Agios Pharmaceuticals (AGIO) 2015年年度報告「NASDAQ」.pdf

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1、T H E OT H E R S I D E O F P O S S I B L E 2 0 1 5 A N N UA L R E P O R T2015 ANNUAL REPORTNASDAQ:AGIOTHE OTHER SIDE OF POSSIBLEAt Agios,our vision from the beginning has been to make medicines that are truly meaningful for patients.To make this vision a reality,we are building a science-driven,inde

2、pendent biopharmaceutical company with a completely different approach to treating cancer and rare genetic disorders by targeting cellular metabolism,a disruptive area of biology.We have rapidly advanced from a blank piece of paper when our labs opened in 2009 to having five internally discovered mo

3、lecules in clinical trials that meet our high bar for development.I am incredibly proud of the tremendous achievements our team made over the last year,and we are focused on advancing our programs in 2016 as we work to deliver on the promise of impacting patients lives.In 2015,we executed against al

4、l of the milestones we set out to achieve,including:Rapidly advancing our isocitrate dehydrogenase(IDH)inhibitors,AG-221 and AG-120,into late-stage clinical development and launching the first Phase 3 study Presenting the first data in solid tumors for AG-120 Advancing our fifth molecule and second

5、pyruvate kinase-R(PKR)activator,AG-519,into clinical developmentWe recognize that in order to allow us to do great science and bring new medicines to patients,we must use our resources thoughtfully and strategically.Ending 2015 with$376 million in cash,Agios is in a strong position to advance our cl

6、inical stage programs and research as we build a sustainable,multi-product company.Our people and culture are central to our success,and we added many talented individuals to our team in 2015.We now have over 200 employees and continue to build late-stage development and commercial capabilities,hiri

7、ng the best and the brightest in their fields of expertise.Our focus on people and culture comes from our OSOP(Other Side of Possible)philosophy where employees are empowered to work together to accomplish something extraordinary while keeping the patient at the center of every decision we make.Our

8、work in the IDH space is driven by a clear long-term goal:to one day provide a therapy for every patient who has IDH mutant cancer,regardless of their tumor type or stage of disease.We are committed to a development strategy of speed and breadth for acute myeloid leukemia(AML)and other hematological

9、 malignancies to help patients who are waiting for more effective and tolerable treatment options.Simultaneously,exploring our IDH inhibitors in solid tumors remains a priority based on our encouraging early Phase 1 data and the potential to help a large number of people with cancer.Beyond cancer me

10、tabolism,our first program in rare genetic metabolic diseases is focused on a severe and rare inherited hemolytic anemia called pyruvate kinase(PK)deficiency.PK deficiency can result in lifelong medical problems including blood transfusion requirements and extreme fatigue that limits participation i

11、n normal day-to-day activities.Currently,there are no approved or disease modifying treatments.AG-348 is an oral investigational medicine designed to correct the underlying genetic defect that causes PK deficiency by activating both the normal and mutated PKR enzyme,and is currently in a Phase 2 cli

12、nical trial.This trial,known as DRIVE PK,is designed to establish proof-of-concept in patients with PK deficiency,and we plan to share the first clinical data from this study in the first half of 2016.Additionally,we expect to present initial clinical data on AG-519,our second novel,oral PKR activat

13、or,in healthy volunteers during the first half of the year.dear stockholdersGoalIDH Mutant CancerNextNowAll IDHm patients screened and treated with an IDHm inhibitor for the entire course of their disease Solid tumorsFrontline AMLCombination trialsMaintenanceMDS Other hematologicmalignancies Relapse

14、d/Refractory AMLContinue rapid and broad late-stage clinical development of our lead IDH mutant inhibitors in hematologic and solid tumorsDemonstrate clinical activity of our wholly owned,global PKR activators in patientsAdvance research and initiate preclinical development of a program from our nex

15、t wave of researchIn 2016,we are excited about the opportunities ahead,and our priorities are clear:David Schenkein,M.D.Chief Executive OfficerWith the heart and soul of Agios strongly rooted in research,we are excited to move the first program in our next wave of investigational medicines into prec

16、linical development this year.This new program is focused on methylthioadenosine phosphorylase(MTAP),a metabolic gene that is deleted in approximately 15%of all cancers.Across our research organization,we continue to focus on discovering and validating new targets that meet our high bar for developm

17、ent.We are truly excited to bring that same level of passion to our work in 2016.As Agios grows,we will continue to invest in the two most important components of our business:people and groundbreaking science.We are grateful to our employees,scientific and clinical collaborators,founders,board memb

18、ers 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,nurses and physicians who participate in our clinical trials.Without their support,our

19、work and vision for the future would not be possible.Sincerely,David Schenkein,M.D.Chief Executive OfficerTeam/CultureScienceVisionExecutionWe made extraordinary progress over the last seven years,creating five novel investigational medicines that could have the potential to impact patients lives in

20、 a profound way.Making a Difference for Patients&Building Long-Term Value.March 2016THE OTHER SIDE OF POSSIBLEUNITED STATES SECURITIES AND EXCHANGE COMMISSIONWashington,DC 20549Form 10-K(Mark One)ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1934For the fiscal year e

21、nded December 31,2015ORTRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF1934Commission File Number:001-36014AGIOS PHARMACEUTICALS,INC.(Exact name of registrant as specified in its charter)Delaware26-0662915(State or other jurisdiction ofincorporation or organization)

22、(IRS EmployerIdentification No.)88 Sidney Street,Cambridge,MA02139(Address of principal executive offices)(Zip Code)Registrants telephone number,including area code:(617)649-8600Securities registered pursuant to Section 12(b)of the Act:Title ofClassName of Exchange on WhichRegisteredCommon Stock,Par

23、 Value$0.001 per shareNASDAQ Global Select MarketSecurities registered pursuant to Section 12(g)of the Act:NoneIndicate by check mark if the registrant is a well-known seasoned issuer,as defined in Rule 405 of the SecuritiesAct.Yes No Indicate by check mark if the registrant is not required to file

24、reports pursuant to Section 13 or Section 15(d)of theAct.Yes No Indicate by check mark whether the registrant(1)has filed all reports required to be filed by Section 13 or 15(d)of the SecuritiesExchange Act of 1934 during the preceding 12 months(or for such shorter period that the registrant was req

25、uired to file such reports),and(2)has been subject to such filing requirements for the past 90 days.Yes No Indicate by check mark whether the registrant has submitted electronically and posted on its corporate Web site,if any,everyInteractive Data File required to be submitted and posted pursuant to

26、 Rule 405 of Regulation S-T(232.405 of this chapter)during thepreceding 12 months(or for such shorter period that the registrant was required to submit and post such files).Yes No Indicate by check mark if disclosure of delinquent filers pursuant to Item 405 of Regulation S-K is not contained herein

27、,and will notbe contained,to the best of registrants knowledge,in definitive proxy or information statements incorporated by reference in Part III ofthis Form 10-K or any amendment to this Form 10-K.Indicate by check mark whether the registrant is a large accelerated filer,an accelerated filer,a non

28、-accelerated filer or a smallerreporting company.See definitions of“large accelerated filer,”“accelerated filer”and“smaller reporting company”in Rule 12b-2 of theExchange Act.(Check one):Large accelerated filer Accelerated filer Non-accelerated filer(Do not check if asmaller reporting company)Smalle

29、r reporting company 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 byreference to the price of the registrants Common S

30、tock as of June 30,2015(based on the last reported sale price on the NASDAQ GlobalSelect Market as of such date)was$3,085,361,874.As of February 23,2016,there were 37,850,561 shares of Common Stock,$0.001 par value per share,outstanding.DOCUMENTS INCORPORATED BY REFERENCEPortions of the registrants

31、definitive proxy statement for its 2016 Annual Meeting of Stockholders to be filed pursuant to Regulation14A within 120 days of the end of the registrants fiscal year ended December 31,2015 are incorporated by reference into Part III of thisAnnual Report on Form 10-K to the extent stated herein.Tabl

32、e of contentsPART IPageItem 1.Business3Item 1A.Risk Factors42Item 1B.Unresolved Staff Comments74Item 2.Properties74Item 3.Legal Proceedings74Item 4.Mine Safety Disclosures74PART IIItem 5.Market for Registrants Common Equity,Related Stockholder Matters and IssuerPurchases of Equity Securities75Item 6

33、.Selected Consolidated Financial Data77Item 7.Managements Discussion and Analysis of Financial Condition and Results ofOperations79Item 7A.Quantitative and Qualitative Disclosures about Market Risk95Item 8.Financial Statements and Supplementary Data96Item 9.Changes in and Disagreements with Accounta

34、nts on Accounting and FinancialDisclosure96Item 9A.Controls and Procedures96Item 9B.Other Information99PART IIIItem 10.Directors,Executive Officers and Corporate Governance99Item 11.Executive Compensation99Item 12.Security Ownership of Certain Beneficial Owners and Management and RelatedStockholder

35、Matters99Item 13.Certain Relationships and Related Transactions,and Director Independence99Item 14.Principal Accounting Fees and Services99PART IVItem 15.Exhibits and Financial Statement Schedules1001PART IReferences to AgiosThroughout this Annual Report on Form 10-K,the“Company,”“Agios,”“we,”“us,”a

36、nd“our,”and similarexpressions,except where the context requires otherwise,refer to Agios Pharmaceuticals,Inc.and itsconsolidated subsidiaries,and“our board of directors”refers to the board of directors of Agios Pharmaceuticals,Inc.Forward-looking InformationThis Annual Report on Form 10-K contains

37、forward-looking statements that involve substantial risks anduncertainties.All statements,other than statements of historical facts,contained in this Annual Report on Form10-K,including statements regarding our strategy,future operations,future financial position,future revenue,projected costs,prosp

38、ects,plans and objectives of management,are forward-looking statements.The words“anticipate,”“believe,”“estimate,”“expect,”“intend,”“may,”“plan,”“predict,”“project,”“target,”“potential,”“will,”“would,”“could,”“should,”“continue”and similar expressions are intended to identify forward-lookingstatemen

39、ts,although not all forward-looking statements contain these identifying words.The forward-looking statements in this Annual Report on Form 10-K include,among other things,statementsregarding:the initiation,timing,progress and results of current and future preclinical studies and clinical trials,and

40、our research and development programs;the potential of IDH1/IDH2 and pyruvate kinase-R mutations as therapeutic targets;the potential benefits of our product candidates targeting IDH1/IDH2 or pyruvate kinase-R mutations,including AG-120,AG-221,AG-881,AG-348 and AG-519;our plans to develop and commer

41、cialize our product candidates;our collaborations with Celgene Corporation,or Celgene;our ability to establish and maintain additional collaborations or obtain additional funding;the timing or likelihood of regulatory filings and approvals;the implementation of our business model,strategic plans for

