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Item 1. Business

2021-02-25 compared with 2020-02-19 · 373 added, 372 removed, 831 unchanged (47% of the section changed)

We are a biopharmaceutical company committed to the fundamental transformation of patients’ lives through scientific leadership in the field of cellular metabolism and adjacent areas of biology, with the goal of creating differentiated, small molecule medicines for patients in the areas of hematologic malignancies, solid tumors and rare genetic diseases, or RGDs.

To address these focus areas, we take a systems biology approach to deeply understand disease states, drive the discovery and validation of novel therapeutic targets, and define patient selection strategies, thereby increasing the probability that our experimental medicines will have the desired therapeutic effect.

We are a biopharmaceutical company committed to transforming patients’ lives through scientific leadership in the field of cellular metabolism and adjacent areas of biology, with the goal of creating differentiated, small molecule medicines in the areas of genetically defined diseases, or GDDs, and, until the completion of the sale of our oncology business to Servier as described below, hematologic malignancies and solid tumors.

To address our focus areas, we take a systems biology approach to deeply understand disease states, drive the discovery and validation of novel therapeutic targets, and define patient selection strategies, thereby increasing the probability that our experimental medicines will have the desired therapeutic effect.

Proposed Sale of Oncology Business to Servier Pharmaceuticals, LLC (Servier)

On December 20, 2020, we entered into a Purchase and Sale Agreement, or the Purchase Agreement, with Servier.

The Purchase Agreement provides for the sale of our commercial, clinical and research-stage oncology portfolio assets and pipeline, or oncology business, for a payment of $1.8 billion in cash at the closing, subject to certain adjustments for working capital of the oncology business at the closing and amounts for a representation and warranty insurance policy, and a payment of $200 million in cash, if, prior to January 1, 2027, vorasidenib is granted new drug application, or NDA, approval from the U.S.

Food and Drug Administration, or FDA, with an approved label that permits vorasidenib’s use as a single agent for the adjuvant treatment of patients with Grade 2 glioma that have an isocitrate dehydrogenase 1 or 2, or IDH1 or IDH2, mutation (and, to the extent required by such approval, the vorasidenib companion diagnostic test is granted an FDA premarket approval), as well as a royalty of 5% of U.S.

net sales of TIBSOVO® from the close of the transaction through loss of exclusivity of TIBSOVO® and a royalty of 15% of U.S.

net sales of vorasidenib from the first commercial sale of vorasidenib through loss of exclusivity of vorasidenib.

The transaction includes the proposed sale of our oncology business, including TIBSOVO®, our clinical-stage product candidates vorasidenib, AG-270 and AG-636, and our oncology research programs.

Servier will also acquire our co-commercialization rights for Bristol Myers Squibb’s IDHIFA®, the $25.0 million potential milestone payment, and conduct certain clinical development activities within the IDHIFA® development program.

The proposed sale has been approved by our Board of Directors.

The parties’ obligations to consummate the proposed sale are subject to customary conditions, including the approval of the sale by the holders of at least a majority of our outstanding shares of common stock, the expiration or termination of the applicable waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976, as amended, and the receipt of required regulatory approvals in Germany.

Our Board of Directors may cause us to terminate the Purchase Agreement in order to enter into a definitive agreement relating to a superior proposal, subject to complying with certain conditions set forth in the Purchase Agreement, including giving Servier the opportunity to negotiate changes to the terms of the Purchase Agreement so that such superior proposal no longer constitutes a superior proposal.

If we terminate the Purchase Agreement in order to enter into a definitive agreement with respect to a superior proposal, we may be required to pay to Servier a termination fee of $45 million prior to or concurrently with such termination.

We currently expect to complete the transaction at the end of the first quarter of or in the beginning of the second quarter of 2021, although we cannot assure completion by any particular date, if at all.

If the transaction is completed, we will no longer operate the oncology business and our Board of Directors expects to use the proceeds from the completion of the transaction to focus on advancing our GDD business and returning a significant portion of the proceeds to our stockholders.

Notwithstanding this present expectation, our Board may use the proceeds of the transaction for other purposes for the benefit of us and our stockholders, and in connection therewith may find it necessary or advisable to use portions of the proceeds from the transaction for different or presently non-contemplated purposes.

The discussion of our business in his Annual Report on Form 10-K reflects our business as it exists on the date hereof and does not give effect to the proposed sale of our oncology business to Servier.

If the transaction closes, we will be a smaller, less diversified company with a more limited business concentrated on GDDs.

As a result, we may be more susceptible to changing market conditions, including fluctuations and risks particular to the markets for patients with GDDs, than a more diversified company, which could adversely affect our business, financial condition and results of operations.

In addition, the diversification of our revenues, costs and cash flows will diminish following the transaction, such that our results of operations, cash flows, working capital and financing requirements may be subject to increased volatility and our ability to fund capital expenditures and investments or satisfy other financial commitments may be diminished.

Business Overview

Hematologic Malignancies and Solid Tumors

Our wholly-owned product, TIBSOVO® (ivosidenib) is an oral targeted inhibitor of the mutated isocitrate dehydrogenase 1, or IDH1 enzyme.

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Food and Drug Administration, or FDA-approved therapy for the treatment of adult patients with (i) relapsed or refractory acute myeloid leukemia, or R/R AML, with a susceptible IDH1 mutation as detected by an FDA-approved test (approved by the FDA in July 2018) and (ii) newly diagnosed AML with a susceptible IDH1 mutation as detected by an FDA-approved test who are at least 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy (approved by the FDA in May 2019).

In December 2018, we submitted an Marketing Authorization Application, or MAA, to the European Medicines Agency, or EMA, for TIBSOVO® for the treatment of adult patients with R/R AML with an IDH1 mutation.

In December 2018, we submitted a Marketing Authorization Application, or MAA, to the European Medicines Agency, or EMA, for TIBSOVO® for the treatment of adult patients with R/R AML with an IDH1 mutation.

In October 2020, we announced the withdrawal of the MAA based on feedback from the EMA's Committee for Medicinal Products for Human Use (CHMP) that the available clinical data from our single arm, uncontrolled Phase 1 trial did not sufficiently support a positive benefit-risk balance for the proposed indication.

In addition, we are currently evaluating ivosidenib in the clinical trials described below.

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In August 2017, the FDA granted our collaboration partner Celgene approval of IDHIFA® for the treatment of adult patients with R/R AML and an IDH2, mutation as detected by an FDA-approved test.

We are eligible to receive royalties at tiered low-double digit to mid-teen percentage rates on any net sales of IDHIFA® and have exercised our rights to provide up to one-third of the field-based commercialization efforts in the United States.

We were eligible to receive royalties at tiered low-double digit to mid-teen percentage rates on any net sales of IDHIFA® and have exercised our rights to provide up to one-third of the field-based commercialization efforts in the United States.

In June 2018, Celgene submitted an MAA to the EMA for IDHIFA® for IDH2 mutant-positive AML which it subsequently withdrew in December 2019.

On June 11, 2020 we sold our tiered, sales-based royalty rights on worldwide net sales of IDHIFA®, as well as our rights to receive up to $55.0 million in outstanding regulatory milestone payments from Bristol Myers Squibb, or BMS, to Royalty Pharma, or RPI, for $255.0 million.

In addition, we and Celgene are currently evaluating enasidenib in the clinical trials described below.

Our pre-commercial clinical cancer product candidates are vorasidenib, AG-270, and AG-636.

Our pre-commercial clinical cancer product candidates are vorasidenib and AG-270.

We are developing vorasidenib for the treatment of IDH mutant-positive low grade glioma.

Vorasidenib is an orally available, selective brain-penetrant pan-IDH mutant inhibitor.

We are developing vorasidenib for the treatment of IDH mutant-positive low grade glioma and are currently evaluating vorasidenib in the clinical trials described below.

We are currently evaluating vorasidenib in the clinical trials described below.

We are developing AG-270 for the treatment of cancers carrying a methylthioadenosine phosphorylase, or MTAP, deletion, which is present in approximately 15 percent of all cancers.

AG-270 is an orally available selective potent inhibitor of methionine adenosyltransferase 2a, or MAT2A.

We are currently evaluating AG-270 in a phase 1 dose-escalation and expansion trial in multiple tumor types carrying a methylthioadenosine phosphorylase, or MTAP, deletion, described below.

AG-636 is an inhibitor of the metabolic enzyme dihydroorotate dehydrogenase, or DHODH.

We are currently evaluating AG-636 in the phase 1 dose-escalation trial in lymphoma described below.

The lead product candidate in our RGD portfolio, mitapivat, is an activator of both wild-type and mutant pyruvate kinase-R for the potential treatment of hemolytic anemias.

On March 25, 2020, Celgene declined to exercise its right to opt into co-development and co-commercialization for AG-270, our MAT2A inhibitor development program, under our 2016 global research and collaboration agreement with Celgene, or the 2016 Agreement.

We are currently evaluating AG-270 in a phase 1 dose-escalation and expansion trial in multiple tumor types carrying a MTAP, deletion, described below.

In the first quarter of 2020, we made the decision to cease the internal development of AG-636 for the treatment of hematologic malignancies, including lymphoma due to limited enrollment in our phase 1 trial in lymphoma.

AG-636 is an inhibitor of the metabolic enzyme dihydroorotate dehydrogenase, or DHODH , licensed by us from Aurigene Discovery Technologies Limited, or Aurigene.

Genetically defined diseases

The lead product candidate in our genetically defined disease, or GDD, portfolio, mitapivat, is an activator of both wild-type and mutant pyruvate kinase-R, or PKR, for the potential treatment of hemolytic anemias.

We are currently evaluating mitapivat for the treatment of pyruvate kinase, or PK, deficiency, thalassemia and sickle cell disease, or SCD, in the clinical trials described below.

In addition to the aforementioned development programs, we are seeking to advance a number of early-stage discovery programs in our focus areas of malignant hematology, solid tumors and RGDs based on our scientific leadership in the field of cellular metabolism and adjacent areas of biology.

We are also developing AG-946, a next-generation PKR activator, for the potential treatment of hemolytic anemias and other indications.

In addition to the aforementioned development programs, we are seeking to advance a number of early-stage discovery programs in our focus areas of GDDs, malignant hematology and solid tumors based on our scientific leadership in the field of cellular metabolism and adjacent areas of biology.

Our approach to drug discovery involves collaboration across our core capabilities in bioinformatics, functional genomics, proteomics and metabolomics.

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Our Strategy and Long Term Goals

We aim to build a sustainable, multi-product company, based on our expertise in cellular metabolism and adjacent biology that creates differentiated, small molecule medicines for patients in the areas of malignant hematology, solid tumors and RGDs.

As part of our long term strategy, we have developed and articulated a strategic vision that delineates our expected evolution in light of our expected singular focus on accelerating and expanding our GDD business and our proposed sale of our oncology business to Servier.

We aim to build a sustainable, multi-product company, based on our expertise in cellular metabolism and adjacent biology that creates differentiated, small molecule medicines for patients.

Key elements of our strategy include:

• Building a preeminent independent biopharmaceutical company by aggressively pursuing the discovery, development and commercialization of novel medicines to transform the lives of patients with hematological malignancies, solid tumors and RGDs.

• Building a preeminent independent biopharmaceutical company by aggressively pursuing the discovery, development and commercialization of novel medicines to transform the lives of patients.

• Maintaining our focus on bio-marker driven drug discovery and development for defined patient subsets with high unmet need.

• Collaborating closely with the FDA and other regulatory bodies to aggressively pursue early registration potential for our product candidates.

As part of our long term strategy, we have developed and articulated a strategic vision that delineates our view for growth over the next six years, which we call “Agios 2025.” Under this plan, by the end of 2025, our goal is to have four marketed medicines discovered and developed by us, with regulatory approvals in at least eight indications spanning hematologic malignancies, solid tumors and RGDs;

to have at least six molecules in clinical development fueled by our internal research discovery engine;

and to become cash flow positive.

Specifically, our plan includes (i) obtaining regulatory approvals for mitapivat in PK deficiency, thalassemia and SCD, (ii) advancing at least five internally discovered molecules in clinical development spanning ten indications, (iii) fostering a robust research pipeline enabling us to submit IND applications every 12-24 months, and (iv) funding our operations through major catalysts as we approach cash-flow positivity without the need for additional follow-on equity offerings.

Our Guiding Principles

We are driven by a disciplined focus on developing medicines that transform the lives of patients with hematological malignancies, solid tumors and RGDs.

We are driven by a disciplined focus on developing medicines that transform the lives of patients.

We maintain a culture of high integrity that embraces the following guiding principles, which we believe will provide long-term benefits for all our stakeholders:

• Follow the science and do what is right for patients.

• Follow the science based on our chosen focus and do what is right for patients.

• Maintain a culture of incisive decision-making driven by deep scientific interrogation and respectful irreverence.

• Foster a collaborative spirit that includes all employees regardless of function or level.

• Leverage deep strategic relationships with our academic and commercial partners to improve the quality of our discovery and development efforts.

• Leverage deep strategic relationships with our academic and commercial partners to continuously improve the quality of our discovery and development efforts.

Cellular Metabolism

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Enzymes catalyze quick and efficient reactions, serve as key regulators of metabolic pathways, and respond to changes in the cell’s environment or signals from other cells.

We believe our deep understanding of metabolic pathways within normal cells enables us to identify altered metabolic pathways within abnormal cells such as in rapidly-proliferating hematologic malignancies, solid tumors and RGDs.

Cancer and cancer metabolism

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Surgery and radiation therapy are particularly effective in patients in whom the disease is localized.

Physicians generally use systemic drug therapies in situations in which the cancer has spread

beyond the primary site or cannot otherwise be treated through surgery.

Physicians generally use systemic drug therapies in situations in which the cancer has spread beyond the primary site or cannot otherwise be treated through surgery.

The goal of drug therapy is to kill cancer cells or to damage cellular components required for rapid growth and survival of cancer cells.

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Examples of effective oncogene-targeted therapies include Herceptin®, Avastin® and Zelboraf®.

Initial oncogene-targeted therapies were directed against mutant forms of cell surface receptors or enzymes involved in cellular signaling and cell growth control.

Initial oncogene-targeted therapies were directed against mutant forms of cell surface receptors or enzymes

involved in cellular signaling and cell growth control.

Recently, the breadth of targets that have been drugged has been expanded to include other classes of mutant enzymes, including epigenetic enzymes, such as genetically altered forms of EZH2, and metabolic enzymes, such as genetically altered forms of IDH1 and IDH2.

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This includes evidence that specific metabolites can act locally in the tumor microenvironment as immuno-suppressants.

We are leveraging our capabilities in bioinformatics, functional genomics, proteomics and metabolomics to identify, validate and drug novel immuno-oncology targets in metabolism and adjacent biology areas, and our efforts in this field are governed by our 2016 global research and collaboration agreement with Celgene, described in more detail below.

Rare genetic diseases

RGDs, a subset of orphan genetic metabolic diseases, are a broad group of more than 600 rare diseases caused by mutations of single metabolic genes.

