Agios Pharmaceuticals (AGIO) 2019年年度報告「NASDAQ」.pdf

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1、THE OTHER SIDE OF POSSIBLE2019 ANNUAL REPORTT H E OT H E R S I D E O F P O S S I B L E 2 0 1 9 A N N UA L R E P O R TMEET MOLLY Molly was diagnosed with pyruvate kinase(PK)deficiency when she was 9 months old.Shes a part-time gymnastics coach and loves backyard bonfires and making smores with her fa

2、mily.She went to school to be a nurse but hasnt been able to practice because of the toll PK deficiency takes on her body and the debilitating fatigue she deals with every day.She is dependent on regular transfusions and has undergone countless surgeries to manage her condition.PK deficiency has a s

3、ignificant impact on her daily living,relationships and career.She continues to advocate for improved understanding of PK deficiency and hope for better treatment options.Agios is proud to work toward improving the lives of people like Molly.FELLOW STOCKHOLDERS As I reflect on my first full year as

4、CEO of Agios,I have more confidence than ever in the quality of our science,the strength of our team,our differentiated portfolio of preclinical,clinical and commercial programs and our potential to meaningfully improve the lives of people with hematologic malignancies,solid tumors and rare genetic

5、diseases.A NEW CHAPTER OF INNOVATIONIn our first 10+years,we completed a full cycle of innovation,having advanced two precision oncology medications based on our pioneering work with isocitrate dehydrogenase(IDH)inhibitorsIDHIFA(enasidenib)and TIBSOVO(ivosidenib tablets)from discovery in our own lab

6、s,through clinical development and into the hands of IDH mutant acute myeloid leukemia(AML)patients in need.During that same period,we developed and discovered six additional investigational new drug(IND)candidates and fostered a productive research engine that continues to yield promising preclinic

7、al molecules and new therapeutic approaches.We will leverage the expertise and learnings from our first decade of success as we begin a new chapter for Agios by advancing our first late-stage rare genetic disease molecule,the pyruvate kinase-R(PKR)activator mitapivat,across three opportunities in py

8、ruvate kinase(PK)deficiency,thalassemia and sickle cell disease.We are also continuing our work on IDH inhibitors,expanding that franchise into solid tumors as well as to additional indications in hematologic malignancies.Based on the strength of our existing clinical and late-stage preclinical prog

9、rams,we have line of sight to value-generating milestones each year for the foreseeable future.Because of this,we recently unveiled our Agios 2025 strategic vision,sharing for the first time how we believe the company will evolve as our portfolio progresses.By the end of 2025,we expect:4 marketed me

10、dicines discovered and developed at Agios Approvals in 8+indications spanning hematologic malignancies,solid tumors and rare genetic diseases 6+molecules in the clinic generated by our internal research discovery engine Cash-flow positivity within the six-year timeframe My confidence in our ability

11、to achieve this vision is bolstered by my confidence in our people.The work we do is incredibly important,meaningful work and each and every person who works at Agios is driven to think big and push just beyond their comfort zones.Trusting each other has been a key,proven element of our team dynamic

12、 throughout our existence,and it will continue to be central as we execute on this strategic vision.2019:BUILDING THE FOUNDATIONThis long-term vision is built on the foundation of our 2019 achievements.Some highlights of the year included:Malignant Hematology Achieved approval of our supplemental Ne

13、w Drug Application(sNDA)for TIBSOVO as a treatment for newly diagnosed patients with IDH1 mutant AML Received two Breakthrough Therapy Designations for TIBSOVO:(1)in combination with azacitidine for the treatment of newly diagnosed AML patients with an IDH1 mutation who are ineligible for intensive

14、chemotherapy,and(2)for the treatment of relapsed or refractory myelodysplastic syndrome(MDS)patients with an IDH1 mutation Initiated the Phase 1 dose-escalation trial of AG-636,an inhibitor of the metabolic enzyme dihydroorotate dehydrogenase(DHODH),in advanced lymphomaSolid Tumors Announced positiv

15、e data from our first Phase 3 trial,ClarIDHy,evaluating TIBSOVO as a treatment for previously treated patients with IDH1 mutant cholangiocarcinoma Initiated the Phase 3 INDIGO study of vorasidenib,our brain-penetrant pan-IDH inhibitor,in patients with Grade 2 non-enhancing glioma with an IDH mutatio

16、n Presented the first data from a Phase 1 study of AG-270 in methylthioadenosine phosphorylase(MTAP)-deleted tumors;initiated combination arms of the Phase 1 study evaluating AG-270 in combination with taxanes in non-small cell lung cancer and pancreatic cancerRare Genetic Diseases Established proof

17、-of-concept for mitapivat in non-transfusion-dependent thalassemia based on preliminary Phase 2 results Advanced pivotal trials evaluating mitapivat as a treatment for patients with PK deficiency,completing enrollment of the Phase 3 ACTIVATE-T study and nearly completing enrollment of the Phase 3 AC

18、TIVATE studyCorporate Strengthened the Agios leadership team with several key leadership appointments,including Bruce Car as chief scientific officer;Jonathan Biller as chief legal officer;Orlando Oliveira as senior vice president and general manager,international;and Darrin Miles as senior vice pre

19、sident,U.S.commercial and global marketing Opened our EU headquarters in Zug,Switzerland2020 OUTLOOKAs Im writing thisjust a few months into 2020Agios is part of the global community that is grappling with the rapid and unpredictable outbreak of the SARS-CoV-2 virus.While this pandemic has impacted

20、each of our lives both personally and professionally,were prioritizing the health and wellbeing of our employees and their families,our communities and the patients we serve.The teamwork and resilience Ive witnessed in these last few weeks has truly been remarkable and gives me hope and comfort as w

21、e face the uncertainty that lies ahead.At the beginning of the year,we shared our ambitious 2020 priorities aimed at enabling us to meet or exceed our 2025 vision.The impact of the pandemic on these milestones remains to be seen,but we are actively working on creative,thoughtful ways to minimize the

22、 long-term implications for each of our programs so that we can continue our mission of delivering new medicines to patients.This year will be pivotal for our first rare genetic disease program,with important milestones across three different hemolytic anemias.We expect to announce topline results f

23、rom our two Phase 3 trials evaluating mitapivat in adults with PK deficiency.In anticipation of a potential U.S.approval for this indication,our commercial and medical affairs teams are ramping up pre-launch efforts,including educating patients and the healthcare community about this serious chronic

24、 anemia and raising awareness about the importance of diagnosis and testing.In addition,we are focused on expanding the clinical application of mitapivat into thalassemia and sickle cell disease,and we hope to share clinical data in both diseases this year.2020 will also be a year of significant mom

25、entum for our malignant hematology focus area.We saw strong continued growth of TIBSOVO use in both newly diagnosed and relapsed or refractory AML patients heading into the new year.Today,were focused on Solid Tumors Announced positive data from our first Phase 3 trial,ClarIDHy,evaluating TIBSOVO as

26、 a treatment for previously treated patients with IDH1 mutant cholangiocarcinoma Initiated the Phase 3 INDIGO study of vorasidenib,our brain-penetrant pan-IDH inhibitor,in patients with Grade 2 non-enhancing glioma with an IDH mutation Presented the first data from a Phase 1 study of AG-270 in methy

27、lthioadenosine phosphorylase(MTAP)-deleted tumors;initiated combination arms of the Phase 1 study evaluating AG-270 in combination with taxanes in non-small cell lung cancer and pancreatic cancerRare Genetic Diseases Established proof-of-concept for mitapivat in non-transfusion-dependent thalassemia

28、 based on preliminary Phase 2 results Advanced pivotal trials evaluating mitapivat as a treatment for patients with PK deficiency,completing enrollment of the Phase 3 ACTIVATE-T study and nearly completing enrollment of the Phase 3 ACTIVATE studyCorporate Strengthened the Agios leadership team with

29、several key leadership appointments,including Bruce Car as chief scientific officer;Jonathan Biller as chief legal officer;Orlando Oliveira as senior vice president and general manager,international;and Darrin Miles as senior vice president,U.S.commercial and global marketing Opened our EU headquart

30、ers in Zug,Switzerland2020 OUTLOOKAs Im writing thisjust a few months into 2020Agios is part of the global community that is grappling with the rapid and unpredictable outbreak of the SARS-CoV-2 virus.While this pandemic has impacted each of our lives both personally and professionally,were prioriti

31、zing the health and wellbeing of our employees and their families,our communities and the patients we serve.The teamwork and resilience Ive witnessed in these last few weeks has truly been remarkable and gives me hope and comfort as we face the uncertainty that lies ahead.At the beginning of the yea

32、r,we shared our ambitious 2020 priorities aimed at enabling us to meet or exceed our 2025 vision.The impact of the pandemic on these milestones remains to be seen,but we are actively working on creative,thoughtful ways to minimize the long-term implications for each of our programs so that we can co

33、ntinue our mission of delivering new medicines to patients.This year will be pivotal for our first rare genetic disease program,with important milestones across three different hemolytic anemias.We expect to announce topline results from our two Phase 3 trials evaluating mitapivat in adults with PK

34、deficiency.In anticipation of a potential U.S.approval for this indication,our commercial and medical affairs teams are ramping up pre-launch efforts,including educating patients and the healthcare community about this serious chronic anemia and raising awareness about the importance of diagnosis an

35、d testing.In addition,we are focused on expanding the clinical application of mitapivat into thalassemia and sickle cell disease,and we hope to share clinical data in both diseases this year.2020 will also be a year of significant momentum for our malignant hematology focus area.We saw strong contin

36、ued growth of TIBSOVO use in both newly diagnosed and relapsed or refractory AML patients heading into the new year.Today,were focused on providing an uninterrupted supply of TIBSOVO to patients despite the COVID-19 outbreak and continued access to our myAgios Patient Support Services.We are working

37、 to expand the impact of TIBSOVO to additional patients through both indication and geographic expansion.We are advancing three ongoing registration-enabling studies:the Phase 3 AGILE trial of TIBSOVO in combination with azacitidine in frontline AML,the Phase 3 trial of TIBSOVO in combination with i