42、 our business,product candidates andtechnology;our commercialization,marketing and manufacturing capabilities and strategy;the rate and degree of market acceptance and clinical utility of our products;our competitive position;our intellectual property position;developments and projections relating t

43、o our competitors and our industry;andour estimates regarding expenses,future revenue,capital requirements and needs for additionalfinancing.We may not actually achieve the plans,intentions or expectations disclosed in our forward-looking statements,and you should not place undue reliance on our for

44、ward-looking statements.Actual results or events could differmaterially from the plans,intentions and expectations disclosed in the forward-looking statements we make.Wehave included important factors in the cautionary statements included in this Annual Report on Form 10-K,particularly in the“Risk F

45、actors”section,that could cause actual results or events to differ materially from theforward-looking statements that we make.Our forward-looking statements do not reflect the potential impact ofany future acquisitions,mergers,dispositions,joint ventures or investments we may make.2You should read t

46、his Annual Report on Form 10-K and the documents that we have filed as exhibits to thisAnnual Report on Form 10-K completely and with the understanding that our actual future results may bematerially different from what we expect.We do not assume any obligation to update any forward-lookingstatement

47、s,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 applying our scientific leadership in the field of cellularmetabolism to transform the lives of patients with cancer and rare genetic metabolic

48、 disorders,or RGDs,whichare a subset of orphan genetic metabolic diseases.Metabolism is a complex biological process involving theuptake and assimilation of nutrients in cells to produce energy and facilitate many of the processes required forcellular division and growth.We focus our efforts on usin

49、g cellular metabolism,an unexploited area of biologicalresearch with disruptive potential,as a platform for developing potentially transformative small moleculemedicines.Our most advanced cancer product candidates are AG-221 and AG-120,which target mutatedisocitrate dehydrogenase 2 and 1,or IDH2 and

50、 IDH1,respectively,and AG-881,which targets both mutatedIDH1 and mutated IDH2.These mutations are found in a wide range of hematological malignancies and solidtumors.The lead product candidate in our RGD programs,AG-348,targets pyruvate kinase-R for the treatmentof pyruvate kinase deficiency.Pyruvat

51、e kinase deficiency is a rare disorder that often results in severe hemolyticanemia due to inherited mutations in the pyruvate kinase enzyme within red blood cells.The clinical development strategy for all of our product candidates includes a precision approach with initialstudy designs that allow f

52、or genetically or biomarker defined patient populations,enabling the potential for proofof concept early in clinical development,along with the potential for accelerated approval.Our ability to identify,validate and drug novel targets is enabled by a set of core capabilities.Key proprietary aspects

53、of our corecapabilities in cellular metabolism include our ability to measure the activities of numerous metabolic pathwaysin cells or tissues in a high throughput fashion and our expertise in“flux biochemistry.”This refers to thedynamic analysis of how metabolites,which are intermediates or small m

54、olecule products of metabolism,accumulate or diminish as they are created or chemically altered by multiple networks of metabolic enzymes.Complex mathematical modeling of metabolic pathways,enzymatic activity and the flux of metabolites throughmetabolic enzymatic reactions within diseased tissues al

55、low us to identify novel biological parameters that can bemeasured to characterize a disease state or the effect of therapy,or biomarkers,and targets for drug discovery.Our StrategyWe aim to build a multi-product company,based on our expertise in cellular metabolism,that discovers,develops and comme

56、rcializes first-and best-in-class medicines to treat cancer and RGDs.Key elements of ourstrategy include:Aggressively pursuing the development of novel medicines to transform the lives of patients with cancerand RGDs.Maintaining our competitive advantage and focus in the field of cellular metabolism

57、.Continuing to build a product engine for cancer and RGDs to generate novel and important medicines.Building a preeminent independent biopharmaceutical company by engaging in discovery,developmentand commercialization of our medicines.Maintaining a commitment to precision medicine in drug developmen

58、t.Our Guiding PrinciplesWe aim to build a long-term company with a disciplined focus on developing medicines that transform the livesof patients with cancer and RGDs.We maintain a culture of high integrity that embraces the following guidingprinciples,which we believe will provide long-term benefits

59、 for all our stakeholders:Follow the science and do what is right for patients.3Maintain a culture of incisive decision-making driven by deep scientific interrogation and“respectfulirreverence.”Foster collaborative spirit that includes all employees regardless of function or level.Leverage deep stra

60、tegic relationships with our academic and commercial partners to improve thequality of our discovery and development efforts.Cellular MetabolismCellular metabolism refers to the set of life-sustaining chemical transformations within the cells of livingorganisms.The conversion of nutrients into energ

61、y via enzyme-catalyzed reactions allows organisms to grow andreproduce,maintain their structures,and respond to their environments.The chemical reactions of metabolismare organized into metabolic pathways,in which one chemical is transformed through a series of steps intoanother chemical,by a sequen

62、ce of enzymes.Enzymes catalyze quick and efficient reactions,serve as keyregulators of metabolic pathways,and respond to changes in the cells environment or signals from other cells.We believe our deep understanding of metabolic pathways within normal cells enables us to identify alteredmetabolic pa

63、thways within abnormal cells such as in rapidly proliferating cancers and RGDs.Fundamental differences in the metabolism of normal cells and rapidly proliferating cancer cells were firstdiscovered by Otto Warburg more than 80 years agoan observation that earned him the Nobel Prize.Warburgdemonstrate

64、d that in contrast to normal cells,which convert nutrients,such as sugar,into energy via a processknown as the Krebs cycle,cancer cells ferment their sugar into lactic acida process known as aerobicglycolysis.It is now known that this allows the cancer cells to generate the building blocks they need

65、 to growrapidly.The ability of the cancer cell to“rewire”its metabolic pathways to fuel its growth and survival hasspawned an entirely new field of cancer biology known as cancer metabolism or tumor metabolism.Cancer and cancer metabolismCancer is a disease characterized by unregulated cell growth.C

66、ancer typically develops when the repair ofgenetic material in normal cells begins to fail and genes that regulate cell growth become disrupted.Carcinogens,or cancer causing agents,such as radiation,chemicals and hormones,can trigger changes to the genetic materialof a cell,and typically prompt this

67、 disruption.Cells that have been disrupted may become cancerous,leading tochanges in the cellsDNA,and ultimately uncontrolled growth.Cancer cells can spread to other areas of thebody,or metastasize,and form tumors,which can destroy normal tissue or organs.Risk factors for cancerinclude family histor

68、y,age,diet,and exogenous factors,such as exposure to ultraviolet sunlight and smoking.Cancers can be classified in stages to document disease severity,measured in stages of I to IV,generally basedon tumor size,involvement of lymph nodes,and metastases.The most common methods of treating patients wit

69、h cancer are surgery,radiation and drug therapy.A cancerpatient often receives treatment with a combination of these methods.These treatment regimens are oftenassociated with side effects,including fatigue,infection,nausea and vomiting and pain.Surgery and radiationtherapy are particularly effective

70、 in patients in whom the disease is localized.Physicians generally use systemicdrug therapies in situations in which the cancer has spread beyond the primary site or cannot otherwise be treatedthrough surgery.The goal of drug therapy is to kill cancer cells or to damage cellular components required

71、forrapid growth and survival of cancer cells.In many cases,drug therapy entails the administration of severaldifferent drugs in combination.Over the past several decades,drug therapy has evolved from non-specific drugsthat kill both healthy and cancerous cells to drugs that target specific molecular

72、 pathways involved in cancer.Cytotoxic chemotherapiesThe earliest approach to cancer treatment was to develop drugs,referred to as cytotoxic drugs,that kill rapidlyproliferating cancer cells through non-specific mechanisms,such as disrupting cell metabolism or causingdamage to cellular components re

73、quired for survival and rapid growth.While these drugs,(e.g.,CYTOXAN,4Adriamycin)have been effective in the treatment of some cancers they act in an indiscriminate manner,killinghealthy as well as cancerous cells.Due to their mechanism of action,many cytotoxic drugs have a narrow doserange above whi

74、ch the toxicity causes unacceptable or even fatal levels of damage and below which the drugs arenot effective in eradicating cancer cells.Targeted therapiesThe next approach to pharmacological cancer treatment was to develop drugs,referred to as targetedtherapeutics,that target specific biological m

75、olecules in the human body that play a role in rapid cell growth andthe spread of cancer.Targeted therapeutics are designed to preferentially kill cancer cells and spare normal cells,to improve efficacy and minimize side effects.The drugs are designed to either attack a target that causesuncontrolle

76、d growth of cancer cells because of either a specific genetic alteration primarily found in cancer cellsbut not in normal cells or a target that cancer cells are more dependent on for their growth in comparison tonormal cells.Examples of effective targeted therapies include Herceptin,Avastinand Zelb

77、oraf.Emerging areasSeveral new approaches to develop novel cancer treatments are underway.They include:treatment with drugs orother methods that stimulate the normal immune system to attack the cancer(immuno-oncology);antibody drugconjugates(e.g.,Kadcyla)that carry a powerful chemotherapy payload th

78、at is only released into the cancer cell;and drugs that target the changes in gene activity that occurs in cancer cells(epigenetics).Cancer metabolism is a new and exciting field of biology that provides a fundamentally different approach totreating cancer.Cancers become addicted to certain fuel sou

79、rces and inherently alter their cellular machinery tochange how they consume and utilize nutrients.Cancer cells increase the transport of nutrients into the cell by200-400 fold compared to normal cells while also mutating metabolic enzymes to generate metabolites that fuelgrowth and altering gene ex

80、pression of enzymes to divert energy production.Collectively,these changes affordcancer cells the ability to generate the building blocks that drive tumor growth.Inhibiting key enzymes in cancercell specific metabolic pathways has the potential to disrupt tumor cell proliferation and survival withou

81、taffecting normal cells,thus providing a powerful new intervention point for discovery and development of noveltargeted cancer therapeutics.Our research is directed at identifying such metabolic targets and discoveringmedicines against them.Validation of the concept of cancer cell metabolic rewiring

82、 and excessive nutrient uptake comes from thewidespread use of positron emission tomography,or PET,to detect cancers.This medical imaging technologyrelies on the uptake of nutrients,namely sugar,into cells.Patients are injected with a radioactively labeled formof sugar,which is more rapidly consumed

83、 by cancer cells given their profound requirement for nutrients relativeto normal tissues.PET imaging precisely locates cancerous areas throughout the body and provides for both adiagnostic and prognostic tool throughout cancer therapy.The metabolic rewiring of cancer cells can also be linked to spe

84、cific genetic alterations in oncogenes(which aregenes that transform normal cells into tumor cells)and tumor suppressor genes(which are genes that are anti-oncogenic)responsible for cell signaling.These mutations in signaling pathways can drive excessive uptake ofnutrients and altered metabolic path

