which is developing an antibody to CD45 that is conjugated to engineered Shiga-toxin.
−Removed: C300 program:
+Added: a peptide that functions as a high-affinity antagonist for CXCR4 (in China);
+Added: TaiGen Biotechnology Co., Ltd.
+Added: & GPCR Therapeutics, Inc., which are developing burixafor, a CXCR4 receptor antagonist.
+Added: Competitors for our research programs include the following:
Allogene Therapeutics, Inc., which is developing an antibody to CD52 that is not conjugated to any toxin;
−Removed: G100 program:
−Removed: 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;
−Removed: Bristol Myers Squibb Company, which is developing a selective T-cell
−Removed: co-stimulation
−Removed: inhibitor, abatacept, for the prevention of acute GvHD;
−Removed: Sanofi S.A., which is developing an antibody to CD52, alemtuzumab, for the prevention of acute GvHD;
−Removed: Mesoblast Ltd., which is developing a cellular therapy, remestemcel-L,
−Removed: composed of ex vivo
−Removed: -expanded mesenchymal stromal cells, for the treatment of acute GvHD;
−Removed: Abbvie Inc., which has a Bruton’s tyrosine kinase inhibitor, ibrutinib, that is approved for use in steroid-refractory chronic GvHD;
−Removed: Kadmon Holdings, Inc., which is developing a Rho-associated
−Removed: kinase 2 (ROCK2) inhibitor, belumosudil, for the treatment of steroid-refractory chronic GvHD;
−Removed: Bellicum Pharmaceuticals, Inc., which is developing a cellular therapy composed of genetically modified allogeneic T-cells
−Removed: with the activator agent rimiducid, for the prevention of GvHD.
−Removed: Competitors for our cell therapy programs include the following:
−Removed: Intellia Therapeutics, Inc., which has exclusively licensed from Novartis the AHR antagonist that we use to manufacture MGTA-456
−Removed: for expansion of gene-modified HSCs only;
−Removed: Gamida Cell Ltd., which is developing a UCB-derived
−Removed: cell product that uses a small molecule to inhibit differentiation and enhance functionality of ex vivo-
−Removed: expanded HSCs;
−Removed: ExCellThera Inc., which is focused on ex vivo
−Removed: expansion of stem cells using a pyrimidoindole-derivative small molecule;
−Removed: Angiocrine Bioscience, Inc., which is expanding cord blood and gene-modified HSCs using an endothelial cell feeder layer.
+Added: Telix Pharmaceuticals Ltd, which is developing a CD66-radioconjugate;
+Added: Cellectis S.A.,
+Added: which is developing an anti-CD52 monoclonal antibody for lymphodepletion;
+Added: Precision Biosciences, Inc., which is developing foralumab, a humanized anti-CD3
+Added: monoclonal antibody (Phase 1).
Licenses and Collaborations
−Removed: Alliance with Novartis
−Removed: 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
−Removed: We refer to this agreement as the Novartis Agreement.
−Removed: 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.
−Removed: Certain of the rights licensed to us under the Novartis Agreement are also subject to any retained rights of the U.S.
−Removed: government in the licensed patents.
−Removed: The Novartis Agreement led to the establishment of MGTA-456
−Removed: as one of our programs.
−Removed: Under the terms of the Novartis Agreement, we are responsible for all research, development, regulatory and commercialization activities related to licensed products.
−Removed: 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.
−Removed: 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.
−Removed: 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.
−Removed: 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.
−Removed: 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.
−Removed: 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.
−Removed: 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.
−Removed: 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.
−Removed: Royalties are payable on a licensed product-by-licensed
−Removed: product and country-by-country
−Removed: 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.
−Removed: Novartis controls the filing, prosecution, maintenance and enforcement of the licensed patent rights at its expense.
−Removed: We have the right to assume these responsibilities should Novartis not wish to pursue them.
−Removed: We own all rights in any intellectual property related to the licensed compound or licensed products that we solely develop under the Novartis Agreement.
−Removed: The Novartis Agreement does not otherwise allocate ownership of improvements developed thereunder;
−Removed: however, Novartis grants us a non-exclusive,
−Removed: royalty-free license to practice any improvements that Novartis owns under the Novartis Agreement in connection with non-gene-edited/-modified
−Removed: HSCs, and we grant a non-exclusive,
−Removed: royalty-free license to Novartis to practice any improvements that we own under the agreement outside of such field.
−Removed: The Novartis Agreement will continue until the last-to-expire
−Removed: royalty term for a licensed product unless terminated earlier by either party.
−Removed: Each party may terminate the Novartis Agreement due to the other party’s insolvency or uncured breach of a material obligation.
−Removed: We have the right to terminate the Novartis Agreement in its entirety or on a product-by-product
−Removed: or country-by-country
−Removed: basis for convenience upon 90 days’ prior written notice to Novartis.
−Removed: 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
−Removed: 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.
−Removed: Collaboration with National Marrow Donor Program (as successor in interest to Be The Match Biotherapies, LLC)
−Removed: 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.
−Removed: We refer to this agreement, as amended, as the NMDP Agreement.
−Removed: 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.
−Removed: 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.
−Removed: Under the NMDP Agreement, we will make quarterly payments to NMDP of $17,500.
−Removed: The term of the NMDP Agreement will continue until December 31, 2021 unless terminated earlier by either party.
−Removed: 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
6 unchanged sentences
Pursuant to the Harvard Agreement, we made an upfront payment to Harvard of $85,000 and issued to Harvard and the other co-owners
−Removed: of the licensed patent rights (The General Hospital Corporation d/b/a
−Removed: Massachusetts General Hospital, and Children’s Medical Center Corporation) 385,063 shares of our common stock.