In these disorders, the defect of a single metabolic enzyme disrupts the normal functioning of a metabolic pathway, leading to either aberrant accumulation of “upstream” metabolites which may be toxic or interfere with normal function, or reduced ability to synthesize essential “downstream” metabolites or other critical cellular components.

RGDs are also referred to as congenital metabolic diseases or rare genetic disorders of metabolism.

Most of these diseases are rare or ultra-rare orphan diseases, often with severe or life-threatening features.

A disorder is considered orphan if it affects fewer than 200,000 people in the United States, or fewer than five per 10,000 people in the European Union, or EU.

In a study in British Columbia, the overall incidence of RGDs was estimated to be 70 per 100,000 live births or one in 1,400 births, overall representing more than approximately 15% of single gene disorders in the population.

Incidence of a single RGD can vary widely but is generally rare, usually equal to or less than one per 100,000 births.

Many RGDs are likely to be under-diagnosed given the lack of available therapies or diagnostics and the rarity of the condition.

Current treatment options for these disorders are limited.

Diet modification or nutrient supplementation can be beneficial in some RGDs.

We are leveraging our capabilities in bioinformatics, functional genomics, proteomics and metabolomics to identify, validate and drug novel immuno-oncology targets in metabolism and adjacent biology areas, and our efforts in this field were governed by our 2016 Agreement, which expired in May 2020, described in more detail below.

Genetically defined diseases

GDDs range from a broad group of more than 600 rare diseases caused by mutations of single genes to conditions resulting from alterations in one or many genes (polygenic diseases) that affect up to millions of patients worldwide.

In these disorders, the defect of single or multiple genes leads to a deficient expression or function in one or several gene products which collectively manifest in organ dysfunction.

As these conditions are by nature congenital and frequently hereditary, they are often detected either by genetic testing or phenotypic diagnosis in newborns or in early childhood.

A typical course of many such diseases is inexorable deterioration until death or to significant irreversible life-long disability and or suffering.

Many of these diseases carry severe or life-threatening features.

Within this disease grouping, a disorder is considered orphan if it affects fewer than 200,000 people in the United States, or fewer than five per 10,000 people in France, Germany, Italy, Spain, United Kingdom, or the EU5.

Many GDDs are likely to be under-diagnosed given the lack of available therapies or diagnostics, the rarity of the condition, or limited understanding of how the disease genetics relate to disease phenotype.

Through the study or GDDs, and other conditions, it has been shown that small molecule therapies able to specifically correct genetic deficiencies and their associated organ dysfunction may have application in conditions that arise independent of patient genetics but for which identical organ dysfunction occurs.

For example, a treatment for an hereditary hemolytic anemia may find direct application in the treatment of a secondarily acquired hemolytic anemia.

Current treatment options for these disorders are generally limited.

Severe and sustained diet modification or nutrient supplementation can be beneficial in certain GDDs.

Several of these disorders, from a group known as lysosomal storage diseases, have been treated successfully with enzyme replacement therapy, or ERT, the therapeutic administration of a functional version of the defective enzyme.

Examples of ERTs for lysosomal storage disorders include Fabrazyme® for Fabry disease, Myozome® for Pompe disease, Cerezyme® for Gaucher disease, and Elaprase® for Hunter syndrome.

Unfortunately, most mutations driving RGDs are intracellular and not amenable for treatment with enzyme replacement therapies.

As a result, despite the promising progress made for patients with a small group of these diseases, the vast majority of patients with RGDs have few therapeutic options available, and the standard of care is palliative, meaning treatment of symptoms with no effect on underlying disease mechanisms.

We are taking a novel small molecule approach to correct the metabolic defects within diseased cells with a goal of developing transformative medicines for patients.

We focus on RGDs that share the following common set of features:

• single gene defect;

• severe clinical presentation with evidence that disease damage is progressive but potentially reversible;

• adequate number of patients for prospective clinical trials;

• an assessment of the target, based upon a detailed mutational, structural, and metabolomic analysis, to determine if a small molecule approach to correcting the disease is possible.

In addition, treatment of polygenic conditions such as achondroplasia by Vosoritide® and the monogenic condition, spinal muscular atrophy by gene therapy with Zolgensma® represent novel technologic approaches to addressing GDDs.

Most mutations driving GDDs are intracellular and not amenable to corrective treatment with enzyme replacement therapies.

Novel technologic approaches such as gene therapy are also being tested in a minority of conditions and is a technology with limited application based on cost, complexity and patient selection factors.

Despite the promising progress made for patients with a small group of these diseases, the majority of patients with GDDs have few therapeutic options, and the standard of care for many such conditions is palliative, meaning treatment of symptoms with no effect on underlying disease mechanisms.

Our goal is to develop mechanistically specific, small molecule approaches with the potential to have disease modifying and long

term rather than palliative effects.

We are taking a novel small molecule approach to correct the defects within diseased cells with a goal of developing transformative medicines for patients.

We focus on GDDs that share the following common set of features:

• Genetic definition of single or multiple gene sets linked to a consistent and recognizable disease phenotype;

• severe clinical presentation coupled with significant unmet medical need and evidence that disease damage while progressive is potentially reversible;

• sufficient patients to allow facile recruitment and statistical powering of prospective clinical trials;

• a rigorous validation of the target, based upon a detailed mutational, structural, cell biological and biochemical analysis, to determine if a small molecule approach to correcting or significantly modifying the disease is both safe and feasible in newborn to elderly patients.

Precision Medicine Approach

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Our Development Programs

We believe that leveraging our core capabilities in cellular metabolism combined with a precision medicine approach has significantly enhanced our ability to build a research and development engine that is focused in the therapeutic areas of malignant hematology, solid tumors and RGDs.

This engine has permitted us to discover proprietary first-in-class orally-available small molecules as potential lead product candidates for each of several novel programs in development.

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The following summarizes our products and most advanced product candidates as of February 1, 2021, each of which is described in further detail below.

As noted above, upon the completion of the sale of our oncology business to Servier we will have a singular focus on accelerating and expanding our development programs in GDDs.

Targeting Mutated IDH for the Treatment of Cancer

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We have shown that the excessive levels of the metabolite 2HG produced by the tumor fuel cancer growth and survival via multiple cellular changes that lead to a block in cell maturation, or differentiation.

We have also shown that inhibition of these mutated proteins can lead to clinical benefit for the subset of cancer patients whose tumors carry these mutations.

We have also shown that inhibition of these mutated proteins can lead to clinical benefit for the

subset of cancer patients whose tumors carry these mutations.

By reducing elevated 2HG levels, our IDH inhibitors reverse the block in cellular differentiation, allowing tumorous cells to differentiate into normally functioning cells in patients with AML.

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To date, our clinical data with ivosidenib and enasidenib, our lead inhibitors of mutant IDH1 and IDH2, respectively, demonstrate evidence of cellular differentiation, normalization of cell counts and mutational clearance in the bone marrow and blood, a mechanism of response that is consistent with preclinical studies, including substantial reduction of plasma 2HG levels.

This targeted differentiation effect is distinct from that seen with traditional cytotoxic chemotherapeutics, commonly used to treat

cancer, which lead to cell death.

This targeted differentiation effect is distinct from that seen with traditional cytotoxic chemotherapeutics, commonly used to treat cancer, which lead to cell death.

Our goal is to establish our IDH mutation inhibitors as a cornerstone of AML therapy spanning all treatment lines, and to leverage our understanding of IDH mutation inhibition to develop our IDH mutation inhibitors to treat solid tumors such as low grade glioma and cholangiocarcinoma.

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Ivosidenib is an orally available, selective, potent inhibitor of the mutated IDH1 protein, making it a highly targeted therapy for the treatment of patients with cancers that harbor IDH1 mutations.

We hold worldwide development and commercial rights to ivosidenib and have licensed certain development and commercialization rights to ivosidenib in mainland China, Hong Kong, Macau, and Taiwan to CStone, pursuant to an exclusive license agreement with CStone, or the CStone Agreement, discussed more fully below.

We will fund the future development and commercialization costs related to this program with the exception of development and commercialization activities of CStone under the CStone Agreement.

We hold worldwide development and commercial rights to ivosidenib and have licensed certain development and commercialization rights to ivosidenib in mainland China, Hong Kong, Macau, Singapore and Taiwan to CStone, pursuant to an exclusive license agreement with CStone, or the CStone Agreement, discussed more fully below.

We are required to fund the future development and commercialization costs related to this program with the exception of development and commercialization activities of CStone under the CStone Agreement.

Mutations in IDH1 have been identified in difficult to treat hematologic and solid tumor cancers, including AML, MDS, cholangiocarcinoma and low grade glioma, where both the treatment options and prognosis for patients are poor.

In July 2018, the FDA approved TIBSOVO® for the treatment of adult patients with R/R AML and a susceptible IDH1 mutation.

The FDA's approval of TIBSOVO® in R/R AML was based on clinical data from a phase 1 open-label, single-arm, multicenter dose-escalation and expansion trial of adult patients with advanced R/R AML and an IDH1 mutation.

In December 2018, we submitted an MAA to the EMA for TIBSOVO® for the treatment of adult patients with R/R AML.

In May 2019, the FDA approved our sNDA to update the U.S.

Prescribing Information for TIBSOVO® to include patients with newly diagnosed AML with a susceptible IDH1 mutation as detected by an FDA-approved test who are at least 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.

The FDA has approved TIBSOVO® for the treatment of adult patients with R/R AML and a susceptible IDH1 mutation and for the treatment of patients with newly diagnosed AML with a susceptible IDH1 mutation as detected by an FDA-approved test who are at least 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.

In December 2018, we submitted a MAA to the EMA for TIBSOVO® for the treatment of adult patients with IDH1 mutant-positive R/R AML.

In October 2020, we withdrew the MAA based on feedback from the EMA's CHMP that the available clinical data from our single arm, uncontrolled Phase 1 trial did not sufficiently support a positive benefit-risk balance for the proposed indication.

The FDA granted orphan drug designation for ivosidenib for the treatment of cholangiocarcinoma, granted Breakthrough Therapy designation for ivosidenib in combination with azacitidine for the treatment of newly diagnosed AML with an IDH1 mutation in adult patients who are at least 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy, and granted Breakthrough Therapy designation for ivosidenib for the treatment of adult patients with relapsed or refractory MDS with a susceptible IDH1 mutation as detected by an FDA-approved test.

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• AGILE, a global, registration-enabling phase 3 clinical trial, combining ivosidenib and VIDAZA® (azacitidine) in newly diagnosed AML patients with an IDH1 mutation who are ineligible for intensive chemotherapy.

The trial is enrolling patients and we expect to complete enrollment in 2020.

The trial is enrolling patients.

Although we experienced disruptions related to the COVID-19 pandemic, we expect to complete enrollment in 2021.

• HO150/AMLSG29, an intergroup sponsored, global, registration-enabling phase 3 trial, supported in collaboration with Celgene, combining ivosidenib or enasidenib with standard induction and consolidation chemotherapy in frontline AML patients with an IDH1 or IDH2 mutation.

The trial is currently enrolling patients.

The trial is currently enrolling patients, although we experienced disruptions related to the COVID-19 pandemic.

• A phase 1 multicenter, open-label, dose-escalation and expansion clinical trial, designed to assess its safety, clinical activity and tolerability as a single agent in patients with advanced hematologic malignancies with an IDH1 mutation.

The trial recently reopened enrollment of its relapsed or refractory MDS arm, for which we expect to complete enrollment in 2020.

The trial reopened enrollment of its relapsed or refractory MDS arm and although we experienced disruptions related to the COVID-19 pandemic, we expect to complete enrollment in 2021.

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• ClarIDHy, a registration-enabling phase 3, multicenter, randomized, double-blind, placebo-controlled clinical trial of ivosidenib in previously-treated patients with nonresectable or metastatic cholangiocarcinoma with an IDH1 mutation.

The primary endpoint of the trial was met and we expect to file an sNDA with the FDA for TIBSOVO® in cholangiocarcinoma by year-end 2020.

The trial has completed enrollment.

The primary endpoint of the trial of progression-free survival was met and, although we experienced disruptions related to the COVID-19 pandemic, we expect to file an sNDA with the FDA for TIBSOVO® in cholangiocarcinoma in the first quarter of 2021.

• A phase 1 multi-center, open-label clinical trial of ivosidenib in patients with advanced IDH1 mutant-positive solid tumors, including glioma.

The trial has completed enrollment.

• A perioperative study with ivosidenib and vorasidenib in low grade glioma to further investigate their effects on brain tumor tissue.

The trial has completed enrollment.

Enasidenib (mutant IDH2 inhibitor)

Celgene, pursuant to the 2010 Agreement, discussed below, is developing enasidenib for the treatment of IDH2 mutant-positive hematologic malignancies.

Celgene, pursuant to our collaboration with Celgene focused on cancer metabolism, or the 2010 Agreement, is developing enasidenib for the treatment of IDH2 mutant-positive hematologic malignancies.

Enasidenib is an orally available, selective, potent inhibitor of the mutated IDH2 protein, making it a highly targeted therapeutic candidate for the treatment of patients with cancers that harbor IDH2 mutations, including those with AML, who have a historically poor prognosis.

In August 2017, the FDA granted Celgene approval of IDHIFA® for the treatment of adult patients with R/R AML and an IDH2 mutation.

In June 2018, Celgene submitted an MAA to the EMA for IDHIFA® for IDH2 mutant-positive AML, which it subsequently withdrew in December 2019.

The FDA has granted Celgene approval of IDHIFA® for the treatment of adult patients with R/R AML and an IDH2 mutation.

Celgene maintains worldwide development and commercial rights to enasidenib and will fund the future development and commercialization costs related to this program.

In April 2010, we entered into a collaboration agreement with Celgene focused on cancer metabolism, or the 2010 Agreement.

Under the remaining terms of the 2010 Agreement, Celgene is responsible for all development costs for enasidenib, and we are eligible to receive up to $80.0 million in potential milestone payments, which are comprised of:

(i) up to $55.0 million in milestone payments upon achievement of specified ex-U.S.

regulatory milestone events, of which $35.0 million relates to the first regulatory approval in any of China, Japan or a major European country, and (ii) a $25.0 million milestone payment upon achievement of a specified ex-U.S.

commercial milestone event.

Additionally, we are eligible to receive royalties at tiered low-double digit to mid-teen percentage rates on any net sales of IDHIFA®.

Under the 2010 Agreement, we were eligible to receive royalties at tiered low-double digit to mid-teen percentage rates on any net sales of IDHIFA® and exercised our rights to provide up to one-third of the field-based commercialization efforts in the United States.

On June 11, 2020, we sold our tiered, sales-based royalty rights on worldwide net sales of IDHIFA® (enasidenib), as well as our rights to receive up to $55.0 million in outstanding regulatory milestone payments from BMS, to RPI for $255.0 million.

Under the 2010 Agreement, we are eligible to receive a $25.0 million potential milestone payment for the enasidenib program upon achievement of a specified ex-U.S.

commercial milestone event, as well as reimbursement for costs incurred for our co-commercialization efforts and development activities.

