1、UNITED STATES SECURITIES AND EXCHANGE COMMISSIONWashington,D.C.20549Form 10-K(Mark One)ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1934For the fiscal year ended December 31,2024 ORTRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 19
2、34Commission File Number:001-36014AGIOS PHARMACEUTICALS,INC.(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)(
3、Zip Code)Registrants telephone number,including area code:(617)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 S
4、ection 12(g)of the Act:NoneIndicate by check mark if the registrant is a well-known seasoned issuer,as defined in Rule 405 of the 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
5、mark whether the registrant(1)has filed all reports required to be filed by Section 13 or 15(d)of the Securities Exchange Act of 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 to such filing requirements fo
6、r the past 90 days.Yes No Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T(232.405 of this chapter)during the preceding 12 months(or for such shorter period that the registrant was r
7、equired to submit such files).Yes No Indicate by check mark whether the registrant is a large accelerated filer,an accelerated filer,a non-accelerated filer,a smaller reporting company,or an emerging growth company.See the definitions of“large accelerated filer,”“accelerated filer,”“smaller reportin
8、g company,”and emerging growth company in Rule 12b-2 of the Exchange Act.Large accelerated filer Accelerated filer Non-accelerated filer Smaller reporting company Emerging growth company If an emerging growth company,indicate by check mark if the registrant has elected not to use the extended transi
9、tion period for complying with any new or revised financial accounting 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 its internal control over f
10、inancial reporting under Section 404(b)of the Sarbanes-Oxley Act(15 U.S.C.7262(b)by the registered public accounting firm that 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 registran
11、t included in the filing reflect the correction of an error to previously issued financial statements.Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by any of the registrants executive officers
12、 during the relevant recovery period pursuant to 240.10D-1(b).Indicate by check mark whether the registrant is a shell company(as defined in Rule 12b-2 of the Act).Yes No The aggregate market value of the voting and non-voting Common Stock held by non-affiliates of the registrant computed by referen
13、ce to the price of the registrants Common Stock as of June 28,2024(based on the last reported sale price on the Nasdaq Global Select Market as of such date)was$2,416,161,200.As of February 7,2025,there were 57,296,167 shares of Common Stock,$0.001 par value per share,outstanding.Table of ContentsDOC
14、UMENTS INCORPORATED BY REFERENCEPortions of the registrants definitive proxy statement for its 2025 Annual Meeting of Stockholders to be filed pursuant to Regulation 14A within 120 days of the end of the registrants fiscal year ended December 31,2024 are incorporated by reference into Part III of th
15、is Annual Report on Form 10-K to the extent stated herein.Table of ContentsTable of ContentsPART IPageItem 1.Business3Item 1A.Risk Factors36Item 1B.Unresolved Staff Comments64Item 1C.Cybersecurity64Item 2.Properties65Item 3.Legal Proceedings65Item 4.Mine Safety Disclosures65PART IIItem 5.Market for
16、Registrants Common Equity,Related Stockholder Matters and Issuer Purchases of Equity Securities66Item 6.Reserved67Item 7.Managements Discussion and Analysis of Financial Condition and Results of Operations68Item 7A.Quantitative and Qualitative Disclosures about Market Risk82Item 8.Financial Statemen
17、ts and Supplementary Data82Item 9.Changes in and Disagreements with Accountants on Accounting and Financial Disclosure82Item 9A.Controls and Procedures82Item 9B.Other Information83Item 9C.Disclosure Regarding Foreign Jurisdictions that Prevent Inspections84PART IIIItem 10.Directors,Executive Officer
18、s and Corporate Governance85Item 11.Executive Compensation85Item 12.Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters85Item 13.Certain Relationships and Related Transactions,and Director Independence85Item 14.Principal Accountant Fees and Services85PART I
19、VItem 15.Exhibits and Financial Statement Schedules86Item 16.Form 10-K Summary89Table of ContentsiPART IReferences to AgiosThroughout this Annual Report on Form 10-K,“the Company,”“Agios,”“we,”“us,”and“our,”and similar expressions,except where the context requires otherwise,refer to Agios Pharmaceut
20、icals,Inc.and its consolidated subsidiaries,and“our board of directors”refers to the board of directors of Agios Pharmaceuticals,Inc.Cautionary Note Regarding Forward-looking InformationThis Annual Report on Form 10-K contains forward-looking statements that involve substantial risks and uncertainti
21、es.All statements,other than statements of historical fact,contained in this Annual Report on Form 10-K,including statements regarding our strategy,future operations,future financial position,future revenue,projected costs,prospects,plans,and objectives of management,are forward-looking statements.T