85、ways,thereby causing cancer formation.This cross talk between cellsignaling and metabolism offers multiple opportunities to treat cancer by combining our therapies directedagainst metabolic enzymes with existing or emerging standards of care.Rare genetic metabolic disordersRare genetic metabolic dis

86、orders,a subset of orphan genetic metabolic diseases,are a broad group of more than600 orphan genetic diseases caused by mutations of single metabolic genes.In these disorders,the defect of asingle metabolic enzyme disrupts the normal functioning of a metabolic pathway,leading to either aberrantaccu

87、mulation of“upstream”metabolites which may be toxic or interfere with normal function or reduced abilityto synthesize essential“downstream”metabolites or other critical cellular components.RGDs are also referred toas congenital metabolic diseases or rare genetic disorders of metabolism.5Most of thes

88、e diseases are rare or ultra-rare orphan diseases,often with severe or life-threatening features.Adisorder is considered orphan if it affects fewer than 200,000 people in the United States,or fewer than five per10,000 people in the European Union.In a study in British Columbia,the overall incidence

89、of RGDs wasestimated to be 70 per 100,000 live births or one in 1,400 births,overall representing more than approximately15%of single gene disorders in the population.Incidence of a single RGD can vary widely but is generally rare,usually equal to or less than one per 100,000 births.Many RGDs are li

90、kely to be under-diagnosed given the lackof available therapies or diagnostics and the rarity of the condition.Current treatment options for these disorders are limited.Diet modification or nutrient supplementation can bebeneficial in some RGDs.Several of these disorders,from a group known as lysoso

91、mal storage diseases,havebeen treated successfully with enzyme replacement therapy,or ERT,the therapeutic administration of afunctional version of the defective enzyme.Examples of ERTs for lysosomal storage disorders includeFabrazymefor Fabry disease,Myozomefor Pompe disease,Cerezymefor Gaucher dise

92、ase,and Elaprasefor Hunter syndrome.Unfortunately,most mutations driving RGDs are intracellular and not amenable for treatment with enzymereplacement therapies.As a result,despite the promising progress made for patients with a small group of thesediseases,the vast majority of patients with RGDs hav

93、e few therapeutic options available,and the standard of careis palliative,meaning treatment of symptoms with no effect on underlying disease mechanisms.We are taking anovel small molecule approach to correct the metabolic defects within diseased cells with a goal of developingtransformative medicine

94、s for patients.We focus on RGDs that share the following common set of features:single gene defect;severe clinical presentation with evidence that disease damage is progressive but potentially reversible;adequate number of patients for prospective clinical trials;andan assessment of the target,based

95、 upon a detailed mutational,structural,and metabolomic analysis,todetermine if a small molecule approach to correcting the disease is possible.Precision Medicine ApproachOur understanding of cellular metabolism within diseased tissues enables the development of methods tomeasure the effect of a drug

96、 on the target of interest and the patient,or pharmacodynamic markers,and patientselection strategies for clinical development.Utilizing our approach we identify altered metabolic pathwayswithin abnormal cells.Altered metabolic pathways generate disease-specific metabolic fingerprints,comprisingpatt

97、erns of metabolite levels,which are the amounts of particular metabolites,that can be exploited in bothdiscovery and development of novel therapeutics.Metabolites make ideal biomarkers because they are readilymeasured in the target tissues and blood.Metabolic biomarkers can identify appropriate pati

98、ents for clinicaltrials,serve as pharmacodynamics markers to characterize medicine/target engagement in patients,and permitthe monitoring of patient response to therapy.We will only progress our drug candidates forward into phase 1 clinical trials if we have the ability to selectpatients who are mos

99、t likely to respond to a given therapy based on biomarkers,for example,genetic ormetabolic markers.While many factors are considered critical to maximize the probability of technical success inthe drug development process,perhaps none is more important than identifying highly specific and selectivem

100、olecules aimed at the best possible targets for therapy coupled with the patients most likely to respond to thattherapy.Our goal is to develop increasing confidence in the target and the patient population prior to enteringhuman clinical trials and then initiate those first human trials in a patient

101、 population that has been selected basedon target dependence using a biomarker.This approach,known as personalized or precision medicine,is used inthe industry to lead to the potential for clear proof of concept in early human trials,along with the potential foraccelerated approval.6Our Development

102、ProgramsWe believe that leveraging our core capabilities in cellular metabolism combined with a precision medicineapproach has significantly enhanced our ability to build a research and development engine that is focused in thetherapeutic areas of cancer and RGDs.This engine has permitted us to disc

103、over proprietary first-in-class orallyavailable small molecules as potential lead product candidates for each of several novel programs indevelopment.All of our lead programs focus on diagnostically identified patient populations with the potentialfor early clinical proof of concept and accelerated

104、approval paths.The following table summarizes key information about our most advanced product candidates as of February 1,2016,each of which is described and discussed in further detail below:ProductCandidateBiomarker(s)Initial IndicationsStage ofDevelopmentCommercialRightsCancer metabolism:AG-221(I

105、DH2 mutantinhibitor)Genotyping ofIDH2 mutation;2HGIDH2 mutantpositive hematologicmalignanciesPhase 1/2 clinical trialon-going;phase 1bcombination clinicaltrial on-going;phase 3 IDHENTIFYclinical trial on-goingAgios:milestonesand royaltiesIDH2 mutantpositive solid tumorsincluding AITLPhase 1/2 clinic

106、al trialon-goingCelgene:worldwideAG-120(IDH1 mutantinhibitor)Genotyping ofIDH1 mutation;2HGIDH1 mutantpositive hematologicmalignanciesPhase 1 clinical trialon-going;phase 1bcombination clinicaltrial on-goingAgios:Milestones,cross-royalties,andU.S.rightsIDH1 mutantpositive solid tumorsPhase 1 clinica

107、l trialon-goingCelgene:ex-U.S.rights,cross-royaltiesAG-881(pan-IDH mutantinhibitor)Genotyping ofpan-IDHmutation;2HGPan-IDH mutantpositive hematologicmalignanciesPhase 1 clinical trialon-goingAgios:MilestonesAgios and Celgene:Pan-IDH mutantpositive solid tumorsPhase 1 clinical trialon-goingJoint worl

108、dwidecollaborationRare genetic metabolic disorders:AG-348(Pyruvate kinase-Ractivator)Genetic testingfor mutation inthe pyruvatekinase-R genePatients withpyruvate kinasedeficiencyPhase 2 DRIVE PKclinical trial on-goingAgios:worldwideAG-519(Pyruvate kinase-Ractivator)Genetic testingfor mutation inthe

109、pyruvatekinase-R genePatients withpyruvate kinasedeficiencyPhase 1 clinical trialin healthy volunteerson-goingAgios:worldwide7Targeting Mutated Isocitrate Dehydrogenase(IDH)for the Treatment of CancerThe isocitrate dehydrogenase,or IDH,protein is a critical enzyme in the citric acid cycle,also known

110、 as thetricarboxylic acid,or Krebs,cycle.The Krebs cycle is centrally important to many biochemical pathways and isone of the earliest established components of cellular metabolism.The Krebs cycle converts an essential cellularmetabolite called isocitrate into another metabolite,alpha-ketoglutarate(

111、-ketoglutarate),both of which arecritically important for cellular function and the creation of energy.In humans,there are three forms of the IDHenzyme,IDH1,IDH2,and IDH3,but only IDH1 and IDH2 appear to be mutated in cancers.IDH1 and IDH2catalyze the same reaction but in different cellular compartm

112、ents:IDH1 is found in the cytoplasm of the cell andIDH2 in the mitochondria.Tumor cells are generally observed to carry either an IDH1 or IDH2 mutation,but notboth.Using our proprietary metabolic platform,we and our collaborators examined the mutated pathway anddiscovered that the mutated IDH enzyme

113、s had adopted a novel“gain of function”activity that allows only themutated IDH enzyme to produce large amounts of a metabolite called 2-hydroxygluturate,or 2HG.We believethat the excessive levels of the metabolite 2HG produced by the tumor fuel cancer growth and survival viamultiple cellular change

114、s that lead to a block in cell maturation,or differentiation.We believe that inhibition ofthese mutated proteins will lead to clinical benefit for the subset of cancer patients whose tumors carry thesemutations.We have identified selective development candidates that target and inhibit the mutated f

115、orms ofIDH1 and IDH2.To date,our early clinical data of AG-221 and AG-120,our lead inhibitors of mutant IDH2 andIDH1,respectively,demonstrate a mechanism of response that is consistent with preclinical studies,includingsubstantial reduction of plasma 2HG levels,as well as evidence of cellular differ

116、entiation and normalization ofcell counts in the bone marrow and blood.This differentiation effect is distinct from that seen with traditionalchemotherapeutics commonly used to treat acute myeloid leukemia,or AML.To date,IDH1 and IDH2 mutations have been found to be prevalent in a broad range of adv

117、anced hematologicand solid tumors.The following tables summarize our current initial estimates on the occurrence of IDH2 andIDH1 mutations in hematologic and solid tumors.We believe our estimates may expand as more cancertreatment centers screen for these IDH mutations.MutationIndications%with IDH m

118、utationsIDH1Low grade glioma&2aryGlioblastomas(GBM)68-74Chondrosarcoma40-52Acute Myeloid Leukemia(AML)6-10Myelodysplastic Syndromes(MDS)/Myeloproliferative neoplasms(MPN)3Intrahepatic Cholangiocarcinoma11-24Ollier/Maffucci80Others*(colon,melanoma,lung,prostate)1-3IDH2Acute Myeloid Leukemia(AML)9-13M

119、DS/MPN3-6Angio-immunoblastic non-Hodgkin lymphoma(NHL)30Intrahepatic Cholangiocarcinoma2-6Giant Cell Tumor of the Bone80D-2-hydroxyglutarate(D2HG)Aciduria50Others*(melanoma,glioma)3-5Based on literature analysis;estimates will continue to evolve with additional future data.*Includes“basket”of emergi

120、ng unconfirmed indications8AG-221:lead IDH2 programAG-221 is an orally available,selective,potent inhibitor of the mutated IDH2 protein,making it a highly targetedtherapeutic candidate for the treatment of patients with cancers that harbor IDH2 mutations,including those withacute myeloid leukemia,or

121、 AML,who have a historically poor prognosis.In June 2014,the U.S.Food and DrugAdministration(FDA)granted us orphan drug designation for AG-221 for treatment of patients with AML.InAugust 2014,we announced that the FDA granted fast track designation to AG-221 for treatment of patients withAML that ha

122、rbor an IDH2 mutation.We have been evaluating AG-221 in several clinical trials evaluating bothhematological and solid tumor cancers with IDH2 mutations.To date,all clinical data reported by us inhematological cancers highlights that the mechanism of response is consistent with preclinical studies,i