In addition to the clinical trials discussed above, enasidenib is also being evaluated by Celgene in IDHENTIFY, an international phase 3, multi-center, open-label, randomized clinical trial designed to compare the efficacy and safety of enasidenib versus conventional care regimens in patients 60 years or older with IDH2 mutant-positive AML that is refractory to or relapsed after second- or third-line therapy.

This trial has completed enrollment.

In August 2020, BMS announced that the trial did not meet the primary endpoint of overall survival in patients with IDH2 mutant positive AML.

brain penetrant pan-IDH program

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Vorasidenib is an orally available, selective, brain-penetrant, pan-IDH mutant inhibitor.

In connection with the termination of the AG-881 Agreements discussed below, Celgene is eligible to receive royalties from us at a low single-digit percentage rate on worldwide net sales of products containing vorasidenib.

Celgene is eligible to receive royalties from us at a low single-digit percentage rate on worldwide net sales of products containing vorasidenib.

We continue to evaluate vorasidenib in the following clinical trials:

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The trial has completed enrollment.

• A perioperative study with ivosidenib and vorasidenib in low grade glioma to further investigate their effects on brain tumor tissue.

• The above mentioned perioperative study with ivosidenib and vorasidenib in low grade glioma to further investigate their effects on brain tumor tissue.

The trial has completed enrollment.

• INDIGO, a registration-enabling phase 3 clinical trial of vorasidenib in low-grade (grade 2) glioma with an IDH1 or IDH 2 mutation.

The trial is enrolling patients.

The trial is enrolling patients, although we experienced disruptions related to the COVID-19 pandemic.

PKR Activator Program

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This enzyme has several tissue-specific isoforms (PKR, PKL, PKM1 and PKM2).

PKR is the isoform of pyruvate kinase that is present in red blood cells, or RBCs.

Mutations in PKR cause defects in RBC glycolysis and lead to a hematological RGD known as pyruvate kinase deficiency, or PK deficiency.

PKR is the isoform of PK that is present in red blood cells, or RBCs.

Mutations in PKR cause defects in RBC glycolysis and lead to a hematological GDD known as PK deficiency.

Glycolysis is the only pathway available for RBCs to maintain the production of adenosine triphosphate, or ATP, which is a form of chemical energy within cells.

Accordingly, we believe that activation of mutant forms of PKR can restore glycolytic pathway activity and increase RBC health in patients with PK deficiency, and

activation of wild-type (non-mutated) PKR can serve as an effective compensatory mechanism in hemolytic anemias such as thalassemia and SCD.

Accordingly, we believe that activation of mutant forms of PKR can restore glycolytic pathway activity and increase RBC health in patients with PK deficiency, and activation of wild-type (non-mutated) PKR can serve as an effective compensatory mechanism in hemolytic anemias such as thalassemia and SCD.

PK Deficiency

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We believe that the activation of wild-type PKR may increase ATP production and improve red cell fitness and survival of thalassemic RBCs, by increasing the clearance globin chain aggregates through ATP-dependent proteolytic mechanisms.

In December 2019, we announced preliminary clinical data from our ongoing phase 2 trial of mitapivat in patients with non-transfusion-dependent thalassemia demonstrating proof of concept that activation of wild-type PKR has the potential to convey clinical benefit in thalassemia by increasing hemoglobin levels and reducing hemolysis in trial subjects.

In December 2019, we announced preliminary clinical data from our ongoing phase 2 trial of mitapivat in patients with non-transfusion-dependent α- and β-thalassemia demonstrating proof of concept that

activation of wild-type PKR has the potential to convey clinical benefit in thalassemia by increasing hemoglobin levels and reducing hemolysis in trial subjects.

Sickle Cell Disease

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We estimate that the prevalence of SCD is between 120,000 and 135,000 individuals in the United States and EU.

RBC deoxygenation is modulated by several factors, including the levels of 2,3-DPG, which is found to be elevated in sickle cell patient RBCs.

RBC deoxygenation is modulated by several factors, including the levels of 2,3-diphosphoglycerate, or 2,3-DPG, which is found to be elevated in sickle cell patient RBCs.

Current treatment strategies focus on managing and preventing acute RBC sickling, and include hydroxyurea, L-glutamine and blood transfusions, as well as recently approved therapies such as Adakveo® and Oxbryta®.

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Reducing the level of 2,3-DPG in RBCs would increase the oxygenation state of hemoglobin to reduce sickling, while increasing the levels of ATP may improve RBC hydration status which would also inhibit the sickling process.

PKR activator

We are developing mitapivat for the treatment of PK deficiency and other hemolytic anemias such as thalassemia and SCD.

Mitapivat is an orally available small molecule and a potent activator of the wild-type and mutated PKR enzymes.

have demonstrated in clinical trials that treatment with mitapivat can lead to durable sustained increases in hemoglobin in patients with amenable mutations in the PKR gene, and observed early signs of improvements in hemoglobin in thalassemia patients who have wild-type PKR.

To date, we have demonstrated in clinical trials that treatment with mitapivat can lead to durable sustained increases in hemoglobin in patients with amenable mutations in the PKR gene and a statistically significant and clinically meaningful reduction in transfusion burden in regularly-transfused patients with PK deficiency, and we have observed early signs of improvements in hemoglobin in thalassemia patients who have wild-type PKR.

We have worldwide development and commercial rights to mitapivat and expect to fund the future development and commercialization costs related to this program.

The FDA granted orphan drug and fast track designations for mitapivat for the treatment of patients with PK deficiency.

Mitapivat has been granted orphan drug designation for the treatment of PK deficiency by the FDA and the EMA.

Additionally, mitapivat has received orphan drug designation from the FDA for the treatment of thalassemia and sickle cell disease.

We are evaluating mitapivat in the following clinical trials:

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This trial has completed enrollment.

• ACTIVATE-T, a single arm, global, pivotal trial of mitapivat in up to 40 regularly-transfused patients with PK deficiency.

• ACTIVATE-T, a single arm, global, pivotal trial of mitapivat in regularly-transfused patients with PK deficiency.

The trial has completed enrollment.

• ACTIVATE, a 1:1 randomized, placebo-controlled, global, pivotal trial of mitapivat in approximately 80 patients with PK deficiency who do not receive regular transfusions.

The trial has closed enrollment.

• A phase 2, open-label safety and efficacy clinical trial of mitapivat in approximately 20 adult patients with non-transfusion-dependent thalassemia.

The trial is currently enrolling patients.

• In addition, in collaboration with the National Institutes of Health, or NIH, we are evaluating mitapivat in patients with SCD pursuant to a cooperative research and development agreement.

Although we experienced disruptions related to the COVID-19 pandemic, we reported in January 2021 that this trial met its primary endpoint of a statistically significant and clinically meaningful reduction in transfusion burden.

• ACTIVATE, a 1:1 randomized, placebo-controlled, global, pivotal trial of mitapivat in patients with PK deficiency who do not receive regular transfusions.

The trial has completed enrollment.

Although we experienced disruptions related to the COVID-19 pandemic, we reported in December 2020 that this trial met its primary endpoint of a statistically significant, sustained increase in hemoglobin compared to placebo.

In addition, data from the trial demonstrated that treatment with mitapivat showed statistically significant improvement in key pre-specified secondary endpoints regarding patient reported outcomes.

• A phase 2, open-label safety and efficacy clinical trial of mitapivat in adult patients with non-transfusion-dependent α- and β-thalassemia.

The trial has completed enrollment.

• In collaboration with the National Institutes of Health, or NIH, we are evaluating mitapivat in a phase 1 trial in patients with sickle cell disease pursuant to a cooperative research and development agreement.

The trial is ongoing and enrolling patients, although the NIH experienced disruptions related to the COVID-19 pandemic.

We anticipate filing for regulatory approval for mitapivat in adults with PK deficiency in the U.S.

in the second quarter of 2021 and in the EU in mid-2021, with a potential 2022 commercial launch in both geographies.

We will continue to grow our US commercial infrastructure and evaluate all options for the commercialization and continued development of mitapivat outside of the United States in order to maximize the benefit to patients and value to our shareholders, including through exploring potential partnership opportunities.

We expect to initiate two phase 3 trials of mitapivat, ENERGIZE and ENERGIZE-T, in not regularly transfused and regularly transfused adults with thalassemia in the second half of 2021.

We expect to initiate a phase 2/3 trial of mitapivat in patients with SCD by year-end 2021.

Next-Generation PKR Activator

We are developing AG-946, a next-generation PKR activator, for the potential treatment of hemolytic anemias.

We are evaluating AG-964, in a phase 1 trial of AG-946 in healthy volunteers and in patients with SCD.

The trial is currently enrolling healthy volunteers, although we experienced disruptions related to the COVID-19 pandemic.

Targeting MAT2A for the treatment of MTAP-deleted cancers

AG-270, an orally available selective potent inhibitor of MAT2A, is our development candidate focused on MTAP-deleted cancer.

AG-270, an orally available selective potent inhibitor of MAT2A, is our development candidate focused on MTAP-deleted cancers.

MTAP is a metabolic gene that is deleted in approximately 15 percent of all cancers.

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MTAP deletion is readily detected by a genomic or immunohistochemistry test, thus allowing the selection of patients predicted to be sensitive to the therapy.

In March 2017, we announced that Celgene designated AG-270 as a development candidate under our 2016 research agreement with Celgene, or the 2016 Agreement.

Pursuant to the 2016 Agreement, Celgene paid us an $8.0 million designation fee upon its designation of AG-270 as a development candidate.

Exploratory research, drug discovery and early development of AG-270 is led by us, and Celgene will have an opt-in right on AG-270 up through phase 1 dose escalation for at least a $30.0 million fee.

In October 2019, we formally submitted the opt-in package to Celgene and they have up to 150 days to make a decision.

Should Celgene opt-in, we and Celgene would share global co-development and co-commercialization rights with a worldwide 50/50 cost and profit share on AG-270, and we will be eligible for up to $168.8 million in clinical and regulatory milestone payments.

On April 10, 2020 Celgene notified us that they declined to elect any program as a continuation program under the 2016 Agreement.

In March 2017, we previously announced that Celgene designated AG-270 as a development candidate under the 2016 Agreement and Celgene paid us an $8.0 million designation fee upon this designation.

Exploratory research, drug discovery and early development of AG-270 is led by us, and Celgene had an an opt-in right on AG-270 up through phase 1 dose escalation for at least a $30.0 million fee.

On March 25, 2020, Celgene declined to exercise its right to opt into co-development and co-commercialization for AG-270.

As a result of these decisions we are no longer eligible for up to $168.8 million in clinical and regulatory milestone payments under the 2016 Agreement.

We are evaluating AG-270 in a phase 1 trial in multiple tumor types carrying an MTAP deletion.

The first part of the trial, which is complete, is a single agent dose-escalation phase in which cohorts of patients received ascending doses of AG-270 to determine the pharmacokinetics, pharmacodynamics and optimal dose, and schedule.

The next phase of development, which was initiated in September 2019, is evaluating AG-270 in combination with taxanes in two areas of high unmet needs.

One arm of the study will test AG-270 in combination with docetaxel in MTAP-deleted non-small cell lung cancer and the other arm will test AG-270 in combination with nab-paclitaxel and gemcitabine in MTAP-deleted pancreatic ductal adenocarcinoma.

Both combination arms have initiated and are enrolling patients.

The first part of the trial, was a dose-escalation of AG-270 and is complete.

The next part of the trial consists of two arms evaluating AG-270 in combination with taxanes.

One arm of the trial will test AG-270 in combination with docetaxel in MTAP-deleted non-small cell lung cancer and the other arm will test AG-270 in combination with nab-paclitaxel and gemcitabine in MTAP-deleted pancreatic ductal adenocarcinoma.

Both combination arms are enrolling patients, although we experienced disruptions related to the COVID-19 pandemic.

Targeting DHODH for the treatment of hematologic malignancies

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We believe that DHODH inhibition will be differentiated from standard-of-care therapies, both by exhibiting activity in cancers that are resistant to standard-of-care chemotherapeutics and through a mechanism of anti-tumor effect that combines cell growth arrest and cellular differentiation.

We are evaluating AG-636, an inhibitor of DHODH, licensed to us from Aurigene Discovery Technologies Limited in a phase 1 dose-escalation trial in subjects with advanced lymphomas.

This trial is currently enrolling patients.

We were evaluating AG-636, an inhibitor of DHODH, licensed to us from Aurigene in a phase 1 dose-escalation trial in subjects with advanced lymphomas.

In the first quarter of 2020, we made the decision to halt internal development of AG-636, due to limited enrollment in this trial, and will continue to wind down the trial until the close of the proposed sale to Servier.

Collaborations with Celgene

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We will continue to refer to our collaboration agreements with Celgene throughout this Form 10-K as being with Celgene Corporation.

Since December 31, 2019, there have been no material changes to the key terms of our collaboration or license agreements.

For further information on the terms and conditions of our existing collaboration and license agreements, please see Item 1, Business included in our Annual Report on Form 10-K for the year ended December 31, 2019.

2016 Agreement

In May 2016, we entered into the 2016 Agreement focused on metabolic immuno-oncology, a developing field which aims to modulate the activity of relevant immune cells by targeting critical metabolic nodes, thereby enhancing the immune mediated anti-tumor response.

In addition to new programs identified under the 2016 Agreement, both parties also agreed that all future development and commercialization of two remaining cancer metabolism programs discovered under the 2010 Agreement, including AG-270, an inhibitor of MAT2A, will now be governed by the 2016 Agreement.

During the research term of the 2016 Agreement, we plan to conduct research programs focused on discovering compounds that are active against metabolic targets in the immuno-oncology, or IO, field.

The initial four-year research term will expire on May 17, 2020, and may be extended for up to two, or in specified cases, up to four additional one-year terms.

For each program under the 2016 Agreement, we may nominate compounds that meet specified criteria as development candidates and, in limited circumstances, Celgene may also nominate compounds as development candidates for each such program.

Celgene may designate the applicable program for further development following any such nomination, after which we may conduct, at our expense, additional preclinical and clinical development for such program through the completion of an initial phase 1 dose escalation study.

At the end of the research term, Celgene may designate for continued development up to three research programs for which development candidates have yet to be nominated, which are referred to as continuation programs.

We may conduct further research and preclinical and clinical development activities on any continuation program, at our expense, through the completion of an initial phase 1 dose escalation study.

We granted Celgene the right to obtain exclusive options for development and commercialization rights for each program that Celgene has designated for further development and for each continuation program.

Celgene may exercise each such option beginning on the designation of a development candidate for such program (or on the designation of such program as a continuation program) and ending on the earlier of:

(i) the end of a specified period after we have furnished Celgene with specified information about the initial phase 1 dose escalation study for such program, or (ii) January 1, 2030.

Research programs that have applications in the inflammation or autoimmune, or I&I, field that may result from the 2016 Agreement will also be subject to the exclusive options described above.

We will retain rights to any program that Celgene does not designate for further development or as to which it does not exercise its option.