22、he words“aim,”“anticipate,”“believe,”“continue,”“could,”“estimate,”“expect,”“goal,”“intend,”“may,”“might,”“plan,”“potential,”“predict,”“project,”“should,”“strategy,”“target,”“vision,”“will,”“would”or the negatives of these words and similar expressions are intended to identify forward-looking statem
23、ents,although not all forward-looking statements contain these identifying words.The forward-looking statements in this Annual Report on Form 10-K include,among other things,statements regarding:our commercialization efforts and plans to commercialize PYRUKYND(mitapivat);the initiation,timing,progre
24、ss and results of current,planned and future preclinical studies and clinical trials,and our research and development programs;the potential of the isoforms of pyruvate kinase,including pyruvate kinase-R,or PKR,as therapeutic targets;the potential benefits of our products and product candidates targ
25、eting PKR,including PYRUKYND(mitapivat)and tebapivat,and of our product candidate in our phenylalanine hydroxylase,or PAH,stabilizer program,AG-181,and our siRNA targeting the transmembrane serine protease 6,or TMPRSS6,gene,AG-236;our plans to develop and commercialize any additional product candida
26、tes for which we may receive approval,either alone or with partners;our ability to establish and maintain collaborations or to obtain additional funding,if needed;the timing or likelihood of regulatory filings and approvals,including our regulatory applications for approval of PYRUKYND(mitapivat)for
27、 the treatment of adult patients with non-transfusion-dependent and transfusion-dependent alpha-or beta-thalassemia;our strategic vision;the timing,likelihood and amount of royalty payments we may receive from Servier Pharmaceuticals LLC with respect to certain U.S.net sales of vorasidenib;the amoun
28、t and timing of future milestone and royalty payments potentially payable to Alnylam Pharmaceuticals,Inc.pursuant to the license agreement entered into in July 2023;the implementation of our business model and strategic plans for our business,product candidates and technology;our commercialization,s
29、ales,marketing and manufacturing capabilities and strategy;the rate and degree of market acceptance and clinical utility of our products;our competitive position;our intellectual property position;developments and projections relating to our competitors and our industry;our estimates regarding our e
30、xpenses,future revenue,capital requirements and needs for additional financing;andthe potential impact of public health epidemics or pandemics,global economic developments and geopolitical events on our business,operations,strategy and goals.We may not actually achieve the plans,intentions or expect
31、ations disclosed in our forward-looking statements,and you should not place undue reliance on our forward-looking statements.Actual results or events could differ materially from the plans,intentions and expectations disclosed in the forward-looking statements we make.We have included important fact
32、ors in this Annual Report on Form 10-K,particularly in the“Summary Risk Factors”and“Risk Factors”sections,that could cause actual results or events to differ materially from the forward-looking statements that we make.Our forward-looking statements do not reflect the potential impact of any future a
33、cquisitions,in-licensing arrangements,mergers,dispositions,joint ventures or investments we may make.You should read this Annual Report on Form 10-K and the documents that we have filed as exhibits to this Annual Report on Form 10-K completely.We do not assume any obligation to update any forward-lo
34、oking statements,whether as a result of new information,future events or otherwise,except as required by law.Table of Contents1This Annual Report on Form 10-K includes statistical and other industry and market data that we obtained from industry publications and research,surveys and studies conducte
35、d by third parties as well as our own estimates of potential market opportunities.All of the market data used in this Annual Report on Form 10-K involves a number of assumptions and limitations,and you are cautioned not to give undue weight to such data.We believe that the information from these ind
36、ustry publications,research,surveys and studies is reliable.The industry in which we operate is subject to a high degree of uncertainty and risk due to a variety of important factors,including those described in the sections titled“Summary Risk Factors”and“Risk Factors.”Summary Risk Factors Our busi
37、ness is subject to a number of risks that if realized could materially affect our business,financial condition,results of operations,cash flows and access to liquidity.These risks are discussed more fully in the“Risk Factors”section of this Annual Report on Form 10-K.Our principal risks include the
38、following:If we do not successfully commercialize PYRUKYND and other products for which we receive approval,our prospects may be substantially harmed.Our ability to generate product revenue from PYRUKYND depends heavily on our successful development and commercialization of the product.We depend hea