123、ncludingsubstantial reduction of plasma 2HG levels,as well as evidence of cellular differentiation and normalization ofcell counts in the bone marrow and blood.This differentiation effect is distinct from that seen with traditionalchemotherapeutics commonly used to treat AML.In September 2013,we ini

124、tiated our first phase 1 multicenter,open-label,dose-escalation clinical trial to assessthe safety,clinical activity,and tolerability of AG-221 in patients with advanced hematologic malignancies withan IDH2 mutation.In June 2014,Celgene exercised its option to an exclusive global license for develop

125、ment andcommercialization of AG-221 under a collaboration agreement between us and Celgene,which focuses on cancermetabolism,or the 2010 Agreement.Under the 2010 Agreement,Celgene is responsible for all developmentcosts for AG-221.We are eligible to receive up to$120.0 million in milestone payments

126、and a tiered royalty onany net sales of products containing AG-221.In January 2016,in conjunction with the initiation of AG-221phase 3 trials we received a milestone payment of$25.0 million.We also have the right to conduct a portion ofany commercialization activities for AG-221 in the United States

127、.In addition to contributing our scientific andtranslational expertise,we will continue to conduct some clinical development and regulatory activities withinthe AG-221 development program in collaboration with Celgene.In October 2014,we initiated four expansion cohorts in our ongoing phase 1 clinica

128、l trial of AG-221 in patientswith IDH2 mutant-positive hematologic malignancies to assess the safety and tolerability of AG-221 at 100 mgonce daily oral dose in approximately 100 patients with IDH2 mutant-positive hematologic malignancies,including AML.In the expansion cohorts,we evaluated relapsed

129、or refractory AML patients 60 years of age andolder,relapsed or refractory AML patients under age 60,untreated AML patients who decline standard of carechemotherapy and patients with other IDH2 mutant-positive advanced hematologic malignancies.In May 2015,we announced that our ongoing phase 1 clinic

130、al trial of AG-221 had been expanded to add anadditional more homogenous cohort of 125 patients with IDH2 mutant-positive AML who are in second or laterrelapse,are refractory to second-line induction or reinduction treatment,or have relapsed after allogeneictransplantation.Consistent with the previo

131、us expansion cohorts,AG-221 is administered at a dose of 100 mgonce daily.The primary objectives of the trial are to confirm the safety and clinical activity of AG-221 in aselect,highly resistant AML population.In October 2015,Celgene,in collaboration with us,initiated IDHENTIFY,an international pha

132、se 3,multi-center,open-label,randomized clinical trial designed to compare the efficacy and safety of AG-221 versus conventionalcare regimens in patients 60 years or older with IDH2 mutant-positive AML that is refractory to or relapsed aftersecond-or third-line therapy.In December 2015,we reported a

133、dditional clinical data,as of September 1,2015,from the dose escalation phaseand expansion cohorts of the ongoing phase 1 clinical trial,which was transitioned to a phase 1/2 trial in May2015,evaluating single agent AG-221,which included 209 response-evaluable enrolled patients with IDH2mutant-posit

134、ive AML.The new data were presented at the 2015 American Society of Hematology(ASH)AnnualMeeting and Exposition in Orlando,Florida and showed investigator-assessed objective responses in 79 out of209 response-evaluable patients.Of the 79 patients who achieved an objective response,there were 37 comp

135、leteremissions(CR),three complete remissions with incomplete platelet recovery(CRp),14 marrow completeremissions(mCR),three complete remissions with incomplete hematologic recovery(CRi)and 22 partial9remissions(PR).A CR is determined by using well-established criteria,which requires no evidence of l

136、eukemiain the bone marrow and blood accompanied by full restoration of all blood counts to normal ranges.A CRpmeans all the criteria for CR are met except that platelet counts are outside of the normal range.Platelets are oneof the three major types of blood cells.A mCR means that there is no eviden

137、ce for leukemia in the marrow butthe blood counts have not fully restored.A CRi means there is no evidence for leukemia in the marrow but theneutrophils,a subset of white blood cells responsible for fighting bacterial infections,are outside the normalrange.A partial response means all the criteria f

138、or CR are met except that the immature defective blood cells,orleukemia,in the bone marrow are in the 5%to 25%range and have been decreased by at least 50%overpretreatment.Of the 159 patients with relapsed or refractory AML,59 achieved an objective response,including29 CRs,one CRp,nine mCRs,three CR

139、is and 17 PRs.Of the 24 patients with AML who declined standard ofcare chemotherapy,10 achieved an objective response,including four CRs,one CRp,one mCR and four PRs.Ofthe 14 patients with MDS,seven achieved an objective response,including three CRs,one CRp and three mCRs.Responding relapsed or refr

140、actory AML patients were on the trial for up to 18 months with a median duration oftreatment of 6.8 months,ranging from 1.8 to 18 months.Responses were durable,with median response durationof 6.9 months in patients with relapsed or refractory AML.A safety analysis was conducted for all 231 treatedpa

141、tients.The majority of adverse events reported by investigators were mild to moderate,with the most commonbeing nausea,diarrhea,fatigue and febrile neutropenia.The serious adverse events,or SAEs,observed during thetrial were mainly disease related.Twenty-three percent of patients had treatment-relat

142、ed SAEs,including notablydifferentiation syndrome(4 percent),leukocytosis(4 percent)and nausea(2 percent).Drug-related Grade 5 SAEsincluded atrial flutter(one patient),cardiac tamponade(one patient),pericardial effusion(one patient)andrespiratory failure(one patient).Dose escalation has been complet

143、ed and a maximum tolerated dose,or MTD,has not been reached.The first four expansion cohorts have completed enrollment.AG-221 continued to showfavorable drug exposure and pharmacokinetics at all doses tested with substantial reductions in plasma levels of2HG,which is produced by the mutated IDH2 and

144、 IDH1 proteins,to the level observed in healthy volunteers.In2016,Celgene,in collaboration with us,intends to initiate an expansion arm of our phase 1/2 clinical trial,evaluating AG-221 in high-risk MDS patients.Also in December 2015,we announced the initiation of a phase 1b,multicenter,internationa

145、l,open-label clinicaltrial to evaluate the safety and clinical activity of AG-221 or AG-120 in combination with induction andconsolidation therapy in patients with newly diagnosed AML with an IDH2 or IDH2 mutation who are eligiblefor intensive chemotherapy.The trial will evaluate continuous dosing f

146、or up to one year with AG-221administered at an initial oral dose of 100 mg once daily in patients with an IDH2 mutation or AG-120administered at an initial oral dose of 500 mg once daily in patients with an IDH1 mutation.AG-221 or AG-120will be administered with two types of AML induction therapies

147、(cytarabine with either daunorubicin oridarubicin)and two types of AML consolidation therapies(mitoxantrone with etoposide ME or cytarabine).In the first quarter of 2016,Celgene,in collaboration with us,intends to initiate a phase 1/2 frontline combinationclinical trial,to be conducted by Celgene,of

148、 either AG-221 or AG-120 in combination with VIDAZA(azacitidine)in newly diagnosed AML patients not eligible for intensive chemotherapy,with a phase 1component to determine the safety of the combinations,followed by a phase 2 randomized component evaluatingthe safety and clinical activity of each in

149、vestigational combination versus single-agent VIDAZAusing aprimary endpoint of overall response rate.In October 2014,we announced the initiation of a phase 1/2 multicenter clinical trial of AG-221 in patients withadvanced solid tumors,including gliomas,as well as angioimmunoblastic T-cell lymphoma,i

150、ncluding AITL,ineach case that carry an IDH2 mutation.This phase 1/2 multicenter,open-label,dose-escalation clinical trial ofAG-221,conducted in collaboration with Celgene,is designed to assess the safety,clinical activity,andtolerability of AG-221 among patients who have an IDH2 mutant-positive adv

151、anced solid tumor or AITL.Thephase 1/2 clinical trial includes a dose expansion phase where three cohorts of patients with glioma,AITL andother solid tumors that are IDH2 mutant-positive are receiving AG-221 to further evaluate safety,tolerability andclinical activity in advanced solid tumors.10AG-1

152、20:lead IDH1 programAG-120 is an orally available,selective,potent inhibitor of the mutated IDH1 protein,making it a highly targetedtherapeutic candidate for the treatment of patients with cancers that harbor IDH1 mutations.Mutations in IDH1have been identified in difficult to treat hematologic and

153、solid tumor cancers,including AML,chondrosarcomaand cholangiocarcinoma where both the treatment options and prognosis for patients are poor.In March 2014,weinitiated two phase 1,multicenter,open-label,dose-escalation and expansion clinical trials for AG-120,onedesigned to assess the safety,clinical

154、activity and tolerability of AG-120 in patients with advanced hematologicmalignancies and the second designed to evaluate the safety,clinical activity and tolerability of AG-120 inpatients with advanced solid tumors,each as a single agent.Both trials are only enrolling patients that carry anIDH1 mut

155、ation.On May 18,2015,we announced that the FDA granted fast track designation to AG-120 fortreatment of patients with AML that harbor an IDH1 mutation.On June 10,2015,the FDA granted us orphandrug designation for AG-120 for treatment of patients with AML.Four expansion cohorts have been added to the

156、 ongoing phase 1 clinical trial of AG-120 in patients withadvanced hematologic malignancies.These four expansion cohorts will evaluate AG-120 in 200 patients withIDH1 mutant-positive advanced hematologic malignancies.The first cohort will evaluate a more homogenouspopulation of 125 AML patients who

157、are in second or later relapse,are refractory to second-line induction orreinduction treatment,or have relapsed after allogeneic transplantation.The second cohort will evaluate 25untreated AML patients.The third cohort will evaluate 25 patients with other non-AML IDH1 mutant-positiverelapsed or refr

158、actory advanced hematologic malignancies.The fourth cohort will evaluate patients with relapsedIDH1 mutant-positive AML not eligible for the first arm or standard of care chemotherapy.AG-120 isadministered at a 500 mg once daily oral dose,in 28-day cycles.The trials primary objectives are to confirm

159、 thesafety and clinical activity of AG-120.In November 2015,we reported clinical data from the dose-escalation portion of our ongoing phase 1 clinicaltrial evaluating AG-120 in patients with IDH1 mutant-positive advanced solid tumors,including glioma,intrahepatic cholangiocarcinoma,or IHCC,and chond

160、rosarcomas who received AG-210 administered from 200mg to 1200 mg total daily doses.The data were presented at the AACR-NCI-EORTC International Conferenceon Molecular Targets and Cancer Therapeutics in Boston.As of the September 3,2015 data cut-off,62 patientshad been treated with single agent AG-12

161、0,of which 55 were response-evaluable.Seven of the 11 response-evaluable patients with IDH1 mutant-positive chondrosarcoma had stable disease,with five of these patientsmaintaining stable disease for six months or more.One of the 20 patients with IDH1 mutant-positive IHCC had apartial response and 1

