Agios Pharmaceuticals (AGIO) 2022年年度報告「NASDAQ」.pdf

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1、Fueled by ConnectionsA leader in the field of cellular metabolism pioneering therapies for rare diseases2022 Annual ReportDominique,sickle cell disease Jim,PK deficiency NinaMaria,thalassemia John,PK deficiencyMeet JimJim is an aspiring physicians assistant,student,beach volleyball player and PK def

2、iciency advocate.He was diagnosed with PK deficiency at birth after being rushed to the NICU with severe jaundice.Throughout his childhood,he faced jaundice,fatigue,regular transfusions,iron overload and splenectomy.When he went to college,he noticed the negative impact of his disease on his quality

3、 of life,including his ability to balance his schoolwork,sports activities and social life.Jims doctor informed him about Agios clinical studies in PK deficiency,and he decided to enroll.Agios is proud to work toward improving the lives of people like Jim.Jim,living with PK deficiencyI decided it wa

4、s in my best interest to advocate for myself to try to feel better with my PK deficiency.I wanted to make sure that I was doing everything in my power to help myself.Jim says,reflecting on that decision.Jim continues to take the medication today.“Our ability to work together with patient communities

5、,healthcare professionals,partners and colleagues and honor each of their perspectives powers our continued success in creating groundbreaking therapies for the patients who need them.In 2022,our first-in-class PK activator was approved in the U.S.,EU,and Great Britain and became the first disease-m

6、odifying treatment for adults with pyruvate kinase(PK)deficiency,a rare,debilitating,lifelong blood disorder.We are grateful for the partnership of the patient community,healthcare providers and all who were involved in delivering this important therapy for patients.At Agios,we are fueled by connect

7、ions.“2022 Annual ReportSince our founding,Agios has been a pioneering leader in cellular metabolism,advancing therapies for patients with unmet needs.This focus led us to develop a novel therapeutic approach,called pyruvate kinase(PK)activation,and today Agios is dedicated to improving the lives of

8、 those touched by life-altering rare diseases.2022 was a transformative year for Agios as we received our first rare disease approval for PYRUKYND(mitapivat)in the U.S.,EU,and Great Britain,a significant milestone in our journey to improve the lives of people living with rare diseases.But it doesnt

9、stop there.We are advancing a robust pipeline of therapies for other rare diseases as we partner with and listen to patients and healthcare providers,and as we advance health equity for all.Patient AlliesPeople living with rare diseases are at the center of everything we do and every decision we mak

10、e.Their needs,concerns,input and collaboration are essential to fulfilling our mission.As such,we strive to be allies for people who have historically been overlooked,underdiagnosed and underserved.We build true partnerships and believe that the best outcomes are achieved when we work together to cr

11、eate them.For example,Agios strives for patient voices to be central when developing clinical trial protocols and creating communications for trial participants.By seeking input from patients early on,and incorporating their feedback,our trials are better equipped to address the aspects of the disea

12、se that are most important to patients,and are more inclusive and accommodating of patients needs which paves the way for more representative diversity in our trials.Expanding AccessOur goal is for as many eligible patients as possible to have access to our medicines and for out-of-pocket costs for

13、the individual patients to be as reasonable as possible.PYRUKYND was approved in the U.S.in February 2022 and since approval,88%of eligible U.S.patients with commercial health insurance have utilized the PYRUKYND Copay Program which lowers copay costs to$0 per prescription.Eligible U.S.patients who

14、are uninsured,underinsured,or rendered uninsured may get help from our Patient Assistance Program which offers free prescriptions.We also developed myAgios Patient Support Services in close collaboration with the patient,caregiver and provider communities;this program supports patients and caregiver

15、s as they navigate access to treatment regardless of their insurance carrier or coverage status.Outside of the U.S,Agios Global Managed Access Program(GMAP)provides a pathway for adult PK deficiency patients receiving care in the EU and Great Britain to have access to PYRUKYND at no charge to the pa

16、tient while Agios evaluates commercialization approaches and advances clinical programs for PYRUKYND in more prevalent disease states.Advancing Our PipelineWe are focusing our PK activator molecules on classical hematologic diseases that share a common underlying pathophysiology,and data we generate

17、 in one disease area has direct implications for our probability of success in other areas.The data weve generated to date is striking.We have seen compelling and consistent data across multiple disease areas,including hemoglobin,hemolysis,ineffective erythropoiesis,transfusion burden,iron overload,

18、and bone health,suggesting that PK activation may have the potential to transform patient function,quality of life,and long-term outcomes in each of these indications.Our pipeline has grown dramatically since we announced the divestiture of our oncology business and focused exclusively on rare disea

19、ses just two years ago.This is a true testament to the dedication and expertise of our development team.Reflecting on our 2022 milestones,I am very proud of the teams ability to innovate,execute and deliver on behalf of patients including the full enrollment in our RISE UP study for sickle cell dise

20、ase,over 50%enrollment in our Phase 3 ENERGIZE and ENERGIZE-T studies for thalassemia,and the initiation of the Phase 2a study of our novel PK activator AG-946 in lower-risk myelodysplastic syndrome(MDS).This commitment and excellence of our team positions Agios to expand our impact to many more pat

21、ients and this year we expect to:Complete enrollment of the Phase 3 ENERGIZE and ENERGIZE-T studies of PYRUKYND in thalassemia by mid-year Enroll at least half of patients in the Phase 3 ACTIVATE-kids and ACTIVATE-kidsT studies of PYRUKYND in Pediatric PK Deficiency by year-end Announce data readout

22、 from the Phase 2 portion of RISE UP study of PYRUKUND in sickle cell disease and go/no-go to Phase 3 decision by mid-year Complete enrollment of our Phase 2a study of novel PK activator AG-946 in lower-risk MDS by year-end File an investigational new drug(IND)application for PAH stabilizer for the

23、treatment of phenylketonuria(PKU)by year-endFellow Stockholders The Road AheadWhen I joined Agios as CEO in August 2022,I was drawn to the company because I could see it had a unique set of ingredients,including a strong purpose focused on serving rare disease patients,a legacy of developing transfo

24、rmative therapies such as PYRUKYND,an impressive late-stage clinical and emerging pipeline,an enviable balance sheet and an inspiring Board,leadership team and company culture.Ahead of us is a catalyst-rich period;by 2026,we expect to have a classical hematology franchise with approvals in three ind

25、ications as well as an expanded portfolio beyond PK activation.I am deeply grateful to our team,scientific and clinical collaborators,patients and their caregivers,advocates,founders,board members and stockholders for your ongoing support.Thank you for your collaboration and for sharing our vision t

26、o make a meaningful impact for people with rare udnRnerAheBrian Goff,Chief Executive OfficerMitapivat (PK Activator)MDS-associated AnemiaPhase 2Healthy Volunteers/Sickle Cell DiseaseAdult PK DeficiencyACTIVATE and ACTIVATE-TNon-transfusion Dependent Adult ThalassemiaENERGIZETransfusion Dependent Adu

27、lt ThalassemiaENERGIZE-TAdult Sickle Cell DiseaseRISE UPTransfusion Dependent Pediatric PK DeficiencyACTIVATE-kidsTNon-transfusion Dependent Pediatric PK DeficiencyACTIVATE-kidsPediatric ThalassemiaPlanning underwayPediatric Sickle Cell DiseasePlanning underwayAG-946 (PK Activator)Clinical ProgramsD

28、rug DiscoveryEarly Stage Clinical DevelopmentLate Stage Clinical DevelopmentRegulatory SubmissionApprovedPipelinePhenylalanine Hydroxylase (PAH)StabilizerOther PKR/PKM2 Development CandidatesPreclinicalAPPROVEDin the U.S.,Great Britain and EUUNITED STATES SECURITIES AND EXCHANGE COMMISSIONWashington

29、,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 ended December 31,2022ORTRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF1934Commission File Number:001-36014AGIOS PHARMACEUTICALS,INC.(

30、Exact name of registrant as specified in its charter)Delaware26-0662915(State or other jurisdiction ofincorporation or organization)(IRS EmployerIdentification No.)88 Sidney Street,Cambridge,MA02139(Address of principal executive offices)(Zip Code)Registrants telephone number,including area code:(61

31、7)649-8600Securities registered pursuant to Section 12(b)of the Act:Title of ClassTrading symbol(s)Name of Exchange on Which RegisteredCommon Stock,Par Value$0.001 per shareAGIONasdaq Global Select MarketSecurities registered pursuant to Section 12(g)of the Act:NoneIndicate by check mark if the regi

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

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

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

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

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

37、 standards provided pursuant to Section 13(a)of the Exchange Act.Indicate by check mark whether the registrant has filed a report on and attestation to its managements assessment of the effectiveness of itsinternal control over financial reporting under Section 404(b)of the Sarbanes-Oxley Act(15 U.S

38、.C.7262(b)by the registered public accounting firmthat prepared or issued its audit report.If securities are registered pursuant to Section 12(b)of the Act,indicate by check mark whether the financial statements of the registrant includedin the filing reflect the correction of an error to previously

39、 issued financial statements.Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensationreceived by any of the registrants executive officers during the relevant recovery period pursuant to 240.10D-1(b).Indicate by

40、check mark whether the registrant is a shell company(as defined in Rule 12b-2 of the Act).Yes No The aggregate market value of the voting and non-voting Common Stock held by non-affiliates of the registrant computed by reference to theprice of the registrants Common Stock as of June 30,2022(based on

41、 the last reported sale price on the Nasdaq Global Select Market as of such date)was$1,200,277,504.As of February 17,2023,there were 55,285,223 shares of Common Stock,$0.001 par value per share,outstanding.DOCUMENTS INCORPORATED BY REFERENCEPortions of the registrants definitive proxy statement for

42、its 2023 Annual Meeting of Stockholders to be filed pursuant to Regulation 14A within120 days of the end of the registrants fiscal year ended December 31,2022 are incorporated by reference into Part III of this Annual Report on Form10-K to the extent stated herein.Table of contentsPART IPageItem 1.B

43、usiness3Item 1A.Risk Factors31Item 1B.Unresolved Staff Comments60Item 2.Properties60Item 3.Legal Proceedings60Item 4.Mine Safety Disclosures60PART IIItem 5.Market for Registrants Common Equity,Related Stockholder Matters and IssuerPurchases of Equity Securities61Item 6.Reserved62Item 7.Managements D