+Added: 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.
2 unchanged sentences
In addition, we must pay Harvard low-single
−Removed: digit royalties on net sales of licensed products.
+Added: 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.
4 unchanged sentences
We have the first right, but not the obligation, to enforce licensed patent rights against third-party infringement.
−Removed: 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.
+Added: 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 royalty period.
+Added: 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.
1 unchanged sentence
Upon termination of the Harvard Agreement for any reason, the license granted to us by Harvard will terminate.
−Removed: Research, Development Option and License Agreement with Heidelberg Pharma Research GmbH
+Added: Exclusive 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.
20 unchanged sentences
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.
−Removed: In addition, we may be required to pay development, regulatory and commercial milestones totaling up to approximately $83.5 million per target.
+Added: In addition, we may be required to pay development, regulatory and commercial milestones totaling up to approximately $83.5 million
We will pay Heidelberg Pharma mid-single
13 unchanged sentences
The term of the Heidelberg Agreement will continue until the last to expire royalty term unless terminated earlier by either party.
−Removed: 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
+Added: Each party has the right to terminate the Heidelberg Agreement due to the other party’s uncured material breach on a product-by-product
or target-by-target
3 unchanged sentences
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.
+Added: Furthermore, each party has the right to terminate the Heidelberg Agreement if the other party experiences an insolvency event (as such term is defined in the Heidelberg Agreement), provided that, in the case of any involuntary bankruptcy proceeding, such right to terminate is only effective if the party that is subject to the insolvency event consents to the involuntary bankruptcy proceeding or such proceeding is not dismissed within a certain time-period after filing thereof.
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.
+Added: Master Services Agreement with Heidelberg Pharma
+Added: In May 2019 and in connection with the Heidelberg Agreement, we entered into a master services agreement with Heidelberg Pharma.
+Added: We refer to this agreement as the Heidelberg MSA.
+Added: Under the terms of the Heidelberg MSA, Heidelberg Pharma agrees to perform, and cause certain of its subcontractors to perform, certain services related to development, synthesis, analytical purification, formulation, packaging, storage, stability, release testing, quality control and other related services for the purpose of supplying us with certain targeted amanitin conjugates for use in our preclinical and clinical trials.
+Added: Payment terms to Heidelberg Pharma include the payment of service fees set forth in applicable work orders.
+Added: The term of the Heidelberg MSA is indefinite unless terminated earlier by either party.
+Added: We have the right to terminate the Heidelberg MSA for convenience in its entirety upon 60 days’ prior written notice to Heidelberg Pharma.
+Added: In addition, each party has the right to terminate the Heidelberg MSA (i) if the agreement between Heidelberg Pharma and certain of its subcontractors relating to the work to be performed under the Heidelberg MSA is terminated, (ii) upon a general assignment by one of the parties for the benefit of creditors or if a petition in bankruptcy or under any insolvency law is filed by or against the other party and such petition is not dismissed within a certain time-period after it has been filed, or (iii) upon a material uncured breach of the other party that relates to the Heidelberg MSA as a whole (subject, in the case of (iii), to a cure period).
Bachem Master Development and Manufacturing Agreement
6 unchanged sentences
Financial terms related to this agreement will be determined on a project-by-project
−Removed: In April 2018, we entered into an initial one-year
−Removed: project plan pursuant to which Bachem will be responsible for producing batches of MGTA-145
−Removed: for GLP toxicology studies completed in 2018, as well as GMP material for the Phase 1 trial of MGTA-145,
−Removed: which commenced in the second quarter of 2019.
+Added: Bachem has produced Phase 1/2 clinical drug substance, and we are contracted with them to perform Phase 3 process development and Phase 3 GMP manufacturing of the MGTA-145
+Added: drug substance.
The term of the Bachem Agreement is initially five years and will be automatically renewed for one-year
1 unchanged sentence
Each party may terminate the agreement upon a material uncured breach of the other party.
−Removed: term, Bachem will be restricted from producing a pre-defined
+Added: During the term, Bachem will be restricted from producing a pre-defined
set of agonists, including MGTA-145,
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Each project plan may be terminated independently of the agreement as a whole.
−Removed: Clinical Trial Agreement with University of Minnesota
−Removed: 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
−Removed: for the treatment of inherited metabolic disorders.
−Removed: Under this agreement, UMinn is also responsible for the manufacture and supply of the required quantities of MGTA-456
−Removed: for the trial, subject to specified quality assurance provisions.
−Removed: The term of the agreement will run through the course of the trial, unless earlier terminated.
−Removed: 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
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.
−Removed: 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.
+Added: As of December 31, 2021, our patent portfolio was composed of more than 15 issued patents and more than 250 pending patent applications in the U.S.
and foreign jurisdictions.
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Company-Owned Patent Rights Relating to Our Targeted Conditioning and Post-Transplant Complications Programs
−Removed: With regard to our targeted conditioning and post-transplant complications programs, our owned patent portfolio includes approximately five issued U.S.
−Removed: patents, approximately four issued foreign patents, and more than 140 pending patent applications in the U.S.
+Added: With regard to our targeted conditioning and post-transplant complications programs, our owned patent portfolio includes six issued U.S.
+Added: patents, six issued foreign patents, and more than 200 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.
−Removed: 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
+Added: Our CD117 patent portfolio contains patent families directed to compositions and methods for the depletion of CD117+ cells as well as patent families directed to the MGTA-117
composition of matter and methods of use.