Under the terms of the 2016 Agreement, following Celgene’s exercise of its option with respect to a program, the parties will enter into either a co-development and co-commercialization agreement if such program is in the IO field, or a license agreement if such program is in the I&I field.

Under each co-development and co-commercialization agreement, the two parties will co-develop and co-commercialize licensed products worldwide.

Either we or Celgene will lead development and commercialization of licensed products for the United States, and Celgene will lead development and commercialization of licensed products outside of the United States.

Depending on the country, the parties will each have the right to provide a portion of field-based marketing activities.

Under each license agreement, Celgene will have the sole right to develop and commercialize licensed products worldwide.

Co-development and co-commercialization agreements.

Under each co-development and co-commercialization agreement entered into under the 2016 Agreement, the parties will split all post-option exercise worldwide development costs, subject to specified exceptions, as well as any profits from any net sales of, or commercialization losses related to, licensed products in the IO field.

Celgene has the option to designate one program in the IO field as the 65/35 program, for which Celgene will be the lead party for the United States and will have a 65% profit or loss share.

For programs in the IO field other than the 65/35 program, we and Celgene will alternate, on a program-by-program basis, being the lead party for the United States, with us having the right to be the lead party for the first such program, and each party will have a 50% profit or loss share.

The lead party for the United States will book commercial sales of licensed products, if any, in the United States, and Celgene will book commercial sales of licensed products, if any, outside of the United States.

License agreements.

Under each license agreement under the 2016 Agreement, Celgene will be responsible for all post-option exercise worldwide development and associated costs, subject to specified exceptions, as well as worldwide commercialization and associated costs, for licensed products in the I&I field.

Financial terms.

Under the terms of the 2016 Agreement, we received an initial upfront payment in the amount of $200.0 million.

The 2016 Agreement provides specified rights to extend the research term for up to two, or in specified cases, up

to four, additional years by paying a $40.0 million per-year extension fee.

Celgene will pay an $8.0 million designation fee for each program that Celgene designates for further development and for each continuation program.

During the year ended December 31, 2017, we received $8.0 million from Celgene upon the designation of AG-270, our MAT2A inhibitor, as a development candidate.

For each program as to which Celgene exercises its option to develop and commercialize, subject to antitrust clearance, Celgene will pay an option exercise fee of at least $30.0 million for any designated development program and at least $35.0 million for any continuation programs.

In certain cases, Celgene may exercise its option to develop and commercialize two early-stage I&I programs, prior to Celgene designating the program for further development, by paying an option exercise fee of $10.0 million per program.

We are eligible to receive the following milestone-based payments associated with the 2016 Agreement:

Program Milestone Amount

65/35 program in IO field Specified clinical development event $25.0 million

65/35 program in IO field Specified regulatory milestone events Up to $183.8 million

50/50 program in IO field Specified clinical development event $20.0 million

50/50 program in IO field Specified regulatory milestone events Up to $148.8 million

I&I field Specified clinical development event $25.0 million

I&I field Specified regulatory milestone events Up to $236.3 million

I&I field Specified commercial milestone events Up to $125.0 million

Additionally, for each licensed program in the I&I field, we are eligible to receive royalties at tiered, low double-digit percentage rates on Celgene’s net sales, if any, of the applicable licensed products.

Opt-out right.

Under the 2016 Agreement, we may elect to opt out of the cost and profit share under any co-development and co-commercialization agreement, subject to specified exceptions.

Upon opting out, Celgene will have the sole right to develop, manufacture and commercialize the applicable licensed products throughout the world, at its cost, and we will undertake transitional activities reasonably necessary to transfer the development, manufacture and commercialization of such licensed products to Celgene, at our expense.

Further, in lieu of the profit or loss sharing described above, we would be eligible to receive royalties at tiered, low double-digit percentage rates on Celgene’s net sales, if any, of the applicable licensed products.

However, we would continue to be eligible to receive the developmental and regulatory milestone-based payments described above.

The term of the 2016 Agreement commenced on May 17, 2016 and, if not terminated earlier, will expire upon the later of the last-to-expire of the research term and all option exercise periods, or, if an option is exercised by Celgene for one or more programs in the collaboration, upon the termination or expiration of the last-to-exist co-development and co-commercialization agreement or license agreement, as applicable, for any such program.

Subject to specified exceptions, Celgene may terminate the 2016 Agreement in its entirety for any reason by providing us with prior written notice if there are no active co-development and co-commercialization agreements or license agreements in place or on a program-by-program basis if there are no active co-development and co-commercialization agreements or license agreements in place for the terminated program(s).

Under specified circumstances, either party may terminate the 2016 Agreement either in its entirety or on a program-by-program basis.

Either party also has the right to terminate the co-development and co-commercialization agreement or license agreement if the other party or any of its affiliates challenges the validity, scope or enforceability of or otherwise opposes, any patent included within the intellectual property rights licensed to the other party under such agreement.

While any of Celgene’s options remain available under the 2016 Agreement, subject to specified exceptions, we may not directly or indirectly develop, manufacture or commercialize, outside of the 2016 Agreement, any therapeutic modality in the IO or I&I field with specified activity against a metabolic target.

During the term of each co-development and co-commercialization agreement and license agreement, subject to specified exceptions, neither we nor Celgene may directly or indirectly develop, manufacture or commercialize outside of such agreement any therapeutic modality in any field with specified activity against the metabolic target that is the focus of the program licensed under such agreement.

Ivosidenib Letter Agreement

On May 17, 2016, we entered into a letter agreement with Celgene regarding ivosidenib, or the Ivosidenib Letter Agreement.

Under the Ivosidenib Letter Agreement, the parties agreed to terminate the 2010 Agreement, effective as of August 15, 2016, as to the program directed to the IDH1 target, for which ivosidenib is the lead development candidate.

Under the 2010 Agreement, Celgene had held development and commercialization rights to the IDH1 program outside of the United States, and we held such rights inside the United States.

As a result of the Ivosidenib Letter Agreement, we obtained global rights to ivosidenib and

the IDH1 program.

Neither party will have any further financial obligation, including royalties or milestone payments, to the other concerning ivosidenib or the IDH1 program.

Under the terms of the Ivosidenib Letter Agreement, the parties also agreed to conduct specified transitional activities in connection with the termination.

In addition, pursuant to the Ivosidenib Letter Agreement, the parties are released from their exclusivity obligations under the 2010 Agreement with respect to the IDH1 program.

The Ivosidenib Letter Agreement does not affect the AG-881 Agreements, which were directed to both the IDH1 target and the IDH2 target, and were subsequently terminated in September 2018 as discussed below.

Termination of AG-881 Agreements

In September 2018, we and Celgene agreed to terminate our joint worldwide collaboration focused on the development and commercialization of vorasidenib products, or the AG-881 Agreements, effective as of September 4, 2018.

From and after September 4, 2018, we obtained sole global rights to vorasidenib.

Neither we nor Celgene will have any further financial obligation under the AG-881 Agreements, including milestones, royalties or other payments, except that (a) Celgene is eligible to receive royalties from us at a low single-digit percentage rate on worldwide net sales of products containing vorasidenib and (b) we and Celgene agreed to split certain agreed-upon worldwide development costs for vorasidenib until December 31, 2018.

In addition, for a specified period and subject to specified exceptions, Celgene and its affiliates are prohibited from developing, manufacturing or commercializing any product that inhibits IDH1 at specified levels of binding for any indication and we are prohibited from developing, manufacturing or commercializing vorasidenib in hematologic indications.

In May 2016, we entered into the 2016 Agreement focused on metabolic immuno-oncology.

The initial four-year research term expired on May 17, 2020.

On March 25, 2020 Celgene declined the option to extend the research agreement for up to two, or in specified cases, up to four additional one-year terms which would have required the payment of a $40.0 million extension fee.

Further, on April 10, 2020 Celgene notified us that they declined to elect any program as a continuation program under the 2016 Agreement.

Celgene had designated AG-270 as a development candidate under the 2016 Agreement.

On March 25, 2020, Celgene notified us of their decision to decline their option to enter into a development & commercialization agreement with respect to the MAT2A program under the 2016 Agreement which would have required the payment of a $30.0 million fee to us.

As a result of these decisions, the research services were fully satisfied as of May 17, 2020, no additional performance

obligations remain under the 2016 Agreement and we are no longer eligible for any milestone payments under the 2016 Agreement.

2010 Agreement

The 2010 Agreement, which was entered into in April 2010, was amended in October 2011 and July 2014.

The goal of the collaboration was to discover, develop and commercialize disease-altering therapies in oncology based on our cancer metabolism research platform.

We initially led discovery, preclinical and early clinical development for all cancer metabolism programs under the collaboration.

The discovery phase of the 2010 Agreement expired in April 2016.

Upon agreement to terminate the 2010 Agreement, effective as of August 15, 2016, as to the program directed to the IDH1 target, for which ivosidenib is the lead development candidate, the sole program remaining under the 2010 Agreement is IDHIFA®, a co-commercialized licensed program for which Celgene leads and funds global development and commercialization activities.

We have exercised our right to participate in a portion of commercialization activities in the United States for IDHIFA® in accordance with the applicable commercialization plan.

Exclusivity .

Until termination or expiration of the agreement, either in its entirety or with respect to the relevant program, we may not directly or indirectly develop, manufacture or commercialize, outside of the collaboration, any therapeutic modality with specified activity against any collaboration target that is within a licensed program or against any former collaboration target against which Celgene is conducting an independent program under the agreement.

Financial terms.

Under the remaining terms of the 2010 Agreement, we are eligible to receive up to $80.0 million in potential milestone payments for the IDHIFA® program.

The potential milestone payments are comprised of:

(i) up to $55.0 million in milestone payments upon achievement of specified ex-U.S.

Under the 2010 Agreement, we are eligible to receive royalties at tiered, low-double digit to mid-teen percentage rates on net sales of IDHIFA®.

Assuming all other revenue recognition criteria are met, royalty payments will be recognized as revenue in the period in which they are earned.

During the year ended December 31, 2019, we earned $10.5 million in royalty revenue under the 2010 Agreement.

Unless terminated earlier by either party, the term of the 2010 Agreement will continue until the expiration of all royalty terms with respect to IDHIFA®.

Celgene may terminate the 2010 Agreement for convenience in its entirety or with respect to IDHIFA® upon ninety days written notice to us.

Under specified circumstances, either we or Celgene may terminate the 2010 Agreement, in its entirety or with respect to IDHIFA®.

If Celgene terminates the 2010 Agreement as a result of our uncured material breach, then certain of our rights and certain of Celgene’s obligations described above would change with respect to the terminated program(s), including, for example:

the licenses we granted to Celgene would become perpetual;

milestone payments to which we may be entitled may be reduced or eliminated;

and royalties to which we may be entitled may be reduced or eliminated.

If Celgene terminates the 2010 Agreement for convenience or if we terminate the agreement as a result of Celgene’s uncured material breach, the license we granted to Celgene with respect to IDHIFA® will end, and we will have specified rights for, and Celgene will take specified actions to assist us in continuing, the development, manufacture and commercialization of medicines from the IDHIFA® program.

Under the 2010 Agreement, we are eligible to receive a $25.0 million potential milestone payment for the enasidenib program upon achievement of a specified ex-U.S.

commercial milestone event, as well as reimbursement for costs incurred for our co-commercialization efforts and development activities.

Further information on the terms and conditions of our existing collaboration and license agreements is included within Note 13:

Collaboration and License Agreements ” of the consolidated financial statements in this Annual Report on this Form 10-K.

CStone Agreement

In June 2018, we entered into the CStone Agreement for the development and commercialization of certain products containing ivosidenib in mainland China, Hong Kong, Macau, and Taiwan for therapeutic uses in humans, excluding brain cancer, unless added by us in our sole discretion.

In June 2018, we entered into the CStone Agreement for the development and commercialization of certain products containing ivosidenib in mainland China, Hong Kong, Macau, Singapore, and Taiwan, the CStone Territory, for therapeutic uses in humans, excluding brain cancer, unless added by us in our sole discretion.

On March 2, 2020, we amended the CStone Agreement to include Singapore as part of the CStone Territory.

We retain development and commercialization rights for the rest of the world.

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We granted CStone specified intellectual property licenses to enable CStone to perform its obligations and exercise its rights under the CStone Agreement, including license grants to enable CStone to conduct development and commercialization activities pursuant to the terms of the CStone Agreement.

CStone is responsible for all costs it incurs in developing, obtaining regulatory approval of, and commercializing ivosidenib in mainland China, Hong Kong, Macau, and Taiwan, as well as certain costs incurred by us.

During the term of the CStone Agreement, each party and its affiliates are prohibited from developing or commercializing any other compound or product that inhibits IDH1 mutations at specified levels of binding, in the case of CStone, anywhere in the world, and in the case of us, in mainland China, Hong Kong, Macau, and Taiwan.

CStone is responsible for all costs it incurs in developing, obtaining regulatory approval of, and commercializing ivosidenib in the Cstone Territory, as well as certain costs incurred by us.

Subject to specified exceptions, CStone and its affiliates are also prohibited from developing or commercializing certain other compounds or products that directly or indirectly treat AML, cholangiocarcinoma or, if applicable, glioma in patients who have an IDH1 mutation.

Pursuant to the CStone Agreement, we have entered into a clinical supply agreement and pharmacovigilance agreement with CStone, and will enter into further ancillary agreements, including commercial supply agreements.

Pursuant to the CStone Agreement, we have entered into a clinical supply agreement and pharmacovigilance agreement with CStone, and may enter into further ancillary agreements, including commercial supply agreements.

Intellectual Property

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and foreign patent applications related to our proprietary technology, inventions and improvements that are important to the development and implementation of our business.

We also rely on trade secrets, know-how and continuing technological innovation to develop and maintain our proprietary and intellectual property position.

We file, or collaborate with third parties to file, patent applications directed to our key product candidates, including TIBSOVO® (ivosidenib), IDHIFA® (enasidenib), vorasidenib, mitapivat, AG-270 and AG-636, in an effort to establish intellectual property positions regarding new chemical entities relating to these product candidates as well as uses of new chemical entities in the treatment of diseases.

We also seek patent protection with respect to biomarkers that may be useful in selecting the right patient population for therapies with our product candidates.

As of February 1, 2020 we owned or licensed approximately issued 31 U.S.

patents, 316 issued foreign patents, 37 pending U.S.

patent applications, 460 pending foreign patent applications, and 13 pending Patent Cooperation Treaty, or PCT, patent applications, directed to our key product candidates, related compounds and potential backup compounds.

The foreign issued patents and patent applications are in a number of jurisdictions, including Argentina, Australia, Austria, Belgium, Brazil, Canada, China, the Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Japan, Lithuania, Mexico, the Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey, and the United Kingdom.

We also rely on confidential information, know-how and continuing technological innovation to develop and maintain our proprietary and intellectual property position.

We may also choose to rely on trade secrets to protect certain aspects of our business that are not suitable or appropriate for patent protection.