44、iscussion and Analysis of Financial Condition and Results ofOperations63Item 7A.Quantitative and Qualitative Disclosures about Market Risk75Item 8.Financial Statements and Supplementary Data76Item 9.Changes in and Disagreements with Accountants on Accounting and FinancialDisclosure76Item 9A.Controls

45、 and Procedures76Item 9B.Other Information77Item 9C.Disclosure Regarding Foreign Jurisdictions that Prevent Inspections77PART IIIItem 10.Directors,Executive Officers and Corporate Governance78Item 11.Executive Compensation78Item 12.Security Ownership of Certain Beneficial Owners and Management and R

46、elatedStockholder Matters78Item 13.Certain Relationships and Related Transactions,and Director Independence78Item 14.Principal Accountant Fees and Services78PART IVItem 15.Exhibits and Financial Statement Schedules79Item 16.Form 10-K Summary82iPART IReferences to AgiosThroughout this Annual Report o

47、n Form 10-K,“the Company,”“we,”“us,”and“our,”and similar expressions,except wherethe context requires otherwise,refer to Agios Pharmaceuticals,Inc.and its consolidated subsidiaries,and“our board ofdirectors”refers to the board of directors of Agios Pharmaceuticals,Inc.Cautionary Note Regarding Forwa

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

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

50、”“will,”“would”and similar expressions are intended to identify forward-looking statements,although not all forward-lookingstatements contain these identifying words.The forward-looking statements in this Annual Report on Form 10-K include,among other things,statements regarding:our plans to commerc

51、ialize PYRUKYND(mitapivat);the initiation,timing,progress and results of current and future preclinical studies and clinical trials,and ourresearch and development programs;the potential of the isoforms of pyruvate kinase,including PKR,as therapeutic targets;the potential benefits of our products an

52、d product candidates targeting PKR,including PYRUKYND(mitapivat)and AG-946,and our PAH stabilizer program;our plans to develop and commercialize any additional product candidates for which we may receive approval,either alone or with partners;our ability to establish and maintain collaborations or t

53、o obtain additional funding,if needed;the timing or likelihood of regulatory filings and approvals;our strategic vision;the timing,likelihood and amount of contingent consideration we may receive from Servier Pharmaceuticals LLC,or Servier,in connection with the sale of our oncology business to Serv

54、ier that we consummated in March 2021;the implementation of our business model and strategic plans for our business,product candidates and technology;our commercialization,marketing and manufacturing capabilities and strategy;the rate and degree of market acceptance and clinical utility of our produ

55、cts;our competitive position;our intellectual property position;developments and projections relating to our competitors and our industry;the impact of the COVID-19 pandemic on our business,operations,strategy,goals and anticipated milestones;andour estimates regarding our ability to achieve cash fl

56、ow positivity,expenses,future revenue,capital requirementsand needs for additional financing.We may not actually achieve the plans,intentions or expectations disclosed in our forward-looking statements,and you shouldnot place undue reliance on our forward-looking statements.Actual results or events

57、could differ materially from the plans,intentions and expectations disclosed in the forward-looking statements we make.We have included important factors in thisAnnual Report on Form 10-K,particularly in the Summary Risk Factors and“Risk Factors”sections,that could cause actualresults or events to d

58、iffer materially from the forward-looking statements that we make.Our forward-looking statements do notreflect the potential impact of any future acquisitions,in-licensing arrangements,mergers,dispositions,joint ventures orinvestments we may make.You should read this Annual Report on Form 10-K and t

59、he documents that we have filed as exhibits to this Annual Report onForm 10-K completely and with the understanding that our actual future results may be materially different from what weexpect.We do not assume any obligation to update any forward-looking statements,whether as a result of new inform

60、ation,future events or otherwise,except as required by law.This Annual Report on Form 10-K includes statistical and other industry and market data that we obtained from industrypublications and research,surveys and studies conducted by third parties.All of the market data used in this Annual Report

61、onForm 10-K involves a number of assumptions and limitations,and you are cautioned not to give undue weight to such data.We1believe that the information from these industry publications,research,surveys and studies is reliable.The industry in which weoperate is subject to a high degree of uncertaint

62、y and risk due to a variety of important factors,including those described in thesections titled“Summary Risk Factors”and“Risk Factors.”Summary Risk FactorsOur business is subject to a number of risks that if realized could materially affect our business,financial condition,results ofoperations,cash

63、 flows and access to liquidity.These risks are discussed more fully in the“Risk Factors”section of this AnnualReport on Form 10-K.Our principal risks include the following:If we do not successfully commercialize PYRUKYND for the treatment of adults with PK deficiency in the approvedjurisdictions and

64、 other products for which we receive approval,our prospects may be substantially harmed.Our ability togenerate product revenue from PYRUKYND depends heavily on our successful development and commercializationof the product.We depend heavily on the success of our clinical product candidates,including

65、,upon approval,PYRUKYND for usein indications other than PK deficiency and in other jurisdictions.Clinical trials of our product candidates may not besuccessful for a number of important reasons.If we or our collaborators are unable to commercialize our productcandidates or experience significant de

66、lays in doing so,our business will be materially harmed.We may engage in in-licensing transactions or acquisitions that could disrupt our business,cause dilution to ourstockholders or reduce our financial resources.We may expend our limited resources to pursue a particular product candidate or indic

67、ation and fail to capitalize onproduct candidates or indications that may be more profitable or for which there is a greater likelihood of success.The COVID-19 pandemic has and may continue to affect our ability to initiate or continue our planned,ongoing andfuture preclinical studies,clinical trial

68、s,disrupt regulatory activities,disrupt our ability to maintain a commercialinfrastructure for PYRUKYND or have other adverse effects on our business and operations.PYRUKYND,or any of our product candidates that may receive marketing approval in the future,may be lesseffective than previously believ

69、ed or cause undesirable side effects that were not previously identified in clinical trials ormay fail to achieve the degree of market acceptance by physicians,patients,healthcare payors and others in the medicalcommunity necessary for commercial success,which could compromise our ability,or that of

70、 any collaborators,tomarket the product.If we are unable to establish and maintain sales and marketing capabilities or enter into agreements with third parties tosell and market our products,we may not be successful in commercializing PYRUKYND or our product candidates ifand when they are approved.W

71、e face substantial competition,which may result in others discovering,developing or commercializing products beforeor more successfully than we do.There are a number of large pharmaceutical and biotechnology companies thatcurrently market and sell products or are pursuing the development of products

72、 for the treatment of the diseaseindications for which we are developing our product or our product candidates.Our competitors may develop productsthat are more effective,safer,more convenient or less costly than PYRUKYND or any product candidates that we aredeveloping or that would render PYRUKYND

73、or our product candidates obsolete or non-competitive.We are singularly focused on products and product candidates for the treatment of rare diseases.As a result,we may bemore susceptible to changing market conditions,including fluctuations and risks particular to the markets for patientswith rare d

74、iseases,than a more diversified company,which could adversely affect our business,financial condition andresults of operations.If our existing capital is insufficient to execute our operating plan through major catalysts and to cash-flow positivity,wewill need to raise capital,and if we are unable t

75、o raise capital when needed,we would be forced to delay,reduce oreliminate our product development programs or commercialization efforts.We have historically incurred operating losses.We expect to incur losses in the future and may never achieve ormaintain profitability.Our net loss for the year end

76、ed December 31,2022 was$231.8 million,our net income for theyear ended December 31,2021 was$1,604.7 million and our net loss for the year ended December 31,2020 was$327.4million.The net income we generated in the year ended December 31,2021 was due to the sale of our oncology businessto Servier in M

77、arch 2021.As of December 31,2022,we had an accumulated deficit of$470.6 million.We currently rely and expect to continue to rely on third parties for the manufacture of our product candidates forpreclinical and clinical testing and for commercial supply of PYRUKYND and any product candidate for whic

78、h weobtain marketing approval.Any performance failure on the part of our existing or future third-party manufacturers coulddelay clinical development,marketing approval or our commercialization efforts.2We rely and expect to continue to rely on third parties to conduct our clinical trials and some a

79、spects of our research andpreclinical testing,and those third parties may not perform satisfactorily,including failing to meet deadlines for thecompletion of such trials,research or testing.We may depend on collaborations with third parties for the development and commercialization of our productcan

80、didates.If those collaborations are not successful,we may not be able to capitalize on the market potential of theseproduct candidates.If we are unable to obtain and maintain patent or trade secret protection for our medicines and technology,or if the scopeof the patent protection obtained is not su

81、fficiently broad,our competitors could develop and commercialize medicinesand technology similar or identical to ours,and our ability to successfully commercialize our medicines and technologymay be adversely affected.If we do not,or are unable to,obtain or maintain any issued patents for any of our

82、 mostadvanced product candidates,it could have a material adverse effect on our competitive position,business,financialcondition,results of operations,and prospects.Item 1.BusinessGeneralWe are a biopharmaceutical company committed to transforming patients lives through leadership in the field of ce

83、llularmetabolism,with the goal of creating differentiated,small molecule medicines for rare diseases.With a history of focused studyon cellular metabolism,we have a deep and mature understanding of this biology,which is involved in the healthy functioningof nearly every system in the body.We acceler

84、ate the impact of our portfolio by cultivating connections with patientcommunities,healthcare professionals,partners and colleagues to discover,develop and deliver potential therapies for rarediseases.Sale of Oncology Business to Servier Pharmaceuticals,LLC(Servier)On March 31,2021,we completed the

85、sale of our oncology business to Servier Pharmaceuticals,LLC,or Servier,whichrepresented a discontinued operation.The transaction included the sale of our oncology business,including TIBSOVO,ourclinical-stage product candidates vorasidenib,AG-270 and AG-636,and our oncology research programs for a p

86、ayment ofapproximately$1.8 billion in cash at the closing,subject to certain adjustments,and a payment of$200.0 million in cash,if,prior to January 1,2027,vorasidenib is granted new drug application,or NDA,approval from the U.S.Food and DrugAdministration,or FDA,with an approved label that permits v

87、orasidenibs use as a single agent for the adjuvant treatment ofpatients with Grade 2 glioma that have an isocitrate dehydrogenase 1 or 2 mutation(and,to the extent required by suchapproval,the vorasidenib companion diagnostic test is granted an FDA premarket approval),as well as a royalty of 5%of U.