39、vily on the success of our clinical-stage product candidates,including the potential approval of PYRUKYND for the treatment of thalassemia or sickle cell disease,or SCD,in the United States and in other jurisdictions.Clinical trials of our product candidates may not be successful for a number of imp
40、ortant reasons.If we or our collaborators are unable to commercialize our product candidates or experience significant delays 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 our stockholde
41、rs or reduce our financial resources.The outcome of preclinical studies and early clinical trials may not be predictive of the success of later clinical trials,and positive results of completed clinical trials do not necessarily predict success in future clinical trials.The results of completed clin
42、ical trials of PYRUKYND for the treatment of PK deficiency and thalassemia are not predictive of our ongoing clinical trials of PYRUKYND in other indications,such as SCD,and the results of our early-stage clinical trials of tebapivat are not predictive of our later stage clinical trials of tebapivat
43、.Interim and preliminary data from clinical trials that we announce or publish from time to time may change as more patient data becomes available and are subject to audit and verification procedures that could result in material changes in the final data.We may expend our limited resources to pursu
44、e a particular product candidate or indication and fail to capitalize on product candidates or indications that may be more profitable or for which there is a greater likelihood of success.PYRUKYND,or any of our product candidates that may receive marketing approval in the future,may be less effecti
45、ve than previously believed or cause undesirable side effects that were not previously identified in clinical trials or may fail to achieve the degree of market acceptance by physicians,patients,healthcare payors and others in the medical community necessary for commercial success,which could compro
46、mise our ability,or that of any collaborators,to market the product.If we are unable to establish and maintain sales and marketing capabilities or enter into agreements with third parties to sell and market our products,we may not be successful in commercializing PYRUKYND or our product candidates i
47、f they are approved.We provide certain development estimates related to the development and regulatory approval of PYRUKYND and our product candidates.If we do not achieve our projected development or regulatory approval estimates in the timeframes we announce and expect,the commercialization of our
48、 products may be delayed and,as a result,our stock price may decline.We face substantial competition,which may result in others discovering,developing or commercializing products before or more successfully than we do.There are a number of large pharmaceutical and biotechnology companies that curren
49、tly market and sell products or are pursuing the development of products for the treatment of the indications for which we are developing PYRUKYND or our product candidates.Our competitors may develop products that are more effective,safer,more convenient or less costly than PYRUKYND or any product
50、candidates that we are developing or that would render PYRUKYND 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 be more susceptible to changing market conditions,including fluctua
51、tions and risks particular to the markets for patients with rare diseases,than a more diversified company,which could adversely affect our business,financial condition and results of operations.Table of Contents2If our existing capital is insufficient to fund our operating expenses and capital expen
52、ditures,we will need to raise capital,and if we are unable to raise capital when needed,we would be forced to delay,reduce or eliminate our product development programs or commercialization efforts.We have historically incurred operating losses.We expect to incur losses in the future and may never a
53、chieve or maintain profitability.Our net income for the year ended December 31,2024 was$673.7 million,our net loss for the year ended December 31,2023 was$352.1 million and our net loss for the year ended December 31,2022 was$231.8 million.The net income we generated in the year ended December 31,20
54、24 was primarily due to the sale of the Vorasidenib Royalty Rights to Royalty Pharma and our receipt of the Vorasidenib Milestone Payment discussed below in Item 1.Business.As of December 31,2024,we had an accumulated deficit of$148.9 million.We currently rely and expect to continue to rely on third
55、 parties for the manufacture of our product candidates for preclinical and clinical testing and for commercial supply of PYRUKYND and any product candidate for which we may obtain marketing approval.Any performance failure on the part of our existing or future third-party manufacturers could delay c