We file, or may collaborate with third parties to file, patent applications directed to our key product candidates, including TIBSOVO® (ivosidenib), IDHIFA® (enasidenib), vorasidenib, mitapivat, AG-946, and AG-270 and AG-636, in addition to related compounds and potential back-up compounds, in an effort to establish intellectual property positions to protect these new chemical entities as well as methods of using these compounds in the treatment of diseases, formulations, solid state forms, and manufacturing processes.

We may also seek patent protection for certain biomarkers that may be useful in selecting the right patient population for therapies with our product candidates.

As part of our patent portfolio, as of February 1, 2021 we own or license 50 US issued patents as well as 483 issued patents in certain foreign countries and have pending patent applications in the US and in various foreign jurisdictions.

The foreign issued patents and pending applications are in a number of jurisdictions, including Argentina, Australia, Austria, Belgium, Brazil, Canada, China, the Czech Republic, Denmark,

Finland, France, Germany, Greece, Hungary, Ireland, Italy, Japan, Lithuania, Mexico, the Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey, and the United Kingdom.

The intellectual property portfolios for our most advanced programs as of February 1, 2021 are summarized below.

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IDH mutant inhibitor programs

The intellectual property portfolio for our IDH mutant inhibitor programs contains patent applications directed to compositions of matter for TIBSOVO® (ivosidenib), IDHIFA® (enasidenib), and vorasidenib, as well as analogs thereof, methods of use, various solid state forms of these compounds and diagnostic methods for detecting various IDH1 and IDH2 mutations.

The patent portfolio for our IDH mutant inhibitor programs contains issued patents and pending patent applications directed to compositions of matter for our key product compounds TIBSOVO®, IDHIFA®, and vorasidenib, as well as to related compounds, methods of use, various solid state forms of these product compounds, formulations, manufacturing processes and diagnostic methods for detecting various IDH1 and/or IDH2 mutations.

As of February 1, 2021, we owned approximately 38 issued U.S.

patents, 152 issued foreign patents, 24 pending U.S.

patent applications, 327 pending foreign patent applications in a number of jurisdictions, and 5 pending PCT patent applications, directed to our IDH mutant product candidates.

patents and 310 issued foreign patents and have pending patent applications in the US and in various foreign jurisdictions.

The patents that have issued or will issue for our IDH mutant product candidates will have a statutory expiration date of at least 2033 to 2039.

Patent term adjustments or patent term extensions could result in later expiration dates.

In some cases, the term of a US patent can be shortened by the filing of a terminal disclaimer which operates to reduce the term of a patent to that of an earlier expiring patent.

PK activator program

The intellectual property portfolio for our PK activator program contains patent applications directed to compositions of matter for mitapivat and AG-946, as well as analogs thereof, various solid state forms of these compounds, as well as methods of use for these novel compounds.

The patent portfolio for our PK activator program contains issued patents and pending patent applications directed to compositions of matter for mitapivat, as well as to related compounds, various solid state forms of mitapivat, compositions of matter for second generation PKR activators, such as AG-946, as well as methods of use for these novel compounds.

As of February 1, 2021, we owned approximately 6 issued U.S.

patents, 116 issued foreign patents, 6 pending U.S.

patent applications, 44 pending foreign patent applications in a number of jurisdictions, and 3 pending PCT patent applications, directed to our PK activator program, including our product candidates.

patents and 128 issued foreign patents, and have pending patent applications in the US and in various foreign jurisdictions.

The patents that have issued or will issue for our PK activator program will have a statutory expiration date of at least 2030 to 2040.

Patent term adjustments or patent term extensions could result in later expiration dates.

In some cases, the term of a US patent can be shortened by the filing of a terminal disclaimer which operates to reduce the term of a patent to that of an earlier expiring patent.

MTAP-deleted cancer program

The intellectual property portfolio for our MTAP-deleted cancer program contains patent applications directed to compositions of matter for AG-270, as well as analogs thereof and other related compound families including potential backup compounds, as well as methods of use for these novel compounds and diagnostic methods for detecting MTAP deletions.

The intellectual property portfolio for our MTAP-deleted cancer program contains issued patents and pending patent applications directed to compositions of matter for AG-270, as well as to related compounds and other chemotypes including potential back-up compounds, as well as methods of use, combination therapies, and diagnostic methods for detecting MTAP deletions.

As of February 1, 2021, we owned approximately 2 issued U.S.

patent, 4 pending U.S.

patent applications, 1 foreign issued patent, 46 pending foreign patent applications, and 3 pending PCT patent applications, directed to our MTAP-deleted cancer program.

The patents that would issue for our MTAP-deleted cancer program will have a statutory expiration date of at least 2036 to 2039.

patents and 1 issued foreign patent and have pending patent applications in the US and in various foreign jurisdictions.

The patents that have issued or will issue for our MTAP-deleted cancer program will have a statutory expiration date of at least 2036 to 2040.

Patent term adjustments or patent term extensions could result in later expiration dates.

In some cases, the term of a US patent can be shortened by the filing of a terminal disclaimer which operates to reduce the term of a patent to that of an earlier expiring patent.

DHODH inhibitor program

The intellectual property portfolio for our DHODH inhibitor program contains patents and patent applications, exclusively licensed to us by Aurigene, directed to compositions of matter for AG-636, as well as analogs thereof and other compound families, as well as methods of use for these novel compounds.

The intellectual property portfolio for our DHODH inhibitor program further contains patent applications, assigned solely to Agios, that are directed to solid state forms and formulations of AG-636 and methods of use for these forms of AG-636, other methods of use for AG-636 and methods of use and diagnostic methods relating to AG-636 and other DHODH inhibitors.

The patent portfolio for our DHODH inhibitor program contains issued patents and pending patent applications, exclusively licensed to us by Aurigene, directed to compositions of matter for AG-636, as well as to related compounds and other chemotypes, as well as to methods of use for these novel compounds.

The patent portfolio for our DHODH inhibitor program further contains patent applications, assigned solely to Agios, that are directed to solid state forms and formulations of AG-636 and to methods of use for these forms of AG-636, other methods of use for AG-636 and methods of use and diagnostic methods relating to AG-636 and other DHODH inhibitors.

As of February 1, 2021, we exclusively licensed or independently filed approximately 4 issued U.S.

patents, 47 issued foreign patents, 3 pending U.S.

patent applications, 43 pending foreign patent applications, and 2 pending PCT patent applications directed to our DHODH inhibitor program.

patents and 44 issued foreign patents and have pending patent applications in the US and in various foreign jurisdictions.

The patents that have issued or will issue for our DHODH inhibitor program will have a statutory expiration date of at least 2030 to 2039.

Patent term adjustments or patent term extensions could result in later expiration dates.

In some cases, the term of a US patent can be shortened by the filing of a terminal disclaimer which operates to reduce the term of a patent to that of an earlier expiring patent.

The term of individual patents depends upon the legal term for patents in the countries in which they are obtained.

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In the United States, a patent’s term may be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the USPTO in examining and granting a patent, or may be shortened if a patent is terminally disclaimed over an earlier filed patent.

The term of a patent that covers a drug or biological product may also be eligible for patent term extension when FDA approval is granted, provided statutory and regulatory requirements are met.

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, provided statutory and regulatory

requirements are met.

The extension of the term of foreign patents varies, in accordance with local law.

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In the future, if and when our product candidates receive approval by the FDA or foreign regulatory authorities, we expect to apply for patent term extensions on issued patents covering those products, depending upon the length of the clinical trials for each medicine and other factors.

There can be no assurance that any of our pending patent applications will be issued or that we will benefit from any patent term extension or favorable adjustment to the term of any of our patents.

There can be no assurance that any of our pending patent applications will issue or that we will benefit from any patent term extension or favorable adjustment to the term of any of our patents.

As with other biotechnology and pharmaceutical companies, our ability to maintain and solidify our proprietary and intellectual property position for our product candidates and technologies will depend on our success in obtaining effective patent claims and enforcing those claims if granted.

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For example, we cannot be certain of the priority of inventions covered by pending third-party patent applications.

If third parties prepare and file patent applications in the United States that also claim technology or therapeutics to which we have rights, we may have to participate in interference proceedings with the USPTO to determine priority of invention, which could result in substantial costs to us, even if the eventual outcome is favorable to us.

If third parties prepare and file patent applications in the United States that also claim technology or therapeutics to which we have rights, we may have to participate in interference proceedings in the USPTO to determine priority of invention, which could result in substantial costs to us, even if the eventual outcome is favorable to us.

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 reducing any advantage of any such patent.

In addition to patents, we rely upon unpatented trade secrets and know-how and continuing technological innovation to develop and maintain our competitive position.

We seek to protect our proprietary information, in part, using confidentiality agreements with our collaborators, third-party service providers, scientific advisors, employees and consultants, and invention assignment agreements with our employees.

In addition to patent protection, we also rely upon unpatented confidential information, including confidential technical information, know-how and continuing technological innovation to develop and maintain our competitive position.

We seek to protect our proprietary information, in part, by using confidentiality agreements with our collaborators, third-party service providers, scientific advisors, employees and consultants, and by invention assignment agreements with our employees.

We also have agreements requiring assignment of inventions with selected consultants, scientific advisors and collaborators.

The confidentiality agreements are designed to protect our proprietary information and, in the case of agreements or clauses requiring invention assignment, to grant us ownership of technologies that are developed through a relationship with a third party.

With respect to our proprietary cellular metabolism technology platform, we consider trade secrets and know-how to be our primary intellectual property.

Trade secrets and know-how can be difficult to protect.

In particular, we anticipate that with respect to this technology platform, these trade secrets and know-how will over time be disseminated within the industry through independent development, the publication of journal articles describing the methodology, and the movement of personnel from academic to industry scientific positions.

With respect to our proprietary cellular metabolism technology platform, we consider confidential information and know-how related to our cellular metabolism technology platform to be our primary intellectual property in this space.

Confidential information and know-how can be difficult to protect.

In particular, we anticipate that with respect to this technology platform, at least some of the technical information and know-how will, over time, become known within the industry through independent development, the publication of journal articles describing the methodology, and the movement of personnel skilled in the art from academic to industry scientific positions.

The pharmaceutical and biotechnology industries are characterized by rapidly advancing technologies, intense competition and a strong emphasis on proprietary products.

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Any product candidates that we successfully develop and commercialize will compete with existing therapies and new therapies that may become available in the future.

We compete in the areas of pharmaceutical, biotechnology and other related markets that address hematologic malignancies, solid tumors and RGDs.

There are other companies working to develop therapies in the fields of hematologic malignancies, solid tumors and RGDs.

We compete in the areas of pharmaceutical, biotechnology and other related markets that address hematologic malignancies, solid tumors and GDDs.

There are other companies working to develop therapies in the fields of hematologic malignancies, solid tumors and GDDs.

These companies include divisions of large pharmaceutical companies and biotechnology companies of various sizes.

Malignant Hematology and Solid Tumors .

In the fields of malignant hematology and solid tumors, our principal competitors include AbbVie Inc., ASLAN Pharmaceuticals Limited;

AstraZeneca Plc.;

Astellas Pharma Inc.;

In the fields of malignant hematology and solid tumors, our principal competitors include AbbVie Inc., or AbbVie;

Astellas Pharma Inc., or ASLAN;

Bayer AG, or Bayer;

BeiGene Ltd.;

Clear Creek Bio;

Daiichi Sankyo Company, Ltd.;

Daiichi Sankyo Company, Ltd., or Daiichi Sankyo;

Eli Lilly and Company;

Forma Therapeutics Holdings, LLC;

Forma Therapeutics Holdings, LLC, or Forma;

GlaxoSmithKline plc;

Jazz Pharmaceuticals plc;

Novartis International AG;

Pfizer, Inc.;

and Roche Holdings, Inc.

and its subsidiary Genentech, Inc.

Jazz Pharmaceuticals plc, or Jazz;

Merck & Co., or Merck;

Novartis International AG, or Novartis;

Pfizer, Inc., or Pfizer;

and Roche Holdings, Inc., or Roche, and its subsidiary Genentech, Inc.

The most common methods of treating patients with hematologic malignancies and solid tumors are surgery, radiation and drug therapy, including chemotherapy, hormone therapy and targeted drug therapy, and there are a variety of available drug therapies marketed for these cancer types.

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Vyxeos® from Jazz;

and Daurismo® and Mylotarg® from Pfizer.

Recently approved treatments for solid tumors include Keytruda® from Merck, Rozlytrek® from Roche and Vitrakvi® from Bayer (in collaboration with Loxo Oncology, Inc.), and in some cases, these drugs are administered in combination to enhance efficacy.

and Daurismo® and Mylotarg® from Pfizer and Onureg® from BMS.

Recently approved treatments for solid tumors

include Keytruda® from Merck, Rozlytrek® from Genentech and Vitrakvi® from Bayer (in collaboration with Loxo Oncology, Inc.), and in some cases, these drugs are administered in combination to enhance efficacy.

While our products and product candidates may compete with many existing drug and other therapies, to the extent they are ultimately used in combination with or as an adjunct to these therapies, our product candidates may not be competitive with them.

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are conducting clinical trials of their DHODH inhibitors in hematologic malignancies;

and IDEAYA Biosciences, Inc is developing a MAT2A inhibitor for the treatment of MTAP-deleted solid tumors.

and IDEAYA Biosciences, Inc., or IDEAYA, is developing a MAT2A inhibitor for the treatment of MTAP-deleted solid tumors.

These medicines in development may provide efficacy, safety, convenience and other benefits that are not provided by currently marketed therapies.

As a result, they may provide significant competition for any of our product candidates for which we obtain market approval.

For example, several investigators have reported that IDH mutant AML and glioma are sensitive to poly (ADP-ribose) polymerase inhibition in cell culture and animal models.

Rare genetic diseases .

In the field of RGDs, our principal competitors include:

Acceleron Pharma Inc.;

BioMarin Pharmaceutical, Inc.;

bluebird bio, Inc.;

Global Blood Therapeutics;

and Rocket Pharma LTD.

The most common methods for treating patients with RGDs are dietary restriction, dietary supplementation or replacement, treatment of symptoms and complications, gene therapy, organ transplant and enzyme replacement therapies.

There are a number of marketed therapies available for treating patients with RGDs.

For example, recently-approved treatments for thalassemia, sickle cell disease, and phenylketonuria include Reblozyl® from Acceleron (in collaboration with BMS);

Genetically defined diseases .

In the field of GDDs, our competitors include:

Acceleron Pharma Inc., or Acceleron;

BioMarin Pharmaceutical, Inc., or BioMarin;

bluebird bio, Inc., or bluebird;

Global Blood Therapeutics, or Global Blood;

IMARA Inc., or IMARA;

Rocket Pharma LTD, or Rocket Pharma;

and Vertex Pharmaceuticals Incorporated, or Vertex.

The most common methods for treating patients with GDDs are dietary restriction, dietary supplementation or replacement, treatment of symptoms and complications, gene therapy, blood transfusions, organ transplant and enzyme replacement therapies.

There are a number of marketed therapies available for treating patients with GDDs.