88、S.net sales of TIBSOVO from the close of the transaction through loss of exclusivity,and a royalty of 15%of U.S.net sales ofvorasidenib from the first commercial sale of vorasidenib through loss of exclusivity.The milestone payment for approval ofvorasidenib and royalty payments related to vorasiden

89、ib and TIBSOVO represent contingent consideration.Servier alsoacquired our co-commercialization rights for Bristol Myers Squibbs IDHIFA and the right to receive a$25.0 millionpotential milestone payment under our prior collaboration agreement with Celgene Corporation,and following the sale Servierwi

90、ll conduct certain clinical development activities within the IDHIFA development program.We recorded income from royalties of approximately$9.9 million and$6.6 million on U.S.net sales of TIBSOVO by Servierin the royalty income from gain on sale of oncology business line item within the consolidated

91、 statements of operations for theyear ended December 31,2022 and December 31,2021,respectively.Sale of Contingent PaymentsThe consideration for the sale of our oncology business to Servier includes a royalty of 5%of U.S.net sales of TIBSOVOfrom the close of the transaction through loss of exclusivit

92、y,referred to as contingent payments.We recognize the contingentpayments in the royalty income from gain on sale of oncology business line item in our consolidated statements of operations inthe period when realizable.On October 27,2022,we sold our rights to future contingent payments to entities af

93、filiated withSagard Healthcare Partners,or Sagard,and recognized income of$127.9 million within the gain on sale of contingent paymentsline item in our consolidated statements of operations for the year ended December 31,2022.We retained our rights to thepotential milestone payment and royalties fro

94、m Servier if vorasidenib is approved by the FDA.Evolution of our Research OrganizationIn May 2022,we announced our determination to evolve our approach to exploratory research and drug discovery to focus onour existing late-lead optimization programs and to prioritize in-licensing or acquiring asset

95、s for pipeline growth.We reduced approximately 45 roles focused on exploratory research in connection with this evolution of our researchorganization,and plan to retain an internal research team focused on roles critical to advancing our current and future late-stage3research and early clinical prog

96、rams.We estimate that this initiative may provide annual average cost savings of approximately$40 million to$50 million associated with research and related expenses between 2023 and 2026.Business OverviewRare diseasesThe lead product candidate in our portfolio,PYRUKYND(mitapivat),is an activator of

97、 both wild-type and mutant pyruvatekinase,or PK,enzymes for the potential treatment of hemolytic anemias.In February 2022,the FDA approved PYRUKYNDfor the treatment of hemolytic anemia in adults with PK deficiency in the United States.In November 2022,we receivedmarketing authorization from the Euro

98、pean Commission for PYRUKYND for the treatment of PK deficiency in adult patientsin the European Union,or EU.In December 2022,we received marketing authorization in Great Britain for PYRUKYND forthe treatment of PK deficiency in adult patients under the European Commission Decision Reliance Procedur

99、e.In addition,weare currently evaluating PYRUKYND in clinical trials for the treatment of thalassemia,sickle cell disease,or SCD,and inpediatric patients with PK deficiency.We are also developing AG-946,a novel PK activator,for the potential treatment oflower-risk myelodysplastic syndrome,or LR MDS,

100、and hemolytic anemias.In addition to the aforementioned clinical development programs,we continue to invest in our late-stage research programfocused on advancing a phenylalanine hydroxylase,or PAH,stabilizer for the treatment of phenylketonuria,or PKU.With nearly 15 years of focused study in cellul

101、ar metabolism,we have a deep understanding of this biology,which is involvedin the healthy functioning of nearly every system in the body.Building on this expertise,these learnings can be rapidly appliedto our clinical trials with the goal of developing medicines that can have a significant impact f

102、or patients.Our Strategy and Long-term GoalsAs part of our long-term strategy,we have developed and articulated a strategic vision that delineates our expected evolution inlight of our singular focus on rare diseases.We aim to build a sustainable,value-creating company,based on our expertise incellu

103、lar metabolism and classical hematology,that develops and delivers differentiated medicines for patients.By 2026,our vision is to:establish a classical hematology franchise with PYRUKYND approvals across PK deficiency,thalassemia and SCD;expand our portfolio by advancing AG-946 and our preclinical p

104、ipeline as well as through disciplinedbusiness development aligned with our core therapeutic focus areas and capabilities;and achieve cash-flow positivity.Our Core ValuesOur companys values cultivate an environment that promotes collaboration,contribution,engagement and high regard forothers points

105、of view.This foundation helps our people push the boundaries of our science and create transformativemedicines,which we believe will provide long-term benefits for all our stakeholders.Our connections with each other andwith external parties fuel the development of new therapies for the people who n

106、eed them.Our core values include:Aim High:We set the bar high for ourselves,and we keep working to raise it.At our core,were guided by a deeprespect for the science and a commitment always to act with the utmost integrity.Come Together:We grow supportive relationships with patients and caregivers.We

107、 build trusting connections withcollaborators.Together,we make a bigger impact than we ever could alone.Embrace Differences:Because opportunities and insights come from anywhere and anyone,we honor all voices andencourage honest dialogue.We learn equally from success and failure,bringing an open min

108、d and a flexible approachto everything we do.Bring Your Whole Self:We know we make the biggest impact when each of us can contribute and lead in our own way.Blaze New Trails:We ask the tough questions that can lead to groundbreaking scientific advances.We nurture acreative mindset and resourceful ap

109、proach that spark life-changing innovations for patients.Cellular MetabolismCellular metabolism is involved in the healthy functioning of nearly every system in the body and refers to the set of life-sustaining chemical transformations within the cells of living organisms.The conversion of nutrients

110、 into energy via enzyme-catalyzed reactions allows organisms to grow and reproduce,maintain their structures,and respond to their environments.Additionally,metabolites serve as key regulators of diverse aspects of cellular biology,and pharmacologic targeting ofmetabolism can therefore have disease-m

111、odifying effects in a wide variety of pathologies.The chemical reactions ofmetabolism are organized into metabolic pathways,in which one chemical is transformed through a series of steps into anotherchemical,by a sequence of enzymes.Enzymes catalyze quick and efficient reactions,serve as key regulat

112、ors of metabolicpathways,and respond to changes in the cells environment or signals from other cells.We believe our deep understanding of4cellular metabolism can be rapidly applied to our clinical trials with the goal of developing medicines that can have a significantimpact for patients.Rare diseas

113、esDiseases are typically considered rare if they affect fewer than 200,000 people in the United States,or fewer than five per10,000 people in France,Germany,Italy,Spain,United Kingdom,or the EU5.Many rare diseases are likely to be under-diagnosed given the lack of available therapies or diagnostics,

114、the rarity of the condition,or limited understanding of how thedisease genetics relate to the disease phenotype.It has been shown that small molecule therapies able to specifically correctgenetic deficiencies and their associated organ dysfunction may have application in conditions that arise indepe

115、ndent of patientgenetics but for which identical organ dysfunction occurs.For example,a treatment for a hereditary hemolytic anemia may finddirect application in the treatment of a secondarily acquired hemolytic anemia.Many rare diseases carry severe or life-threatening features.In many of these dis

116、orders,the defect of single or multiple genesleads to a deficient expression or function in one or several gene products which collectively manifest in organ dysfunction.Asthese conditions are by nature congenital and frequently hereditary,they are often detected either by genetic testing orphenotyp

117、ic diagnosis in newborns or in early childhood.A typical course of many such diseases is inexorable deterioration untildeath or significant irreversible life-long disability and/or suffering.Current treatment options for these disorders are generally limited.Severe and sustained diet modification or

118、 nutrientsupplementation can be beneficial in certain rare diseases.Several of these disorders,from a group known as lysosomal storagediseases,have been treated successfully with enzyme replacement therapy,or ERT,the therapeutic administration of afunctional version of the defective enzyme.Examples

119、of ERTs for lysosomal storage disorders include Fabrazyme for Fabrydisease,Myozome for Pompe disease,Cerezyme for Gaucher disease,and Elaprase for Hunter syndrome.In addition,treatment of polygenic conditions such as achondroplasia by Vosoritide and the monogenic condition,spinal muscularatrophy by

120、gene therapy with Zolgensma and Spinraza represent novel technologic approaches to addressing rare diseases.Most mutations driving rare diseases are intracellular and not amenable to corrective treatment with enzyme replacementtherapies.Novel technologic approaches such as gene therapy are also bein

121、g tested in a minority of conditions and aretechnologies with limited application based on cost,complexity and patient selection factors.Despite the promising progressmade for patients with a small group of rare diseases,the majority of patients with these diseases have few therapeutic options,and t

122、he standard of care for many such conditions is palliative,meaning treatment of symptoms with no effect on underlyingdisease mechanisms.Our goal is to develop mechanistically specific,small molecule approaches with the potential to havedisease modifying and long-term rather than palliative effects.W

123、e are taking a novel small molecule approach to correct thedefects within diseased cells with a goal of developing transformative medicines for patients.Classical hematologyClassical hematology refers to the study and treatment of blood disorders that are not cancerous,including thrombotic andhemorr

124、hagic disorders,anemia,thrombocytopenia,disorders of iron metabolism and hemoglobin disorders.Many of thesediseases are debilitating,have a negative impact on patients quality of life and are associated with severe complications and/orshortened life expectancy.Despite the significant need for novel

125、therapies and improved patient care,there is a shortage ofresearch and trained specialists in the field of classical hematology,and patients with these disorders are often underserved andexperience health disparities and inequity.In addition,even in diseases in which some progress has been made,larg

126、e subsets ofthe disease may remain underserved.Our goal is to develop transformative oral treatments for patients with various classicalhematological disorders through broad clinical development programs in order to address the unmet needs of a large range ofpatients.Our Development ProgramsWe belie

127、ve that leveraging our core capabilities in cellular metabolism combined with our singular focus on rare diseases andour differentiated expertise in classical hematology has significantly enhanced our ability to advance new therapeutic candidatesand bring innovative medicines to patients in need.We