162、1 patients had stable disease,with six such patients maintaining stable disease for sixmonths or more.Ten of the 20 patients with IDH1 mutant-positive glioma had stable disease,with four of thesepatients maintaining stable disease for six months or more.One of the four patients with other IDH1 mutan

163、t-positive solid tumors had stable disease.Treatment with AG-120 showed substantial reduction of 2HG in plasmaand tumor tissue,and imaging results suggest that AG-120 can lower 2HG levels in the brain.AG-120 was welltolerated,with the majority of adverse events reported by investigators being mild t

164、o moderate.The mostcommon investigator-reported adverse events were nausea,diarrhea,vomiting,anemia and QT prolongation.Themajority of reported SAEs were disease related.A MTD has not been reached.We are currently enrolling fourexpansion cohorts of 25 patients each in(i)low grade glioma with at leas

165、t six months of prior scans to assessvolumetric changes,(ii)second-line cholangiocarcinoma,(iii)high grade,or metastatic,chondrosarcoma,and(iv)other solid tumors with an IDH1 mutation,who will receive the recommended dose of 500 mg of AG-120once daily.In December 2015,we reported new data,as of Octo

166、ber 1,2015,from the ongoing phase 1 clinical trialevaluating single agent AG-120,which included 87 enrolled patients with IDH1 mutant-positive advancedhematologic malignancies,of which 78 were from the dose-escalation phase and nine were from the expansionphase.The data were presented at the 2015 AS

167、H Annual Meeting and Exposition in Orlando,Florida and showedinvestigator-assessed objective responses in 27 out of 78 response-evaluable patients on AG-120.Of the 27patients who achieved an objective response,there were 12 CRs,seven CRps,six mCRs,one CRi and one PR.11Patients were on the trial trea

168、tment for up to 14.1 months,with a median duration of treatment of 2.9 months,ranging from 0.1 to 14.1 months.Data continued to show durable clinical activity for AG-120,with responsesmaintained for up to 12.5 months and a median duration of response of 5.6 months.AG-120 continued to showfavorable d

169、rug exposure and pharmacokinetics at all doses tested and also substantially reduced plasma levels of2HG to the level observed in healthy volunteers.The mechanism of response is consistent with differentiation,asevidenced by the maturation of the leukemic cells into infection fighting white blood ce

170、lls,or neutrophils.Themajority of adverse events reported by investigators were mild to moderate,with the most common being fatigue,diarrhea,pyrexia and nausea.A MTD has not been reached,and dose escalation is now complete.As described above,in December 2015,we announced the initiation of a phase 1b

171、,multicenter,international,open-label clinical trial of AG-221 or AG-120 in combination with induction and consolidation therapy inpatients with newly diagnosed AML with an isocitrate dehydrogenase(IDH)mutation who are eligible forintensive chemotherapy.Together with Celgene,we intend to initiate a

172、global registration-enabling phase 3 clinical trial in frontline AMLpatients who harbor an IDH1 mutation in the second half of 2016.In addition,we intend to(i)initiate arandomized phase 2 clinical trial of AG-120 in patients with IDH1 mutant-positive cholangiocarcinoma in thesecond half of 2016 and(

173、ii)as described above,initiate a phase 1/2 frontline combination clinical trial,to beconducted by Celgene,of either AG-221 or AG-120 in combination with VIDAZA(azacitidine)in newlydiagnosed AML patients not eligible for intensive chemotherapy in the first quarter of 2016,with a phase 1component to d

174、etermine the safety of the combinations,followed by a phase 2 randomized component evaluatingthe safety and clinical activity of each investigational combination versus single-agent VIDAZAusing aprimary endpoint of overall response rate.Celgene exercised its exclusive option to license development a

175、nd commercialization rights to AG-120 outsidethe United States in January 2015.We had previously elected to exercise our option to retain development andcommercialization rights to AG-120 in the United States in January 2014.Upon Celgenes exercise of itsexclusive option under the terms of our 2010 A

176、greement,Celgene leads development and commercializationoutside the United States,and we lead development and commercialization in the United States.Celgene isresponsible for future development and commercialization costs specific to countries outside the United States,we are responsible for future

177、development and commercialization costs specific to the United States,and we andCelgene will equally fund the future global development costs of AG-120 that are not specific to any particularregion or country.Celgene is eligible to receive tiered royalties on any net sales in the United States.We ar

178、eeligible to receive tiered royalties on any net sales outside the United States and up to$120.0 million in paymentson achievement of certain milestones.We also are eligible to receive an additional one-time payment of$25.0million upon the dosing of the last patient in an Agios-sponsored phase 2 cli

179、nical trial for AG-120.AG-881:lead pan-IDH programAG-881 is an orally available,selective,brain-penetrant,pan-IDH mutant inhibitor,which provides addedflexibility to our current portfolio of IDH mutant inhibitors.AG-881 successfully completed IND-enabling studiesin April 2015.We and Celgene are join

180、tly collaborating on a worldwide development program,wherein we shareworldwide development costs and profits and Celgene would book any worldwide commercial sales.We will leadcommercialization in the United States with both companies sharing equally in field-based commercial activities,and Celgene w

181、ill lead commercialization outside of the United States with us providing one third of field-basedcommercial activities in the major EU markets.In June 2015,we initiated a phase 1 clinical trial for AG-881 inpatients with advanced solid tumors.This phase 1 multi-center,open-label clinical trial is t

182、o evaluate the safety,pharmacokinetics,pharmacodynamics and clinical activity of AG-881 in advanced solid tumors,including gliomas.AG-881 will be administered continuously as a single agent dosed orally in a 28-day cycle.The first portion of thetrial includes a dose-escalation phase in which cohorts

183、 of patients will receive ascending oral doses of AG-881 todetermine the maximum tolerated dose and/or the recommended phase 2 dose based on safety and tolerability.Thesecond portion of the trial is a dose expansion phase where patients will receive AG-881 to further evaluate thesafety,tolerability

184、and clinical activity of the recommended phase 2 dose.12In August 2015,we initiated a second dose escalation and expansion phase 1 clinical trial for AG-881 in patientswith advanced IDH1 or IDH2 mutant-positive hematologic malignancies whose cancer has progressed on a priorIDH inhibitor therapy.This

185、 phase 1 multi-center,open-label clinical trial is to evaluate the safety,pharmacokinetics,pharmacodynamics and clinical activity of AG-881 in advanced hematological malignancies.AG-881 will be administered continuously as a single agent dosed orally in a 28-day cycle.The first portion ofthe trial i

186、ncludes a dose-escalation phase in which cohorts of patients will receive ascending oral doses of AG-881 to determine the maximum tolerated dose and/or the recommended phase 2 dose based on safety andtolerability.The second portion of the trial is a dose expansion phase where patients will receive A

187、G-881 tofurther evaluate the safety,tolerability and clinical activity of the recommended phase 2 dose.Pyruvate Kinase Deficiency ProgramPyruvate kinase,or PK,is the enzyme involved in the second to last reaction in glycolysisthe conversion ofglucose into lactic acid.This enzyme is critical for the

188、survival of the cell and has several tissue-specific isoforms(PKR,PKL,PKM1 and PKM2).PKR is the isoform of pyruvate kinase that is present in red blood cells.Mutations in PKR cause defects in red cell glycolysis and lead to a hematological RGD known as pyruvatekinase deficiency,or PK deficiency.Glyc

189、olysis is the only pathway available for red blood cells to maintain theproduction of ATP,or Adenosine-5-triphosphate,which transports chemical energy within cells for metabolism.Accordingly,total absence of the PKR gene is not compatible with life.PK deficiency leads to a shortened lifespan for red

190、 blood cells and is the most common form of non-spherocytic hemolytic anemia in humans.Thedisease is autosomal recessive,meaning children inherit one mutated form of PKR from one parent and thesecond mutated form from the other parent.Children with the disease produce PKR enzyme that has only afract

191、ion of the normal level of activity(generally 50%).Parents of affected children have only one copy of themutated PKR enzyme and are clinically normal.PK deficiency is a rare genetic disorder and disease understanding is still evolving.Several publishedepidemiology studies estimated prevalence of PK

192、deficiency between three to nine affected patients per million.We estimate that there are approximately 2,400 diagnosed patients in the United States and EU5 countries(United Kingdom,France,Germany,Italy,Spain),and we believe that the disease is likely under-diagnosed.There is no unique ethnic or ge

193、ographic representation of the disease.The disease manifests by mild to severeforms of anemia caused by the excessive premature destruction of red blood cells.The precise mechanism for thedestruction is not well understood but is thought to result from membrane instability secondary to the metabolic

194、defect caused by the low level of PKR enzyme.The hemolysis is“extra-vascular”in that the red blood cells aredestroyed in small capillaries or organs and not spontaneously breaking open in the circulation.AG-348:lead pyruvate kinase(PK)deficiency programAG-348 is an orally available small molecule an

195、d a potent activator of the wild-type(normal)and mutated PKRenzyme,which has resulted in restoration of ATP levels and a decrease in 2,3-DPG levels in blood sampled frompatients with PK deficiency in nonclinical studies.The wild-type PKR activity of AG-348 allowed the study ofenzyme activation in he

196、althy volunteers,providing an opportunity to understand the safety,dosing andpharmacodynamic activity of AG-348 prior to entering a proof-of-concept study in patients.On March 24,2015,the FDA granted us orphan drug designation for AG-348 for treatment of patients with PK deficiency.In April 2014,we

197、initiated a single ascending dose,or SAD,escalation phase 1 clinical trial for AG-348 inhealthy volunteers and in June 2014,we initiated a multiple ascending dose,or MAD,escalation phase 1 clinicaltrial for healthy volunteers.In late 2014,we reported the SAD trial was completed and met its primary e

198、ndpoint.The MAD trial completed dosing in early 2015 and has also met its primary endpoint.The primary endpoint isdefined in the protocol to identify a safe and pharmacodynamically active dose and dosing schedule for AG-348to be used in subsequent clinical studies in patients with pyruvate kinase de

199、ficiency.In December 2014,during a poster session at ASH 2014,we reported the first clinical data from the phase 1 SADand MAD clinical trials of AG-348 in healthy volunteers.These results provided early proof-of-mechanism for13AG-348 as a novel,first-in-class,oral activator of both wild-type and mut

200、ated PKR enzymes.In these phase 1clinical trials,dosing of AG-348 over 14-days in healthy volunteers resulted in a dose-dependent activation of thePKR pathway as evidenced by a substantial increase in ATP and decrease in 2,3-DPG levels,which are keybiomarkers of PKR activity and primary indicators o

201、f PK deficiency.These data support the hypothesis that AG-348 treatment may similarly enhance PKR activity in patients with PK deficiency and thus correct the underlyingdefect of the disease.Results presented were from 64 healthy volunteers who received either AG-348 or placebo,which included 48 peo