For example, recently-approved treatments for thalassemia, SCD, and phenylketonuria include Reblozyl® from Acceleron (in collaboration with BMS);

Lentiglobin® from bluebird;

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While our product candidates may compete with existing medicines and other therapies, to the extent they are ultimately used in combination with or as an adjunct to these therapies, our product candidates may not be competitive with them.

In addition to currently marketed therapies, there are also a number of products that are either small molecules, enzyme replacement therapies or gene therapies in various stages of clinical development to treat RGDs.

For example, Forma is conducting phase 1 clinical trial of their PKR activator, FT-4202, in patients with SCD.

For example, Rocket Pharma is conducting a clinical trial of a gene therapy targeting PK deficiency and Forma is developing a PKR activator for the treatment of hemolytic anemias, including PK deficiency and SCD, and Vertex is developing a gene therapy targeting SCD.

These products in development may provide efficacy, safety, convenience and other benefits that are not provided by currently marketed therapies.

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Smaller or early stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.

The key competitive factors affecting the success of all of our product candidates, if approved, are likely to be their efficacy, safety, convenience, price, the effectiveness of companion diagnostics in guiding the use of related therapeutics, the level of generic competition and the availability of reimbursement from government and other third-party payors.

The key competitive factors affecting the success of all of our product candidates, if approved, are likely to be their efficacy, safety, convenience, price, the effectiveness of companion diagnostics in guiding the use of related therapeutics where appropriate, the level of generic competition and the availability of reimbursement from government and other third-party payors.

Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize medicines that are safer, more effective, have fewer or less severe side effects, are more convenient or are less expensive than any medicines that we may develop.

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In addition, our ability to compete may be affected in many cases by insurers or other third-party payors seeking to encourage the use of generic or other branded medicines.

There are many generic medicines currently on the market for the indications that we are pursuing, and additional medicines are expected to become available on a generic basis over the coming years.

There are many generic medicines currently on the market for the indications that we are pursuing, and additional medicines are expected to become available on a generic basis over the

coming years.

If our therapeutic product candidates are approved, we expect that they will be priced at a significant premium over competitive generic medicines.

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We currently rely, and expect to continue to rely, on third parties for the manufacture of our product candidates for preclinical and clinical testing, as well as for commercial manufacture of any products that we may commercialize.

To date, we have obtained materials for ivosidenib, enasidenib, vorasidenib, mitapivat, AG-270 and AG-636 for our ongoing and planned clinical testing from third-party manufacturers.

To date, we have obtained materials for ivosidenib, enasidenib, vorasidenib, mitapivat, AG-270, AG-636 and AG-946 for our ongoing and planned clinical testing from third-party manufacturers.

Although we have long-term supply arrangements in place for the commercial supply of TIBSOVO®, we primarily obtain our supplies from these manufacturers on a purchase order basis.

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As we have done for TIBSOVO®, for all of our other product candidates we intend to identify and qualify additional manufacturers to provide the active pharmaceutical ingredient and fill-and-finish services prior to submission of a NDA to the FDA.

Ivosidenib, enasidenib, vorasidenib, mitapivat, AG-270 and AG-636 are organic compounds of low molecular weight, generally called small molecules.

Ivosidenib, enasidenib, vorasidenib, mitapivat, AG-270, AG-636 and AG-946 are organic compounds of low molecular weight, generally called small molecules.

They can be manufactured in reliable and reproducible synthetic processes from readily available starting materials.

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Government Regulation and Product Approvals

Government authorities in the United States, at the federal, state and local level, and in other countries and jurisdictions, including the EU, extensively regulate, among other things, the research, development, testing, manufacture, pricing, quality control, approval, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval

monitoring and reporting, and import and export of biopharmaceutical products.

The processes for obtaining marketing approvals in the United States and in foreign countries and jurisdictions, along with compliance with applicable statutes and regulations and other regulatory authorities, require the expenditure of substantial time and financial resources.

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• preclinical testing including laboratory tests, animal studies and formulation studies which must be performed in accordance with the FDA’s good laboratory practice, or GLP, regulations and standards;

• submission to the FDA of an investigational new drug application, or IND, for human clinical testing, which must become effective before human clinical trials may begin;

• submission to the FDA of an IND for human clinical testing, which must become effective before human clinical trials may begin;

• approval by an independent institutional review board, or IRB, representing each clinical site before each clinical trial may be initiated;

• performance of adequate and well-controlled human clinical trials to establish the safety, potency and purity of the product candidate for each proposed indication, in accordance with current good clinical practices, or GCP;

• preparation and submission to the FDA of a new drug application, or NDA, for a drug product which includes not only the results of the clinical trials, but also, detailed information on the chemistry, manufacture and quality controls for the product candidate and proposed labeling for one or more proposed indication(s);

• preparation and submission to the FDA of a NDA for a drug product which includes not only the results of the clinical trials, but also, detailed information on the chemistry, manufacture and quality controls for the product candidate and proposed labeling for one or more proposed indication(s);

• review of the product candidate by an FDA advisory committee, where appropriate or if applicable;

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In support of a request for an IND, applicants must submit a protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of the IND.

In addition, 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, must be submitted to the FDA as part of an IND.

The FDA requires a 30-day waiting period after the

filing of each IND before clinical trials may begin.

The FDA requires a 30-day waiting period after the filing of each IND before clinical trials may begin.

This waiting period is designed to allow the FDA to review the IND to determine whether human research subjects will be exposed to unreasonable health risks.

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When a foreign clinical study is conducted under an IND, all FDA IND requirements must be met unless waived.

When a foreign clinical study is not conducted under an IND, the sponsor must ensure that the study complies with certain regulatory requirements of the FDA in order to use the study as support for an IND or application for marketing approval.

Specifically, on April 28, 2008, the FDA amended its regulations governing the acceptance of foreign clinical studies not conducted under an investigational new drug application as support for an IND or a NDA.

The final rule provides that such studies must be conducted in accordance with GCP, including review and approval by an independent ethics committee and informed consent from subjects.

The GCP requirements in the final rule encompass both ethical and data integrity standards for clinical studies.

When a foreign clinical study is not conducted under an IND, the sponsor must ensure that the study complies with certain regulatory requirements, including GCP requirements, of the FDA in order to use the study as support for an IND or application for marketing approval.

The GCP requirements encompass both ethical and data integrity standards for clinical studies.

The FDA’s regulations are intended to help ensure the protection of human subjects enrolled in non-IND foreign clinical studies, as well as the quality and integrity of the resulting data.

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An IRB can suspend or terminate approval of a clinical trial at its institution, or an institution it represents, if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the product candidate has been associated with unexpected serious harm to patients.

Additionally, some trials are overseen by an independent group of qualified experts organized by the trial sponsor, known as a data safety monitoring board or committee, or DSMB.

Additionally, some trials are overseen by an independent group of qualified experts organized by the trial sponsor, known as a data safety monitoring board or committee.

This group provides authorization as to whether or not a trial may move forward at designated check points based on access that only the group maintains to available data from the study.

Suspension or termination of development during any phase of clinical trials can occur if it is determined that the participants or patients are being exposed to an unacceptable health risk.

Suspension or

termination of development during any phase of clinical trials can occur if it is determined that the participants or patients are being exposed to an unacceptable health risk.

Other reasons for suspension or termination may be made by us based on evolving business objectives and/or competitive climate.

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the potential patient benefit justifies the potential risks of the treatment and the potential risks are not unreasonable in the context or condition to be treated;

and the expanded use of the investigational drug for the requested treatment will not interfere initiation, conduct, or completion of

clinical investigations that could support marketing approval of the product or otherwise compromise the potential development of the product.

On December 13, 2016, the 21st Century Cures Act established (and the 2017 FDA Reauthorization Act later amended) a requirement that sponsors of one or more investigational drugs for the treatment of a serious disease or condition make publicly available their policy for evaluating and responding to requests for expanded access for individual patients.

Although these requirements were rolled out over time, they have now come into full effect.

This provision requires drug and biologic companies to make publicly available their policies for expanded access for individual patient access to products intended for serious diseases.

Sponsors are required to make such policies publicly available upon the earlier of initiation of a Phase 2 or Phase 3 study, or 15 days after the drug or biologic receives designation as a breakthrough therapy, fast track product, or regenerative medicine advanced therapy.

In addition, on May 30, 2018, the Right to Try Act was signed into law.

and the expanded use of the investigational drug for the requested treatment will not interfere initiation, conduct, or completion of clinical investigations that could support marketing approval of the product or otherwise compromise the potential development of the product.

Sponsors are required to make policies for evaluating and responding to requests for expanded access for patients policies publicly available upon the earlier of initiation of a Phase 2 or Phase 3 clinical trial, or 15 days after the drug or biologic receives designation as a breakthrough therapy, fast track product, or regenerative medicine advanced therapy.

In addition to and separate from expanded access, on May 30, 2018, the Right to Try Act was signed into law.

The law, among other things, provides a federal framework for certain patients to access certain investigational new drug products that have completed a Phase I clinical trial and are undergoing investigation for FDA approval.

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Phase 3 clinical trials are undertaken within an expanded patient population to further evaluate dosage, provide substantial evidence of clinical efficacy, and further test for safety in an expanded and diverse patient population at multiple, geographically dispersed clinical trial sites.

A well-controlled, statistically robust Phase 3 clinical trial may be designed to deliver the data that regulatory authorities will use to decide whether or not to approve, and, if approved, how to appropriately label a drug;

A well-controlled, statistically robust Phase 3 clinical

trial may be designed to deliver the data that regulatory authorities will use to decide whether or not to approve, and, if approved, how to appropriately label a drug;

such Phase 3 studies are referred to as “pivotal.”

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Furthermore, 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 are being exposed to an unacceptable health risk.

Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution, or an institution it represents, if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the product has been associated with

unexpected serious harm to patients.

The FDA will typically inspect one or more clinical sites to assure compliance with GCP and the integrity of the clinical data submitted.

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Additionally, before approving an NDA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP.

Under the FDA Reauthorization Act of 2017, the FDA must implement a protocol to expedite review of responses to inspection reports pertaining to certain applications, including applications for products in shortage or those for which approval is dependent on remediation of conditions identified in the inspection report.

Under the FDA Reauthorization Act of 2017, the FDA must implement a protocol to expedite review of responses to inspection reports pertaining to certain

applications, including applications for products in shortage or those for which approval is dependent on remediation of conditions identified in the inspection report.

In addition, as a condition of approval, the FDA may require an applicant to develop a REMS.

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The FDA may grant accelerated approval to a product for a serious or life-threatening condition that provides meaningful therapeutic advantage to patients over existing treatments based upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit.

The FDA may also grant accelerated approval for such a condition when the product has an effect on an intermediate clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality, or IMM, and that is reasonably likely to predict an effect on IMM or other clinical benefit, taking into account the severity, rarity or prevalence of the condition and the availability or lack of alternative treatments.

taking into account the severity, rarity or prevalence of the condition and the availability or lack of alternative treatments.

Products granted accelerated approval must meet the same statutory standards for safety and effectiveness as those granted traditional approval.

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Thus, accelerated approval has been used extensively in the development and approval of products for treatment of a variety of cancers in which the goal of therapy is generally to improve survival or decrease morbidity, and the duration of the typical disease course requires lengthy and sometimes large trials to demonstrate a clinical or survival benefit.

Thus, the benefit of accelerated approval derives from the potential to receive approval based on surrogate

endpoints sooner than possible for trials with clinical or survival endpoints, rather than deriving from any explicit shortening of the FDA approval timeline, as is the case with priority review.

Thus, the benefit of accelerated approval derives from the potential to receive approval based on surrogate endpoints sooner than possible for trials with clinical or survival endpoints, rather than deriving from any explicit shortening of the FDA approval timeline, as is the case with priority review.

The accelerated approval pathway is usually contingent on a sponsor’s agreement to conduct, in a diligent manner, additional post-approval confirmatory studies to verify and describe the product’s clinical benefit.

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An approval letter authorizes commercial marketing of the product with specific prescribing information for the approved indications.

A complete response letter generally outlines the deficiencies in the submission and may require substantial additional testing or information in order for the FDA to reconsider the application.

A complete response letter generally outlines the deficiencies in the submission and may require substantial additional testing or information in order

for the FDA to reconsider the application.

If and when those deficiencies have been addressed to the FDA’s satisfaction in a resubmission of the NDA, the FDA will issue an approval letter.

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If regulatory approval for marketing of a product or new indication for an existing product is obtained, the sponsor will be required to comply with all regular post-approval regulatory requirements as well as any post-approval requirements that the FDA may have imposed as part of the approval process.

The sponsor will be required to report, among other things, certain

adverse reactions and manufacturing problems to the FDA, provide updated safety and efficacy information and comply with requirements concerning advertising and promotional labeling requirements.

The sponsor will be required to report, among other things, certain adverse reactions and manufacturing problems to the FDA, provide updated safety and efficacy information and comply with requirements concerning advertising and promotional labeling requirements.

Manufacturers and certain of their subcontractors are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with ongoing regulatory requirements, including cGMP regulations.

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The FDA is, however, authorized to approve an alternative type of NDA under Section 505(b)(2) of the FDCA.

This type of application allows the applicant to rely, in part, on the FDA’s previous findings of safety and efficacy for a similar

product, or published literature.

This type of application allows the applicant to rely, in part, on the FDA’s previous findings of safety and efficacy for a similar product, or published literature.

Specifically, Section 505(b)(2) applies to NDAs for a drug for which the investigations made to show whether or not the drug is safe for use and effective in use and relied upon by the applicant for approval of the application “were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted.”

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Abbreviated New Drug Applications for Generic Drugs

In 1984, with passage of the Hatch-Waxman Amendments to the FDCA, Congress established an abbreviated regulatory scheme authorizing the FDA to approve generic drugs that are shown to contain the same active ingredients as, and to be bioequivalent to, drugs previously approved by the FDA pursuant to NDAs.

To obtain approval of a generic drug, an applicant must submit an abbreviated new drug application, or ANDA, to the agency.

An ANDA is a comprehensive submission that contains, among other things, data and information pertaining to the active pharmaceutical ingredient, bioequivalence, drug product formulation, specifications and stability of the generic drug, as well as analytical methods, manufacturing process validation data and quality control procedures.

ANDAs are “abbreviated” because they generally do not include preclinical and clinical data to demonstrate safety and effectiveness.

Instead, in support of such applications, a generic manufacturer may rely on the preclinical and clinical testing previously conducted for a drug product previously approved under an NDA, known as the reference-listed drug, or RLD.

Specifically, in order for an ANDA to be approved, the FDA must find that the generic version is identical to the RLD with respect to the active ingredients, the route of administration, the dosage form, the strength of the drug and the conditions of use of the drug.

At the same time, the FDA must also determine that the generic drug is “bioequivalent” to the innovator drug.

Abbreviated new drug applications, or ANDAs, generally do not include preclinical and clinical data to demonstrate safety and effectiveness.

Instead, the applicant may rely on the preclinical and clinical testing previously conducted for the RLD.

To approve an ANDA, the FDA must find that the generic version is identical to the RLD, with respect to the active ingredients, the route of administration, the dosage form, the strength of the drug and the conditions of use of the drug.