128、have a proven track record of developing new therapeutic approachesand multiple proprietary first-in-class orally available small molecules.5The following summarizes our approved product and most advanced clinical product candidates,each of which is described infurther detail below.PK Activator Prog

129、ramPK is the enzyme involved in the second to last reaction in glycolysis the conversion of glucose into lactic acid.This enzymehas several tissue-specific isoforms(PKR,PKL,PKM1 and PKM2).Pyruvate kinase-R,or PKR,is the isoform of PK that ispresent in red blood cells,or RBCs.Mutations in PKR cause d

130、efects in RBC glycolysis and lead to a hematological rare diseaseknown as PK deficiency.Glycolysis is the only pathway available for RBCs to maintain the production of adenosinetriphosphate,or ATP,which is a form of chemical energy within cells.Accordingly,we believe that activation of mutant formso

131、f PKR can restore glycolytic pathway activity and increase RBC health in patients with PK deficiency,and activation of wild-type(non-mutated)PKR can increase ATP which can then meet the increased demands resulting from metabolic stress in RBCsof patients with hemolytic anemias such as thalassemia an

132、d SCD.6PK DeficiencyPK deficiency is a rare genetic disorder and disease understanding is still evolving.We estimate that the prevalence of PKdeficiency is between approximately 3,000 and 8,000 individuals in the United States and EU5 and we believe that the diseaseis likely under-diagnosed.PK defic

133、iency leads to a shortened life span for RBCs and is the most common form of non-spherocytic hemolytic anemia in humans.There is currently no known unique ethnic or geographic representation of the disease.The disease manifests by mild to severeforms of anemia caused by the excessive premature destr

134、uction of RBCs.The chronic hemolysis can lead to long-termcomplications and comorbidities,regardless of the degree of the anemia,often resulting in jaundice and lifelong conditionsassociated with chronic anemia and secondary complications.The precise mechanism for the hemolysis is not well understoo

135、dbut is thought to result from membrane instability secondary to the metabolic defect caused by the low level of PKR enzyme.The hemolysis is“extra-vascular”in that the RBCs are destroyed in small capillaries or organs and do not spontaneously breakopen in the circulation.PK deficiency is an autosoma

136、l recessive disease whereby all patients inherit two mutations,one fromeach parent.Children with the disease produce PKR enzyme that has only a fraction of the normal level of activity(generally50%).Current management strategies for PK deficiency,including blood transfusion and splenectomy,are assoc

137、iated withboth short-and long-term risks.More than 350 different mutations have been identified to date.As a result,there are manydifferent possible mutant combinations and no one clear mutational profile.The mutations observed in PK deficiency patientsare classified in two main categories.A missens

138、e mutation causes a single amino acid change in the protein,generally resultingin some functional protein in the RBCs.A non-missense mutation is any mutation other than a missense mutation,generallyresulting in little functional protein in the RBCs.It is estimated that 58 percent of patients with PK

139、 deficiency have twomissense mutations,27 percent have one missense and one non-missense mutation,and 15 percent have two non-missensemutations.Boston Childrens Hospital,in collaboration with us,is conducting a Natural History Study to better understand thesymptoms and complications of PK deficiency

140、,identify patients and treatment centers,and capture other clinical data,includinggenetic information.We initiated a global registry,called Peak,for up to 500 adult and pediatric patients with PK deficiency inthe first quarter of 2018 to increase understanding of the long-term disease burden of this

141、 chronic hemolytic anemia.ThalassemiaThalassemia is a hereditary blood disorder in which mutations in the-or-globin chains of hemoglobin lead to globin chainprecipitates and aggregates that disturb the RBC membrane and induce oxidative stress,leading to decreased survival of RBCprecursors,ineffectiv

142、e erythropoiesis,hemolysis of mature RBCs,and anemia.We estimate that the prevalence of thalassemiais between 18,000 and 23,000 individuals in the United States and EU5.In addition to anemia,patients with thalassemia canexperience enlarged spleen,bone deformities,iron overload,fatigue,and infection.

143、Current treatment strategies for thalassemiainclude blood transfusion and bone marrow transplantation,as well as newer therapies such as Reblozyl for the treatment of-thalassemia.We believe that the activation of wild-type PKR may increase ATP production and improve red cell fitness andsurvival of t

144、halassemic RBCs,by increasing the clearance globin chain aggregates through ATP-dependent proteolyticmechanisms.Sickle Cell DiseaseSCD is an inherited blood disorder caused by mutations in hemoglobin that enable the hemoglobin to form long polymericchains under certain conditions such as low oxygena

145、tion,or deoxygenation.Polymerization of this irregular hemoglobin resultsin RBCs taking on a sickle shape,causing them to aggregate and obstruct small blood vessels,restricting blood flow to organsresulting in pain,cell death and organ damage.We estimate that the prevalence of SCD is between 120,000

146、 and 135,000individuals in the United States and EU5.RBC deoxygenation is modulated by several factors,including the levels of 2,3-diphosphoglycerate,or 2,3-DPG,which is found to be elevated in sickle cell patient RBCs.Current treatment strategies focuson managing and preventing acute RBC sickling,a

147、nd include hydroxyurea,L-glutamine and blood transfusions,as well asrecently approved therapies such as Adakveo and Oxbryta.We believe that activation of wild-type PKR in patients withSCD may reduce hemoglobin polymerization and the sickling process by at least two mechanisms.Reducing the level of 2

148、,3-DPG in RBCs would increase the oxygenation state of hemoglobin to reduce sickling,while increasing the levels of ATP mayimprove RBC hydration status which may also inhibit the sickling process.Lower Risk MDSMDS is a heterogeneous group of rare hematological malignancies characterized by dysfuncti

149、onal hematopoiesis(or formationof blood cells),progressive cytopenia(or lower-than-normal number of blood cells)and an increased risk of progression toacute myeloid leukemia.The most common type of MDS is lower risk,or LR,MDS,but many existing therapies and therapiesunder development focus on high r

150、isk MDS.Among patients with LR MDS,which is less likely to progress to acute myeloidleukemia,the primary concern is symptomatic anemia.We estimate that the prevalence of LR MDS in the United States andEU5 is between 75,000 and 80,000 individuals.We believe that activation of wild-type PK in LR MDS p

151、atients may improvedeficient PK activity in MDS erythrocytes.Current treatment options for LR MDS often require in-office visits andtransfusions,and erythropoiesis stimulating agents and Reblozyl(luspatercept-aamt)are the only approved therapies to treat7anemia in a subset of patients.Despite approv

152、ed therapies in subsets of patients,LR MDS associated anemia remains a diseasewith a high unmet medical need.PhenylketonuriaPhenylketonuria,or PKU,is a rare,genetic disease caused by deficiency of the PAH enzyme.Lack of PAH activity leads to theaccumulation of phenylalanine and downstream neurocogni

153、tive deficits.Patients with PKU are therefore often advised toconsume a highly restricted diet to in order to minimize phenylalanine intake,which can further reduce patient quality of life.We estimate that the prevalence of PKU in the United States and EU5 is between 35,000 and 40,000 individuals.To

154、 directlyaddress the underlying cause of PKU,we are developing a PAH stabilizer with a goal of reducing phenylalanine levels.PYRUKYND(mitapivat):First-in-Class PK ActivatorWe are developing PYRUKYND for the treatment of PK deficiency and other hemolytic anemias such as thalassemia andSCD.PYRUKYND is

155、 an orally available small molecule and a potent activator of the wild-type and mutated PK enzymes.In February 2022,the FDA approved PYRUKYND for the treatment of hemolytic anemia in adults with PK deficiency in theUnited States.In November 2022,we received marketing authorization from the European

156、Commission for PYRUKYND forthe treatment of PK deficiency in adult patients in the EU.In December 2022,we received marketing authorization in GreatBritain for PYRUKYND for the treatment of PK deficiency in adult patients under the European Commission DecisionReliance Procedure.In addition,we are cur

157、rently evaluating PYRUKYND in clinical trials for the treatment of thalassemia,SCD,and in pediatric patients with PK deficiency.We have worldwide development and commercial rights to PYRUKYNDand expect to fund the future development and commercialization costs related to this program.PYRUKYND has be

158、engranted orphan drug designation for the treatment of PK deficiency by the FDA and the European Medicines Agency,or EMA.Additionally,PYRUKYND has received orphan drug designation from the FDA for the treatment of thalassemia and SCD.We have built our commercial infrastructure to support the commerc

159、ial launch of PYRUKYND in adult PK deficiency in theUnited States.We are currently providing access to PYRUKYND free of charge for eligible patients in the EU and GreatBritain through a global managed access program.Beyond the global managed access program,we continue to evaluate optionsfor the comm

160、ercialization of PYRUKYND outside of the United States,including through exploring potential partnershipopportunities.We are evaluating PYRUKYND in the following clinical trials:ENERGIZE,a phase 3,double-blind,randomized,placebo-controlled multicenter study evaluating the efficacy andsafety of PYRUK

161、YND as a potential treatment for adults with non-transfusion-dependent-or-thalassemia,definedas 5 RBC units during the 24-week period before randomization and no RBC transfusions 8 weeks before providinginformed consent or during the screening period.The primary endpoint of the trial is percentage o

162、f patients withhemoglobin response,defined as a 1.0 g/dL increase in average hemoglobin concentration from Week 12 through Week24 compared with baseline.Secondary endpoints include markers of hemolysis and ineffective erythropoiesis,as well aspatient-reported outcome measures.This trial is enrolling

163、 patients,and we expect to complete enrollment by mid-year2023.ENERGIZE-T,a phase 3,double-blind,randomized,placebo-controlled multicenter study evaluating the efficacy andsafety of PYRUKYND as a potential treatment for adults with transfusion-dependent-or-thalassemia,defined as 6to 20 RBC units tra

164、nsfused and 6-week transfusion-free period during the 24-week period before randomization.Theprimary endpoint of the trial is percentage of patients with transfusion reduction response,defined as a 50%reductionin transfused RBC units with a reduction of 2 units of transfused RBCs in any consecutive

165、12-week period throughWeek 48 compared with baseline.Secondary endpoints include additional transfusion reduction measures and percentageof participants with transfusion-independence.This trial is enrolling patients,and we expect to complete enrollment bymid-year 2023.RISE UP,a phase 2/3 study evalu