38、ntensive chemotherapy in frontline AML and the relapsed or refractory myelodysplastic syndrome arm of the TIBSOVO Phase 1 study.In addition,we are working with European regulators on the potential approval of TIBSOVO in relapsed or refractory AML.Beyond these malignant hematology opportunities,we ar

39、e also excited about the potential of IDH inhibition to improve the lives of patients with solid tumors.We anticipate filing an sNDA for TIBSOVO in previously treated cholangiocarcinoma based on a mature overall survival data readout,and we are focused on enrolling the Phase 3 INDIGO trial of vorasi

40、denib in patients with low-grade glioma.We will continue to invest in our long-term future by advancing the work of our highly productive research engine.We received our eighth IND clearance in March and currently have more than 15 preclinical programs.And well continue to invest in our peopleeach o

41、f whom believes in the importance of our work and in each other.Weve made it clear to each employee that during the COVID-19 pandemic,we are not operating in“business as usual”circumstances,and were here to support them throughout these uncertain times.No matter what,were driven by a culture where p

42、eople strive to be their best selves,connect with each other and welcome different perspectives and backgrounds.From early research to commercialization,well continue to focus on delivering for patients in need.Before I close,I would like to take this opportunity to thank Drs.David Schenkein,our CEO

43、 from 2009 to February 1,2019 and Scott Biller,our Chief Scientific Officer from 2010 to December 31,2019,for their invaluable contributions over their many years of service with Agios.They were instrumental in creating the amazing company I now have the privilege of leading into its second decade.I

44、 am grateful to our employees,scientific and clinical collaborators,founders,board members and stockholders for their continued support as we make important progress toward realizing our goal of making a difference in patients lives.Most importantly,I want to thank the patients and their caregivers,

45、nurses and physicians who participate in our clinical trials;without their support,our work and vision for the future could not move forward.Together,we can achieve the other side of possible.Jacqualyn Fouse,Ph.D.Chief Executive OfficerMEDICINESINDICATIONSCASHMOLECULES IN THE CLINIC2025NOWCOMMERCIAL

46、LABEL EXPANSIONFINANCIALPRODUCTIVE DISCOVERY ENGINESOLID TUMORScholangiocarcinomalow-grade gliomaMTAP-deleted non-small cell lung cancerMTAP-deleted pancreatic cancer 2RARE GENETIC DISEASES adult pyruvate kinase deficiencypediatric pyruvate kinase deficiency-and-thalassemiasickle cell disease 3MALIG

47、NANT HEMATOLOGYacute myeloid leukemiamyelodysplastic syndromelymphoma12428+46+$105115M EXPECTED U.S.TIBSOVO 2020 REVENUECASH FLOW POSITIVE2025 VISIONFocused Innovation.Ambitious Development.Transformative Treatments for Patients Across Three Focus Areas.For more than a decade,our mission has been to

48、 create differentiated,small molecule medicines for patients in three focus areasmalignant hematology,solid tumors and rare genetic diseasesbased on our unique expertise in cellular metabolism and adjacent areas of biology.THREE FOCUS AREASUNITED STATES SECURITIES AND EXCHANGE COMMISSIONWashington,D

49、C 20549Form 10-K(Mark One)ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1934For the fiscal year ended December 31,2019ORTRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF1934Commission File Number:001-36014AGIOS PHARMACEUTICALS,INC.(Ex

50、act name of registrant as specified in its charter)Delaware26-0662915(State or other jurisdiction ofincorporation or organization)(IRS EmployerIdentification No.)88 Sidney Street,Cambridge,MA02139(Address of principal executive offices)(Zip Code)Registrants telephone number,including area code:(617)

51、649-8600Securities registered pursuant to Section 12(b)of the Act:Title of ClassTrading symbol(s)Name of Exchange on Which RegisteredCommon Stock,Par Value$0.001 per shareAGIONasdaq Global Select MarketSecurities registered pursuant to Section 12(g)of the Act:NoneIndicate by check mark if the regist

52、rant is a well-known seasoned issuer,as defined in Rule 405 of the Securities Act.Yes No Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d)of the Act.Yes No Indicate by check mark whether the registrant(1)has filed all reports required to

53、 be filed by Section 13 or 15(d)of the Securities Exchange Actof 1934 during the preceding 12 months(or for such shorter period that the registrant was required to file such reports),and(2)has been subject tosuch filing requirements for the past 90 days.Yes No Indicate by check mark whether the regi

54、strant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule405 of Regulation S-T(232.405 of this chapter)during the preceding 12 months(or for such shorter period that the registrant was required to submitsuch files).Yes No Indicate by check mark whether

55、 the registrant is a large accelerated filer,an accelerated filer,a non-accelerated filer,a smaller reportingcompany,or an emerging growth company.See the definitions of“large accelerated filer,”“accelerated filer,”“smaller reporting company,”andemerging growth company in Rule 12b-2 of the Exchange

56、Act.Large accelerated filer Accelerated filer Non-accelerated filer Smaller reportingcompany Emerging growthcompany If an emerging growth company,indicate by check mark if the registrant has elected not to use the extended transition period for complying withany new or revised financial accounting s

57、tandards provided pursuant to Section 13(a)of the Exchange Act.Indicate by check mark whether the registrant is a shell company(as defined in Rule 12b-2 of the Act).Yes No The aggregate market value of the voting and non-voting Common Stock held by non-affiliates of the registrant computed by refere

58、nce to theprice of the registrants Common Stock as of June 28,2019(based on the last reported sale price on the Nasdaq Global Select Market as of such date)was$2,563,418,196.As of February 13,2020,there were 68,513,573 shares of Common Stock,$0.001 par value per share,outstanding.DOCUMENTS INCORPORA

59、TED BY REFERENCEPortions of the registrants definitive proxy statement for its 2020 Annual Meeting of Stockholders to be filed pursuant to Regulation 14A within120 days of the end of the registrants fiscal year ended December 31,2019 are incorporated by reference into Part III of this Annual Report

60、on Form10-K to the extent stated herein.Table of contentsPART IPageItem 1.2Item 1A.38Item 1B.70Item 2.70Item 3.71Item 4.BusinessRisk FactorsUnresolved Staff CommentsPropertiesLegal ProceedingsMine Safety Disclosures71PART IIItem 5.72Item 6.74Item 7.75Item 7A.89Item 8.89Item 9.89Item 9A.89Item 9B.90I

61、tem 10.91Item 11.91Item 12.91Item 13.91Item 14.91Item 15.92Item 16.Market for Registrants Common Equity,Related Stockholder Matters and IssuerPurchases of Equity SecuritiesSelected Consolidated Financial DataManagements Discussion and Analysis of Financial Condition and Results ofOperationsQuantitat

62、ive and Qualitative Disclosures about Market RiskFinancial Statements and Supplementary DataChanges in and Disagreements with Accountants on Accounting and FinancialDisclosureControls and ProceduresOther InformationPART IIIDirectors,Executive Officers and Corporate GovernanceExecutive CompensationSe

63、curity Ownership of Certain Beneficial Owners and Management and RelatedStockholder MattersCertain Relationships and Related Transactions,and Director IndependencePrincipal Accounting Fees and ServicesPART IVExhibits and Financial Statement SchedulesForm 10-K Summary95iPART IReferences to AgiosThrou

64、ghout this Annual Report on Form 10-K,“we,”“us,”and“our,”and similar expressions,except where the contextrequires otherwise,refer to Agios Pharmaceuticals,Inc.and its consolidated subsidiaries,and“our board of directors”refers tothe board of directors of Agios Pharmaceuticals,Inc.Cautionary Note Reg

65、arding Forward-looking InformationThis Annual Report on Form 10-K contains forward-looking statements that involve substantial risks and uncertainties.Allstatements,other than statements of historical facts,contained in this Annual Report on Form 10-K,including statementsregarding our strategy,futur

66、e operations,future financial position,future revenue,projected costs,prospects,plans,andobjectives of management,are forward-looking statements.The words“anticipate,”“believe,”“estimate,”“expect,”“goal,”“intend,”“may,”“plan,”“predict,”“project,”“strategy,”“target,”“potential,”“will,”“would,”“could,

67、”“should,”“continue,”vision and similar expressions are intended to identify forward-looking statements,although not all forward-lookingstatements contain these identifying words.The forward-looking statements in this Annual Report on Form 10-K include,among other things,statements regarding:the ini

68、tiation,timing,progress and results of current and future preclinical studies and clinical trials,and our research anddevelopment programs;the potential of isocitrate dehydrogenase 1 and 2,or IDH1 and IDH2,respectively,mutations,pyruvate kinase-R,orPKR,methionine adenosyltransferase 2a,or MAT2A,and

69、dihydroorotate dehydrogenase,or DHODH,as therapeutictargets;the potential benefits of our product and product candidates targeting IDH1 or IDH2 mutations,pyruvate kinase-R,MAT2A or DHODH,including TIBSOVO(ivosidenib),IDHIFA(enasidenib),vorasidenib,mitapivat,AG-270 andAG-636;our plans to develop and

70、commercialize our product candidates,including our ability to successfully commercializeTIBSOVO and successfully commercialize IDHIFA with our partner Celgene Corporation,or Celgene,a wholly-owned subsidiary of Bristol-Myers Squibb Company,or BMS;our collaborations with Celgene and CStone Pharmaceut

71、icals,or CStone;our ability to establish and maintain additional collaborations or obtain additional funding;the timing or likelihood of regulatory filings and approvals,including:the Marketing Authorization Application,or MAA,that we submitted in December 2018 to the EuropeanMedicines Agency,or EMA

72、,for TIBSOVO for the treatment of adult patients with relapsed or refractoryacute myeloid leukemia,or R/R AML,with an IDH1 mutation;the supplemental new drug application,or sNDA,for TIBSOVO for previously treated IDH1 mutant-positivecholangiocarcinoma that we expect to submit to the U.S.Food and Dru

73、g Administration,or FDA,by the end of2020;our strategic vision for 2025;the implementation of our business model and strategic plans for our business,product candidates and technology;our commercialization,marketing and manufacturing capabilities and strategy;the rate and degree of market acceptance