56、linical development,marketing approval or our commercialization efforts.We rely and expect to continue to rely on third parties to conduct our clinical trials and some aspects of our research and preclinical testing,and those third parties may not perform satisfactorily,including failing to meet dea
57、dlines for the completion of such trials,research or testing.We may depend on collaborations with third parties for the development and commercialization of our product candidates.If those collaborations are not successful,we may not be able to capitalize on the market potential of these product can
58、didates.If we are unable to obtain and maintain patent or trade secret protection for our medicines and technology,or if the scope of the patent protection obtained is not sufficiently broad,our competitors could develop and commercialize medicines and technology similar or identical to ours,and our
59、 ability to successfully commercialize our medicines and technology may be adversely affected.If we do not,or are unable to,obtain or maintain any issued patents for any of our most advanced product candidates,it could have a material adverse effect on our competitive position,business,financial con
60、dition,results of operations,and prospects.Item 1.BusinessGeneralWe are a biopharmaceutical company committed to transforming patients lives through leadership in the field of cellular metabolism,with the goal of creating differentiated medicines for rare diseases,with a focus on classical hematolog
61、y.With a history of focused study on cellular metabolism,we have a deep and mature understanding of this biology,which is involved in the healthy functioning of nearly every system in the body.Building on this expertise,these learnings can be rapidly applied to our clinical trials with the goal of d
62、eveloping medicines that can have a significant impact for patients.We accelerate the impact of our portfolio by cultivating connections with patient communities,healthcare professionals,partners and colleagues to discover,develop and deliver potential therapies for rare diseases.Business OverviewRa
63、re diseasesThe lead product candidate in our portfolio,PYRUKYND(mitapivat),is an activator of both wild-type and mutant pyruvate kinase,or PK,enzymes for the potential treatment of hemolytic anemias.PYRUKYND is approved for use by the U.S.Food and Drug Administration,or FDA,for the treatment of hemo
64、lytic anemia in adults with PK deficiency in the United States and by the European Commission for the treatment of PK deficiency in adult patients in the European Union,or EU.Additionally,we received marketing authorization in Great Britain for PYRUKYND for the treatment of PK deficiency in adult pa
65、tients under the European Commission Decision Reliance Procedure.In December 2024,we announced that we submitted a supplemental new drug application,or sNDA,to the FDA for PYRUKYND for the treatment of adult patients with non-transfusion dependent and transfusion-dependent alpha-or beta-thalassemia,
66、which was accepted with standard review by the FDA and granted a Prescription Drug User Fee Act,or PDUFA,goal date of September 7,2025.Also in December 2024,we announced that we submitted a marketing authorization application,or MAA,to the European Medicines Agency,or EMA,and regulatory applications
67、 to the Kingdom of Saudi Arabia and United Arab Emirates health authorities for PYRUKYND for the treatment of adult patients with non-transfusion dependent and transfusion-dependent alpha-or beta-thalassemia.In addition,we are currently evaluating PYRUKYND in Phase 3 clinical trials for the treatmen
68、t of sickle cell disease,or SCD,and in pediatric patients with PK deficiency.We are also developing(i)tebapivat,a novel PK activator,for the potential treatment of lower-risk myelodysplastic syndromes,or LR MDS,and hemolytic anemias;(ii)AG-181,our phenylalanine hydroxylase,or PAH,stabilizer for the
69、potential treatment of phenylketonuria,or PKU;and(iii)AG-236,an siRNA in-licensed Table of Contents3from Alnylam Pharmaceuticals,Inc.,or Alnylam,targeting the transmembrane serine protease 6,or TMPRSS6 gene for the potential treatment of polycythemia vera,or PV.Alnylam License AgreementIn accordance
70、 with the license agreement we entered into with Alnylam in July 2023,we made an up-front payment to Alnylam and recognized in-process research and development of$17.5 million in the year ended December 31,2023.We will also pay Alnylam for certain expenses associated with the development of AG-236,a
71、n siRNA targeting the TMPRSS6 gene,and these will be recorded in our consolidated statements of operations as incurred.Additionally,we are responsible to pay up to$130.0 million in potential development and regulatory milestones,in addition to sales milestones as well as tiered royalties on annual n
72、et sales,if any,of licensed products,which may be subject to specified reductions and offsets.Because the acquired assets under the license agreement with Alnylam do not meet the definition of a business in accordance with Accounting Standards Codification,or ASC,805,Business Combinations,we account