166、ating the efficacy and safety of PYRUKYND in SCD patients who are 16 years ofage or older,have had between two and 10 sickle cell pain crises in the past 12 months,and have hemoglobin within therange of 5.5 to 10.5 g/dL during screening.The phase 2 portion of the trial includes a 12-week randomized,

167、placebo-controlled period in which participants will be randomized in a 1:1:1 ratio to receive 50 mg PYRUKYND twice daily,100 mg PYRUKYND twice daily or matched placebo.The primary endpoints are hemoglobin response,defined as 1g/dL increase in average hemoglobin concentration from Week 10 through We

168、ek 12 compared to baseline,and safety.These data will be used to establish a clear dosing paradigm for the phase 3 portion.The phase 3 portion includes a 52-week randomized,placebo-controlled period in which participants will be randomized in a 2:1 ratio to receive therecommended PYRUKYND dose level

169、 or placebo.The primary endpoints are hemoglobin response,defined as 1 g/dL increase in average hemoglobin from baseline to Week 52,and annualized rate of sickle cell pain crises.Participantswho complete either the phase 2 or phase 3 portion will have the option to move into a 216-week open-label ex

170、tensionperiod to continue to receive PYRUKYND.The phase 2 portion of this trial has been fully enrolled,and we expect to8announce the data from the phase 2 portion of this trial and decide whether we are initiating the phase 3 portion of thistrial by mid-year 2023.ACTIVATE-kids and ACTIVATE-kidsT,do

171、uble-blind phase 3 studies evaluating the efficacy and safety ofPYRUKYND as a potential treatment for PK deficiency in not regularly transfused and regularly transfused patientsbetween one and 18 years old,respectively.The primary endpoint of ACTIVATE-kids is percentage of patients withhemoglobin re

172、sponse,defined as 1.5 g/dL increase in hemoglobin concentration from baseline that is sustained at twoor more scheduled assessments at weeks 12,16,and 20 during the double-blind period.The primary endpoint ofACTIVATE-kidsT is transfusion reduction response,defined as 33%reduction in total RBC transf

173、usion volume fromweek 9 through week 32 of the double-blind period.Both trials are enrolling patients,and we expect to enroll at leasthalf of the patients by year-end 2023.An extension study evaluating the long-term safety,tolerability and efficacy of treatment with PYRUKYND in patientsfrom ACTIVATE

174、 and ACTIVATE-T,our completed pivotal trials of PYRUKYND in not regularly transfused andregularly transfused adult patients with PK deficiency.An extension study evaluating the long-term safety,tolerability and efficacy of treatment with PYRUKYND in patientsfrom DRIVE PK,our completed global phase 2

175、,first-in-patient,open-label safety and efficacy clinical trial ofPYRUKYND in adult,not regularly transfused patients with PK deficiency.An extension study evaluating the safety,tolerability and efficacy of treatment with PYRUKYND in patients from ourcompleted phase 2,open-label safety and efficacy

176、clinical trial of PYRUKYND in adults with non-transfusion-dependent-and-thalassemia.In collaboration with the Company,the National Institutes of Health,or NIH,is evaluating PYRUKYND in a phase 1trial in patients with SCD pursuant to a cooperative research and development agreement.The core trial per

177、iod hascompleted,and the long-term extension study is ongoing.In June 2020,clinical proof of concept was established basedon a preliminary analysis of the data from this trial.In collaboration with the Company,UMC Utrecht,or UMC,is evaluating PYRUKYND in patients with SCD pursuantto an investigator

178、sponsored trial agreement.The trial has completed enrollment and patient follow-up is ongoing,and a2-year extension study has been activated for patients who complete the follow-up period.AG-946 and Other ProgramsWe are developing AG-946,a novel PK activator,for the potential treatment of LR MDS and

179、 hemolytic anemias.We areevaluating AG-946,in a phase 1 trial of AG-946 in healthy volunteers and in patients with SCD.We have presented data fromthe healthy volunteer cohort,and we have initiated the SCD patient cohort of this trial.We are evaluating AG-946 in a phase 2astudy in adults with LR MDS,

180、and we expect to complete enrollment by year-end 2023.In addition to the aforementioned development programs,we are advancing our late-stage research program focused on a PAHstabilizer for the treatment of PKU,for which we expect to file an investigational new drug application by year-end 2023.Intel

181、lectual PropertyOur commercial success depends in part on our ability to obtain and maintain proprietary or intellectual property protection forour product candidates and our core technologies,including novel biomarker and diagnostic discoveries,and other know-how,to operate without infringing on th

182、e proprietary rights of others and to prevent others from infringing on our proprietary orintellectual property rights.Our policy is to seek to protect our proprietary and intellectual property position by,among othermethods,filing U.S.and foreign patent applications related to our proprietary techn

183、ology,inventions and improvements that areimportant to the development and implementation of our business.We also rely on confidential information,know-how andcontinuing technological innovation to develop and maintain our proprietary and intellectual property position.We may alsochoose to rely on t

184、rade secrets to protect certain aspects of our business that are not suitable or appropriate for patent protection.We file,or may collaborate with third parties to file,patent applications directed to our key products and product candidates,including PYRUKYND and AG-946,in addition to related compou

185、nds and potential back-up compounds,in an effort toestablish intellectual property positions to protect these new chemical entities as well as methods of using these compounds inthe treatment of diseases,formulations,solid state forms,and manufacturing processes.We may also seek patent protection fo

186、rcertain biomarkers that may be useful in identifying the appropriate patient population for therapies with our productcandidates.PK activator programThe patent portfolio for our PK activator program contains issued patents and pending patent applications directed tocompositions of matter for PYRUKY

187、ND,as well as to related compounds,various solid state forms of PYRUKYND,compositions of matter for additional PKR activators,such as AG-946,as well as methods of use for these novel compounds.As of February 1,2023,we owned 11 issued U.S.patents and 190 issued foreign patents,and have pending patent

188、 applications9in the US and in various foreign jurisdictions.The patents that have issued or will issue for our PK activator program will havea statutory expiration date of at least 2030 to 2042.Patent term adjustments or patent term extensions could result in laterexpiration dates.In some cases,the

189、 term of a US patent can be shortened by the filing of a terminal disclaimer which operatesto reduce the term of a patent to that of an earlier expiring patent.The foreign issued patents and pending patent applications arein a number of jurisdictions,including Argentina,Australia,Austria,Belgium,Bra

190、zil,Canada,China,the Czech Republic,Denmark,Finland,France,Germany,Greece,Hungary,Ireland,Italy,Japan,Lebanon,Lithuania,Mexico,the Netherlands,Norway,Poland,Portugal,Romania,Russia,Saudi Arabia,Slovakia,Slovenia,Spain,Sweden,Switzerland,Taiwan,Turkey,and the United Kingdom.Prosecution is a lengthy p

191、rocess,during which the scope of the claims initially submitted forexamination by the U.S.Patent and Trademark Office,or USPTO,can be significantly narrowed by the time they issue,if theyissue at all.We expect this could be the case with respect to some of our pending patent applications referred to

192、 above.Patent TermThe term of individual patents depends upon the legal term for patents in the countries in which they are obtained.In mostcountries,including the United States,the patent term is 20 years from the earliest filing date of a non-provisional patentapplication,although term extensions

193、may be available.In the United States,a patents term may be lengthened by patent termadjustment,which compensates a patentee for administrative delays by the USPTO in examining and granting a patent,or maybe shortened if a patent is terminally disclaimed over an earlier filed patent.The term of a pa

194、tent that covers a drug or biologicalproduct may also be eligible for patent term extension when FDA approval is granted,provided statutory and regulatoryrequirements are met.The extension of the term of foreign patents varies,in accordance with local law.Although certain of thepatents granted by th

195、e regulatory authorities of the EU may expire at specific dates,the terms of patents granted in certainEuropean countries may extend beyond such EU patent expiration date if we were to obtain a supplementary protectioncertificate.In addition,because of the extensive time required for clinical develo

196、pment and regulatory review of a productcandidate we may develop,it is possible that,before any of our product candidates can be commercialized,any related patentmay expire or remain in force for only a short period following commercialization,thereby reducing any advantage of any suchpatent.In the

197、future,if and when our product candidates receive approval by the FDA or foreign regulatory authorities,we expect toapply for patent term extensions on issued patents covering those products,depending upon the length of the clinical trials foreach medicine and other factors.There can be no assurance

198、 that any of our pending patent applications will issue or that we willbenefit from any patent term extension or favorable adjustment to the term of any of our patents.Additional ConsiderationsAs with other biotechnology and pharmaceutical companies,our ability to maintain and solidify our proprieta

199、ry and intellectualproperty position for our product,product candidates and technologies will depend on our success in obtaining effective patentclaims and enforcing those claims if granted.However,patent applications that we may file or license from third parties maynot result in the issuance of pa

200、tents.We also cannot predict the breadth of claims that may be allowed or enforced in ourpatents.Any issued patents that we may receive in the future may be challenged,invalidated or circumvented.For example,athird party can challenge the patentability of one or more of the claims of an issued paten

201、t in a post-grant proceeding before theUSPTO or a foreign patent office such as the European Patent Office,which can result in the loss of certain claims or the lossof an entire patent.In addition,it is possible that a third party has filed a patent application in the United States,or abroad,thatcla

202、ims the same technology or chemical structures that are claimed in our own patent applications or patents.In such cases,wemay have to participate in legal proceedings or enter into a licensing arrangement,which could result in substantial costs to us,even if the eventual outcome is favorable to us.I

203、n addition to patent protection,we also rely upon unpatented confidentialinformation,including confidential technical information,know-how and continuing technological innovation to develop andmaintain our competitive position.We seek to protect our proprietary information,in part,by using confident

204、iality agreementswith our collaborators,third-party service providers,scientific advisors,employees and consultants,and by inventionassignment agreements with our employees.We also have agreements requiring assignment of inventions with selectedconsultants,scientific advisors and collaborators.The c

205、onfidentiality agreements are designed to protect our proprietaryinformation and,in the case of agreements or clauses requiring invention assignment,to grant us ownership of technologies thatare developed through a relationship with a third party.With respect to our proprietary cellular metabolism t