74、 and clinical utility of our products;our competitive position;our intellectual property position;developments and projections relating to our competitors and our industry;andour estimates regarding expenses,future revenue,capital requirements and needs for additional financing.We may not actually a

75、chieve the plans,intentions or expectations disclosed in our forward-looking statements,and you shouldnot place undue reliance on our forward-looking statements.Actual results or events could differ materially from the plans,intentions and expectations disclosed in the forward-looking statements we

76、make.We have included important factors in thisAnnual Report on Form 10-K,particularly in the“Risk Factors”section,that could cause actual results or events to differmaterially from the forward-looking statements that we make.Our forward-looking statements do not reflect the potentialimpact of any f

77、uture acquisitions,mergers,dispositions,joint ventures or investments we may make.You should read this Annual Report on Form 10-K and the documents that we have filed as exhibits to this Annual Report onForm 10-K completely and with the understanding that our actual future results may be materially

78、different from what we1expect.We do not assume any obligation to update any forward-looking statements,whether as a result of new information,future events or otherwise,except as required by law.Item 1.BusinessWe are a biopharmaceutical company committed to the fundamental transformation of patients

79、 lives through scientificleadership in the field of cellular metabolism and adjacent areas of biology,with the goal of creating differentiated,smallmolecule medicines for patients in the areas of hematologic malignancies,solid tumors and rare genetic diseases,or RGDs.Toaddress these focus areas,we t

80、ake a systems biology approach to deeply understand disease states,drive the discovery andvalidation of novel therapeutic targets,and define patient selection strategies,thereby increasing the probability that ourexperimental medicines will have the desired therapeutic effect.Our wholly-owned produc

81、t,TIBSOVO(ivosidenib)is an oral targeted inhibitor of the mutated isocitrate dehydrogenase 1,orIDH1 enzyme.TIBSOVO is the first and only U.S.Food and Drug Administration,or FDA-approved therapy for thetreatment of adult patients with(i)relapsed or refractory acute myeloid leukemia,or R/R AML,with a

82、susceptible IDH1mutation as detected by an FDA-approved test(approved by the FDA in July 2018)and(ii)newly diagnosed AML with asusceptible IDH1 mutation as detected by an FDA-approved test who are at least 75 years old or who have comorbidities thatpreclude use of intensive induction chemotherapy(ap

83、proved by the FDA in May 2019).In December 2018,we submitted anMarketing Authorization Application,or MAA,to the European Medicines Agency,or EMA,for TIBSOVO for the treatmentof adult patients with R/R AML with an IDH1 mutation.In addition,we are currently evaluating ivosidenib in the clinical trial

84、sdescribed below.Our other marketed product is IDHIFA(enasidenib),an oral targeted inhibitor of the mutated isocitrate dehydrogenase 2,orIDH2 enzyme and the first and only FDA-approved therapy for patients with R/R AML and an IDH2 mutation.In August 2017,the FDA granted our collaboration partner Cel

85、gene approval of IDHIFA for the treatment of adult patients with R/R AML andan 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-

86、third of the field-basedcommercialization efforts in the United States.In June 2018,Celgene submitted an MAA to the EMA for IDHIFA for IDH2mutant-positive AML which it subsequently withdrew in December 2019.In addition,we and Celgene are currently evaluatingenasidenib in the clinical trials describe

87、d below.Our pre-commercial clinical cancer product candidates are vorasidenib,AG-270,and AG-636.Vorasidenib is an orally available,selective brain-penetrant pan-IDH mutant inhibitor.We are developing vorasidenib for thetreatment of IDH mutant-positive low grade glioma and are currently evaluating vo

88、rasidenib in the clinical trials describedbelow.AG-270 is an orally available selective potent inhibitor of methionine adenosyltransferase 2a,or MAT2A.We are currentlyevaluating AG-270 in a phase 1 dose-escalation and expansion trial in multiple tumor types carrying a methylthioadenosinephosphorylas

89、e,or MTAP,deletion,described below.AG-636 is an inhibitor of the metabolic enzyme dihydroorotate dehydrogenase,or DHODH.We are currently evaluatingAG-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

90、 wild-type and mutant pyruvate kinase-R forthe 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 deve

91、lopment programs,we are seeking to advance a number of early-stage discoveryprograms in our focus areas of malignant hematology,solid tumors and RGDs based on our scientific leadership in the field ofcellular metabolism and adjacent areas of biology.Our approach to drug discovery involves collaborat

92、ion across our core capabilities in bioinformatics,functional genomics,proteomics and metabolomics.We leverage these capabilities to identify under-researched targets,validate these targets usinggenetic and chemical approaches,and advance them rapidly into and through drug discovery.We believe that

93、we haveestablished state-of-the-art capabilities to study and drug metabolic targets including our ability to measure the activities ofnumerous metabolites in cells or tissues in a high throughput fashion,and measure metabolic fluxes.This refers to the analysisof how metabolites,which are intermedia

94、tes or small molecule products of metabolism,accumulate or diminish as they arecreated or chemically altered by multiple networks of metabolic enzymes.Through our historic efforts to drug metabolicenzymes we have established strong capabilities in the enzymology and structural biology of metabolic e

95、nzymes,facilitatingour drug discovery efforts.2We focus on the identification,validation,and drugging of targets with compelling patient selection biomarkers and robustpharmacodynamic readouts,thus increasing the potential for establishing proof of concept early in clinical development,alongwith the

96、 potential for accelerated approval.Our Strategy and Long Term GoalsWe aim to build a sustainable,multi-product company,based on our expertise in cellular metabolism and adjacent biology thatcreates differentiated,small molecule medicines for patients in the areas of malignant hematology,solid tumor

97、s and RGDs.Keyelements of our strategy include:Building a preeminent independent biopharmaceutical company by aggressively pursuing the discovery,developmentand commercialization of novel medicines to transform the lives of patients with hematological malignancies,solidtumors and RGDs.Maintaining ou

98、r focus on bio-marker driven drug discovery and development for defined patient subsets with high unmetneed.Collaborating closely with the FDA and other regulatory bodies to aggressively pursue early registration potential for ourproduct candidates.As part of our long term strategy,we have developed

99、 and articulated a strategic vision that delineates our view for growth overthe next six years,which we call“Agios 2025.”Under this plan,by the end of 2025,our goal is to have four marketedmedicines discovered and developed by us,with regulatory approvals in at least eight indications spanning hemat

100、ologicmalignancies,solid tumors and RGDs;to have at least six molecules in clinical development fueled by our internal researchdiscovery engine;and to become cash flow positive.Our Guiding PrinciplesWe are driven by a disciplined focus on developing medicines that transform the lives of patients wit

101、h hematologicalmalignancies,solid tumors and RGDs.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.Maintain a culture of incisive decis

102、ion-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 ourdiscovery and developme

103、nt efforts.Cellular MetabolismCellular metabolism refers to the set of life-sustaining chemical transformations within the cells of living organisms.Theconversion of nutrients into energy via enzyme-catalyzed reactions allows organisms to grow and reproduce,maintain theirstructures,and respond to th

104、eir environments.Additionally,metabolites serve as key regulators of diverse aspects of cellularbiology,and pharmacologic targeting of metabolism can therefore have disease-modifying effects in a wide variety ofpathologies.The chemical reactions of metabolism are organized into metabolic pathways,in

105、 which one chemical istransformed through a series of steps into another chemical,by a sequence of enzymes.Enzymes catalyze quick and efficientreactions,serve as key regulators of metabolic pathways,and respond to changes in the cells environment or signals from othercells.We believe our deep unders

106、tanding of metabolic pathways within normal cells enables us to identify altered metabolicpathways within abnormal cells such as in rapidly-proliferating hematologic malignancies,solid tumors and RGDs.Cancer and cancer metabolismCancer is a disease characterized by unregulated cell growth.Cancer typ

107、ically develops when the repair of genetic material innormal cells begins to fail and genes that regulate cell growth become altered.Carcinogens,or cancer causing agents,such asradiation,chemicals and hormones,can trigger changes to the genetic material of a cell,increasing the rate of new genetical

108、terations and thus promoting cancer.Cancer cells can spread to other areas of the body,or metastasize,and form tumors,which can destroy normal tissue or organs.Risk factors for cancer include family history,age,diet,and exogenous factors,suchas exposure to ultraviolet sunlight and smoking.Cancers ca

109、n be classified in stages to document disease severity,measured instages of I to IV,generally based on tumor size,involvement of lymph nodes,and metastases.The most common methods of treating patients with cancer are surgery,radiation and drug therapy.A cancer patient oftenreceives treatment with a

110、combination of these methods.These treatment regimens are often associated with severe side effects,including fatigue,infection,nausea and vomiting and pain.Surgery and radiation therapy are particularly effective in patients inwhom the disease is localized.Physicians generally use systemic drug the

111、rapies in situations in which the cancer has spread3beyond the primary site or cannot otherwise be treated through surgery.The goal of drug therapy is to kill cancer cells or todamage cellular components required for rapid growth and survival of cancer cells.Historically,cancer drug developmentfocus

112、ed on design of cytotoxic drugs,which kill rapidly proliferating cells and are efficacious because of the unregulated cellgrowth that is characteristic of cancers.These drugs such as Cytoxan andAdriamycinhave been effective in the treatment ofsome cancers,and remain in use today,but they act in an i

113、ndiscriminate manner,killing healthy as well as cancerous cells.Dueto their mechanism of action,many cytotoxic drugs have a narrow dose range,above which the toxicity causes unacceptable oreven fatal levels of damage,and below which the drugs are not effective in eradicating cancer cells.In many cas

114、es,drugtherapy entails the administration of several different drugs,known as combination chemotherapy.Over the past several decades,drug therapy has evolved from non-specific drugs that kill both healthy and cancerous cells todrugs that target specific molecular pathways involved in cancer.These ne

115、wer therapies include:targeted therapies that inhibit the activity of specific enzymes that are mutated in specificsubsets of cancers;drugs that stimulate the normal immune system to attack the cancer,also known as immuno-oncology;chimeric antigen receptor and T cell receptor technologies to genetic

116、ally engineer T cells to recognize and kill cancer cells;antibody drug conjugates,for example Kadcyla,that carry a powerful chemotherapy payload that is only released into thecancer cell;and drugs that target the changes in gene activity that occurs in cancer cells,also known as epigenetics.Emerging