73、ed for the agreement as an asset acquisition.Sale of Oncology Business to Servier and Sale of Contingent PaymentsOn March 31,2021,we completed the sale of our oncology business to Servier Pharmaceuticals,LLC,or Servier,which represented a discontinued operation.The transaction included the sale of o
74、ur oncology business,including TIBSOVO,our clinical-stage product candidates vorasidenib,AG-270 and AG-636,and our oncology research programs,for a payment of approximately$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,
75、2027,vorasidenib is granted new drug application,or NDA,approval from the FDA with an approved label that permits vorasidenibs use as a single agent for the adjuvant treatment of patients with Grade 2 glioma that have an isocitrate dehydrogenase,or IDH,1 or 2 mutation(and,to the extent required by s
76、uch approval,the vorasidenib companion diagnostic test is granted an FDA premarket approval),or the Vorasidenib Milestone Payment,as well as a royalty of 5%of U.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 of vorasidenib fr
77、om the first commercial sale of vorasidenib through loss of exclusivity,or the Vorasidenib Royalty Rights.The Vorasidenib Milestone Payment,Vorasidenib Royalty Rights and royalty payments related to TIBSOVO are referred to as contingent payments and recognized as income when realizable.Servier also
78、acquired our co-commercialization rights for Bristol Myers Squibbs IDHIFA and the right to receive a$25.0 million potential milestone payment under our prior collaboration agreement with Celgene Corporation,or Celgene,and following the sale Servier agreed to conduct certain clinical development acti
79、vities within the IDHIFA development program.In October 2022,we sold our rights to future contingent payments associated with the royalty of 5%of U.S.net sales of TIBSOVO from the close of the transaction through the loss of exclusivity to entities affiliated with Sagard Healthcare Partners,or Sagar
80、d,and recognized income of$127.9 million within the gain on sale of contingent payments line item in our consolidated statements of operations for the year ended December 31,2022.In August 2024,the FDA approved vorasidenib for adult and pediatric patients 12 years and older with Grade 2 astrocytoma
81、or oligodendroglioma with a susceptible IDH1 or IDH2 mutation,following surgery including biopsy,sub-total resection,or gross total resection.In September 2024,we received the Vorasidenib Milestone Payment from Servier and recognized income of$200.0 million within the milestone payment from gain on
82、sale of oncology business line item in our consolidated statements of operations for the year ended December 31,2024.In May 2024,we entered into a purchase and sale agreement to sell the Vorasidenib Royalty Rights to Royalty Pharma Investments 2019 ICAV,or Royalty Pharma,for$905.0 million in cash,or
83、 the Upfront Payment.The sale was contingent upon FDA approval of vorasidenib and other customary closing conditions.Upon consummation of the sale in August 2024,Royalty Pharma acquired 100%of the Vorasidenib Royalty Rights payments made by Servier on account of up to$1.0 billion in U.S.net sales fo
84、r each calendar year.In addition,any such Vorasidenib Royalty Rights payments made by Servier on account of U.S.net sales in each calendar year in excess of$1.0 billion will be split,with Royalty Pharma having the rights to a 12%earn-out on those excess payments and Agios retaining the rights to a 3
85、%earn-out on those excess payments,or the Retained Earn-Out Rights.As a result of the sale,we recognized income of$889.1 million($905.0 million net of fees of$15.9 million)within the gain on sale of contingent payments line item in our consolidated statements of operations for the year ended Decembe
86、r 31,2024.Royalty income related to the Retained Earn-Out Rights,if any,will be recognized in the period when realizable.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 in light of our focus
87、 on rare diseases.We are building a sustainable,value-creating company,based on our expertise in cellular 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 a
88、cross PK deficiency,thalassemia and SCD;and expand our portfolio by advancing tebapivat,AG-181 and AG-236 and the rest of our preclinical pipeline as well as through disciplined business development aligned with our core therapeutic focus areas and capabilities.Table of Contents4Our Core ValuesOur v
89、alues cultivate an environment that promotes collaboration,contribution,engagement and high regard for others points of view.This foundation helps our people push the boundaries of our science and create transformative medicines,which we believe will provide long-term benefits for all our stakeholde
90、rs.Our connections with each other and with external parties fuel the development of new therapies for the people who need 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 deep respect for the science and a commitmen
91、t always to act with the utmost integrity.Come Together:We grow supportive relationships with patients and caregivers.We build trusting connections with collaborators.Together,we make a bigger impact than we ever could alone.Embrace Differences:Because opportunities and insights come from anywhere a