206、echnology platform,we consider confidential information and know-howrelated to our cellular metabolism technology platform to be our primary intellectual property in this space.Confidentialinformation and know-how can be difficult to protect.In particular,we anticipate that with respect to this tech

207、nology platform,at least some of the technical information and know-how will,over time,become known within the industry throughindependent development,the publication of journal articles describing the methodology,and the movement of personnelskilled in the art from academic to industry scientific p

208、ositions.10CompetitionThe pharmaceutical and biotechnology industries are characterized by rapidly advancing technologies,intense competition anda strong emphasis on proprietary products.While we believe that our technology,development experience and scientificknowledge provide us with competitive a

209、dvantages,we face potential competition from many different sources,includingmajor pharmaceutical,specialty pharmaceutical and biotechnology companies,academic institutions and governmentalagencies,and public and private research institutions.PYRUKYND and any product candidates that we successfully

210、developand commercialize will compete with existing therapies and new therapies that may become available in the future.We compete in the areas of pharmaceutical,biotechnology and other related markets that address rare diseases,particularlyhemolytic anemias and PKU.There are other companies working

211、 to develop therapies in the field of rare diseases,includingdivisions of large pharmaceutical companies and biotechnology companies of various sizes.Our competitors include:Bristol-Myers Squibb Company,or BMS;BioMarin Pharmaceutical,Inc.,or BioMarin;bluebird bio,Inc.,or bluebird;Merck&Co.,Inc.,or M

212、erck;Novartis International AG,or Novartis;Novo Nordisk A/S,or Novo;Pfizer,Inc.,or Pfizer;Rocket Pharma LTD,or Rocket Pharma;Vertex Pharmaceuticals Incorporated,or Vertex,Emmaus LifeSciences,or Emmaus,Fibrogen,Inc.,or Fibrogen,Fulcrum Therapeutics,Inc.,or Fulcrum,and Geron Corporation,or Geron.The m

213、ost common methods for treating patients with rare diseases include dietary restriction,dietary supplementation orreplacement,treatment of symptoms and complications,gene therapy,blood transfusions,stem cell transplant and enzymereplacement therapies.There are a number of marketed therapies availabl

214、e for treating patients with hemolytic anemias andPKU.For example,recently approved treatments for thalassemia,SCD,LR MDS and PKU include Reblozyl from Merck/BMS(formerly Acceleron/BMS);Revlimid from BMS;Lentiglobin from bluebird;Adakveo from Novartis;Oxbrytafrom Pfizer;Kuvan and Palynziq from BioMa

215、rin and Endari from Emmaus.While our product and product candidatesmay compete with existing medicines and other therapies,to the extent they are ultimately used in combination with or as anadjunct to these therapies,our product or product candidates may not be competitive with them.In addition to c

216、urrentlymarketed therapies,there are also a number of products that are either small molecules,biologics,enzyme replacementtherapies or gene therapies in various stages of clinical development to treat hemolytic anemias and PKU.For example,RocketPharma is conducting a clinical trial of a gene therap

217、y targeting PK deficiency,Novo is developing etavopivat(a PKRactivator)for the treatment of hemolytic anemias,including thalassemia,SCD and MDS,Pfizer is developing inclacumab andGBT-601 for the treatment of SCD,Fibrogen is developing roxadustat for the treatment of anemia in MDS patients,Geron isde

218、veloping imetelstat for the treatment of LR MDS,Vertex is developing a gene therapy targeting SCD,and Fulcrum isdeveloping FTX-6058 in SCD,and a number of companies,including PTC Therapeutics,Inc.,or PTC,Synlogic,Inc.,orSynlogic,and Jnana Therapeutics,Inc.,or Jnana,are developing therapies to treat

219、PKU.These products in development mayprovide efficacy,safety,convenience and other benefits that are not provided by currently marketed therapies.As a result,theymay provide competition for any of our product or product candidates for which we obtain market approval.Many of our competitors may have

220、significantly greater financial resources and expertise in research and development,manufacturing,preclinical testing,conducting clinical trials,obtaining regulatory approvals and globally marketing approvedmedicines than we do.Mergers and acquisitions in the pharmaceutical,biotechnology and diagnos

221、tic industries may result ineven more resources being concentrated among a smaller number of our competitors.These competitors also compete with usin recruiting and retaining qualified scientific and management personnel,and establishing clinical trial sites and patientregistration for clinical tria

222、ls,as well as in acquiring or in-licensing technologies complementary to,or necessary for,ourprograms.Smaller or early stage companies may also prove to be significant competitors,particularly through collaborativearrangements with large and established companies.The key competitive factors affectin

223、g the success of PYRUKYND and any of our product candidates that we develop,ifapproved,are likely to be their efficacy,safety,convenience,price,the effectiveness of companion diagnostics in guiding theuse of related therapeutics where appropriate,the level of generic competition and the availability

224、 of reimbursement fromgovernment and other third-party payors.Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize medicines that aresafer,more effective,have fewer or less severe side effects,are more convenient or are less expensive than any medici

225、nes thatwe may develop.Our competitors also may obtain FDA or other regulatory approval for their medicines more rapidly than wemay obtain approval for ours,which could result in our competitors establishing a strong market position before we are able toenter the market.In addition,our ability to co

226、mpete may be affected in many cases by insurers or other third-party payorsseeking to encourage the use of generic or other branded medicines.There are many generic medicines currently on the marketfor the indications that we are pursuing,and additional medicines are expected to become available on

227、a generic basis over thecoming years.We expect that PYRUKYND and any of our product candidates that may receive marketing approval in thefuture will be priced at a significant premium over competitive generic medicines.11Manufacturing and Supply ChainPYRUKYND,AG-946,and PAH are organic compounds of

228、low molecular weight,generally called small molecules.Theycan be manufactured in reliable and reproducible synthetic processes from readily available starting materials.The chemistry isamenable to scale-up and does not require unusual equipment in the manufacturing process.We expect to continue to d

229、evelopdrug candidates that can be produced cost-effectively at contract manufacturing facilities.We do not own or operate,and currently have no plans to establish,any manufacturing or supply chain related facilities.Wecurrently,and expect to continue to,rely on third parties for the manufacture and

230、supply of our clinical and preclinical productcandidates,as well as for commercial manufacture of PYRUKYND and any product for which we may receive marketingapproval in the future.We conduct extensive prequalification programs to ensure the compliance,quality and reliability ofthird-party manufactur

231、ing and supply operations.To date,we have obtained materials for PYRUKYND and AG-946 for our ongoing and planned clinical testing from third-party manufacturers.We have long-term commercial manufacture and supply agreements in place for PYRUKYND,and weobtain our supplies from these manufacturers on

232、a purchase order basis.Due to the volatility of the supply networks globally,we have gained regulatory approval for redundant supply of raw materialsand active pharmaceutical ingredient,or API,for PYRUKYND,and have an ongoing program to ensure this risk mitigationremains effective,including establis

233、hing safety stocks.We do not currently have arrangements in place for redundant supply fordrug product,but maintain a broad safety stock program.As we have done for PYRUKYND,we intend to identify andqualify additional manufacturing and supply related services for our other product candidates prior t

234、o submission of an NDA tothe FDA.Government Regulation and Product ApprovalsGovernment authorities in the United States,at the federal,state and local level,and in other countries and jurisdictions,including the EU,extensively regulate,among other things,the research,development,testing,manufacture,

235、pricing,qualitycontrol,approval,packaging,storage,recordkeeping,labeling,advertising,promotion,distribution,marketing,post-approvalmonitoring and reporting,and import and export of biopharmaceutical products.The processes for obtaining marketingapprovals in the United States and in foreign countries

236、 and jurisdictions,along with compliance with applicable statutes andregulations and other regulatory authorities,require the expenditure of substantial time and financial resources.Approval and Regulation of Drugs in the United StatesIn the United States,drug products are regulated under the Federa

237、l Food,Drug and Cosmetic Act,or FDCA,and applicableimplementing regulations and guidance.A company,institution,or organization which takes responsibility for the initiation andmanagement of a clinical development program for such products,and for their regulatory approval,is typically referred to as

238、 asponsor.A sponsor seeking approval to market and distribute a new drug in the United States generally must satisfactorily complete eachof the following steps before the product candidate will be approved by the FDA:preclinical testing including laboratory tests,animal studies and formulation studi

239、es which must be performed inaccordance with the FDAs good laboratory practice,or GLP,regulations and standards;design of a clinical protocol and submission to the FDA of an IND for human clinical testing,which must becomeeffective before human clinical trials may begin;approval by an independent in

240、stitutional review board,or IRB,representing each clinical site before each clinical trialmay be initiated;performance of adequate and well-controlled human clinical trials to establish the safety and efficacy of the productcandidate for each proposed indication,in accordance with current good clini

241、cal practices,or GCP;preparation and submission to the FDA of a NDA for a drug product which includes not only the results of the clinicaltrials,but also,detailed information on the chemistry,manufacture and quality controls for the product candidate andproposed labeling for one or more proposed ind

242、ication(s);review of the product candidate by an FDA advisory committee,where appropriate or if applicable;satisfactory completion of FDA inspection of the manufacturing facility or facilities,including those of third parties,atwhich the product candidate or components thereof are manufactured to as

243、sess compliance with current goodmanufacturing practices,or cGMP,requirements and to assure that the facilities,methods and controls are adequate topreserve the products identity,strength,quality and purity;satisfactory completion of any FDA audits of the non-clinical and clinical trial sites to ass

244、ure compliance with GCP andthe integrity of clinical data in support of the NDA;12payment of user fees and securing FDA approval of the NDA to allow marketing of the new drug product;andcompliance with any post-approval requirements,including the potential requirement to implement risk evaluation an

245、dmitigation strategies,or REMS,and the potential requirement to conduct any post-approval studies required by the FDA.Preclinical StudiesBefore a sponsor begins testing a product candidate with potential therapeutic value in humans,the product candidate enters thepreclinical testing stage.Preclinica

246、l tests include laboratory evaluations of product chemistry,formulation and stability,as wellas other studies to evaluate,among other things,the toxicity of the product candidate.The conduct of the preclinical tests andformulation of the compounds for testing must comply with federal regulations and