At the same time, the FDA must also determine that the generic drug is “bioequivalent” to the RLD.

Under the statute, a generic drug is bioequivalent to an RLD if “the rate and extent of absorption of the drug do not show a significant difference from the rate and extent of absorption of the listed drug.” Upon approval of an ANDA, the FDA indicates whether the generic product is “therapeutically equivalent” to the RLD in its publication “Approved Drug Products with Therapeutic Equivalence Evaluations,” also referred to as the “Orange Book.” Physicians and pharmacists consider a therapeutic equivalent generic drug to be fully substitutable for the RLD.

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The FDA typically makes decisions about awards of data exclusivity shortly before a product is approved.

The FDA must establish a priority review track for certain generic drugs, requiring the FDA to review a drug application within eight (8) months for a drug that has three (3) or fewer approved drugs listed in the Orange Book and is no longer protected by any patent or regulatory exclusivities, or is on the FDA’s drug shortage list.

The new legislation also authorizes FDA to expedite review of ‘‘competitor generic therapies’’ or drugs with inadequate generic competition, including holding meetings with or providing advice to the drug sponsor prior to submission of the application.

Hatch-Waxman Patent Certification and the 30-Month Stay

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As a result, approval of a Section 505(b)(2) NDA can be stalled until all the listed patents claiming the referenced product have expired, until any non-patent exclusivity, such as exclusivity for obtaining approval of an NCE, listed in the Orange Book for the referenced product has expired, and, in the case of a Paragraph IV certification and subsequent patent infringement suit, until the earlier of 30 months, settlement of the lawsuit or a decision in the infringement case that is favorable to the Section 505(b)(2) applicant.

Pediatric Studies and Exclusivity

Pediatric Studies

Under the Pediatric Research Equity Act of 2003, an NDA or supplement thereto must contain data that are adequate to assess the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

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The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements.

Additional requirements and procedures relating to deferral requests and requests for extension of deferrals are contained in the Food and Drug Administration Safety and Innovation Act, or FDASIA.

Unless otherwise required by regulation, the pediatric data requirements do not apply to products with orphan designation.

Additional requirements and procedures relating to deferral requests and requests for extension of deferrals are contained in the Food and Drug Administration Safety and Innovation Act.

The FDA maintains a list of diseases that are exempt from the requirements of the Pediatric Research Equity Act, or PREA, due to low prevalence of disease in the pediatric population.

Under the amended section 505B of the FDA Reauthorization Act of 2017, beginning on August 18, 2020, the submission of a pediatric assessment, waiver or deferral will be required for certain molecularly targeted cancer indications with the submission of an NDA application or supplement to an NDA application.

Previously, drugs that had been granted orphan drug designation were exempt from the requirements of the PREA.

The FDA Reauthorization Act of 2017 established new requirements to govern certain molecularly targeted cancer indications.

Any company that submits an NDA three years after the date of enactment of that statute must submit pediatric assessments

with the NDA if the drug is intended for the treatment of an adult cancer and is directed at a molecular target that the FDA determines to be substantially relevant to the growth or progression of a pediatric cancer.

Any company that submits an NDA three years after the date of enactment of that statute must submit pediatric assessments with the NDA if the drug is intended for the treatment of an adult cancer and is directed at a molecular target that the FDA determines to be substantially relevant to the growth or progression of a pediatric cancer.

The investigation must be designed to yield clinically meaningful pediatric study data regarding the dosing, safety and preliminary efficacy to inform pediatric labeling for the product.

Pediatric Exclusivity

Pediatric exclusivity is another type of non-patent marketing exclusivity in the United States and, if granted, provides for the attachment of an additional six months of marketing protection to the term of any existing regulatory exclusivity, including the non-patent and orphan exclusivity.

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The restoration period granted on a patent covering a product is typically one-half the time between the effective date of when a clinical investigation involving human beings has begun and the submission date of an application, plus the time between the submission date of an application and the ultimate approval date.

Patent term restoration cannot be used to extend the remaining term of a patent past a total of 14 years from the product’s approval date.

Patent term restoration cannot be used to extend the remaining

term of a patent past a total of 14 years from the product’s approval date.

Only one patent applicable to an approved product is eligible for the extension, and the application for the extension must be submitted prior to the expiration of the patent in question.

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Approval or clearance of the companion diagnostic device will ensure that the device has been adequately evaluated and has adequate performance characteristics in the intended population.

The review of in vitro companion diagnostics in conjunction with the review of our therapeutic treatments for cancer will, therefore, likely involve coordination of review by the FDA’s Center for Drug Evaluation and Research and the FDA’s Center for Devices and Radiological Health Office of In Vitro Diagnostics Device Evaluation and Safety.

The guidance also explains that a companion diagnostic device used to make treatment decisions in clinical trials of a biologic product candidate generally will be considered an investigational device, unless it is employed for an intended use for which the device is already approved or cleared.

If used to make critical treatment decisions, such as patient selection, the diagnostic device generally will be considered a significant risk device under the FDA’s Investigational Device Exemption, or IDE, regulations.

Thus, the sponsor of the diagnostic device will be required to comply with the IDE regulations.

According to the guidance, if a diagnostic device and a drug are to be studied together to support their respective approvals, both products can be studied in the same investigational study, if the study meets both the requirements of the IDE regulations and the IND regulations.

The guidance provides that depending on the details of the study plan and subjects, a sponsor may seek to submit an IND alone, or both an IND and an IDE.

In July 2016, the FDA issued a draft guidance document intended to further assist sponsors of therapeutic products and sponsors of in vitro companion diagnostic devices on issues related to co-development of these products.

Under the FDCA, in vitro diagnostics, including companion diagnostics, are regulated as medical devices.

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It involves a rigorous premarket review during which the applicant must prepare and provide the FDA with reasonable assurance of the device’s safety and effectiveness, and information about the device and its components regarding, among other things, device design, manufacturing and labeling.

PMA applications are subject to an application fee, which exceeds $250,000 for most PMAs.

PMA applications are subject to an application fee.

For federal fiscal year 2021, the standard fee is $365,657 and the small business fee is $91,414.

In addition, PMAs for certain devices must generally include the results from extensive preclinical and adequate and well-controlled clinical trials to establish the safety and effectiveness of the device for each indication for which FDA approval is sought.

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The FDA may also determine that additional clinical trials are necessary, in which case the PMA approval may be delayed for several months or years while the trials are conducted and the data submitted in an amendment to the PMA.

If the FDA concludes that the applicable criteria have been met, the FDA will issue a PMA for the approved indications, which can be more limited than those originally sought by the applicant.

If the FDA concludes that the applicable criteria have been met, the FDA

will issue a PMA for the approved indications, which can be more limited than those originally sought by the applicant.

The PMA can include post-approval conditions that the FDA believes necessary to ensure the safety and effectiveness of the device, including, among other things, restrictions on labeling, promotion, sale and distribution.

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Significant uncertainty exists as to the coverage and reimbursement status of products approved by the FDA and other government authorities.

Thus, even if a product candidate is approved, sales of the product will depend, in part, on the extent to which third-party payors, including government health programs in the United States such as Medicare and Medicaid, commercial health insurers and managed care organizations, provide coverage and establish adequate reimbursement levels for the product.

The process for determining whether a 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.

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Coverage policies and third-party reimbursement rates may change at any time.

Even if favorable coverage and reimbursement

status is attained for one or more products for which a company or its collaborators receive marketing approval, less favorable coverage policies and reimbursement rates may be implemented in the future.

Even if favorable coverage and reimbursement status is attained for one or more products for which a company or its collaborators receive marketing approval, less favorable coverage policies and reimbursement rates may be implemented in the future.

There have been a number of federal and state proposals during the last few years regarding the pricing of pharmaceutical and biopharmaceutical products, limiting coverage and reimbursement for drugs, biologics and other medical products, government control and other changes to the health care system in the United States.

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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.

This includes aggregate reductions of Medicare payments to providers up to 2% per fiscal year, which went into effect in April 2013 and, due to subsequent legislative amendments, will remain in effect through 2027 unless additional Congressional action is taken.

In January 2013, President Obama signed into law the American Taxpayer Relief Act of 2012, which, among other things, further reduced Medicare payments to several providers, including hospitals, imaging centers and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

Since enactment of the ACA, there have been numerous legal challenges and Congressional actions to repeal and replace provisions of the law.

For example, with enactment of the Tax Cuts and Jobs Act of 2017, or TCJA, which was signed by the President on December 22, 2017, Congress repealed the “individual mandate.” The repeal of this provision, which requires most Americans to carry a minimal level of health insurance, which became effective in 2019.

According to the Congressional Budget Office, the repeal of the individual mandate will cause 13 million fewer Americans to be insured in 2027 and premiums in insurance markets may rise.

Additionally, on January 22, 2018, President Trump signed a continuing resolution on appropriations for fiscal year 2018 that delayed the implementation of certain ACA-mandated fees, including the so-called “Cadillac” tax on certain high cost employer-sponsored insurance plans, the annual fee imposed on certain health insurance providers based on market share, and the medical device excise tax on non-exempt medical devices.

Further, the Bipartisan Budget Act of 2018, among other things, amends the ACA, effective January 1, 2019, to increase from 50 percent to 70 percent the point-of-sale discount that is owed by pharmaceutical manufacturers who participate in Medicare Part D and to close the coverage gap in most Medicare drug plans, commonly referred to as the “donut hole”.

On December 14, 2018, a U.S.

District Court judge in the Northern District of Texas ruled that the individual mandate portion of the ACA is an essential and inseverable feature of the ACA, and therefore because the mandate was repealed as part of the TCJA, the remaining provisions of the ACA are invalid as well.

The Trump Administration and CMS have both stated that the ruling will have no immediate effect, and on December 30, 2018 the same judge issued an order staying the judgment pending appeal.

The Trump Administration thereafter represented to the Court of Appeals considering this judgment that it does not oppose the lower court's ruling.

On July 10, 2019, the Court of Appeals for the Fifth Circuit heard oral argument in this case.

those arguments, the Trump Administration argued in support of upholding the lower court decision.

On December 18, 2019, that court affirmed the lower court’s ruling that the individual mandate portion of the ACA is unconstitutional and remanded the case to the district court for reconsideration of the severability question and additional analysis of the provisions of the ACA.

On January 21, 2020, the U.S.

Supreme Court declined to review this decision on an expedited basis.

Litigation and legislation over the ACA are likely to continue, with unpredictable and uncertain results.

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.

In January 2013, President Obama signed into law the American Taxpayer Relief Act of 2012, which, among

other things, further reduced Medicare payments to several providers, including hospitals, imaging centers and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

Since enactment of the ACA, there have been, and continue to be, numerous legal challenges and Congressional actions to repeal and replace provisions of the law.

For example, with enactment of the Tax Cuts and Jobs Act of 2017, which was signed by the President on December 22, 2017, Congress repealed the “individual mandate.” The repeal of this provision, which requires most Americans to carry a minimal level of health insurance, became effective in 2019.

Additionally, the 2020 federal spending package permanently eliminated, effective January 1, 2020, the ACA-mandated “Cadillac” tax on high-cost employer-sponsored health coverage and the medical device tax and, effective January 1, 2021, also eliminated the health insurer tax.

Further, the Bipartisan Budget Act of 2018, among other things, amended the ACA, effective January 1, 2019, to increase from 50 percent to 70 percent the point-of-sale discount that is owed by pharmaceutical manufacturers who participate in Medicare Part D and to close the coverage gap in most Medicare drug plans, commonly referred to as the “donut hole.” Congress may consider other legislation to replace elements of the ACA during the next Congressional session.

The Trump Administration also took executive actions to undermine or delay implementation of the ACA.

During his term, President Trump 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.

One Executive Order directs 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 or regulatory burden on states, individuals, healthcare providers, health insurers, or manufacturers of pharmaceuticals or medical devices.

The second Executive Order terminates the cost-sharing subsidies that reimburse insurers under the ACA.

Several state Attorneys General filed suit to stop the administration from terminating the subsidies, but their request for a restraining order was denied by a federal judge in California on October 25, 2017.

In addition, the CMS has recently proposed regulations that would give states greater flexibility 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.

Further, on June 14, 2018, the U.S.

Court of Appeals for the Federal Circuit ruled that the federal government was not required to pay more than $12 billion in ACA risk corridor payments to third-party payors who argued were owed to them.

The effects of this gap in reimbursement on third-party payors, the viability of the ACA marketplace, providers, and potentially our business, are not yet known.

Further, there have been several recent U.S.

congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, reduce the costs of drugs under Medicare and reform government program reimbursement methodologies for drug products.

At the federal level, the Trump administration’s budget proposal for fiscal year 2019 contains further drug price control measures that could be enacted during the 2019 budget process or in other future legislation, including, for example, measures to permit Medicare Part D plans to negotiate the price of certain drugs under Medicare Part B, allow some states to negotiate drug prices under Medicaid, and eliminate cost sharing for generic drugs for low-income patients.

While any proposed measures will require authorization through additional legislation to become effective, Congress and the Trump administration have each indicated that it will continue to seek new legislative and/or administrative measures to control drug costs.

For example, on December 23, 2019, the Trump Administration published a proposed rule that, if finalized, would allow states or certain other non-federal government entities to submit importation program proposals to the FDA for review and approval.

Applicants would be required to demonstrate their importation plans pose no additional risk to public health and safety and will result in significant cost savings for consumers.

At the same time, the FDA issued draft guidance that would allow manufacturers to import their own FDA-approved drugs that are authorized for sale in other countries (multi-market approved products).

On January 28, 2021, however, President Biden issued a new Executive Order which directs federal agencies to reconsider rules and other policies that limit Americans’ access to health care, and consider actions that will protect and strengthen that access.

Under this Executive Order, federal agencies are directed to re-examine:

policies that undermine protections for people with pre-existing conditions, including complications related to COVID-19;

demonstrations and waivers under Medicaid and the ACA that may reduce coverage or undermine the programs, including work requirements;

policies that undermine the Health Insurance Marketplace or other markets for health insurance;

policies that make it more difficult to enroll in Medicaid and the ACA;

and policies that reduce affordability of coverage or financial assistance, including for dependents.

On November 10, 2020, the Supreme Court heard oral arguments as to whether the individual mandate portion of the ACA is an essential and inseverable feature of the ACA, and therefore because the mandate was repealed as part of the Tax Cuts and Jobs Act, the remaining provisions of the ACA are invalid as well.

On February 10, 2021, the Biden Administration withdrew DOJ’s support for this lawsuit.

A ruling by the Supreme Court is expected sometime this year.

Litigation and legislation over the ACA are likely to continue, with unpredictable and uncertain results.

The costs of prescription pharmaceuticals have also been the subject of considerable discussion in the United States.

To date, there have been several recent U.S.

congressional inquiries, as well as proposed and enacted state and federal legislation designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, reduce the costs of drugs under Medicare and reform government program reimbursement methodologies for drug products.

To those ends, President Trump issued five executive orders intended to lower the costs of prescription drug products but it is unclear whether, and to what extent, these orders will remain in force under the Biden Administration.