−Removed: As of December 31, 2020, our CD117 patent portfolio includes one issued U.S.
−Removed: patent, approximately eight pending U.S.
−Removed: patent applications, two issued Australian patents, more than 40 pending patent applications in foreign jurisdictions, approximately three families of pending U.S.
−Removed: provisional patent applications, and approximately seven pending PCT applications.
+Added: As of December 31, 2021, our CD117 patent portfolio included three issued U.S.
+Added: patents, more than eight pending U.S.
+Added: patent applications, more than 70 patents and pending patent applications in foreign jurisdictions, three families of pending U.S.
+Added: provisional patent applications, and a pending PCT application.
The issued U.S.
−Removed: patent and the issued Australian patents would be expected to expire in 2037, absent any applicable patent term extensions.
+Added: patent 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.
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As of December 31, 2021, we owned one issued U.S.
−Removed: patent, approximately three pending U.S.
−Removed: patent applications, more than 15 pending foreign patent applications, and one pending PCT patent application.
+Added: patent, six pending U.S.
+Added: patent applications, more than 15 pending foreign patent applications, and two pending PCT patent applications.
The issued U.S.
−Removed: patent would be expected to expire in 2037, absent any applicable patent term extensions.
+Added: patent would be
+Added: 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 2042, absent any applicable patent term extensions.
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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.
−Removed: As of December 31, 2020, we owned two issued U.S.
−Removed: patents, approximately five pending U.S.
−Removed: patent applications, more than 30 pending patent applications in foreign jurisdictions, and approximately three pending PCT patent applications.
+Added: As of December 31, 2021, we owned three issued U.S.
+Added: patents, seven pending U.S.
+Added: patent applications, and more than 50 pending patent applications in foreign jurisdictions.
The issued U.S.
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compositions, and methods for mobilizing HSCs, and highly engraftable hematopoietic stem cells and their uses.
−Removed: As of December 31, 2020, this patent portfolio includes two issued U.S.
−Removed: patents, approximately six pending U.S.
−Removed: patent applications, and more than 20 pending patent applications in foreign jurisdictions.
+Added: As of December 31, 2021, this patent portfolio included four issued U.S.
+Added: patents, four pending U.S.
+Added: patent applications, and more than 30 patents and pending patent applications in foreign jurisdictions.
The issued U.S.
−Removed: patents would be expected to expire in 2036, absent any applicable patent term extensions.
+Added: patents would be expected to expire in 2034 and 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.
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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.
−Removed: As of December 31, 2020, these families include more than 90 issued patents and pending patent applications in jurisdictions worldwide.
+Added: As of December 31, 2021, these families included 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.
−Removed: Novartis Portfolio
−Removed: We have licensed a patent family from Novartis applicable to our MGTA-456
−Removed: program that is directed to AHR antagonists and their use in the expansion of HSCs.
−Removed: As of December 31, 2020, this family includes two issued U.S.
−Removed: 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.
−Removed: patent applications, and more than 80 issued patents and pending patent applications in jurisdictions worldwide.
−Removed: The issued U.S.
−Removed: patents are expected to expire in 2032 and 2031, respectively, absent any applicable patent term extensions.
−Removed: The issued foreign patents and any patents that may issue from U.S.
−Removed: 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.
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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.
−Removed: 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
−Removed: FDA regulatory review period, subject to certain limitations and provided statutory and regulatory requirements are met.
+Added: 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.
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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.
−Removed: For more information, see the section entitled “Risk Factors—Risks Related to Intellectual Property”.
+Added: For more information, see the section entitled “Item 1A.
+Added: Risk Factors – Risks Related to Intellectual Property.”
Other IP Rights
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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.
−Removed: For more information, see the section entitled “Risk Factors—Risks Related to Intellectual Property”.
+Added: For more information, see the section entitled “Item 1A.
+Added: 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.
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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.
−Removed: 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.
−Removed: 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.
−Removed: drug development
+Added: In addition to the discussion below, see “Item 1A.
+Added: 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.
+Added: Management’s Discussion and Analysis of Financial Condition and Results of Operations” 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.
+Added: drug and biologic development
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.
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a determination by the FDA within 60 days of its receipt of an NDA or BLA to accept the filing for review;
−Removed: satisfactory completion of an FDA pre-approval
−Removed: 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;
+Added: satisfactory completion of one or more FDA pre-approval
+Added: inspections of the manufacturing facility or facilities where the drug or biologic will be produced to assess compliance with 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;
+Added: payment of user fees for FDA review 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.
−Removed: 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
+Added: The preclinical and clinical testing and approval process requires substantial time, effort and financial resources, and the regulatory scheme for drugs and biologics is evolving and subject to change at any time.
+Added: We cannot be certain that any approvals for MGTA-117,
and any other current or future product candidates will be granted on a timely basis, or at all.
Preclinical studies and IND
+Added: Before testing any drug or biological candidate in humans, the product candidate must undergo rigorous preclinical testing.
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.
−Removed: The conduct of preclinical studies is subject to federal regulations and requirements, including GLP regulations for safety/toxicology studies.
+Added: The conduct of preclinical studies is subject to federal and state 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.
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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.
−Removed: The primary purpose of these clinical trials is to assess the metabolism, pharmacologic action, side effect tolerability and safety of the drug.
−Removed: Phase 2 clinical trials involve studies in disease-affected patients to determine the dose required to produce the desired benefits.
+Added: The primary purpose of these clinical trials is to assess the metabolism, pharmacologic action, side effect tolerability and safety of the product candidate.
+Added: Phase 2 clinical trials involve studies in disease-affected patients to evaluate proof of concept and/or 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.