117、 areasNext generation targeted therapies.Targeted therapies,where the therapy is effective in a discrete subset of cancer patients whohave specific cancer-causing mutations,have become an important component of cancer therapeutics.These drugs are designedto attack oncogenes,which are targets that ar

118、e genetically altered in cancer cells,where the genetic alteration in the targetcauses uncontrolled growth of cancer cells.Examples of effective oncogene-targeted therapies include Herceptin,Avastinand Zelboraf.Initial oncogene-targeted therapies were directed against mutant forms of cell surface re

119、ceptors or enzymesinvolved in cellular signaling and cell growth control.Recently,the breadth of targets that have been drugged has beenexpanded to include other classes of mutant enzymes,including epigenetic enzymes,such as genetically altered forms of EZH2,and metabolic enzymes,such as genetically

120、 altered forms of IDH1 and IDH2.As a class,oncogene-targeted therapies have proven effective in treating patients with the appropriate oncogene mutation,butonly a fraction of cancer patients have mutations in these readily druggable targets.Targeted therapies for patients that do notcurrently benefi

121、t from oncogene-targeted therapies are a critical need,and we believe that synthetic lethal strategies are animportant emerging approach to this problem.Synthetic lethal targets are targets that are more essential for the growth orsurvival of cancers with genetic alteration in a gene other than the

122、target itself.In synthetic lethal approaches,the geneticalteration in the cancer creates a vulnerability to a second target.Poly(ADP-ribose)polymerase,or PARP,inhibitors in breastcancer gene,or BRCA-mutant cancers are an example of a synthetic lethal-targeted therapy.We believe that there areadditio

123、nal druggable targets that have synthetic lethal relationships with prevalent genetic alterations in cancer,and we continueto apply our research platform to identify and drug such targets,including MTAP-deleted cancers.Synthetic lethal targets arean important emerging class of precision medicines.Ne

124、xt generation immuno-oncology therapies.In addition to unregulated growth pathways in the cells within a tumor,thegrowth and survival of the tumor also requires that the tumor is not recognized and attacked by the patients immune system.Tumors employ a variety of strategies to avoid detection and ki

125、lling by the immune system,and therapies that interfere withthese strategies have recently been shown to be effective in multiple types of cancer.These therapies,such as Keytruda,Opdivo and Yervoy,known as immune checkpoint therapies,block the inactivation of endogenous T cells and allow themto atta

126、ck the tumor.While highly effective in some patients,these therapies work in a minority of all cancers.A criticalemerging area is the discovery of next-generation immuno-oncology therapies that,alone or in combination,will enhanceimmune-mediated killing of tumors.There is increasing evidence that th

127、ere are additional immune checkpoints that have not yetbeen discovered or have not yet been therapeutically targeted.This includes evidence that specific metabolites can act locally inthe tumor microenvironment as immuno-suppressants.We are leveraging our capabilities in bioinformatics,functionalgen

128、omics,proteomics and metabolomics to identify,validate and drug novel immuno-oncology targets in metabolism andadjacent biology areas,and our efforts in this field are governed by our 2016 global research and collaboration agreement withCelgene,described in more detail below.Rare genetic diseasesRGD

129、s,a subset of orphan genetic metabolic diseases,are a broad group of more than 600 rare diseases caused by mutations ofsingle metabolic genes.In these disorders,the defect of a single metabolic enzyme disrupts the normal functioning of ametabolic pathway,leading to either aberrant accumulation of“up

130、stream”metabolites which may be toxic or interfere withnormal 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.4Most of these diseases ar

131、e rare or ultra-rare orphan diseases,often with severe or life-threatening features.A disorder isconsidered orphan if it affects fewer than 200,000 people in the United States,or fewer than five per 10,000 people in theEuropean Union,or EU.In a study in British Columbia,the overall incidence of RGDs

132、 was estimated to be 70 per 100,000 livebirths 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.ManyRGDs are likely to

133、 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 insome RGDs.Several of these disorders,from a group known as lysosomal st

134、orage diseases,have been treated successfully withenzyme replacement therapy,or ERT,the therapeutic administration of a functional version of the defective enzyme.Examplesof ERTs for lysosomal storage disorders include Fabrazymefor Fabry disease,Myozomefor Pompe disease,CerezymeforGaucher disease,an

135、d Elaprasefor Hunter syndrome.Unfortunately,most mutations driving RGDs are intracellular and not amenable for treatment with enzyme replacementtherapies.As a result,despite the promising progress made for patients with a small group of these diseases,the vast majority ofpatients with RGDs have few

136、therapeutic options available,and the standard of care is palliative,meaning treatment ofsymptoms with no effect on underlying disease mechanisms.We are taking a novel small molecule approach to correct themetabolic defects within diseased cells with a goal of developing transformative medicines for

137、 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;andan assessment of the target,based upon

138、 a detailed mutational,structural,and metabolomic analysis,to determine if asmall molecule approach to correcting the disease is possible.Precision Medicine ApproachWe will generally progress our drug candidates forward into phase 1 clinical trials if we have the ability to select patients whoare mo

139、st likely to respond to a given therapy based on biomarkers,for example,genetic or metabolic markers.To increase theprobability of discovering and developing such precision medicines,we utilize translational science approaches throughout theresearch process,and we typically begin our efforts to iden

140、tify novel targets by first specifying a biomarker-identifiable subsetof disease with a high unmet need,and then conducting target identification and validation studies to identify targets that will beparticularly well suited to that biomarker-identifiable population.In other words,we begin our rese

141、arch with specific,definedsubsets of patients in mind.While many factors are considered critical to maximize the probability of technical success in the drug development process,perhaps none is more important than identifying highly specific and selective molecules aimed at the best possible targets

142、 fortherapy coupled with the patients most likely to respond to that therapy.Our goal is to develop increasing confidence in thetarget and the patient population prior to entering human clinical trials,and then initiate those first human trials in a patientpopulation that has been selected based on

143、target dependence using a genetic marker and/or biomarker.This approach,knownas personalized or precision medicine,is used in the industry to lead to the potential for clear proof of concept in early humantrials,along with the potential for accelerated approval.Our Development ProgramsWe believe tha

144、t leveraging our core capabilities in cellular metabolism combined with a precision medicine approach hassignificantly enhanced our ability to build a research and development engine that is focused in the therapeutic areas ofmalignant hematology,solid tumors and RGDs.This engine has permitted us to

145、 discover proprietary first-in-class orally-available small molecules as potential lead product candidates for each of several novel programs in development.All of ourlead programs focus on diagnostically identified patient populations with the potential for establishing early clinical proof ofconce

146、pt and accelerated approval paths.5The following summarizes our products and most advanced product candidates as of February 1,2020,each of which isdescribed in further detail below:Targeting Mutated IDH for the Treatment of CancerThe IDH protein is a critical enzyme in the citric acid cycle,also kn

147、own as the tricarboxylic acid cycle or Krebs cycle.TheKrebs cycle is centrally important to many biochemical pathways and is one of the earliest established components of cellularmetabolism.The Krebs cycle converts an essential cellular metabolite called isocitrate into another metabolite,alpha-keto

148、glutarate(a-ketoglutarate),both of which are critically important for cellular function and the creation of energy.Inhumans,there are three forms of the IDH enzyme,IDH1,IDH2,and IDH3,but only IDH1 and IDH2 appear to be mutated incancers.IDH1 and IDH2 catalyze the same reaction but in different cellu

149、lar compartments:IDH1 is found in the cytoplasm ofthe cell and IDH2 in the mitochondria.Tumor cells are generally observed to carry either an IDH1 or IDH2 mutation.Using our proprietary metabolic platform,we and our collaborators examined the mutated pathway and discovered that themutated IDH enzyme

150、s had adopted a novel“gain of function”activity that allows only the mutated IDH enzyme to producelarge amounts of a metabolite called 2-hydroxygluturate,or 2HG.We have shown that the excessive levels of the metabolite2HG produced by the tumor fuel cancer growth and survival via multiple cellular ch

151、anges that lead to a block in cellmaturation,or differentiation.We have also shown that inhibition of these mutated proteins can lead to clinical benefit for thesubset of cancer patients whose tumors carry these mutations.By reducing elevated 2HG levels,our IDH inhibitors reverse theblock in cellula

152、r differentiation,allowing tumorous cells to differentiate into normally functioning cells in patients with AML.We have identified selective development candidates that separately target and inhibit the mutated forms of IDH1 and IDH2.Todate,our clinical data with ivosidenib and enasidenib,our lead i

153、nhibitors of mutant IDH1 and IDH2,respectively,demonstrateevidence of cellular differentiation,normalization of cell counts and mutational clearance in the bone marrow and blood,amechanism of response that is consistent with preclinical studies,including substantial reduction of plasma 2HG levels.Th

154、istargeted differentiation effect is distinct from that seen with traditional cytotoxic chemotherapeutics,commonly used to treat6cancer,which lead to cell death.Our goal is to establish our IDH mutation inhibitors as a cornerstone of AML therapy spanningall treatment lines,and to leverage our unders

155、tanding of IDH mutation inhibition to develop our IDH mutation inhibitors to treatsolid tumors such as low grade glioma and cholangiocarcinoma.To date,IDH1 and IDH2 mutations have been found to be prevalent in a broad range of advanced hematologic malignanciesand solid tumors.The following table sum

156、marizes our current estimates on the occurrence of IDH1 and IDH2 mutations incertain hematologic and solid tumors.We believe our estimates may expand as more cancer treatment centers screen for theseIDH mutations.MutationIndications%with IDH mutationsIDH1AML6-10%Cholangiocarcinoma10-14%Low grade gli

157、oma80%Myelodysplastic Syndromes(MDS)/Myeloproliferative neoplasms(MPN)3%IDH2AML9-13%Based on literature analysis;estimates will continue to evolve with additional future data.Ivosidenib(mutant IDH1 inhibitor)We are developing ivosidenib for the treatment of IDH1 mutant-positive cancers.Ivosidenib is

158、 an orally available,selective,potent inhibitor of the mutated IDH1 protein,making it a highly targeted therapy for the treatment of patients with cancers thatharbor IDH1 mutations.We hold worldwide development and commercial rights to ivosidenib and have licensed certaindevelopment and commercializ

159、ation 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 fundthe future development and commercialization costs related to this program with the exception of dev

160、elopment andcommercialization activities of CStone under the CStone Agreement.Mutations in IDH1 have been identified in difficult totreat hematologic and solid tumor cancers,including AML,MDS,cholangiocarcinoma and low grade glioma,where both thetreatment options and prognosis for patients are poor.