Further, on September 24, 2020, the Trump Administration finalized a rulemaking allowing states or certain other non-federal government entities to submit importation program proposals to the FDA for review and approval.

Applicants are required to demonstrate that their importation plans pose no additional risk to public health and safety and will result in significant cost savings for consumers.

The FDA has issued draft guidance that would allow manufacturers to import their own FDA-approved drugs that are authorized for sale in other countries (multi-market approved products).

At the state level, individual states are increasingly aggressive in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

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Whether or not it obtains FDA approval for a product, an applicant will need to obtain the necessary approvals by the comparable non-U.S.

regulatory authorities before it can commence clinical trials or marketing of the product in those countries or jurisdictions.

regulatory authorities before

it can commence clinical trials or marketing of the product in those countries or jurisdictions.

Specifically, the process governing approval of medicinal products in the EU generally follows the same lines as in the United States.

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The Clinical Trials Directive 2001/20/EC, the Directive 2005/28/EC on Good Clinical Practice, or GCP, and the related national implementing provisions of the individual EU Member States govern the system for the approval of clinical trials in the EU.

Under this system, an applicant must obtain prior approval from the competent national authority of the EU Member

States in which the clinical trial is to be conducted.

Under this system, an applicant must obtain prior approval from the competent national authority of the EU Member States in which the clinical trial is to be conducted.

Furthermore, the applicant may only start a clinical trial at a specific study site after the competent ethics committee has issued a favorable opinion.

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In April 2014, the Clinical Trial (Regulation, (EU)) No 536/2014 was adopted.

The Clinical Trial Regulation was published on June 16, 2014 but is not expected to apply until 2020.

The Clinical Trial Regulation will be directly applicable in all the EU Member States, repealing the current Clinical Trials Directive 2001/20/EC and replacing any national legislation that was put in place to implement the Directive.

Conduct of all clinical trials performed in the EU will continue to be bound by currently applicable provisions until the new Clinical Trial Regulation becomes applicable.

The extent to which on-going clinical trials will be governed by the Clinical Trial Regulation will depend on when the Clinical Trial Regulation becomes applicable and on the duration of the individual clinical trial.

If a clinical trial continues for more than three years from the day on which the Clinical Trial Regulation becomes applicable the Clinical Trial Regulation at that time will begin to apply to the clinical trial.

The new Clinical Trial Regulation aims to simplify and streamline the approval of clinical trials in the EU.

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However, overall related timelines will be defined by the Clinical Trial Regulation.

Conduct of all clinical trials performed in the EU will continue to be bound by currently applicable provisions until the new Clinical Trial Regulation becomes applicable.

In January 2020, the website of the European Commission reported that the implementation of the Clinical Trial Regulation was dependent on the development of a fully functional clinical trials portal and database, which would be confirmed by an independent audit which was conducted in December 2020, and that the new legislation would come into effect six months after the European Commission publishes a notice of this confirmation.

The Clinical Trial Regulation becomes applicable six months after the European Commission publishes notice of this confirmation and has published an expected system “go live” in December 2021.

When the Clinical Trial Regulation becomes applicable, the existing Clinical Trial Directive and national legislation put in place to implement the Directive will be repealed.

Following implementation of the Clinical Trial Regulation, a transitional period will be in effect for one year where new clinical trial applications can be submitted either under the existing Clinical Trials Directive or under the new Clinical Trial Regulation.

PRIME Designation in the EU

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Many benefits accrue to sponsors of product candidates with PRIME designation, including but not limited to, early and proactive regulatory dialogue with the EMA, frequent discussions on clinical trial designs and other development program elements, and accelerated marketing authorization application assessment once a dossier has been submitted.

Importantly, a dedicated Agency contact and rapporteur from the Committee for Human Medicinal Products, or CHMP, or Committee for Advanced Therapies, or CAT, are appointed early in the PRIME scheme facilitating increased understanding of the product at EMA’s Committee level.

Importantly, a dedicated Agency contact and rapporteur from the CHMP or Committee for Advanced Therapies, or CAT, are appointed early in the PRIME scheme facilitating increased understanding of the product at EMA’s Committee level.

A kick-off meeting initiates these relationships and includes a team of multidisciplinary experts at the EMA to provide guidance on the overall development and regulatory strategies.

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Under the centralized procedure, the CHMP is also responsible for several post-authorization and maintenance activities, such as the assessment of modifications or extensions to an existing marketing authorization.

Under the centralized procedure in the

EU, the maximum timeframe for the evaluation of an MAA is 210 days, excluding clock stops, when additional information or written or oral explanation is to be provided by the applicant in response to questions of the CHMP.

Under the centralized procedure in the EU, the maximum timeframe for the evaluation of an MAA is 210 days, excluding clock stops, when additional information or written or oral explanation is to be provided by the applicant in response to questions of the CHMP.

Accelerated evaluation might be granted by the CHMP in exceptional cases, when a medicinal product is of major interest from the point of view of public health and from the viewpoint of therapeutic innovation.

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While the products we have in development do not make use of embryonic stem cells, it is possible that the national laws in certain EU Member States may prohibit or restrict us from commercializing our products, even if they have been granted an EU marketing authorization.

Unlike the centralized authorization procedure, the decentralized marketing authorization procedure requires a separate application to, and leads to separate approval by, the competent authorities of each EU Member State in which the product is to

This application is identical to the application that would be submitted to the EMA for authorization through the centralized procedure.

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141/2000, as implemented by Regulation (EC) No.

847/2000 provides that a drug can be designated as an orphan drug by the European Commission if its sponsor can establish that the product is intended for the diagnosis, prevention

or treatment of:

847/2000 provides that a drug can be designated as an orphan drug by the European Commission if its sponsor can establish that the product is intended for the diagnosis, prevention or treatment of:

(1) a life-threatening or chronically debilitating condition affecting not more than five in ten thousand persons in the EU when the application is made;

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The collection, use, disclosure, transfer, or other processing of personal data regarding individuals in the EU, including personal health data, is subject to the EU General Data Protection Regulation, or GDPR, which became effective on May 25, 2018.

The GDPR is wide-ranging in scope and imposes numerous requirements on companies that process personal data, including requirements relating to processing health and other sensitive data, obtaining consent of the individuals to whom the personal data relates, providing information to individuals regarding data processing activities, implementing safeguards to protect the security and confidentiality of personal data, providing notification of data breaches, and taking certain measures when engaging third-party processors.

The GDPR also imposes rules on the transfer of personal data to countries outside the EU, including the United States, and permits data protection authorities to impose penalties for violations of the GDPR, including potential fines of up to €20 million or 4% of annual global revenues, whichever is greater.

GDPR is wide-ranging in scope and imposes numerous requirements on companies that process personal data, including requirements relating to processing health and other sensitive data, obtaining consent of the individuals to whom the personal data relates, providing information to individuals regarding data processing activities, implementing safeguards to protect the security and confidentiality of personal data, providing notification of data breaches, and taking certain measures when engaging third-party processors.

The GDPR also imposes strict rules on the transfer of personal data to countries outside the EU, including the United States, and permits data protection authorities to impose large penalties for violations of the GDPR, including potential fines of up to €20 million or 4% of annual global revenues, whichever is greater.

The GDPR also confers a private right of action on data subjects and consumer associations to lodge complaints with supervisory authorities, seek judicial remedies, and obtain compensation for damages resulting from violations of the GDPR.

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Following protracted negotiations, the United Kingdom left the EU on January 31, 2020.

Under the withdrawal agreement, there is a transitional period until December 31, 2020 (extendable up to two years).

Discussions between the United Kingdom and the EU have so far mainly focused on finalizing withdrawal issues and transition agreements but have been extremely difficult to date.

To date, only an outline of a trade agreement has been reached.

Much remains open but the Prime Minister has indicated that the United Kingdom will not seek to extend the transitional period beyond the end of 2020.

If no trade agreement

has been reached before the end of the transitional period, there may be significant market and economic disruption.

The Prime Minister has also indicated that the United Kingdom will not accept high regulatory alignment with the EU.

Since the regulatory framework for pharmaceutical products in the United Kingdom covering quality, safety and efficacy of pharmaceutical products, clinical trials, marketing authorization, commercial sales and distribution of pharmaceutical products is derived from EU directives and regulations, Brexit could materially impact the future regulatory regime which applies to products and the approval of product candidates in the United Kingdom.

It remains to be seen how, if at all, Brexit will impact regulatory requirements for product candidates and products in the United Kingdom.

On December 24, 2020, the United Kingdom and the European Union entered into a Trade and Cooperation Agreement, which sets out certain procedures for approval and recognition of medical products in each jurisdiction.

Since the regulatory framework for pharmaceutical products in the United Kingdom covering quality, safety and efficacy of pharmaceutical products, clinical trials, marketing authorization, commercial sales and distribution of pharmaceutical products is derived from EU directives and regulations, Brexit could materially impact the future regulatory regime that applies to products and the approval of product candidates in the United Kingdom.

Furthermore, while the Data Protection Act of 2018 in the United Kingdom that “implements” and complements the EU’s GDPR, is now effective in the United Kingdom, it is still unclear whether transfer of data from the European Economic Area, or EEA, to the United Kingdom will remain lawful under GDPR.

The Trade and Cooperation Agreement provides for a transitional period during which the United Kingdom will be treated like an EU Member State in relation to processing and transfers of personal data for four months from January 1, 2021.

This may be extended by two further months.

After such period, the United Kingdom will be a “third country” under the GDPR unless the European Commission adopts an adequacy decision in respect of transfers of personal data to the United Kingdom.

The United Kingdom has already determined that it considers all of the EU and EEA member states to be adequate for the purposes of data protection, ensuring that data flows from the United Kingdom to the EU and EEA remain unaffected.

Pricing Decisions for Approved Products

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Product revenue, net 59 % 51 % 15 %

Our product sales to one specialty distributor, McKesson, and one specialty pharmacy, Biologics, each accounted for more than 10% of our consolidated revenues for the year ended December 31, 2019.

Our product sales to one specialty distributor, McKesson, and one specialty pharmacy, Biologics, each accounted for more than 10% of our consolidated revenues for the years ended December 31, 2020 and 2019.

No customers accounted for more than 10% of our consolidated revenues for year ended December 31, 2018.

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Children's Medical Center Research Institute at University of Texas Southwestern

Kaelin, Jr., M.D.

Dana-Farber Cancer Institute and Harvard Medical School

University of Toronto and the Campbell Family Institute for Breast Cancer Research

Pier Paolo Pandolfi, M.D., Ph.D.

Beth Israel Deaconess Medical Center

Charles Sawyers, M.D.

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Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology

As of December 31, 2019, we had 536 full-time employees, including 158 employees with M.D.

Of these full-time employees, 368 employees are engaged in research and development activities.

None of our employees are represented by a labor union or covered by a collective bargaining agreement.

We consider our relationship with our employees to be good.

Employees and Human Capital

As of December 31, 2020, we had 562 full-time employees.

Of these employees, 552 were based in the United States and 10 were based in international locations and 108 held Ph.D., Pharm.D.

None of our employees are represented by a labor union or covered under a collective bargaining agreement.

We also retain independent contractors to support the goals of our organization.

We prioritize our employee experience and we are proud of our strong employee and contractor relations.

We understand that attracting, retaining, engaging and supporting our talented team and maintaining a diverse and inclusive organization is critical to our success and to increase the value we can provide for patients, shareholders and all stakeholders.

We strive to cultivate a positive, respectful and fair work environment guided by the following three pillars:

• Flexibility:

We provide flexible work arrangements which results in happier, more engaged and more productive employees.

We encourage a culture that promotes different perspectives, work styles, health and wellness, care of families and productivity.

• Psychological safety:

We aim to ensure our teams experience psychological safety – the belief that risk-taking and failure will not be punished, which leads to higher performing teams, more creativity, candor and better results.

• Deliberate development:

We emphasize providing ongoing opportunities for employees to grow professionally, whether through bringing in external speakers, offering preceptorships in different departments, and providing tuition reimbursement and leadership skills training.

To incentivize and reward strong performance, we have established a competitive and balanced compensation and benefits package, including short-term and long-term incentives, discretionary paid time off policy, generous parental and family leave plans and premium medical benefits.

We are committed to fostering a welcoming and diverse workplace in which individuals from a variety of backgrounds can thrive.

Our diversity and inclusion program focuses on valuing three types of differences:

• Representative differences (demographic diversity, such as gender, race, ethnicity, sexual orientation)

• Experiential differences (identities based on life experiences that may change over time)

• Cognitive differences (unique ways of understanding and interpreting the world)

We are a majority female organization and we maintain significant representation at all levels, including the Board of Directors.

As of December 31, 2020, 57% of our workforce were women.

Racial and ethnic diversity in the aggregate has improved at our company over the last few years.

As of December 31, 2020, 33% of our workforce were ethnically diverse.

However, we recognize that there is still important progress to be made, particularly as relates to Black and Latino representation at our company, and this remains an area of continued emphasis for us.

We regularly evaluate the effectiveness of our human capital management practices through employee surveys and fostering a culture of ongoing feedback and two-way dialogue.

In addition, we track important human capital metrics such as turnover rate.

Voluntary and involuntary turnover rates across all levels (executives/ senior managers, mid-level managers and professionals) are in alignment with, or lower than, the industry average.

In 2020, the onset of the COVID-19 pandemic provided an opportunity and an imperative to demonstrate our commitment to the health and wellbeing of our employees, our patients and our community.

We immediately implemented an action plan that took into consideration local and national public health guidelines and input from our employees.

In response to COVID-19, we took the following actions:

• In the early stages of the pandemic, we temporarily closed our offices and labs and eliminated in-person interactions between our field staff and physicians.

• We implemented a deliberate, phased approach to returning to on-site work under a set of operating procedures designed to protect the health and wellbeing of our team and communities.

• We developed a plan for primary employees who have critical on-site work – such as those who work in our labs – to return to our Cambridge headquarters, and for our field staff to safely interact with physicians on a case-by-case basis.

• We instituted – and continue to follow – many measures to ensure the safety of those who are working on-site, including daily health screenings, requiring the use of masks, clear signage to ensure social distancing can be maintained and providing support to enable employees to commute without using public transit.

• We also partnered with Project Beacon and One Medical to facilitate regular on-site testing for employees in the office, and with Everlywell to help with testing our field-based team members for COVID-19.

• We adjusted our approach to employee communications to maintain our culture in a mostly virtual environment, such as through a dedicated intranet site (called the Stay-at-Home Hub), more frequent and virtual companywide meetings, and expanded resources such as a partnership with Out School, an online learning company, and offering LinkedIn online learning.

Throughout the pandemic, we believe our ability to embrace flexibility has helped us maintain productivity to deliver for patients.

Our Corporate Information

We were incorporated under the laws of the State of Delaware in August 2007.

Our executive offices are located at 88 Sidney Street, Cambridge, Massachusetts 02139, and our telephone number is (617) 649-8600.

6 unchanged sentences

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What changed 10-K

Item 1. Business