−Removed: 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.
+Added: 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 candidate 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.
−Removed: These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication.
+Added: These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication and are commonly intended to generate additional safety data regarding use of the product in a clinical setting.
In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of an NDA or BLA.
−Removed: 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
+Added: 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 15 days after the trial sponsor determines the information qualifies for reporting for serious and unexpected suspected adverse events, findings from other studies or 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.
−Removed: Phase 1, Phase 2 and Phase 3 clinical trials may not be completed successfully within any specified period, if at all.
+Added: The sponsor must also notify the FDA of any unexpected fatal or life-threatening
+Added: suspected adverse reaction as soon as possible but in no case later than seven calendar days after the sponsor’s initial receipt of the information.
+Added: Phase 1, Phase 2, Phase 3 and other types of 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.
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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.
−Removed: This group provides authorization for whether a trial may move forward at designated check points based on access to certain data from the trial.
+Added: This group provides authorization for whether a trial may move forward at designated checkpoints 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.
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The application may include both negative and ambiguous results of preclinical studies and clinical trials, as well as positive findings.
−Removed: 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.
+Added: 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
+Added: 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.
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The FDA adjusts the PDUFA user fees on an annual basis.
−Removed: 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.
−Removed: 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.
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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.
−Removed: The FDA generally makes a decision on accepting an NDA or BLA for filing within 60 days of receipt.
+Added: The FDA generally makes a decision on accepting an NDA or BLA for filing within 60 days of receipt, and such decision could include a refusal to file by the FDA.
Once the submission is accepted for filing, the FDA begins an in-depth
review of the NDA or BLA.
−Removed: 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.
+Added: Under the goals and policies agreed to by the FDA under PDUFA, the FDA targets 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.
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The FDA also may audit data from clinical trials to ensure compliance with GCP requirements.
−Removed: 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.
+Added: Additionally, the FDA may refer applications for novel products or 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.
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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.
−Removed: If a Complete Response Letter is issued, the applicant may either resubmit the NDA or BLA, addressing all of the deficiencies
−Removed: identified in the letter, or withdraw the application.
+Added: 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, withdraw the application, or request an opportunity for a hearing.
Even if such data and information are submitted, the FDA may decide that the NDA or BLA does not satisfy the criteria for approval.
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Orphan drug designation
−Removed: 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.
+Added: Under the Orphan Drug Act, the FDA may grant orphan drug 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.
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Orphan drug designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.
−Removed: 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.
+Added: If a product that has orphan drug 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 drug 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
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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.
−Removed: 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.
+Added: Specifically, new drugs and biologics are eligible for fast track designation if they are intended to treat a serious or life-threatening disease or condition and preclinical or clinical data demonstrate the potential to address unmet medical needs for the condition.
Fast track designation applies to both the product and the specific indication for which it is being studied.
+Added: For a fast track-designated product, the FDA may consider sections of the NDA or BLA for review on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the application, the FDA agrees to accept sections of the application and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the application.
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
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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.
−Removed: 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.
−Removed: 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
−Removed: measured earlier than irreversible morbidity or mortality, or IMM, that is reasonably likely to predict an effect on IMM or other clinical benefit.
+Added: A product may also be eligible for accelerated approval if it is designed to treat a serious or life-threatening disease or condition and demonstrates an effect on either 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, taking into account the severity, rarity, or prevalence of the disease or condition and the availability or lack of alternative treatments.
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.
−Removed: 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.
−Removed: 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.
+Added: The FDA may also withdraw approval of a drug or indication approved under accelerated approval if, for example, the confirmatory trial fails to verify the predicted clinical benefit of the product.
+Added: In addition, the FDA currently requires, unless otherwise informed by the agency, pre-approval
+Added: of promotional materials for products receiving accelerated approval, which could adversely impact the timing of the commercial launch of the product.
+Added: Additionally, a drug or biologic may be
+Added: 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.
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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.
−Removed: 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.
−Removed: 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.
−Removed: 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.
+Added: 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 product candidate has the potential to address unmet medical needs for such disease or condition.
+Added: A sponsor may request that the FDA designate a product candidate as an RMAT concurrently with, or at any time after, submission of an IND.
+Added: The FDA has 60 calendar days to determine whether the product candidate meets the criteria, including whether there is preliminary clinical evidence indicating that the product candidate 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.
−Removed: 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;
−Removed: the collection of larger confirmatory data sets;
−Removed: or post-approval monitoring of all patients treated with such therapy prior to its approval.
+Added: A product candidate 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.
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Post-marketing requirements
−Removed: 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
+Added: 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
+Added: 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.
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Product approvals may be withdrawn for non-compliance
−Removed: with regulatory standards or if problems occur following initial marketing.
+Added: with regulatory standards or if problems occur following initial marketing or if the FDA determines that the product is no longer safe or effective.
FDA regulations require that products be manufactured in specific approved facilities and in accordance with cGMP regulations.
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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.
−Removed: For a novel therapeutic product for which a
−Removed: 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.
+Added: 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.
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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.
+Added: Among other things, HITECH makes HIPAA’s privacy and security standards directly applicable to “business associates,” those independent contractors or agents of covered entities that create, receive, maintain, transmit or obtain protected health information in connection with providing a service on behalf of a covered entity.
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.
−Removed: 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.
−Removed: Effective January 1, 2022, these reporting obligations will extend to include transfers of value made to certain non-physician
+Added: The Physician Payments Sunshine Act of 2010, as amended by the Health Care and Education Reconciliation Act, 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.