161、In July 2018,the FDA approved TIBSOVO for the treatment of adult patients with R/R AML and a susceptible IDH1mutation.The FDAs 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 advance

162、d R/R AML and an IDH1 mutation.In December2018,we submitted an MAA to the EMA for TIBSOVO for the treatment of adult patients with R/R AML.In May 2019,theFDA approved our sNDA to update the U.S.Prescribing Information for TIBSOVO to include patients with newly diagnosedAML with a susceptible IDH1 mu

163、tation as detected by an FDA-approved test who are at least 75 years old or who havecomorbidities that preclude use of intensive induction chemotherapy.The FDA granted orphan drug designation for ivosidenibfor the treatment of cholangiocarcinoma,granted Breakthrough Therapy designation for ivosideni

164、b in combination withazacitidine for the treatment of newly diagnosed AML with an IDH1 mutation in adult patients who are at least 75 years old orwho have comorbidities that preclude use of intensive induction chemotherapy,and granted Breakthrough Therapy designationfor ivosidenib for the treatment

165、of adult patients with relapsed or refractory MDS with a susceptible IDH1 mutation as detectedby an FDA-approved test.We continue to evaluate ivosidenib in the following clinical trials:Hematologic MalignanciesA phase 1b,multicenter,international,open-label clinical trial,to evaluate safety and clin

166、ical activity of ivosidenib orenasidenib in combination with induction and consolidation therapy in patients with newly diagnosed AML with anIDH1 or IDH2 mutation who are eligible for intensive chemotherapy.This trial has completed enrollment.A phase 1/2 frontline combination clinical trial,conducte

167、d by Celgene,of either ivosidenib or enasidenib in combinationwith VIDAZA(azacitidine)in newly diagnosed AML patients not eligible for intensive chemotherapy.The trial hascompleted enrollment.AGILE,a global,registration-enabling phase 3 clinical trial,combining ivosidenib and VIDAZA(azacitidine)in n

168、ewlydiagnosed AML patients with an IDH1 mutation who are ineligible for intensive chemotherapy.The trial is enrollingpatients and we expect to complete enrollment in 2020.HO150/AMLSG29,an intergroup sponsored,global,registration-enabling phase 3 trial,supported in collaboration withCelgene,combining

169、 ivosidenib or enasidenib with standard induction and consolidation chemotherapy in frontline AMLpatients with an IDH1 or IDH2 mutation.The trial is currently enrolling patients.7A phase 1 multicenter,open-label,dose-escalation and expansion clinical trial,designed to assess its safety,clinicalactiv

170、ity 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 completeenrollment in 2020.Solid TumorsA phase 1 multicenter,open-label,dose-escalation

171、and expansion clinical trial,designed to assess its safety,clinicalactivity and tolerability as a single agent in patients with advanced solid tumors with an IDH1 mutation,includingglioma,cholangiocarcinoma,and chondrosarcoma.The trial has completed enrollment.ClarIDHy,a registration-enabling phase

172、3,multicenter,randomized,double-blind,placebo-controlled clinical trial ofivosidenib 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 incholangioca

173、rcinoma by year-end 2020.Enasidenib(mutant IDH2 inhibitor)Celgene,pursuant to the 2010 Agreement,discussed below,is developing enasidenib for the treatment of IDH2 mutant-positivehematologic malignancies.Enasidenib is an orally available,selective,potent inhibitor of the mutated IDH2 protein,making

174、it ahighly targeted therapeutic candidate for the treatment of patients with cancers that harbor IDH2 mutations,including thosewith AML,who have a historically poor prognosis.In August 2017,the FDA granted Celgene approval of IDHIFA for thetreatment of adult patients with R/R AML and an IDH2 mutatio

175、n.In June 2018,Celgene submitted an MAA to the EMA forIDHIFA for IDH2 mutant-positive AML,which it subsequently withdrew in December 2019.Celgene maintains worldwide development and commercial rights to enasidenib and will fund the future development andcommercialization costs related to this progra

176、m.In April 2010,we entered into a collaboration agreement with Celgene focusedon cancer metabolism,or the 2010 Agreement.Under the remaining terms of the 2010 Agreement,Celgene is responsible forall development costs for enasidenib,and we are eligible to receive up to$80.0 million in potential miles

177、tone payments,whichare comprised of:(i)up to$55.0 million in milestone payments upon achievement of specified ex-U.S.regulatory milestoneevents,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 upo

178、n achievement of a specified ex-U.S.commercial milestone event.Additionally,weare eligible to receive royalties at tiered low-double digit to mid-teen percentage rates on any net sales of IDHIFA.In addition to the clinical trials discussed above,enasidenib is also being evaluated by Celgene in IDHEN

179、TIFY,an internationalphase 3,multi-center,open-label,randomized clinical trial designed to compare the efficacy and safety of enasidenib versusconventional care regimens in patients 60 years or older with IDH2 mutant-positive AML that is refractory to or relapsed aftersecond-or third-line therapy.Th

180、is trial has completed enrollment.Vorasidenib:brain penetrant pan-IDH programWe 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.In connection with the termination of the AG-881

181、Agreements discussedbelow,Celgene is eligible to receive royalties from us at a low single-digit percentage rate on worldwide net sales of productscontaining vorasidenib.We continue to evaluate vorasidenib in the following clinical trials:A phase 1 multi-center,open-label clinical trial of vorasiden

182、ib in patients with advanced IDH1 or IDH2 mutant-positivesolid 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 braintumor tissue.The trial has completed enrollment.INDIGO,a re

183、gistration-enabling phase 3 clinical trial of vorasidenib in low-grade(grade 2)glioma with an IDH1 or IDH2 mutation.The trial is enrolling patients.PKR Activator ProgramPK is the enzyme involved in the second to last reaction in glycolysis the conversion of glucose into lactic acid.This enzymehas se

184、veral tissue-specific isoforms(PKR,PKL,PKM1 and PKM2).PKR is the isoform of pyruvate kinase that is present inred blood cells,or RBCs.Mutations in PKR cause defects in RBC glycolysis and lead to a hematological RGD known aspyruvate kinase deficiency,or PK deficiency.Glycolysis is the only pathway av

185、ailable for RBCs to maintain the production ofadenosine triphosphate,or ATP,which is a form of chemical energy within cells.Accordingly,we believe that activation ofmutant forms of PKR can restore glycolytic pathway activity and increase RBC health in patients with PK deficiency,and8activation of wi

186、ld-type(non-mutated)PKR can serve as an effective compensatory mechanism in hemolytic anemias such asthalassemia and SCD.PK DeficiencyPK deficiency is a rare genetic disorder and disease understanding is still evolving.We estimate that the prevalence of PKdeficiency is between approximately 3,000 an

187、d 8,000 individuals in the United States and European Union,and we believe thatthe disease is likely under-diagnosed.PK deficiency leads to a shortened life span for RBCs and is the most common form ofnon-spherocytic hemolytic anemia in humans.There is no currently known unique ethnic or geographic

188、representation of the disease.The disease manifests by mild to severeforms of anemia caused by the excessive premature destruction of RBCs.The chronic hemolysis can lead to long-termcomplications and comorbidities,regardless of the degree of the anemia,often resulting in jaundice and lifelong condit

189、ionsassociated with chronic anemia and secondary complications.The precise mechanism for the hemolysis is not well understoodbut is thought to result from membrane instability secondary to the metabolic defect caused by the low level of PKR enzyme.The hemolysis is“extra-vascular”in that the RBCs are

190、 destroyed in small capillaries or organs and do not spontaneously breakopen in the circulation.PK deficiency is an autosomal recessive disease whereby all patients inherit two mutations,one fromeach parent.Children with the disease produce PKR enzyme that has only a fraction of the normal level of

191、activity(generally50%).Current management strategies for PK deficiency,including blood transfusion and splenectomy,are associated withboth short-and long-term risks.More than 300 different mutations have been identified to date.As a result,there are manydifferent possible mutant combinations and no

192、one clear mutational profile.The mutations observed in PK deficiency patientsare classified in two main categories.A missense mutation causes a single amino acid change in the protein,generally resultingin some functional protein in the RBCs.A non-missense mutation is any mutation other than a misse

193、nse mutation,generallyresulting in little functional protein in the RBCs.It is estimated that 58 percent of patients with PK deficiency have twomissense mutations,27 percent have one missense and one non-missense mutation,and 15 percent have two non-missensemutations.Boston Childrens Hospital,in col

194、laboration with us,is conducting a Natural History Study to better understand thesymptoms and complications of PK deficiency,identify patients and treatment centers,and capture other clinical data,includinggenetic information.We initiated a global registry,called PEAK,for up to 500 adult and pediatr

195、ic patients with PK deficiencyin the first quarter of 2018 to increase understanding of the long-term disease burden of this chronic hemolytic anemia.ThalassemiaThalassemia is a hereditary blood disorder in which mutations in the-or-globin chains of hemoglobin lead to globin chainprecipitates and ag

196、gregates that disturb the RBC membrane and induce oxidative stress,leading to decreased survival of RBCprecursors,ineffective erythropoiesis,hemolysis of mature RBCs,and anemia.We estimate that the prevalence of thalassemiais between 18,000 and 23,000 individuals in the United States and European Un

197、ion.In addition to anemia,patients withthalassemia can experience enlarged spleen,bone deformities,iron overload,fatigue,and infection.Current treatment strategiesfor thalassemia include blood transfusion and bone marrow transplantation,as well as recently improved therapies such asReblozyl for the

198、treatment of beta thalassemia.We believe that the activation of wild-type PKR may increase ATP productionand improve red cell fitness and survival of thalassemic RBCs,by increasing the clearance globin chain aggregates throughATP-dependent proteolytic mechanisms.In December 2019,we announced prelimi