92、nd anyone,we honor all voices and encourage honest dialogue.We learn equally from success and failure,bringing an open mind and a flexible approach to 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
93、ask the tough questions that can lead to groundbreaking scientific advances.We nurture a creative mindset and resourceful approach that spark life-changing innovations for patients.Cellular MetabolismCellular metabolism is involved in the healthy functioning of nearly every system in the body and re
94、fers to the set of life-sustaining chemical transformations within the cells of living organisms.The conversion of nutrients into energy via enzyme-catalyzed reactions allows organisms to grow and reproduce,maintain their structures,and respond to their environments.Additionally,metabolites serve as
95、 key regulators of diverse aspects of cellular biology,and pharmacologic targeting of metabolism can therefore have disease-modifying effects in a wide variety of pathologies.The chemical reactions of metabolism are organized into metabolic pathways,in which one chemical is transformed through a ser
96、ies of steps into another chemical,by a sequence of enzymes.Enzymes catalyze quick and efficient reactions,serve as key regulators of metabolic pathways,and respond to changes in the cells environment or signals from other cells.Rare diseasesDiseases are typically considered rare if they affect fewe
97、r than 200,000 people in the United States,or fewer than five per 10,000 people in France,Germany,Italy,Spain,United Kingdom,or the EU5.Many rare diseases are likely to be under-diagnosed given the lack of available therapies or diagnostics,the rarity of the condition,or limited understanding of how
98、 the disease genetics relate to the disease phenotype.It has been shown that small molecule therapies able to specifically correct genetic deficiencies and their associated organ dysfunction may have application in conditions that arise independent of patient genetics but for which identical organ d
99、ysfunction occurs.For example,a treatment for a hereditary hemolytic anemia may find direct application in the treatment of a secondarily acquired hemolytic anemia.Many rare diseases carry severe or life-threatening features.In many of these disorders,the defect of single or multiple genes leads to
100、a deficient expression or function in one or several gene products which collectively manifest in organ dysfunction.As these conditions are by nature congenital and frequently hereditary,they are often detected either by genetic testing or phenotypic diagnosis in newborns or in early childhood.A typ
101、ical course of many such diseases is inexorable deterioration until death or significant irreversible life-long disability and/or suffering.Classical hematologyClassical hematology refers to the study and treatment of blood disorders that are not cancerous,including thrombotic and hemorrhagic disord
102、ers,anemia,thrombocytopenia,disorders of iron metabolism and hemoglobin disorders.Many of these diseases are debilitating,have a negative impact on patients quality of life and are associated with severe complications and/or shortened life expectancy.Despite the significant need for novel therapies
103、and improved patient care,there is a shortage of research and trained specialists in the field of classical hematology,and patients with these disorders are often underserved and experience health disparities and inequity.In addition,even in diseases in which some progress has been made,large subset
104、s of the disease may remain underserved.Our goal is to develop transformative oral treatments for patients with various classical hematological disorders through broad clinical development programs in order to address the unmet needs of a large range of patients.Our Development ProgramsWe believe th
105、at leveraging our core capabilities in cellular metabolism combined with our singular focus on rare diseases and our differentiated expertise in classical hematology has significantly enhanced our ability to advance new therapeutic candidates and bring innovative medicines to patients in need.We hav
106、e a proven track record of developing new therapeutic approaches and multiple proprietary first-in-class orally available small molecules.Table of Contents5The following summarizes our approved product and most advanced clinical product candidates,each of which is described in further detail below.P
107、K Activator ProgramsPK is an enzyme involved in glycolysis the conversion of glucose into lactic acid.This enzyme has several tissue-specific isoforms(PKR,PKL,PKM1 and PKM2).Pyruvate kinase-R,or PKR,is the isoform of PK that is present in red blood cells,or RBCs.Mutations in PKR cause defects in RBC
108、 glycolysis and lead to a hematological rare disease known as PK deficiency.Glycolysis is the only pathway available for RBCs to maintain the production of adenosine triphosphate,or ATP,which is a form of chemical energy within cells.Accordingly,we believe that activation of mutant forms of PKR can