247、 requirements,including GLP regulationsand standards,and the United States Department of Agricultures Animal Welfare Act,if applicable.The results of thepreclinical tests,together with manufacturing information and analytical data,are submitted to the FDA as part of an IND andare typically referred

248、to as IND-enabling studies.Some long-term preclinical testing,such as animal tests of reproductiveadverse events and carcinogenicity,and long-term toxicity studies,may continue after the IND is submitted.The IND and IRB ProcessesAn IND is an exemption from the FDCA that allows an unapproved product

249、candidate to be shipped in interstate commerce foruse in an investigational clinical trial and a request for FDA authorization to administer such investigational product to humans.Such authorization must be secured prior to interstate shipment and administration of any product candidate that is not

250、thesubject of an approved NDA.In support of a request for an IND,sponsors must submit a protocol for each clinical trial and anysubsequent protocol amendments must be submitted to the FDA as part of the IND.The FDA requires a 30-day waiting periodafter the filing of each IND before clinical trials m

251、ay begin.This waiting period is designed to allow the FDA to review theIND to determine whether human research subjects will be exposed to unreasonable health risks.At any time during this 30-dayperiod,or thereafter,the FDA may raise concerns or questions about the conduct of the trials as outlined

252、in the IND and imposea clinical or partial clinical hold.In this case,the IND sponsor and the FDA must resolve any outstanding concerns beforeclinical trials can begin.Following commencement of a clinical trial under an IND,the FDA may also place a clinical or partial clinical hold on thattrial.A cl

253、inical hold is an order issued by the FDA to the sponsor to delay a proposed clinical investigation or to suspend anongoing investigation.A partial clinical hold is a delay or suspension of only part of the clinical work requested under the IND.For example,a specific protocol or part of a protocol i

254、s not allowed to proceed,while other protocols may do so.No more than30 days after imposition of a clinical hold or partial clinical hold,the FDA will provide the sponsor a written explanation of thebasis for the hold.Following issuance of a clinical or partial clinical hold,an investigation may onl

255、y resume after the FDA hasnotified the sponsor that the investigation may proceed.The FDA will base that determination on information provided by thesponsor correcting the deficiencies previously cited or otherwise satisfying the FDA that the investigation can proceed.A sponsor may choose,but is not

256、 required,to conduct a foreign clinical study under an IND.When a foreign clinical study isconducted under an IND,all FDA IND requirements must be met unless waived.When a foreign clinical study is not conductedunder an IND,the sponsor must ensure that the study complies with certain regulatory requ

257、irements,including GCPrequirements,of the FDA in order to use the study as support for an IND or application for marketing approval.The GCPrequirements encompass both ethical and data integrity standards for clinical studies.The FDAs regulations are intended tohelp ensure the protection of human sub

258、jects enrolled in non-IND foreign clinical studies,as well as the quality and integrity ofthe resulting data.They further help ensure that non-IND foreign studies are conducted in a manner comparable to that requiredfor IND studies.In addition to the foregoing IND requirements,an IRB representing ea

259、ch institution participating in the clinical trial mustreview and approve the plan for any clinical trial before it commences at that institution,and the IRB must conduct continuingreview and reapprove the study at least annually.The IRB must review and approve,among other things,the study protocol

260、andinformed consent information to be provided to study subjects.An IRB must operate in compliance with FDA regulations.AnIRB can suspend or terminate approval of a clinical trial at its institution,or an institution it represents,if the clinical trial is notbeing conducted in accordance with the IR

261、Bs requirements or if the product candidate has been associated with unexpectedserious harm to patients.Additionally,some trials are overseen by an independent group of qualified experts organized by the trial sponsor,known as adata safety monitoring board or committee.This group provides authorizat

262、ion as to whether or not a trial may move forward atdesignated check points based on access that only the group maintains to available data from the study.Suspension ortermination of development during any phase of clinical trials can occur if it is determined that the participants or patients arebe

263、ing exposed to an unacceptable health risk.Other reasons for suspension or termination may be made based on evolvingbusiness objectives and/or competitive climate.13Reporting Clinical Trial ResultsUnder the Public Health Service Act,sponsors of certain clinical trials of certain FDA-regulated produc

264、ts,includingprescription drugs and biologics,are required to register and disclose certain clinical trial information on a public registry(clinicaltrials.gov)maintained by the NIH.Information related to the product,patient population,phase of investigation,studysites and investigators and other aspe

265、cts of the clinical trial is made public as part of the registration of the clinical trial.Withthe issuance of several notices of non-compliance since April 2021,the FDA and NIH have recently signaled the governmentswillingness to begin enforcing these requirements against non-compliant clinical tri

266、al sponsors.The failure to submit clinicaltrial information to clinicaltrials.gov is also a prohibited act under the FDCA with violations subject to potential civil monetarypenalties of up to$10,000 for each day the violation continues.Violations may also result in injunctions and/or criminalprosecu

267、tion or disqualification from federal grants.Expanded Access to an Investigational Drug for Treatment UseExpanded access,sometimes called“compassionate use,”is the use of investigational new drug products outside of clinicaltrials to treat patients with serious or immediately life-threatening diseas

268、es or conditions when there are no comparable orsatisfactory alternative treatment options.The rules and regulations related to expanded access are intended to improve accessto investigational drugs for patients who may benefit from investigational therapies.FDA regulations allow access toinvestigat

269、ional drugs under an IND by the company or the treating physician for treatment purposes on a case-by-case basis for:individual patients(single-patient IND applications for treatment in emergency settings and non-emergency settings);intermediate-size patient populations;and larger populations for us

270、e of the drug under a treatment protocol or Treatment INDApplication.While there is no obligation to make investigational products available for expanded access,sponsors are required to makepolicies for evaluating and responding to requests for expanded access publicly available upon the earlier of

271、initiation of aPhase 2 or Phase 3 clinical trial,or 15 days after the drug or biologic receives designation as a breakthrough therapy,fast trackproduct,or regenerative medicine advanced therapy.In addition,the Right to Try Act,among other things,provides a federal framework for certain patients to a

272、ccess certaininvestigational new drug products that have completed a Phase 1 clinical trial and are undergoing investigation for FDAapproval.Under certain circumstances,eligible patients can seek treatment without enrolling in clinical trials and withoutobtaining FDA permission under the FDA expande

273、d access program.There is no obligation for a drug manufacturer to make itsdrug products available to eligible patients as a result of the Right to Try Act,but the manufacturer must develop an internalpolicy and respond to patient requests according to that policy.Human Clinical Trials in Support of

274、 an NDAClinical trials involve the administration of the investigational product candidate to human subjects under the supervision of aqualified investigator in accordance with GCP requirements which include,among other things,the requirement that allresearch subjects provide their informed consent

275、in writing before their participation in any clinical trial.Clinical trials areconducted under written clinical trial protocols detailing,among other things,the objectives of the study,inclusion andexclusion criteria,the parameters to be used in monitoring safety and the effectiveness criteria to be

276、 evaluated.Human clinical trials are typically conducted in three sequential phases,but the phases may overlap or be combined.Phase 1 clinical trials are initially conducted in a limited population to test the product candidate for safety,including adverseeffects,dose tolerance,absorption,metabolism

277、,distribution,excretion and pharmacodynamics in healthy humans or in patients.During Phase 1 clinical trials,information about the investigational drug products pharmacokinetics and pharmacologicaleffects may be obtained to permit the design of well-controlled and scientifically valid Phase 2 clinic

278、al trials.Phase 2 clinical trials are generally conducted to identify possible adverse effects and safety risks,evaluate the efficacy of theproduct candidate for specific targeted indications,and determine dose tolerance and optimal dosage.Multiple Phase 2 clinicaltrials may be conducted by the spon

279、sor to obtain information prior to beginning larger and more costly Phase 3 clinical trials.Phase 2 clinical trials are well controlled,closely monitored and conducted in a limited patient population.Phase 3 clinical trials proceed if the Phase 2 clinical trials demonstrate that a dose range of the

280、product candidate is potentiallyeffective and has an acceptable safety profile.Phase 3 clinical trials are undertaken within an expanded patient population tofurther evaluate dosage,provide substantial evidence of clinical efficacy,and further test for safety in an expanded and diversepatient popula

281、tion at multiple,geographically dispersed clinical trial sites.The FDA may require more than one Phase 3 clinicaltrial to support approval of a product candidate.A well-controlled,statistically robust Phase 3 clinical trial may be designed todeliver the data that regulatory authorities will use to d

282、ecide whether or not to approve,and,if approved,how to appropriatelylabel a drug;such Phase 3 clinical trials are referred to as“pivotal.”A Phase 2 clinical trial can be a“pivotal”trial if the designprovides a well-controlled and reliable assessment of clinical benefit,particularly in an area of unm

283、et medical need.14A companys designation of the phase of a trial is not necessarily indicative that the trial will be sufficient to satisfy the FDArequirements of that phase.In some cases,the FDA may approve an NDA for a product candidate but require the sponsor to conduct additional clinicaltrials

284、to further assess the product candidates safety and effectiveness after approval.Such post-approval trials are typicallyreferred to as Phase 4 clinical trials.These trials are used to gain additional experience from the treatment of a larger number ofpatients in the intended treatment group and to f

285、urther document a clinical benefit in the case of drugs approved underaccelerated approval regulations.Failure to exhibit due diligence with regard to conducting Phase 4 clinical trials could result inwithdrawal of approval for products.Progress reports detailing the results of clinical trials must

286、be submitted at least annually to the FDA and more frequently ifserious adverse events occur.In addition,IND safety reports must be submitted to the FDA for any of the following:seriousand unexpected suspected adverse reactions;findings from other studies or animal or in vitro testing that suggest a

287、 significantrisk in humans exposed to the product;and any clinically important increase in the case of a serious suspected adverse reactionover that listed in the protocol or investigator brochure.Phase 1,Phase 2 and Phase 3 clinical trials may not be completedsuccessfully within any specified perio

288、d,or at all.The FDA will typically inspect one or more clinical sites to assurecompliance with GCP and the integrity of the clinical data submitted.Review and Approval of an NDAIn order to obtain approval to market a drug product in the United States,a marketing application must be submitted to the