199、nary clinical data from our ongoing phase 2trial 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 intr

200、ial subjects.Sickle Cell DiseaseSCD is an inherited blood disorder caused by mutations in hemoglobin that enable the hemoglobin to form long polymericchains under certain conditions such as low oxygenation,or deoxygenation.Polymerization of this irregular hemoglobin resultsin RBCs taking on a sickle

201、 shape,causing them to aggregate and obstruct small blood vessels,restricting blood flow to organsresulting in pain,cell death and organ damage.We estimate that the prevalence of SCD is between 120,000 and 135,000individuals in the United States and EU.RBC deoxygenation is modulated by several facto

202、rs,including the levels of 2,3-DPG,which is found to be elevated in sickle cell patient RBCs.Current treatment strategies focus on managing and preventing acuteRBC sickling,and include hydroxyurea,L-glutamine and blood transfusions,as well as recently approved therapies such asAdakveo and Oxbryta.We

203、 believe that activation of wild-type PKR in patients with SCD may reduce hemoglobinpolymerization and the sickling process by at least two mechanisms.Reducing the level of 2,3-DPG in RBCs would increasethe oxygenation state of hemoglobin to reduce sickling,while increasing the levels of ATP may imp

204、rove RBC hydration statuswhich would also inhibit the sickling process.Mitapivat:PK activatorWe 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

205、and mutated PKR enzymes.To date,we9have demonstrated in clinical trials that treatment with mitapivat can lead to durable sustained increases in hemoglobin inpatients with amenable mutations in the PKR gene,and observed early signs of improvements in hemoglobin in thalassemiapatients who have wild-t

206、ype PKR.We have worldwide development and commercial rights to mitapivat and expect to fund the future development andcommercialization costs related to this program.The FDA granted orphan drug and fast track designations for mitapivat for thetreatment of patients with PK deficiency.We are evaluatin

207、g mitapivat in the following clinical trials:DRIVE PK,a global phase 2,first-in-patient,open-label safety and efficacy clinical trial of mitapivat in adult,transfusion-independent patients with PK deficiency.This trial has completed enrollment.ACTIVATE-T,a single arm,global,pivotal trial of mitapiva

208、t in up to 40 regularly-transfused patients with PKdeficiency.The trial has completed enrollment.ACTIVATE,a 1:1 randomized,placebo-controlled,global,pivotal trial of mitapivat in approximately 80 patients withPK deficiency who do not receive regular transfusions.The trial has closed enrollment.A pha

209、se 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 w

210、ithSCD pursuant to a cooperative research and development agreement.AG-270:Targeting MAT2A for the treatment of MTAP-deleted cancersAG-270,an orally available selective potent inhibitor of MAT2A,is our development candidate focused on MTAP-deletedcancer.MTAP is a metabolic gene that is deleted in ap

211、proximately 15 percent of all cancers.We have shown in preclinicalstudies that MTAP deletion predicts sensitivity to inhibition of a subset of enzymes involved in the synthesis or utilization ofthe methyl donor S-adenosylmethionine,or SAM.Among this subset of enzymes,we have targeted MAT2A,the enzym

212、eresponsible for the synthesis of SAM in tumor cells.We have discovered small molecule inhibitors of MAT2A,includingAG-270,that reduce SAM production and cause MTAP-null antiproliferative effects in cancer cell lines in vitro and in MTAP-deleted tumor models in vivo.MTAP deletion is readily detected

213、 by a genomic or immunohistochemistry test,thus allowing theselection 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 agreementwith Celgene,or the 2016 Agreement.Pursuant to the 2016 Agr

214、eement,Celgene paid us an$8.0 million designation fee uponits designation of AG-270 as a development candidate.Exploratory research,drug discovery and early development of AG-270is 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 millio

215、nfee.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 worldwide50/50 cost and profit share on AG-270,and we will be eligibl

216、e for up to$168.8 million in clinical and regulatory milestonepayments.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 d

217、oses of AG-270 todetermine the pharmacokinetics,pharmacodynamics and optimal dose,and schedule.The next phase of development,whichwas initiated in September 2019,is evaluating AG-270 in combination with taxanes in two areas of high unmet needs.One armof the study will test AG-270 in combination with

218、 docetaxel in MTAP-deleted non-small cell lung cancer and the other arm willtest AG-270 in combination with nab-paclitaxel and gemcitabine in MTAP-deleted pancreatic ductal adenocarcinoma.Bothcombination arms have initiated and are enrolling patients.AG-636:Targeting DHODH for the treatment of hemat

219、ologic malignanciesWe have discovered a lineage-specific dependence on DHODH in hematologic malignancies,particularly AML and diffuselarge B-cell lymphoma.DHODH catalyzes a critical step in the biosynthesis of pyridimidines,which are critical for theproduction of RNA and DNA.We believe that DHODH in

220、hibition will be differentiated from standard-of-care therapies,bothby exhibiting activity in cancers that are resistant to standard-of-care chemotherapeutics and through a mechanism of anti-tumoreffect that combines cell growth arrest and cellular differentiation.We are evaluating AG-636,an inhibit

221、or of DHODH,licensed to us from Aurigene Discovery Technologies Limited in a phase1 dose-escalation trial in subjects with advanced lymphomas.This trial is currently enrolling patients.10Collaborations with CelgeneIn November 2019,the acquisition of Celgene was completed by BMS,and Celgene became a

222、wholly-owned subsidiary.Wewill continue to refer to our collaboration agreements with Celgene throughout this Form 10-K as being with CelgeneCorporation.2016 AgreementIn May 2016,we entered into the 2016 Agreement focused on metabolic immuno-oncology,a developing field which aims tomodulate the acti

223、vity of relevant immune cells by targeting critical metabolic nodes,thereby enhancing the immune mediatedanti-tumor response.In addition to new programs identified under the 2016 Agreement,both parties also agreed that all futuredevelopment and commercialization of two remaining cancer metabolism pr

224、ograms 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 thatare active against metabolic targets in the immuno-onc

225、ology,or IO,field.The initial four-year research term will expire onMay 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 developmentcandidates and,i

226、n limited circumstances,Celgene may also nominate compounds as development candidates for each suchprogram.Celgene may designate the applicable program for further development following any such nomination,after whichwe may conduct,at our expense,additional preclinical and clinical development for s

227、uch program through the completion of aninitial phase 1 dose escalation study.At the end of the research term,Celgene may designate for continued development up to three research programs for whichdevelopment candidates have yet to be nominated,which are referred to as continuation programs.We may c

228、onduct furtherresearch and preclinical and clinical development activities on any continuation program,at our expense,through thecompletion of an initial phase 1 dose escalation study.We granted Celgene the right to obtain exclusive options for development and commercialization rights for each progr

229、am thatCelgene has designated for further development and for each continuation program.Celgene may exercise each such optionbeginning on the designation of a development candidate for such program(or on the designation of such program as acontinuation program)and ending on the earlier of:(i)the end

230、 of a specified period after we have furnished Celgene withspecified information about the initial phase 1 dose escalation study for such program,or(ii)January 1,2030.Researchprograms that have applications in the inflammation or autoimmune,or I&I,field that may result from the 2016 Agreement willal

231、so 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 exerciseits option.Under the terms of the 2016 Agreement,following Celgenes exercise of its option with respect to a program,

232、the parties willenter into either a co-development and co-commercialization agreement if such program is in the IO field,or a licenseagreement if such program is in the I&I field.Under each co-development and co-commercialization agreement,the two partieswill co-develop and co-commercialize licensed

233、 products worldwide.Either we or Celgene will lead development andcommercialization of licensed products for the United States,and Celgene will lead development and commercialization oflicensed products outside of the United States.Depending on the country,the parties will each have the right to pro

234、vide aportion of field-based marketing activities.Under each license agreement,Celgene will have the sole right to develop andcommercialize licensed products worldwide.Co-development and co-commercialization agreements.Under each co-development and co-commercialization agreemententered into under th

235、e 2016 Agreement,the parties will split all post-option exercise worldwide development costs,subject tospecified exceptions,as well as any profits from any net sales of,or commercialization losses related to,licensed products in theIO field.Celgene has the option to designate one program in the IO f

236、ield as the 65/35 program,for which Celgene will be thelead party for the United States and will have a 65%profit or loss share.For programs in the IO field other than the 65/35program,we and Celgene will alternate,on a program-by-program basis,being the lead party for the United States,with ushavin

237、g the right to be the lead party for the first such program,and each party will have a 50%profit or loss share.The leadparty for the United States will book commercial sales of licensed products,if any,in the United States,and Celgene will bookcommercial sales of licensed products,if any,outside of

238、the United States.License agreements.Under each license agreement under the 2016 Agreement,Celgene will be responsible for all post-optionexercise worldwide development and associated costs,subject to specified exceptions,as well as worldwide commercializationand associated costs,for licensed produc

239、ts in the I&I field.Financial terms.Under the terms of the 2016 Agreement,we received an initial upfront payment in the amount of$200.0million.The 2016 Agreement provides specified rights to extend the research term for up to two,or in specified cases,up11to four,additional years by paying a$40.0 mi

240、llion per-year extension fee.Celgene will pay an$8.0 million designation fee foreach program that Celgene designates for further development and for each continuation program.During the year endedDecember 31,2017,we received$8.0 million from Celgene upon the designation of AG-270,our MAT2A inhibitor

241、,as adevelopment candidate.For each program as to which Celgene exercises its option to develop and commercialize,subject toantitrust clearance,Celgene will pay an option exercise fee of at least$30.0 million for any designated development programand at least$35.0 million for any continuation progra

242、ms.In certain cases,Celgene may exercise its option to develop andcommercialize two early-stage I&I programs,prior to Celgene designating the program for further development,by paying anoption exercise fee of$10.0 million per program.We are eligible to receive the following milestone-based payments

243、associated with the 2016 Agreement:ProgramMilestoneAmount65/35 program in IO fieldSpecified clinical development event$25.0 million65/35 program in IO fieldSpecified regulatory milestone eventsUp to$183.8 million50/50 program in IO fieldSpecified clinical development event$20.0 million50/50 program