202、ple from the completed SAD trial and 16 people in the first two cohorts of the MAD trial,which recently completed dosing.Complete safety results were reported from the SAD phase 1 clinical trial andshowed that AG-348 was well tolerated.Although the MAD trial remained blinded,no serious adverse event

203、shad been reported in the first two analyzed cohorts.AG-348 also showed a favorable pharmacokinetic profilewith rapid absorption,low variability and dose-proportional increase in exposure following both single andmultiple doses.The observed dose-dependent changes in 2,3-DPG and ATP blood levels seen

204、 are consistent witha substantial increase in PKR enzymatic activity.On June 12,2015,we reported final clinical data from the phase 1 MAD clinical trial of AG-348 in healthyvolunteers and the first data from a natural history study of PK deficiency.The data were presented at the 20thCongress of the

205、European Hematology Association(EHA)in Vienna,Austria.Results presented were from 48healthy volunteers who received either AG-348 or placebo for fourteen days at 15 mg,60 mg,120 mg,360 mg or700 mg twice daily or 120 mg once daily in six sequential cohorts.The study showed that AG-348 was welltolerat

206、ed,with most adverse events occurring in the highest dose group(700 mg),with all but one being mild tomoderate.Thirty-two of 36 healthy volunteers receiving AG-348 completed the study.Two volunteers receivingAG-348 withdrew due to adverse events,including drug eruption(60 mg)and Grade 3 liver functi

207、on testabnormalities(700 mg),which resolved after treatment discontinuation.Two additional AG-348 volunteers(both700 mg)withdrew consent due to nausea or vomiting.Serum hormone changes consistent with reversiblearomatase inhibition were observed.AG-348 also showed a favorable pharmacokinetic profile

208、 with rapidabsorption,low to moderate variability and a dose-proportional increase in exposure following multiple doses.As predicted by the mechanism of action of AG-348,there was a robust activation of pyruvate kinase asevidenced by a decrease in 2,3-DPG(2,3-diphosphoglycerate)and increase in ATP(a

209、denosine triphosphate)inblood of healthy volunteers.The decrease in 2,3-DPG was approximately 50 percent for doses 120 mg and higherwith levels returning back to baseline approximately 72 hours after AG-348 was discontinued.There was also anapproximately 50 percent increase in ATP in blood with AG-3

210、48 at doses 60 mg and higher in healthyvolunteers.In June 2015,we initiated DRIVE PK,a global phase 2,first-in-patient,open-label safety and efficacy clinicaltrial of AG-348 in adult,transfusion-independent patients with PK deficiency.The multi-center,randomized trialwill include two arms with 25 pa

211、tients each.The patients in the first arm will receive 50 mg twice daily,and thepatients in the second arm will receive 300 mg twice daily.The trial will include a six-month dosing period withthe opportunity for continued treatment beyond six months based on safety and clinical activity.In July 2015

212、,wedosed the first-patient in this phase 2 clinical trial,and we expect to present the first data from the trial in the firsthalf of 2016.We have worldwide development and commercial rights to AG-348 and expect to fund the future developmentand commercialization costs related to this program.AG-519:

213、a second novel PKR activatorAG-519 is an orally available small molecule and our second product candidate that is a potent activator of thePKR enzyme.We initiated a placebo-controlled phase 1 clinical trial of AG-519 in healthy volunteers in the firstquarter of 2016.This trial will be an integrated

214、single ascending dose and multiple ascending dose trial.Weexpect to present data from this trial in the first half of 2016.We have worldwide development and commercialrights to AG-519 and expect to fund the future development and commercialization costs related to this program.14Collaboration with C

215、elgene2010 Agreement and amendmentsIn April 2010,we entered into the 2010 Agreement with Celgene,a related party through ownership of theCompanys common stock.The agreement was amended in October 2011 and July 2014,as described below.The goal of the collaboration is to discover,develop and commercia

216、lize disease-altering therapies in oncologybased on the Companys cancer metabolism research platform.We will initially lead discovery,preclinical andearly clinical development for all cancer metabolism programs under the collaboration.The discovery phase of the 2010 Agreement was scheduled to expire

217、 in April 2014,subject to Celgenes optionto extend the discovery phase for up to an additional two years with additional funding made to us.In December2013,Celgene elected to extend the term of the initial discovery phase from four years to five years,to April2015,in exchange for the payment of a$20

218、.0 million extension fee which we received in May 2014.InDecember 2014,Celgene elected to exercise its final option to extend the term of the initial discovery phase oneadditional year,to April 2016,in exchange for the payment of a$20.0 million extension fee which was receivedin May 2015.Pursuant to

219、 the 2010 Agreement,we are responsible for nominating development candidates,of which tworequired confirmation by the Joint Research Committee,or JRC,during the discovery phase.During the yearended December 31,2012 we nominated our first development candidate(AG-221)and during the year endedDecember

220、 31,2013 we nominated our second development candidate(AG-120),both of which have beenconfirmed by the JRC pursuant to the 2010 Agreement.For each development candidate,Celgene elected toprogress such development candidate into preclinical development requiring us to conduct studies to meet therequi

221、rements for filing an Investigational New Drug application,or IND,or IND-enabling studies.Subsequently,we were required to file an IND for each of the two development candidates and,upon the FDAs acceptance ofthe INDs,Celgene requested that we conduct an initial phase 1 clinical trial.Discovery prog

222、rams with development candidates.Celgene may elect to progress into preclinical developmenteach discovery program for which we nominate and the JRC confirms a development candidate during thediscovery phase.If Celgene makes such an election,we will,at our expense,conduct studies required to meet the

223、requirements for filing an IND,or IND-enabling studies,and,following their successful completion as confirmedby the JRC,we will file an IND to commence clinical studies of such development candidate.If the FDA acceptsthe IND,Celgene may request that we conduct an initial phase 1 clinical trial at ou

224、r expense,for which Celgenewill pay us at least$5.0 million upon the earlier of the determination of the maximum tolerated dose or Celgeneselection to license the program,unless such program becomes a split licensed program,as described below.Celgene may elect to convert each discovery program for w

225、hich we have nominated a development candidateinto a co-commercialized licensed program,the attributes of which are described below.We have the right,exercisable during a specified period following FDA acceptance of the applicable IND,to convert one of everythree co-commercialized licensed programs

226、into a split licensed program,for which we will retain the UnitedStates rights,other attributes of which are further described below.We may elect to opt out of any split licensedprogram,after which such split licensed program will revert to a co-commercialized licensed program,andCelgene will have t

227、he right,but not the obligation,to commercialize medicines from such program in the UnitedStates.Our IDH2 program is a co-commercialized licensed program and not a split licensed program.In June2014,Celgene exercised its option to an exclusive global license for the development and commercialization

228、 ofour IDH2 program,AG-221.We elected to retain U.S.rights to our IDH1 program,AG-120,in January 2014.Celgene exercised its rights to this program in during the three months ended March 31,2015.In addition,Celgene may license certain discovery programs that we do not nominate or the JRC does not con

229、firm as adevelopment candidate and for which Celgene will lead and fund global development and commercialization.We will retain our rights to the development candidates and certain other compounds from any discoveryprogram for which we nominate and the JRC confirms a development candidate but that C

230、elgene does not elect15to progress into preclinical development or convert into a co-commercialized licensed program.In addition,if theJRC or Celgene elects not to continue collaboration activities with respect to a particular target,either we orCelgene would have the right to independently undertak

231、e a discovery program on such target and would haverights to specified compounds from such program,subject to certain“buy-in”rights granted to the other party.Further development and commercialization of programs.The agreement provides for three types of licensedprograms discussed above:co-commercia

232、lized licensed programs,split licensed programs,and buy-in programs.Celgenes and our rights and obligations under each licensed program vary depending on the type of licensedprogram,as described below.Co-commercialized licensed programs:Celgene will lead and,following either IND acceptance by theFDA

233、 or,if Celgene requests us to conduct the initial phase 1 clinical trial,upon completion of suchphase 1 clinical trial,will fund global development and commercialization of each co-commercializedlicensed program.We have the right to participate in a portion of commercialization activities in theUnit

234、ed States for medicines from co-commercialized programs in accordance with the applicablecommercialization plan.Split licensed programs:Celgene will lead development and commercialization outside the UnitedStates,and we will lead development and commercialization in the United States,for each split

235、licensedprogram.We and Celgene will equally fund the global development costs of each split licensed programthat are not specific to any particular region or country,Celgene will be responsible for development andcommercialization costs specific to countries outside the United States,and we will be

236、responsible fordevelopment and commercialization costs specific to the United States.Buy-in programs:The party that was conducting an independent program that became a buy-in programwill lead the development and commercialization of such program.The party that elects to buy in tosuch program will be

237、 responsible for funding a portion of development costs incurred after acceptance ofan IND for a buy-in program compound,and the lead party will be responsible for all other developmentcosts and all commercialization costs for medicines from such buy-in program.In addition,Celgene may license certai

238、n discovery programs for which we did not nominate or the JRC did notconfirm a development candidate during the discovery phase and for which Celgene will lead and fund globaldevelopment and commercialization.We refer to these as picked licensed programs.Collaboration governance.The collaboration is

239、 managed by a set of joint committees comprised of equalnumbers of representatives from each of Celgene and us.The joint steering committee,or JSC,oversees andcoordinates the overall conduct of the collaboration.The JRC oversees and coordinates discovery,research andpreclinical activities with respe

240、ct to each discovery program during the discovery phase.A joint developmentcommittee,or JDC,for each licensed program will oversee and coordinate development(includingmanufacturing of clinical supply)of medicines under such licensed program.The joint commercializationcommittee,or JCC,will oversee th

241、e commercialization(including manufacturing of commercial supply)ofmedicines under the licensed programs.Diligence.We and Celgene each must use commercially reasonable efforts to perform all activities for whichsuch party is responsible under the collaboration.Exclusivity.During the discovery phase,

242、we may not directly or indirectly develop,manufacture orcommercialize,except pursuant to the agreement,any product or product candidate for any cancer indicationwith specified activity against certain metabolic targets(except in connection with certain specified third-partycollaborations),or with sp

243、ecified activity against any collaboration target(or any target for which Celgene isconducting an independent program that we elected not to buy in to)for any indication.Following the discoveryphase until termination or expiration of the agreement,either in its entirety or with respect to the releva

244、ntprogram,we may not directly or indirectly develop,manufacture or commercialize,outside of the collaboration,16any therapeutic modality with specified activity against any collaboration target that is within a licensed programor against any former collaboration target against which Celgene is condu

245、cting an independent program under theagreement.Pursuant to the terms of the first amendment to the agreement,we have the right to develop,manufacture and commercialize outside of the collaboration certain medicines directed against PKR for certainindications,including PK deficiency,subject to speci