+Added: Effective January 1, 2022, these reporting obligations extend to include transfers of value made to certain non-physician
providers such as physician assistants and nurse practitioners.
+Added: Federal government price reporting laws require us to calculate and report complex pricing metrics in an accurate and timely manner to government programs.
+Added: Additional federal consumer protection and unfair competition laws broadly regulate marketplace activities and activities that potentially harm consumers.
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.
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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.
−Removed: 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.
+Added: Further, the CCPA creates a private right of action for certain data breaches that result in the loss of personal information of California residents, and this private right of action may increase the likelihood of, and risks associated with, data breach litigation.
+Added: Currently, clinical trial data and information governed by HIPAA are exempt from the current version of the CCPA, but 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.
−Removed: 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.
−Removed: 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.
−Removed: 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
−Removed: other healthcare laws and regulations.
−Removed: 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.
−Removed: 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.
−Removed: 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.
+Added: The CPRA also creates a new state agency that will be vested with authority to implement and enforce the CCPA and the CPRA.
+Added: Similar laws have been proposed, and likely will be proposed, in other states and at the federal level, and if passed, such laws may have potentially conflicting requirements that would make compliance challenging.
+Added: For example, on March 2, 2021, the Virginia Consumer Data Protection Act, or CDPA, was signed into law.
+Added: The CDPA becomes effective January 1, 2023 and contains provisions that, in
+Added: addition to other mandates, require businesses subject to the legislation to conduct data protection assessments in certain circumstances and that require opt-in
+Added: consent from Virginia consumers to process certain sensitive personal information.
+Added: Further data privacy and security laws and regulations in foreign jurisdictions may be more stringent than those in the U.S.
+Added: (such as the European Union, which adopted the GDPR, which became effective in May 2018).
+Added: Analogous state laws may additionally govern the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and may not have the same effect.
+Added: Pricing and rebate programs must comply with the Medicaid rebate requirements of the U.S.
+Added: Omnibus Budget Reconciliation Act of 1990 and more recent requirements in the Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, or collectively the ACA.
+Added: If products are made available to authorized users of the Federal Supply Schedule of the General Services Administration, additional laws and requirements apply.
+Added: Products must meet applicable child-resistant packaging requirements under the U.S.
+Added: Poison Prevention Packaging Act.
+Added: Manufacturing, sales, promotion and other activities also are potentially subject to federal and state consumer protection and unfair competition laws.
Current and Future Legislation
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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.
−Removed: 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:
+Added: In March 2010, the Congress enacted 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;
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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.
−Removed: 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.
−Removed: For example the Tax Cuts and Jobs Act of 2017, or TCJA, includes a provision that decreased, effective January 1, 2019, the tax-based
−Removed: 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.
−Removed: On December 14, 2018, a U.S.
−Removed: 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.
−Removed: 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.
−Removed: On March 2, 2020, the U.S.
−Removed: Supreme Court granted the petitions for writs of certiorari to review this case, and held oral arguments on November 10, 2020.
−Removed: It is unclear what effect this will have on the status of the ACA.
−Removed: Congress may also consider other legislation to repeal or replace certain elements of the ACA.
−Removed: 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.
−Removed: 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.
−Removed: Further, on October 13, 2017, President Trump signed an Executive Order terminating the cost-sharing subsidies that reimburse insurers under the ACA.
−Removed: 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.
−Removed: 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.
+Added: Since its enactment, there have been numerous judicial, administrative, executive, and legislative challenges to certain aspects of the ACA.
+Added: On June 17, 2021, the U.S.
+Added: Supreme Court dismissed the most recent judicial
+Added: challenge to the ACA brought by several states without specifically ruling on the constitutionality of the ACA.
+Added: Prior to the Supreme Court’s decision, President Biden issued an executive order to initiate a special enrollment period from February 15, 2021 through August 15, 2021 for purposes of obtaining health insurance coverage through the ACA marketplace.
+Added: The executive order also instructed certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare including, among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the ACA.
+Added: It is unclear how other healthcare reform measures of the Biden administrations or other efforts, if any, to challenge repeal or replace the ACA, will impact our business.
+Added: Prior to the Biden administration, on October 13, 2017, former President Trump signed an executive order terminating the cost-sharing subsidies that reimburse insurers under the ACA.
+Added: The Trump administration 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 those appropriations were made.
+Added: 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.
On August 14, 2020, the U.S.
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Further, on June 14, 2018, the U.S.
−Removed: 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.
−Removed: On April 27, 2020, the U.S.
−Removed: Supreme Court reversed the U.S.
−Removed: Court of Appeals for the Federal Circuit decision and remanded the case to the U.S.
+Added: 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 the payments were owed to them.
+Added: On April 27, 2020, the United States Supreme Court reversed the U.S.
+Added: Court of Appeals for the Federal Circuit’s 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.
−Removed: 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.
+Added: 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 marketplaces, 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.
+Added: In addition, on May 30, 2018, the Right to Try Act was signed into law.
+Added: The Right to Try Act, among other things, provides a federal framework for certain patients to access certain investigational new drug products that have completed a Phase 1 clinical trial and that are undergoing investigation for FDA approval.
+Added: Under certain circumstances, eligible patients can seek treatment without enrolling in clinical trials and without obtaining FDA permission under the FDA expanded access program.
+Added: There is no obligation for a pharmaceutical manufacturer to make its drug products available to eligible patients as a result of the Right to Try Act.
Packaging and Distribution in the U.S.
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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.
+Added: Manufacturers and other parties involved in the drug supply chain for prescription drug products must also comply with product tracking and tracing requirements and requirements to notify the FDA of counterfeit, diverted, stolen and intentionally adulterated products or products that are otherwise unfit for distribution in the U.S.