244、in IO fieldSpecified regulatory milestone eventsUp to$148.8 millionI&I fieldSpecified clinical development event$25.0 millionI&I fieldSpecified regulatory milestone eventsUp to$236.3 millionI&I fieldSpecified commercial milestone eventsUp to$125.0 millionAdditionally,for each licensed program in the

245、 I&I field,we are eligible to receive royalties at tiered,low double-digitpercentage rates on Celgenes 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 andco-commercialization agr

246、eement,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 undertaketransitional activities reasonably necessary to transfer the development,manufacture

247、 and commercialization of such licensedproducts to Celgene,at our expense.Further,in lieu of the profit or loss sharing described above,we would be eligible toreceive royalties at tiered,low double-digit percentage rates on Celgenes net sales,if any,of the applicable licensed products.However,we wou

248、ld continue to be eligible to receive the developmental and regulatory milestone-based payments describedabove.Term.The term of the 2016 Agreement commenced on May 17,2016 and,if not terminated earlier,will expire upon the later ofthe last-to-expire of the research term and all option exercise perio

249、ds,or,if an option is exercised by Celgene for one or moreprograms in the collaboration,upon the termination or expiration of the last-to-exist co-development and co-commercializationagreement or license agreement,as applicable,for any such program.Termination.Subject to specified exceptions,Celgene

250、 may terminate the 2016 Agreement in its entirety for any reason byproviding us with prior written notice if there are no active co-development and co-commercialization agreements or licenseagreements in place or on a program-by-program basis if there are no active co-development and co-commercializ

251、ationagreements or license agreements in place for the terminated program(s).Under specified circumstances,either party mayterminate the 2016 Agreement either in its entirety or on a program-by-program basis.Either party also has the right toterminate the co-development and co-commercialization agre

252、ement or license agreement if the other party or any of its affiliateschallenges the validity,scope or enforceability of or otherwise opposes,any patent included within the intellectual propertyrights licensed to the other party under such agreement.Exclusivity.While any of Celgenes options remain a

253、vailable under the 2016 Agreement,subject to specified exceptions,wemay not directly or indirectly develop,manufacture or commercialize,outside of the 2016 Agreement,any therapeutic modalityin the IO or I&I field with specified activity against a metabolic target.During the term of each co-developme

254、nt and co-commercialization agreement and license agreement,subject to specifiedexceptions,neither we nor Celgene may directly or indirectly develop,manufacture or commercialize outside of suchagreement any therapeutic modality in any field with specified activity against the metabolic target that i

255、s the focus of theprogram licensed under such agreement.Ivosidenib Letter AgreementOn 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

256、 as of August 15,2016,asto 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 heldsuch rights inside the United State

257、s.As a result of the Ivosidenib Letter Agreement,we obtained global rights to ivosidenib and12the IDH1 program.Neither party will have any further financial obligation,including royalties or milestone payments,to theother concerning ivosidenib or the IDH1 program.Under the terms of the Ivosidenib Le

258、tter Agreement,the parties also agreedto conduct specified transitional activities in connection with the termination.In addition,pursuant to the Ivosidenib LetterAgreement,the parties are released from their exclusivity obligations under the 2010 Agreement with respect to the IDH1program.The Ivosid

259、enib Letter Agreement does not affect the AG-881 Agreements,which were directed to both the IDH1target and the IDH2 target,and were subsequently terminated in September 2018 as discussed below.Termination of AG-881 AgreementsIn September 2018,we and Celgene agreed to terminate our joint worldwide co

260、llaboration focused on the development andcommercialization of vorasidenib products,or the AG-881 Agreements,effective as of September 4,2018.From and afterSeptember 4,2018,we obtained sole global rights to vorasidenib.Neither we nor Celgene will have any further financialobligation under the AG-881

261、 Agreements,including milestones,royalties or other payments,except that(a)Celgene is eligibleto 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 co

262、sts 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 areproh

263、ibited from developing,manufacturing or commercializing vorasidenib in hematologic indications.2010 AgreementThe 2010 Agreement,which was entered into in April 2010,was amended in October 2011 and July 2014.The goal of thecollaboration was to discover,develop and commercialize disease-altering thera

264、pies in oncology based on our cancermetabolism research platform.We initially led discovery,preclinical and early clinical development for all cancer metabolismprograms under the collaboration.The discovery phase of the 2010 Agreement expired in April 2016.Upon agreement to terminate the 2010 Agreem

265、ent,effective as of August 15,2016,as to the program directed to the IDH1target,for which ivosidenib is the lead development candidate,the sole program remaining under the 2010 Agreement isIDHIFA,aco-commercialized licensed programforwhichCelgene leadsandfundsglobaldevelopment andcommercialization a

266、ctivities.We have exercised our right to participate in a portion of commercialization activities in theUnited 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 relevan

267、t program,wemay not directly or indirectly develop,manufacture or commercialize,outside of the collaboration,any therapeutic modalitywith specified activity against any collaboration target that is within a licensed program or against any former collaborationtarget against which Celgene is conductin

268、g 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 potentialmilestone payments for the IDHIFA program.The potential milestone payments are comprised of:(i)up to$55.0 million inmilestone payment

269、s upon achievement of specified ex-U.S.regulatory milestone events,of which$35.0 million relates to thefirst regulatory approval in any of China,Japan or a major European country,and(ii)a$25.0 million milestone payment uponachievement of a specified commercial milestone event.Under the 2010 Agreemen

270、t,we are eligible to receive royalties at tiered,low-double digit to mid-teen percentage rates on netsales of IDHIFA.Assuming all other revenue recognition criteria are met,royalty payments will be recognized as revenue inthe period in which they are earned.During the year ended December 31,2019,we

271、earned$10.5 million in royalty revenueunder the 2010 Agreement.Termination.Unless terminated earlier by either party,the term of the 2010 Agreement will continue until the expiration of allroyalty terms with respect to IDHIFA.Celgene may terminate the 2010 Agreement for convenience in its entirety o

272、r withrespect to IDHIFA upon ninety days written notice to us.Under specified circumstances,either we or Celgene may terminatethe 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 an

273、d certain ofCelgenes obligations described above would change with respect to the terminated program(s),including,for example:thelicenses we granted to Celgene would become perpetual;milestone payments to which we may be entitled may be reduced oreliminated;and royalties to which we may be entitled

274、may be reduced or eliminated.If Celgene terminates the 2010 Agreement for convenience or if we terminate the agreement as a result of Celgenes uncuredmaterial breach,the license we granted to Celgene with respect to IDHIFA will end,and we will have specified rights for,andCelgene will take specified

275、 actions to assist us in continuing,the development,manufacture and commercialization ofmedicines from the IDHIFA program.13CStone AgreementIn June 2018,we entered into the CStone Agreement for the development and commercialization of certain products containingivosidenib in mainland China,Hong Kong

276、,Macau,and Taiwan for therapeutic uses in humans,excluding brain cancer,unlessadded by us in our sole discretion.We retain development and commercialization rights for the rest of the world.Pursuant to the CStone Agreement,CStone will initially be responsible for the development and commercializatio

277、n ofivosidenib in AML and cholangiocarcinoma,as well as other indications that the parties mutually agree to in the future;weserve as co-sponsor with CStone for local studies of ivosidenib in AML.CStone will also be responsible,at our discretion,forthe development and commercialization of ivosidenib

278、 in brain cancer indications.We granted CStone specified intellectualproperty licenses to enable CStone to perform its obligations and exercise its rights under the CStone Agreement,includinglicense grants to enable CStone to conduct development and commercialization activities pursuant to the terms

279、 of the CStoneAgreement.CStone is responsible for all costs it incurs in developing,obtaining regulatory approval of,and commercializing ivosidenib inmainland 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 affiliate

280、s are prohibited from developing or commercializing anyother compound or product that inhibits IDH1 mutations at specified levels of binding,in the case of CStone,anywhere in theworld,and in the case of us,in mainland China,Hong Kong,Macau,and Taiwan.Subject to specified exceptions,CStone andits aff

281、iliates are also prohibited from developing or commercializing certain other compounds or products that directly orindirectly 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 a

282、nd pharmacovigilance agreement withCStone,and will enter into further ancillary agreements,including commercial supply agreements.Intellectual PropertyOur commercial success depends in part on our ability to obtain and maintain proprietary or intellectual property protection forour product candidate

283、s and our core technologies,including novel biomarker and diagnostic discoveries,and other know-how,to operate without infringing on the proprietary rights of others and to prevent others from infringing our proprietary orintellectual property rights.Our policy is to seek to protect our proprietary

284、and intellectual property position by,among othermethods,filing U.S.and foreign patent applications related to our proprietary technology,inventions and improvements that areimportant to the development and implementation of our business.We also rely on trade secrets,know-how and continuingtechnolog

285、ical 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,includingTIBSOVO(ivosidenib),IDHIFA(enasidenib),vorasidenib,mitapivat,AG-270 and AG-636,in an effort

286、 to establishintellectual property positions regarding new chemical entities relating to these product candidates as well as uses of newchemical entities in the treatment of diseases.We also seek patent protection with respect to biomarkers that may be useful inselecting the right patient population

287、 for therapies with our product candidates.As of February 1,2020 we owned or licensedapproximately issued 31 U.S.patents,316 issued foreign patents,37 pending U.S.patent applications,460 pending foreignpatent applications,and 13 pending Patent Cooperation Treaty,or PCT,patent applications,directed t

288、o our key productcandidates,related compounds and potential backup compounds.The foreign issued patents and patent applications are in anumber of jurisdictions,including Argentina,Australia,Austria,Belgium,Brazil,Canada,China,the Czech Republic,Denmark,Finland,France,Germany,Greece,Hungary,Ireland,I

289、taly,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 1,2020 are summarized below.Prosecutionis a lengthy process,during wh

290、ich the scope of the claims initially submitted for examination by the U.S.Patent and TrademarkOffice,or USPTO,can be significantly narrowed by the time they issue,if they issue at all.We expect this could be the casewith respect to some of our pending patent applications referred to below.IDH mutan