289、FDAthat provides sufficient data establishing the safety and efficacy of the proposed drug product for its intended indication.Theapplication must include all relevant data available from pertinent preclinical and clinical trials,including negative orambiguous results as well as positive findings,to

290、gether with detailed information relating to the products chemistry,manufacturing,controls and proposed labeling,among other things.Data can come from company-sponsored clinical trialsintended to test the safety and effectiveness of a product use,or from a number of alternative sources,including stu

291、dies initiatedby investigators.To support marketing approval,the data submitted must be sufficient in quality and quantity to establish thesafety and efficacy of the drug product to the satisfaction of the FDA.The NDA is a vehicle through which sponsors formally propose that the FDA approve a new pr

292、oduct for marketing and sale inthe United States for one or more indications.Every new drug product candidate must be the subject of an approved NDAbefore it may be commercialized in the United States.Under federal law,the submission of most NDAs is subject to anapplication user fee,which for federa

293、l fiscal year 2023 is approximately$3.25 million.The sponsor of an approved NDA is alsosubject to an annual program fee,which for fiscal year 2023 is approximately$394,000 per product.Certain exceptions andwaivers are available for some of these fees,such as an exception from the application fee for

294、 products with orphan designationand a waiver for certain small businesses.Following submission of an NDA,the FDA conducts a preliminary review of the application generally within 60 calendar daysof its receipt and must inform the sponsor at that time or before whether the application is sufficientl

295、y complete to permitsubstantive review.The FDA may request additional information rather than accept the application for filing.In this event,theapplication must be resubmitted with the additional information.The resubmitted application is also subject to review beforethe FDA accepts it for filing.O

296、nce the submission is accepted for filing,the FDA begins an in-depth substantive review.Underthe goals and policies agreed to by the FDA under the Prescription Drug User Fee Act,or PDUFA,applications seekingapproval of New Molecular Entities,or NMEs,are meant to be reviewed within ten months from th

297、e date on which the FDAaccepts the application for filing.The review process and the PDUFA goal date may be extended by the FDA for threeadditional months to consider new information or clarification provided by the sponsor to address an outstanding deficiencyidentified by the FDA following the orig

298、inal submission.Before approving an application,the FDA typically will inspect the facility or facilities where the product is or will bemanufactured.These pre-approval inspections may cover all facilities associated with an NDA submission,includingcomponent manufacturing,finished product manufactur

299、ing and control testing laboratories.The FDA will not approve anapplication unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements andadequate to assure consistent production of the product within required specifications.Under the FDA Reauthoriz

300、ation Act of2017,the FDA must implement a protocol to expedite review of responses to inspection reports pertaining to certainapplications,including applications for products in shortage or those for which approval is dependent on remediation ofconditions identified in the inspection report.In addit

301、ion,as a condition of approval,the FDA may require a sponsor to develop a REMS.REMS use risk minimizationstrategies beyond the professional labeling to ensure that the benefits of the product outweigh the potential risks.REMS couldinclude medication guides,communication plans for health care profess

302、ionals,and elements to assure safe use,includingspecial training or certification for prescribing or dispensing,dispensing only under certain circumstances,special monitoringand the use of patent registries.To determine whether a REMS is needed,the FDA will consider the size of the population15likel

303、y to use the product,seriousness of the disease,expected benefit of the product,expected duration of treatment,seriousnessof known or potential adverse events and whether the product is an NME.The FDA may refer an application for a novel product which presents difficult questions of safety or effica

304、cy to an advisorycommittee or explain why such referral was not made.Typically,an advisory committee is a panel of independent experts,including clinicians and other scientific experts,that reviews,evaluates and provides a recommendation as to whether theapplication should be approved and under what

305、 conditions.The FDA is not bound by the recommendations of an advisorycommittee,but it considers such recommendations when making decisions.Fast Track,Breakthrough Therapy,Priority Review and Regenerative Advanced Therapy DesignationsThe FDA is authorized to designate certain products for expedited

306、review if they are intended to address an unmet medical needin the treatment of a serious or life-threatening disease or condition.These programs are referred to as Fast Track designation,Breakthrough Therapy designation,priority review designation and regenerative advanced therapy designation.Fast

307、Track Designation.The FDA may designate a product for Fast Track review if it is intended,whether alone or incombination with one or more other products,for the treatment of a serious or life-threatening disease or condition,and itdemonstrates the potential to address unmet medical needs for such a

308、disease or condition.For Fast Track products,sponsors may have greater interactions with the FDA and the FDA may initiate review of sections of a Fast Trackproducts application before the application is complete.This rolling review process may be available if the FDAdetermines,after preliminary eval

309、uation of clinical data submitted by the sponsor,that a Fast Track product may beeffective.However,the FDAs time period goal for reviewing a Fast Track application does not begin until the lastsection of the application is submitted.In addition,the Fast Track designation may be withdrawn by the FDA

310、if the FDAbelieves that the designation is no longer supported by data emerging in the clinical trial process.Breakthrough Therapy Designation.A product may be designated as a Breakthrough Therapy if it is intended,eitheralone or in combination with one or more other products,to treat a serious or l

311、ife-threatening disease or condition andpreliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapieson one or more clinically significant endpoints.The FDA may take certain actions with respect to BreakthroughTherapies,including:holding mee

312、tings with the sponsor throughout the development process;providing timely advice tothe product sponsor regarding development and approval;involving more senior staff in the review process;assigning across-disciplinary project lead for the review team;and taking other steps to design the clinical tr

313、ials in an efficientmanner.Priority Review.The FDA may designate a product for priority review if it is a product that treats a serious conditionand,if approved,would provide a significant improvement in safety or effectiveness when compared with other availabletherapies.Significant improvement may

314、be illustrated by evidence of increased effectiveness in the treatment of acondition,elimination or substantial reduction of a treatment-limiting product reaction,documented enhancement ofpatient compliance that may lead to improvement in serious outcomes,and evidence of safety and effectiveness in

315、a newsubpopulation.A priority designation is intended to direct overall attention and resources to the evaluation of suchapplications,and to shorten the FDAs goal for review of a marketing application from ten months to six months.Regenerative Advanced Therapy Designation.A product is eligible for r

316、egenerative advanced therapies designation if itis a regenerative medicine therapy that is intended to treat,modify,reverse or cure a serious or life-threatening disease orcondition,and preliminary clinical evidence indicates that the product has the potential to address unmet medical needsfor such

317、disease or condition.The benefits of a regenerative advanced therapy designation include early interactions withFDA to expedite development and review,benefits available to breakthrough therapies,potential eligibility for priorityreview and accelerated approval based on surrogate or intermediate end

318、points.Accelerated Approval PathwayDrug or biologic products studied for their safety and effectiveness in treating serious or life-threatening illnesses and thatprovide meaningful therapeutic benefit over existing treatments may receive accelerated approval.Accelerated approval meansthat a product

319、candidate may be approved on the basis of adequate and well controlled clinical trials establishing that theproduct candidate has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit,or on the basis ofan effect on a clinical endpoint other than survival or irreve

320、rsible morbidity or mortality or other clinical benefit,taking intoaccount the severity,rarity and prevalence of the condition and the availability or lack of alternative treatments.As a conditionof approval,the FDA may require that a sponsor of a drug or biologic product candidate receiving acceler

321、ated approval performadequate and well controlled post-marketing clinical trials.In addition,the FDA currently requires as a condition foraccelerated approval pre-approval of promotional materials.The FDAs Decision on an NDABased on its evaluation of the application and accompanying information,incl

322、uding the results of the inspection of themanufacturing facilities,the FDA may issue an approval letter or a complete response letter.An approval letter authorizes16commercial marketing of the product with specific prescribing information for the approved indications.A complete responseletter genera

323、lly indicates that the review cycle is complete and outlines the deficiencies in the submission and may requiresubstantial additional testing or information in order for the FDA to reconsider the application.A sponsor has one year torespond to the deficiencies identified in the complete response let

324、ter.The FDA has committed to reviewing such resubmissionsin two or six months depending on the type of information included.Even with submission of this additional information,theFDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.If the FDA approves

325、a new product,it may limit the approved indications for use of the product.The FDA may also requirecontraindications,warnings or precautions be included in the product labeling,require post-approval trials,require testing andsurveillance programs to monitor the product after commercialization,or imp

326、ose other conditions,including distribution anduse restrictions or other risk management mechanisms,including REMS,to help ensure that the benefits of the product outweighthe potential risks.The FDA may prevent or limit further marketing of a product based on the results of post-marketing trials ors

327、urveillance programs.After approval,many types of changes to the approved product,such as adding new indications,manufacturing changes and additional labeling claims,are subject to further testing requirements and FDA review andapproval.Under the Ensuring Innovation Act,signed into law in 2021,the F

328、DA must publish action packages summarizing its decisionsto approve new drugs within 30 days of approval of such drugs.Post-Approval RegulationIf regulatory approval for marketing of a product or new indication for an existing product is obtained,the sponsor will berequired to comply with all regula

329、r post-approval regulatory requirements as well as any post-approval requirements that theFDA may have imposed as part of the approval process.The sponsor will be required to report,among other things,certainadverse reactions and manufacturing problems to the FDA,provide updated safety and efficacy

330、information and comply withrequirements concerning advertising and promotional labeling requirements.Manufacturers and certain of their subcontractorsare required to register their establishments with the FDA and certain state agencies,and are subject to periodic unannouncedinspections by the FDA an

331、d certain state agencies for compliance with ongoing regulatory requirements,including cGMPregulations.Accordingly,the sponsor and its third-party manufacturers must continue to expend time,money and effort in theareas of production and quality control to maintain compliance with cGMP and other regu

332、latory requirements.A product may also be subject to official lot release,meaning that the manufacturer is required to perform certain tests on eachlot of the product before it is released for distribution.If the product is subject to official release,the manufacturer must submitsamples of each lot,

333、together with a release protocol showing a summary of the history of manufacture of the lot and the resultsof all of the manufacturers tests performed on the lot,to the FDA.The FDA may in addition perform certain confirmatory testson lots of some products before releasing the lots for distribution.Finally,the FDA will conduct laboratory research related tothe safety,purity,potency and effectivenes