The failure to comply with any of these laws or regulatory requirements subjects firms to possible legal or regulatory action.
−Removed: 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.
+Added: Depending on the circumstances, failure to meet applicable regulatory requirements can result
+Added: 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.
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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.
−Removed: Market exclusivity provisions under the FDCA also can delay the submission or the approval of certain applications.
+Added: Marketing 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
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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.
−Removed: 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
−Removed: required for approval.
+Added: 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.
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basis with data submitted by the sponsor.
−Removed: Pediatric exclusivity is another type of regulatory market exclusivity in the U.S.
+Added: Pediatric exclusivity is another type of regulatory marketing exclusivity in the U.S.
Pediatric exclusivity, if granted, adds six months to existing regulatory exclusivity periods.
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As in the U.S., medicinal products can be marketed only if a marketing authorization from the competent regulatory agencies has been obtained.
−Removed: Similar to the U.S., the various phases of preclinical and clinical research in the European Union are subject to significant regulatory controls.
−Removed: 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.
−Removed: This has led to significant variations in the member state regimes.
−Removed: 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:
−Removed: the National Competent Authority, or NCA, and one or more Ethics Committees, or ECs.
−Removed: 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.
−Removed: 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.
−Removed: 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.
−Removed: 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.
−Removed: 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.
+Added: In April 2014, the European Union adopted a new Clinical Trials Regulation (EU) No 536/2014, which replaced the previous Clinical Trials Directive 2001/20/EC on January 31, 2022.
+Added: It overhauls 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.
+Added: The new Clinical Trials Regulation also 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.
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.
−Removed: 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.
+Added: The provision of benefits or advantages to induce or reward improper performance generally is typically 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.
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European Union drug review and approval
−Removed: 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.
+Added: In the European Union, medicinal products can only be commercialized after obtaining a marketing authorization, or MA.
There are two types of marketing authorizations.
−Removed: 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.
−Removed: 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.
−Removed: 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.
+Added: 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 European Medical Agency, or EMA, and is valid throughout the European Union.
+Added: 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
+Added: HIV, AIDS, cancer, neurodegenerative disorders, diabetes, auto-immune and other immune dysfunctions and viral diseases.
+Added: The centralized procedure is optional for products containing a new active substance not yet authorized in the European Union, 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.
−Removed: Clock stops may extend the timeframe of evaluation of a MAA considerably beyond 210 days.
+Added: Clock stops may extend the timeframe of evaluation of an 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.
−Removed: 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.
−Removed: 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.
−Removed: 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.
−Removed: 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.
−Removed: 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.
−Removed: 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.
−Removed: 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).
−Removed: 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.
+Added: The timeframe for the evaluation of an 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.
+Added: National MAs, which are issued by the competent authorities of the European Union Member States and only cover their respective territory, are available for products not falling within the mandatory scope of the centralized procedure.
+Added: Where a product has already been authorized for marketing in a European Union Member State, this national MA can be recognized in other European Union Member States through the mutual recognition procedure.
+Added: If the product has not received a national MA in any European Union Member State at the time of application, it can be approved simultaneously in various European Union Member States through the decentralized procedure.
+Added: Under the decentralized procedure an identical dossier is submitted to the competent authorities of each of the European Union Member States in which an MA is sought, one of which is selected by the applicant as the Reference Member State, or RMS.
+Added: 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 European Union Member States (referred to as the Concerned Member States) for their approval.
+Added: 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 European Union Member States (i.e., in the RMS and the Concerned Member States).
+Added: Under the above described procedures, before granting a MA, the EMA or the competent authorities of the European Union Member States 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.
−Removed: (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).
+Added: (which comprises Great Britain and Northern Ireland) has left the European Union, Great Britain is no longer covered by centralized MAs (under the Northern Ireland 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.
−Removed: For a period of two years from January 1,
−Removed: 2021, the Medicines and Healthcare products Regulatory Agency, or MHRA, the U.K.
+Added: 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.
−Removed: 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.
+Added: The MHRA also has the power to have regard to MAs approved in the European Union Member States through decentralized or mutual recognition procedures with a view to more quickly granting an MA in the U.K.
or Great Britain.
European Union market and data exclusivity
−Removed: In the EEA, innovative medicinal products qualify for eight years of data exclusivity upon marketing authorization and an additional two years of market exclusivity.
+Added: In the European Union, 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
−Removed: and clinical trial data contained in the dossier of the reference product when applying for a generic or biosimilar marketing authorization in the EAA.
+Added: and clinical trial data contained in the dossier of the reference product when applying for a generic or biosimilar marketing authorization in the European Union.
During the additional two-year
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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.
−Removed: 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.
+Added: 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 a marketing authorization application with a complete independent data package of pharmaceutical tests, preclinical tests and clinical trials.
European Union orphan designation and exclusivity
−Removed: 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.
+Added: In the European Union, the EMA’s Committee for Orphan Medicinal Products grants orphan 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 European Union 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).
−Removed: 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.
−Removed: 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.
−Removed: 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.
−Removed: 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;
−Removed: (ii) the marketing authorization holder consents to such revocation;
−Removed: or (iii) the marketing authorization holder cannot supply enough orphan medicinal product.
−Removed: Orphan drug designation must be requested before submitting an application for marketing approval.
−Removed: Orphan drug designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.
−Removed: From January 1, 2021, a separate process for orphan drug designation will apply in Great Britain.
+Added: In the European Union, orphan 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.