246、fied conditions,including a right of first negotiation thatCelgene may exercise if we intend to license our PKR program to any third party.Financial terms.Under the terms of the 2010 Agreement,we received an upfront payment of approximately$121.2 million.In addition,Celgene purchased 5,190,551 share

247、s of our series B convertible preferred stock at aprice of$1.70 per share,resulting in net proceeds to us of approximately$8.8 million.In connection with the 1-for-2.75 reverse stock split of our common stock,the shares of these series B preferred stock converted into1,887,473 shares of common stock

248、 upon the closing of our initial public offering in July 2013.Celgene made apayment to us of$20.0 million pursuant to an October 2011 amendment in consideration of extending thediscovery phase until April 14,2014.In December 2013,Celgene elected to extend the discovery phase of the2010 Agreement by

249、one year,extending the initial period of exclusivity from four years to five years,until April2015.As a result of the December 2013 extension,we received a$20.0 million extension payment from Celgenein May 2014.In December 2014,Celgene elected to extend the discovery phase of the 2010 Agreement by o

250、neadditional year,extending the period of exclusivity from five years to six years,until April 2016.As a result ofthe December 2014 extension,we received a$20.0 million extension payment from Celgene in May 2015.Under the 2010 Agreement,we are eligible to receive up to$120.0 million in potential mil

251、estone paymentspayable for each program selected by Celgene.The potential milestone payments for each such program arecomprised of:(i)a$25.0 million milestone payment upon achievement of a specified clinical developmentmilestone event,which was earned in January 2016 in relation to our co-commercial

252、ized program(AG-221),(ii)up to$70.0 million in milestone payments upon achievement of specified regulatory milestone events,and(iii)a$25.0 million milestone payment upon achievement of a specified commercial milestone event.We arealso eligible to receive additional milestone payments specific to co-

253、commercialized licensed programs and splitlicensed programs.In addition,we are eligible to receive a substantive milestone payment of$22.5 million uponachievement of an early clinical development milestone event for certain co-commercialized licensed programs.In connection with the first split licen

254、sed program under the collaboration,our IDH1 program,AG-120,we areeligible to receive an additional one-time payment of$25.0 million upon the dosing of the last patient in anAgios-sponsored phase 2 clinical trial.In addition to the milestone payments described above,for each co-commercialized licens

255、ed program,we will bereimbursed for all eligible development costs of the related phase 1 multiple ascending dose clinical trial.Theinitial costs will be reimbursed as a milestone payment equal to the greater of$5.0 million or eligibledevelopment costs incurred by us upon the earlier of the determin

256、ation of the maximum tolerated dose orCelgenes election to license the program.Subsequent to the initial milestone payment,development costs willbe reimbursed on a quarterly basis.In addition to the milestone payments described above,for each split licensedprogram,we are eligible for reimbursement o

257、f the costs of disease-specific expansion cohort(s)that support theinitiation of a subsequent pivotal clinical trial.Costs will be reimbursed as a milestone payment equal to thelesser of$10.0 million or fifty percent of the eligible costs for the disease-specific expansion cohort(s)upon thefirst pat

258、ient dosed under the pivotal clinical trial.The maximum amount for the milestone payment will be$10.0million for each split licensed program regardless of the number of disease-specific expansion cohorts andpivotal trials undertaken for each split licensed program.We are eligible to receive royaltie

259、s at tiered,low-to mid-teen percentage rates on net sales and we have theoption to participate in the development and commercialization of certain products in the United States.Theroyalty payments will be recognized as revenue in the period in which they are earned.No other milestone orroyalty payme

260、nts under the 2010 Agreement have been earned.17In July 2014,we amended the 2010 Agreement to allow for more flexibility in the design and conduct of phase 1clinical trials and additional nonclinical and/or clinical activities that we agreed to perform at Celgenes request.The amendment further modif

261、ied the mechanism and timing for payments to be made with respect to suchdevelopment activities.Termination.Celgene may terminate the 2010 Agreement for convenience in its entirety or with respect to one ormore programs upon ninety days written notice to us.Either we or Celgene may terminate the 201

262、0 Agreement,in its entirety or with respect to one or more programs,if the other party is in material breach and fails to curesuch breach within the specified cure period;however,if such breach relates solely to a specific program,thenon-breaching party may terminate the 2010 Agreement solely with r

263、espect to such program.Either we orCelgene may terminate the 2010 Agreement in the event of specified insolvency events involving the other party.If Celgene terminates the 2010 Agreement as a result of our uncured material breach,then certain of our rightsand certain of Celgenes obligations describe

264、d above would change with respect to the terminated program(s),including,for example:the licenses we granted to Celgene would become perpetual;milestone payments towhich we may be entitled may be reduced or eliminated;royalties to which we may be entitled may be reducedor eliminated;we would lose th

265、e development and commercialization rights for the United States for anyterminated split licensed program;and we would grant Celgene specified rights,and take specified actions,toassist Celgene in continuing the development,manufacture and commercialization of medicines for the UnitedStates from eac

266、h terminated split licensed program.If Celgene terminates the 2010 Agreement for convenience or if we terminate the agreement as a result ofCelgenes uncured material breach,the licenses we granted to Celgene with respect to the terminated program(s)will end,and we will have specified rights for,and

267、Celgene will take specified actions to assist us in continuing,the development,manufacture and commercialization of medicines from each terminated program.AG-881 AgreementsOn April 27,2015,we entered into a joint worldwide development and profit share collaboration and licenseagreement with Celgene

268、and our wholly owned subsidiary,Agios International Sarl,which was organized inSwitzerland in April 2015,and we entered into a collaboration and license agreement with Celgene InternationalII Sarl(collectively,the“AG-881 Agreements”).The AG-881 Agreements establish a worldwide collaborationfocused o

269、n the development and commercialization of AG-881 products.Under the terms of the AG-881Agreements,we received initial upfront payments totaling$10.0 million in May 2015 and are eligible to receivemilestone-based payments described below.We will split all worldwide development costs with Celgene equ

270、ally,subject to specified exceptions,as well as any profits from any net sales of,or commercialization losses relatedto,licensed AG-881 products.Celgene will book commercial sales of licenses AG-881 products,if any,on aworldwide basis.Financial terms.We are eligible to receive up to$70.0 million in

271、potential milestone payments related to AG-881 under the AG-881 Agreements.The potential milestone payments are comprised of:(i)a$15.0 millionmilestone payment for filing of first NDA in a major market and(ii)up to$55.0 million in milestone paymentsupon achievement of specified regulatory milestone

272、events.We may also receive royalties at tiered,low-to mid-teen percentage rates on net sales if Celgene elects to not participate in the development and commercializationof AG-881.Commercialization.Under the terms of the AG-881 Agreements,we will lead commercialization of licensed AG-881 products wi

273、thin the United States and Celgene will lead commercialization of licensed AG-881 productsoutside of the United States.Depending on the market,we and Celgene will each have the right to provide aportion of field-based marketing activities.Opt-out right.Under the AG-881 Agreements,we may elect to opt

274、 out of the cost and profit split of thecollaboration at any time after April 27,2016 by providing at least 12 months written notice to Celgene.If we opt18out,Celgene will have the sole right to develop,manufacture and commercialize licensed AG-881 productsthroughout the world,at its cost,and we wil

275、l undertake transitional activities reasonably necessary to transfer thedevelopment,manufacture and commercialization of licensed AG-881 products to Celgene,at our cost.If we elect to opt-out of the AG-881 Agreements,then,in lieu of the profit or loss sharing described above,wewould be eligible to r

276、eceive royalties at tiered,low to mid-teen percentage rates on Celgenes net sales oflicensed AG-881 products.Term.The term of the AG-881 Agreements will continue,unless earlier terminated,as described below,as longas we and Celgene continue to develop or commercialize licensed AG-881 products,or,in

277、the event we opt outof the AG-881 Agreements,until expiration of the royalty term for AG-881 products.Termination.Celgene may terminate the AG-881 Agreements for convenience upon ninety days written notice tous.Either we or Celgene may terminate the AG-881 Agreements if the other party is in materia

278、l breach and failsto cure such breach within the specified cure period.Either we or Celgene may terminate the AG-881Agreements in the event of specified insolvency events involving the other party.If one of the AG-881Agreements terminates,the other will terminate automatically.Exclusivity.Until term

279、ination or expiration of the AG-881 Agreements,neither we nor Celgene may directly orindirectly develop,manufacture or commercialize,outside of the AG-881 Agreements or the 2010 Agreement,any therapeutic modality with specified activity against both IDH1 and IDH2.Intellectual PropertyOur commercial

280、success depends in part on our ability to obtain and maintain proprietary or intellectual propertyprotection for our product candidates and our core technologies,including novel biomarker and diagnosticdiscoveries,and other know-how,to operate without infringing on the proprietary rights of others a

281、nd to preventothers from infringing our proprietary or intellectual property rights.Our policy is to seek to protect ourproprietary and intellectual property position by,among other methods,filing U.S.,international and foreignpatent applications related to our proprietary technology,inventions and

282、improvements that are important to thedevelopment and implementation of our business.We also rely on trade secrets,know-how and continuingtechnological innovation to develop and maintain our proprietary and intellectual property position.We file patent applications directed to our key product candid

283、ates,including AG-221,AG-120,AG-881,AG-348and AG-519,in an effort to establish intellectual property positions regarding new chemical entities relating tothese product candidates as well as uses of new chemical entities in the treatment of diseases.We also seekpatent protection with respect to bioma

284、rkers that may be useful in selecting the right patient population fortherapies with our product candidates.As of December 31,2015,we had a portfolio of pending U.S.and foreignpatent applications.A significant portion of our pending patent applications pertain to our key developmentprograms,includin

285、g AG-221,AG-120,AG-881,AG-348 and AG-519,some of which have been issued aspatents.In addition to the pending patent applications and issued patents covering our most advanced product candidates,our portfolio also includes pending patent applications relating to diagnostic methods for detecting vario

286、us IDH1and IDH2 mutations,as well as compositions of matter and methods of use directed to modulating othermetabolic targets.The term of individual patents depends upon the legal term for patents in the countries in which they areobtained.In most countries,including the United States,the patent term

287、 is 20 years from the earliest filing date ofa non-provisional patent application.In the United States,a patents term may be lengthened by patent termadjustment,which compensates a patentee for administrative delays by the U.S.Patent and Trademark Office,orthe USPTO,in examining and granting a paten

288、t,or may be shortened if a patent is terminally disclaimed over an19earlier filed patent.The term of a patent that covers a drug or biological product may also be eligible for patentterm extension when FDA approval is granted,provided statutory and regulatory requirements are met.In thefuture,if and