291、t inhibitor programsThe intellectual property portfolio for our IDH mutant inhibitor programs contains patent applications directed to compositionsof matter for TIBSOVO(ivosidenib),IDHIFA(enasidenib),and vorasidenib,as well as analogs thereof,methods of use,various solid state forms of these compoun

292、ds and diagnostic methods for detecting various IDH1 and IDH2 mutations.As ofFebruary 1,2020,we owned approximately 21 issued U.S.patents,152 issued foreign patents,24 pending U.S.patentapplications,327 pending foreign patent applications in a number of jurisdictions,and 5 pending PCT patent applica

293、tions,directed to our IDH mutant product candidates.The patents that have issued or will issue for our IDH mutant productcandidates will have a statutory expiration date of at least 2033 to 2039.Patent term adjustments or patent term extensionscould result in later expiration dates.14PK activator pr

294、ogramThe intellectual property portfolio for our PK activator program contains patent applications directed to compositions of matterfor mitapivat and AG-946,as well as analogs thereof,various solid state forms of these compounds,as well as methods of usefor these novel compounds.As of February 1,20

295、20,we owned approximately 5 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 PCTpatent applications,directed to our PK activator program,including our product candidates.The patents that

296、have issued or willissue for our PK activator program will have a statutory expiration date of at least 2030 to 2038.Patent term adjustments orpatent term extensions could result in later expiration dates.MTAP-deleted cancer programThe intellectual property portfolio for our MTAP-deleted cancer prog

297、ram contains patent applications directed to compositionsof 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.As of February 1,2

298、020,we owned approximately 1 issued U.S.patent,4 pending U.S.patent applications,1 foreign issued patent,46 pendingforeign patent applications,and 3 pending PCT patent applications,directed to our MTAP-deleted cancer program.The patentsthat would issue for our MTAP-deleted cancer program will have a

299、 statutory expiration date of at least 2036 to 2039.Patentterm adjustments or patent term extensions could result in later expiration dates.DHODH inhibitor programThe intellectual property portfolio for our DHODH inhibitor program contains patents and patent applications,exclusivelylicensed to us by

300、 Aurigene,directed to compositions of matter for AG-636,as well as analogs thereof and other compoundfamilies,as well as methods of use for these novel compounds.The intellectual property portfolio for our DHODH inhibitorprogram further contains patent applications,assigned solely to Agios,that are

301、directed to solid state forms and formulations ofAG-636 and methods of use for these forms of AG-636,other methods of use for AG-636 and methods of use and diagnosticmethods relating to AG-636 and other DHODH inhibitors.As of February 1,2020,we exclusively licensed or independentlyfiled approximatel

302、y 4 issued U.S.patents,47 issued foreign patents,3 pending U.S.patent applications,43 pending foreignpatent applications,and 2 pending PCT patent applications directed to our DHODH inhibitor program.The patents that haveissued or will issue for our DHODH inhibitor program will have a statutory expir

303、ation date of at least 2030 to 2039.Patent termadjustments or patent term extensions could result in later expiration dates.The term of individual patents depends upon the legal term for patents in the countries in which they are obtained.In mostcountries,including the United States,the patent term

304、is 20 years from the earliest filing date of a non-provisional patentapplication,although term extensions may be available.In the United States,a patents term may be lengthened by patent termadjustment,which compensates a patentee for administrative delays by the USPTO in examining and granting a pa

305、tent,or maybe shortened if a patent is terminally disclaimed over an earlier filed patent.The term of a patent that covers a drug or biologicalproduct may also be eligible for patent term extension when FDA approval is granted,provided statutory and regulatoryrequirements are met.The extension of th

306、e term of foreign patents varies,in accordance with local law.Although certain of thepatents granted by the regulatory authorities of the EU may expire at specific dates,the terms of patents granted in certainEuropean countries may extend beyond such EU patent expiration date if we were to obtain a

307、supplementary protectioncertificate.In the future,if and when our product candidates receive approval by the FDA or foreign regulatory authorities,we expect toapply for patent term extensions on issued patents covering those products,depending upon the length of the clinical trials foreach medicine

308、and other factors.There can be no assurance that any of our pending patent applications will be issued or that wewill 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

309、solidify our proprietary and intellectualproperty position for our product candidates and technologies will depend on our success in obtaining effective patent claimsand enforcing those claims if granted.However,patent applications that we may file or license from third parties may not resultin the

310、issuance of patents.We also cannot predict the breadth of claims that may be allowed or enforced in our patents.Anyissued patents that we may receive in the future may be challenged,invalidated or circumvented.For example,we cannot becertain of the priority of inventions covered by pending third-par

311、ty patent applications.If third parties prepare and file patentapplications in the United States that also claim technology or therapeutics to which we have rights,we may have to participatein interference proceedings with the USPTO to determine priority of invention,which could result in substantia

312、l costs to us,even if the eventual outcome is favorable to us.In addition,because of the extensive time required for clinical development andregulatory review of a product candidate we may develop,it is possible that,before any of our product candidates can becommercialized,any related patent may ex

313、pire or remain in force for only a short period following commercialization,therebyreducing any advantage of any such patent.15In addition to patents,we rely upon unpatented trade secrets and know-how and continuing technological innovation to developand maintain our competitive position.We seek to

314、protect our proprietary information,in part,using confidentiality agreementswith our collaborators,third-party service providers,scientific advisors,employees and consultants,and invention assignmentagreements with our employees.We also have agreements requiring assignment of inventions with selecte

315、d consultants,scientific advisors and collaborators.The confidentiality agreements are designed to protect our proprietary information and,inthe case of agreements or clauses requiring invention assignment,to grant us ownership of technologies that are developedthrough a relationship with a third pa

316、rty.With respect to our proprietary cellular metabolism technology platform,we consider trade secrets and know-how to be ourprimary intellectual property.Trade secrets and know-how can be difficult to protect.In particular,we anticipate that withrespect to this technology platform,these trade secret

317、s and know-how will over time be disseminated within the industrythrough independent development,the publication of journal articles describing the methodology,and the movement ofpersonnel from academic to industry scientific positions.CompetitionThe pharmaceutical and biotechnology industries are c

318、haracterized by rapidly advancing technologies,intense competition anda strong emphasis on proprietary products.While we believe that our technology,development experience and scientificknowledge provide us with competitive advantages,we face potential competition from many different sources,includi

319、ngmajor pharmaceutical,specialty pharmaceutical and biotechnology companies,academic institutions and governmentalagencies and public and private research institutions.Any product candidates that we successfully develop and commercializewill compete with existing therapies and new therapies that may

320、 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.These c

321、ompanies include divisions of large pharmaceutical companies and biotechnology companiesof various sizes.Malignant Hematology and Solid Tumors.In the fields of malignant hematology and solid tumors,our principal competitorsinclude AbbVie Inc.,ASLAN Pharmaceuticals Limited;AstraZeneca Plc.;Astellas P

322、harma Inc.;Bayer AG;BeiGene Ltd.;BMS;Clear Creek Bio;Daiichi Sankyo Company,Ltd.;Eli Lilly and Company;Forma Therapeutics Holdings,LLC;GlaxoSmithKline plc;Jazz Pharmaceuticals plc;Merck&Co.;Novartis International AG;Pfizer,Inc.;and Roche Holdings,Inc.and its subsidiary Genentech,Inc.The most common

323、methods of treating patients with hematologic malignancies and solidtumors are surgery,radiation and drug therapy,including chemotherapy,hormone therapy and targeted drug therapy,and thereare a variety of available drug therapies marketed for these cancer types.For example,other than TIBSOVO and IDH

324、IFA,recently-approved treatments for AML include Venclexta from AbbVie(in collaboration with Roche);Xospata fromAstellas;Rydapt from Novartis;Vyxeos from Jazz;and Daurismo and Mylotarg from Pfizer.Recently approvedtreatments for solid tumors include Keytruda from Merck,Rozlytrek from Roche and Vitra

325、kvi from Bayer(incollaboration 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 areultimately used in combination with or as

326、an adjunct to these therapies,our product candidates may not be competitive withthem.Some of the currently approved drug therapies are branded and subject to patent protection,and others are available on ageneric basis.Many of these approved drugs are well-established therapies and are widely accept

327、ed by physicians,patients andthird-party payors.In general,although there has been considerable progress over the past few decades in the treatment ofcancer and the currently marketed therapies provide benefits to many patients,these therapies all are limited to some extent intheir efficacy and freq

328、uency of adverse events and none are successful in treating all patients.As a result,the level of morbidityand mortality from cancer remains high.In addition to currently marketed therapies,there are also a number of medicines,including immuno-oncology therapies inclinical development to treat hemat

329、ologic malignancies and solid tumors.For example:Bayer,Daiichi Sankyo and Forma areconducting phase 1 clinical trials of their IDH mutant inhibitors,BAY1436032,DS-1001b and FT-2102,respectively,inpatients with hematologic and solid tumors,including AML,MDS and glioma;ASLAN,Bayer,Clear Creek Bio,and

330、PTCTherapeutics,Inc.are conducting clinical trials of their DHODH inhibitors in hematologic malignancies;and IDEAYABiosciences,Inc is developing a MAT2A inhibitor for the treatment of MTAP-deleted solid tumors.These medicines indevelopment may provide efficacy,safety,convenience and other benefits t

331、hat are not provided by currently marketedtherapies.As a result,they may provide significant competition for any of our product candidates for which we obtain marketapproval.For example,several investigators have reported that IDH mutant AML and glioma are sensitive to poly(ADP-ribose)polymerase inh

332、ibition in cell culture and animal models.Rare genetic diseases.In the field of RGDs,our principal competitors include:Acceleron Pharma Inc.;BioMarinPharmaceutical,Inc.;bluebird bio,Inc.;Forma;Novartis;Pfizer;Global Blood Therapeutics;and Rocket Pharma LTD.16The most common methods for treating pati

333、ents with RGDs are dietary restriction,dietary supplementation or replacement,treatment of symptoms and complications,gene therapy,organ transplant and enzyme replacement therapies.There are anumber of marketed therapies available for treating patients with RGDs.For example,recently-approved treatments forthalassemia,sickle cell disease,and phenylketonuria include Reblozyl from Acceleron(in collab