+Added: During this market exclusivity period, neither the EMA nor the European Commission nor any of the competent authorities in the European Union 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.
+Added: This period may be reduced to six years if the orphan designation criteria are no longer met, including where it is shown that the product is sufficiently profitable not to justify maintenance of market exclusivity.
+Added: 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 to an authorized orphan product;
+Added: (ii) the marketing authorization holder for the authorized orphan product consents to such revocation;
+Added: or (iii) the marketing authorization holder for the authorized orphan product cannot supply enough orphan medicinal product.
+Added: Orphan designation must be requested before submitting an application for marketing approval.
+Added: Orphan designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.
+Added: From January 1, 2021, a separate process for orphan designation will apply in Great Britain.
There will be no pre-marketing
−Removed: 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.
−Removed: 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).
+Added: authorization orphan designation (as there is in the European Union) and the application for orphan designation will be reviewed by the MHRA, at the time of the marketing authorization application.
+Added: The criteria are the same as in the European Union, 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).
+Added: The aforementioned European Union rules are generally applicable in the European Economic Area (comprising the European Union Member States plus Norway, Iceland and Liechtenstein).
Brexit and the Regulatory Framework in the U.K.
On June 23, 2016, the electorate in the U.K.
−Removed: voted in favor of leaving the European Union (commonly referred to as Brexit).
−Removed: 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.
+Added: voted in favor of leaving the European Union (commonly referred to as Brexit) and the U.K.
formally left the European Union on January 31, 2020.
−Removed: A transition period began on February 1, 2020, during which European Union pharmaceutical law remained applicable to the U.K.
−Removed: and ended on December 31, 2020.
−Removed: Since the regulatory framework for pharmaceutical products in the U.K.
−Removed: 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.
−Removed: legislation now has the potential to diverge from European Union legislation.
+Added: A transition period began on February 1, 2020, during which European Union pharmaceutical law remained applicable to the U.K., which ended on December 31, 2020.
+Added: However, the European Union and the U.K.
+Added: have concluded a trade and cooperation agreement, or TCA, which was provisionally applicable since January 1, 2021 and has been formally applicable since May 1, 2021.
+Added: The TCA includes specific provisions concerning pharmaceuticals, which include the mutual recognition of good manufacturing practice, inspections of manufacturing facilities for medicinal products and good manufacturing practice documents issued, but does not foresee wholesale mutual recognition of U.K.
+Added: and European Union pharmaceutical regulations.
+Added: At present, Great Britain has implemented European Union legislation on the marketing, promotion and sale of medicinal products through the Human Medicines Regulations 2012 (as amended) (under the Northern Ireland Protocol, the European Union regulatory framework will continue to apply in Northern Ireland).
+Added: The regulatory regime in Great Britain therefore currently aligns with European Union regulations, however it is possible that these regimes will diverge in future now that Great Britain’s regulatory system is independent from the European Union and the TCA does not provide for mutual recognition of U.K.
+Added: and European Union pharmaceutical 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.
−Removed: 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
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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.
−Removed: This may be onerous and adversely affect our business, financial condition, results of operations and prospects.
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.
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GDPR may result in monetary penalties of up to £17.5 million or 4% of worldwide revenue, whichever is higher.
−Removed: 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.
−Removed: will be restricted unless an appropriate safeguard, as recognized by the European Union’s GDPR, has been put in place.
−Removed: Although, under the EU-U.K.
−Removed: Trade Cooperation Agreement it is lawful to transfer personal data between the U.K.
−Removed: 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.
−Removed: Like the European Union GDPR, the U.K.
−Removed: GDPR restricts personal data transfers outside the U.K.
−Removed: to countries not regarded by the U.K.
−Removed: as providing adequate protection (this means that personal data transfers from the U.K.
−Removed: to the EEA remain free flowing).
−Removed: Compliance with the GDPR and the U.K.
−Removed: 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
−Removed: 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.
+Added: In addition, on June 28, 2021, the European Commission adopted an adequacy decision in respect of transfers of personal data to the U.K.
+Added: for a four-year period (until June 27, 2025).
+Added: Similarly, the U.K.
+Added: has determined that it considers all of the European Economic Area to be adequate for the purposes of data protection.
+Added: This ensures that data flows between the U.K.
+Added: and the European Economic Area remain unaffected.
Rest of the world regulation
−Removed: 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.
+Added: 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
+Added: 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.
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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
−Removed: 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
−Removed: payor will pay for the product once coverage is approved.
+Added: 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.
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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.
−Removed: 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.
+Added: In addition, as 340B drug pricing is determined based on AMP and Medicaid rebate
+Added: 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.
6 unchanged sentences
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.
−Removed: 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 2030 unless additional Congressional action is taken.
−Removed: 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
+Added: These changes included aggregate reductions to Medicare payments to providers of up to 2% per fiscal year.
+Added: These reductions went into effect on April 1, 2013 and, due to subsequent legislative amendments to the statute, will remain in effect through 2030, with the exception of a temporary suspension from May 1, 2020 through March 31, 2022.
+Added: Then, a 1% payment reduction will occur beginning April 1, 2022 through June 30, 2022, and the 2% payment reduction will resume on July 1, 2022.
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.
1 unchanged sentence
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.
−Removed: 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
−Removed: drug costs for patients, and increase patient access to lower-cost generic and biosimilar drugs.
−Removed: 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
−Removed: pharmacy expenses, provide an option to cap Medicare Part D beneficiary monthly out-of-pocket
−Removed: expenses, and place limits on pharmaceutical price increases.
−Removed: Additionally, the Trump administration previously released a “Blueprint” to reduce the cost of drugs.