289、 when our product candidates receive approval by the FDA or foreign regulatory authorities,weexpect to apply for patent term extensions on issued patents covering those products,depending upon the lengthof the clinical trials for each medicine and other factors.There can be no assurance that any of

290、our pending patentapplications will issue or that we will benefit from any patent term extension or favorable adjustment to the termof any of our patents.As with other biotechnology and pharmaceutical companies,our ability to maintain and solidify our proprietaryand intellectual property position fo

291、r our product candidates and technologies will depend on our success inobtaining effective patent claims and enforcing those claims if granted.However,patent applications that wemay file or license from third parties may not result in the issuance of patents.We also cannot predict the breadthof clai

292、ms that may be allowed or enforced in our patents.Any issued patents that we may receive in the futuremay be challenged,invalidated or circumvented.For example,we cannot be certain of the priority of inventionscovered by pending third-party patent applications.If third parties prepare and file paten

293、t applications in theUnited States that also claim technology or therapeutics to which we have rights,we may have to participate ininterference proceedings in the USPTO to determine priority of invention,which could result in substantial coststo us,even if the eventual outcome is favorable to us.In

294、addition,because of the extensive time required forclinical development and regulatory review of a product candidate we may develop,it is possible that,before anyof our product candidates can be commercialized,any related patent may expire or remain in force for only ashort period following commerci

295、alization,thereby reducing any advantage of any such patent.In addition to patents,we rely upon unpatented trade secrets and know-how and continuing technologicalinnovation to develop and maintain our competitive position.We seek to protect our proprietary information,inpart,using confidentiality ag

296、reements with our collaborators,scientific advisors,employees and consultants,andinvention assignment agreements with our employees.We also have agreements requiring assignment ofinventions with selected consultants,scientific advisors and collaborators.The confidentiality agreements aredesigned to

297、protect our proprietary information and,in the case of agreements or clauses requiring inventionassignment,to grant us ownership of technologies that are developed through a relationship with a third party.With respect to our proprietary cellular metabolism technology platform,we consider trade secr

298、ets and know-how to be our primary intellectual property.Trade secrets and know-how can be difficult to protect.In particular,we anticipate that with respect to this technology platform,these trade secrets and know-how will over time bedisseminated within the industry through independent development

299、,the publication of journal articles describingthe methodology,and the movement of personnel skilled in the art from academic to industry scientific positions.CompetitionThe pharmaceutical and biotechnology industries are characterized by rapidly advancing technologies,intensecompetition and a stron

300、g emphasis on proprietary products.While we believe that our technology,developmentexperience and scientific knowledge provide us with competitive advantages,we face potential competition frommany different sources,including major pharmaceutical,specialty pharmaceutical and biotechnology companies,a

301、cademic institutions and governmental agencies and public and private research institutions.Any productcandidates that we successfully develop and commercialize will compete with existing therapies and newtherapies that may become available in the future.We compete in the segments of the pharmaceuti

302、cal,biotechnology and other related markets that address cancermetabolism and RGDs.There are other companies working to develop therapies in the field of cancermetabolism and RGDs.These companies include divisions of large pharmaceutical companies and biotechnologycompanies of various sizes.Cancer m

303、etabolism.In the field of cancer metabolism,our principal competitors include AstraZeneca;CalitheraBiosciences;Cornerstone Pharmaceuticals,Inc.;Eli Lilly and Company;Forma Therapeutics Holdings,LLC;20GlaxoSmithKline plc;Merck&Co.;Novartis International AG,or Novartis;Pfizer,Inc.;and Roche Holdings,I

304、nc.and its subsidiary Genentech,Inc.For example,Novartis is currently conducting a phase 1 clinical trial of itsIDH1 mutant inhibitor,IDH305,in patients with advanced malignancies.The most common methods of treating patients with cancer are surgery,radiation and drug therapy,includingchemotherapy,ho

305、rmone therapy and targeted drug therapy.There are a variety of available drug therapiesmarketed for cancer.In many cases,these drugs are administered in combination to enhance efficacy.While ourproduct candidates may compete with many existing drug and other therapies,to the extent they are ultimate

306、lyused in combination with or as an adjunct to these therapies,our product candidates will not be competitive withthem.Some of the currently approved drug therapies are branded and subject to patent protection,and others areavailable on a generic basis.Many of these approved drugs are well-establish

307、ed therapies and are widelyaccepted by physicians,patients and third-party payors.In general,although there has been considerable progressover the past few decades in the treatment of cancer and the currently marketed therapies provide benefits tomany patients,these therapies all are limited to some

308、 extent in their efficacy and frequency of adverse events andnone are successful in treating all patients.As a result,the level of morbidity and mortality from cancer remainshigh.In addition to currently marketed therapies,there are also a number of medicines in late stage clinicaldevelopment to tre

309、at cancer,including immuno-cancer therapies.These medicines in development may provideefficacy,safety,convenience and other benefits that are not provided by currently marketed therapies.As aresult,they may provide significant competition for any of our product candidates for which we obtain marketa

310、pproval.Rare genetic metabolic disorders.In the field of RGDs,our principal competitors include AlexionPharmaceuticals,Inc.;BioMarin Pharmaceutical,Inc.;Genzyme,a Sanofi company;and Shire Biochem,Inc.The most common methods for treating patients with RGDs are dietary restriction,dietary supplementat

311、ion orreplacement,treatment of symptoms and complications,gene therapy,organ transplant and enzyme replacementtherapies.There are a number of marketed enzyme replacement therapies available for treating patients withRGDs.In some cases,these treatment methods are used in combination to improve effica

312、cy.While our productcandidates may compete with existing medicines and other therapies,to the extent they are ultimately used incombination with or as an adjunct to these therapies,our product candidates will not be competitive with them.Inaddition to currently marketed therapies,there are also a nu

313、mber of products that are either enzyme replacementtherapies or gene therapies in various stages of clinical development to treat RGDs.These products indevelopment may provide efficacy,safety,convenience and other benefits that are not provided by currentlymarketed therapies.As a result,they may pro

314、vide significant competition for any of our product candidates forwhich we obtain market approval.Many of our competitors may have significantly greater financial resources and expertise in research anddevelopment,manufacturing,preclinical testing,conducting clinical trials,obtaining regulatory appr

315、ovals andmarketing approved medicines than we do.Mergers and acquisitions in the pharmaceutical,biotechnology anddiagnostic industries may result in even more resources being concentrated among a smaller number of ourcompetitors.These competitors also compete with us in recruiting and retaining qual

316、ified scientific andmanagement personnel and establishing clinical trial sites and patient registration for clinical trials,as well as inacquiring technologies complementary to,or necessary for,our programs.Smaller or early stage companies mayalso prove to be significant competitors,particularly thr

317、ough collaborative arrangements with large andestablished companies.The key competitive factors affecting the success of all of our product candidates,if approved,are likely to betheir efficacy,safety,convenience,price,the effectiveness of companion diagnostics in guiding the use of relatedtherapeut

318、ics,the level of generic competition and the availability of reimbursement from government and otherthird-party payors.21Our commercial opportunity could be reduced or eliminated if our competitors develop and commercializemedicines that are safer,more effective,have fewer or less severe side effect

319、s,are more convenient or are lessexpensive than any medicines that we may develop.Our competitors also may obtain FDA or other regulatoryapproval for their medicines more rapidly than we may obtain approval for ours,which could result in ourcompetitors establishing a strong market position before we

320、 are able to enter the market.In addition,our abilityto compete may be affected in many cases by insurers or other third-party payors seeking to encourage the use ofgeneric medicines.There are many generic medicines currently on the market for the indications that we arepursuing,and additional medic

321、ines are expected to become available on a generic basis over the coming years.Ifour therapeutic product candidates are approved,we expect that they will be priced at a significant premium overcompetitive generic medicines.ManufacturingWe do not own or operate,and currently have no plans to establis

322、h,any manufacturing facilities.We currentlyrely,and expect to continue to rely,on third parties for the manufacture of our product candidates for preclinicaland clinical testing,as well as for commercial manufacture of any products that we may commercialize.To date,we have obtained materials for AG-

323、221,AG-120,AG-881,AG-348 and AG-519 for our ongoing and plannedclinical testing from third-party manufacturers.We obtain our supplies from these manufacturers on a purchaseorder basis and do not have any long-term supply arrangements in place.We do not currently have arrangementsin place for redunda

324、nt supply for bulk drug substance.For all of our product candidates,we intend to identify andqualify additional manufacturers to provide the active pharmaceutical ingredient and fill-and-finish services priorto submission of a new drug application to the FDA.AG-221,AG-120,AG-881,AG-348 and AG-519 ar

325、e organic compounds of low molecular weight,generallycalled small molecules.They can be manufactured in reliable and reproducible synthetic processes from readilyavailable starting materials.The chemistry is amenable to scale-up and does not require unusual equipment in themanufacturing process.We e

326、xpect to continue to develop drug candidates that can be produced cost-effectivelyat contract manufacturing facilities.We generally expect to rely on third parties for the manufacture of any companion diagnostics we develop.Research and Development ExpensesFor the years ended December 31,2015,2014,a

327、nd 2013,company-sponsored research and developmentexpenses were$141.8 million,$100.4 million and$54.5 million,respectively.Review and Approval of Drugs in the United StatesIn the United States,the FDA approves and regulates drugs under the Federal Food,Drug,and Cosmetic Act,orFDCA,and implementing r

328、egulations.The failure to comply with requirements under the FDCA and otherapplicable laws at any time during the product development process,approval process or after approval maysubject an applicant and/or sponsor to a variety of administrative or judicial sanctions,including refusal by theFDA to

329、approve pending applications,withdrawal of an approval,imposition of a clinical hold,issuance ofwarning letters and other types of letters,product recalls,product seizures,total or partial suspension ofproduction or distribution,injunctions,fines,refusals of government contracts,restitution,disgorge

330、ment ofprofits,or civil or criminal investigations and penalties brought by the FDA and the Department of Justice orother governmental entities.Our product candidates must be approved by the FDA through the NDA.An applicant seeking approval tomarket and distribute a new drug product in the United St

331、ates must typically undertake the following:completion of preclinical laboratory tests,animal studies and formulation studies in compliance with theFDAs good laboratory practice,or GLP,regulations;submission to the FDA of an IND,which must take effect before human clinical trials may begin;22approva

332、l by an independent institutional review board,or IRB,representing each clinical site beforeeach clinical trial may be initiated;performance of adequate and well-controlled human clinical trials in accordance with good clinicalpractices,or GCP,to establish the safety and efficacy of the proposed dru

333、g product for each indication;preparation and submission to the FDA of a NDA requesting marketing for one or more proposedindications;review by an FDA advisory committee,where appropriate or if applicable;satisfactory completion of one or more FDA inspections of the manufacturing facility or facilities atwhich the product,or components thereof,are produced to assess compliance with current GoodMan