−Removed: HHS has solicited feedback on some measures and has implemented others under its existing authority.
−Removed: 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.
+Added: In addition, there has recently been heightened governmental scrutiny of the manner in which manufacturers set prices for their marketed products, which has resulted in several Congressional inquiries, proposed and enacted legislation and executive orders issued by the former Trump administration designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drug products.
+Added: The likelihood of success of these and other measures initiated by the former Trump administration is uncertain, particularly in light of the Biden administration.
+Added: At the federal level, President Biden signed an executive order on July 9, 2021 affirming the administration’s policy to (i) support legislative reforms that would lower the prices of prescription drug and biologics, including by allowing Medicare to negotiate drug prices, imposing inflation caps and supporting the development and market entry of lower-cost generic drugs and biosimilars;
+Added: and (ii) support the enactment of a public health insurance option.
+Added: Among other things, the executive order also directs HHS to provide a report on actions to combat excessive pricing of prescription drugs, to enhance the domestic drug supply chain, to reduce the price that the federal government pays for drugs, and to address price gouging in the industry;
+Added: and directs the FDA to work with states and Indian Tribes that propose to develop section 804 Importation Programs in accordance with the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, and the FDA’s implementing regulations.
+Added: The FDA released such implementing regulations on September 24, 2020, which went into effect on November 30, 2020, providing guidance for states to build and submit importation plans for drugs
+Added: Further, on November 20, 2020, CMS issued an Interim Final Rule implementing the Most Favored Nation, or MFN, Model under which Medicare Part B reimbursement rates will be calculated for certain drugs and biologicals based on the lowest price drug manufacturers receive in Organization for Economic Cooperation and Development countries with a similar gross domestic product per capita.
+Added: On December 29, 2021 CMS rescinded the Most Favored Nations rule.
+Added: Further, authorities in Canada have passed rules designed to safeguard the Canadian drug supply from shortages.
+Added: If implemented, importation of drugs from Canada may materially and adversely affect the price we receive for any of our product candidates.
+Added: Additionally, on December 2, 2020, HHS published a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.
+Added: The rule also creates a new safe harbor for price reductions reflected at the point-of-sale,
+Added: as well as a safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers.
+Added: on December 2, 2020, HHS published a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.
+Added: The rule also creates a new safe harbor for price reductions reflected at the point-of-sale,
+Added: as well as a safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers.
+Added: Pursuant to court order, the removal and addition of the aforementioned safe harbors were delayed and recent legislation imposed a moratorium on implementation of the rule until January 1, 2026.
+Added: On May 2019, CMS issued a final rule to allow Medicare Advantage Plans the option of using step therapy, a type of prior authorization for Medicare Part B drugs, beginning January 1, 2020.
This final rule codified CMS’s policy change that was effective January 1, 2019.
+Added: Although a number of these and other proposed measures may require authorization through additional legislation to become effective, and the Biden Administration may reverse or otherwise change these measures, both the Biden Administration and Congress have indicated that it will continue to seek new legislative measures to control drug costs.
+Added: The Drug Supply Chain Security Act imposes new obligations on manufacturers of pharmaceutical products related to product tracking and tracing.
+Added: Legislative and regulatory proposals have been made to expand post-approval requirements and restrict sales and promotional activities for pharmaceutical products.
+Added: We are not sure whether additional legislative changes will be enacted, or whether the current regulations, guidance or interpretations will be changed, or what the impact of such changes on our business, if any, may be.
At the state level, legislatures have become increasingly aggressive in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing.
6 unchanged sentences
Reference pricing used by various European Union member states and parallel distribution, or arbitrage between low-priced
−Removed: and high-priced member states, can further reduce prices.
+Added: and high-priced member states, can further reduce
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.
1 unchanged sentence
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.
−Removed: Historically, products launched in the European Union do not follow price structures of the U.S.
−Removed: and generally prices tend to be significantly lower.
−Removed: 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.
−Removed: 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.
−Removed: Employees and Human Capital
+Added: An increasing number of countries are taking initiatives to attempt to reduce large budget deficits by focusing cost-cutting efforts on pharmaceuticals for their state-run
+Added: health care systems.
+Added: These international price control efforts have impacted all regions of the world, but have been most drastic in the European Union.
+Added: Human Capital Resources
As of December 31, 2021, we had 75 full-time employees, 25 of our employees have Ph.D.
6 unchanged sentences
For additional information on the impact of COVID-19
−Removed: on our employees, see “Management’s Discussion and Analysis of Financial Condition and Results of Operations—Impact of the COVID-19
+Added: on our employees, see “Item 7.
+Added: Management’s Discussion and Analysis of Financial Condition and Results of Operations – Impact of the Ongoing COVID-19
Our Corporate Information
1 unchanged sentence
In February 2016, we changed our name to Magenta Therapeutics, Inc.
−Removed: 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.
−Removed: Upon the closing of the IPO, our outstanding redeemable convertible preferred stock automatically converted into shares of common stock.
−Removed: 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:
−Removed: (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
−Removed: 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
+Added: (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, as defined in Rule 12b-2
+Added: under the Securities and Exchange Act of 1934, as amended, or the Exchange Act, and (ii) the date on which we have issued more than $1.0 billion in non-convertible
debt during the prior three-year period.
−Removed: We are also a “smaller reporting company” as defined in the Securities and Exchange Act of 1934, as amended, or the Exchange Act.
+Added: We are also a “smaller reporting company” as defined in the Exchange Act.
We may continue to be a smaller reporting company even after we are no longer an emerging growth company.
18 unchanged sentences
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.