109、restore glycolytic pathway activity and increase RBC health in patients with PK deficiency,and activation of wild-type(non-mutated)PKR can Table of Contents6increase ATP which can then meet the increased energy demands resulting from metabolic stress in RBCs of patients with hemolytic anemias such a
110、s thalassemia and SCD.PK DeficiencyPK deficiency is a rare genetic disorder and disease understanding is still evolving.We estimate that the prevalence of PK deficiency is between approximately 3,000 and 8,000 individuals in the United States and EU5,and believe that the disease is likely under-diag
111、nosed.PK deficiency 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 severe forms of anemia caused by the excessive
112、premature destruction of RBCs.The chronic hemolysis can lead to long-term complications and comorbidities,regardless of the degree of the anemia,often resulting in jaundice and lifelong conditions associated with chronic anemia and secondary complications.The precise mechanism for the hemolysis is n
113、ot well understood but 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 break open in the circulation.PK defici
114、ency is an autosomal recessive disease whereby all patients inherit two mutations,one from each parent.Children with the disease produce PKR enzyme that has only a fraction of the normal level of activity(generally 50%).Current management strategies for PK deficiency,including blood transfusion and
115、splenectomy,are associated with both short-and long-term risks.More than 350 different mutations have been identified to date.As a result,there are many different possible mutant combinations and no one clear mutational profile.We maintain a global registry,called Peak,for up to 500 adult and pediat
116、ric patients with PK deficiency to increase understanding of the long-term disease burden of this chronic hemolytic anemia.ThalassemiaThalassemia is a hereditary blood disorder in which mutations in the-or-globin chains of hemoglobin lead to globin chain precipitates and aggregates that disturb the
117、RBC membrane and induce oxidative stress,leading to decreased survival of RBC precursors,ineffective erythropoiesis,hemolysis of mature RBCs,and anemia.We estimate that the prevalence of thalassemia is between 18,000 and 23,000 individuals in the United States and EU5,with approximately 6,000 diagno
118、sed adults in the United States;approximately 70,000 individuals in Bahrain,Kuwait,Oman,Qatar,Saudi Arabia and the United Arab Emirates,also known as the Gulf Council Countries,or GCC;and greater than one million individuals worldwide.In addition to anemia,patients with thalassemia can experience en
119、larged spleen,bone deformities,iron overload,fatigue,and infection.Current treatment strategies for thalassemia include blood transfusion,splenectomy,iron chelation therapy and bone marrow transplantation,as well as recently approved therapies such as Reblozyl(luspatercept-aamt)for the treatment of
120、beta-thalassemia or Casgevy and Zynteglo for the treatment of transfusion-dependent beta-thalassemia.We believe that the activation of wild-type PKR may increase ATP production and improve red cell fitness and survival of thalassemic RBCs,by increasing the clearance globin chain aggregates through A
121、TP-dependent proteolytic mechanisms.Sickle Cell Disease(SCD)SCD is an inherited blood disorder caused by mutations in hemoglobin that enable the hemoglobin to form long polymeric chains under certain conditions such as low oxygenation,or deoxygenation.Polymerization of this irregular hemoglobin resu
122、lts in RBCs taking on a sickle shape,causing them to aggregate and obstruct small blood vessels,restricting blood flow to organs resulting in pain,cell death and organ damage.We estimate that the prevalence of SCD is between 120,000 and 135,000 individuals in the United States and EU5,approximately
123、150,000 individuals in the GCC,and greater than three million individuals worldwide.RBC deoxygenation is modulated by several factors,including the levels of 2,3-diphosphoglycerate,or 2,3-DPG,which is found to be elevated in sickle cell patient RBCs.Current treatment strategies focus on managing and
124、 preventing acute RBC sickling,and include hydroxyurea,L-glutamine and blood transfusions,as well as recently approved therapies such as Adakveo,Casgevy,and Lfygenia.We believe that activation of wild-type PKR in patients with SCD may reduce hemoglobin polymerization and the sickling process by at l
125、east two mechanisms.Reducing the level of 2,3-DPG in RBCs would increase the oxygenation state of hemoglobin to reduce sickling,while increasing the levels of ATP may improve RBC hydration status which may also inhibit the sickling process.Lower Risk MDS(LR MDS)MDS is a heterogeneous group of rare h
126、ematological malignancies characterized by dysfunctional hematopoiesis(or formation of blood cells),progressive cytopenia(or lower-than-normal number of blood cells)and an increased risk of progression to acute myeloid leukemia,or AML.The most common type of MDS is LR MDS,but many existing therapies
127、 and therapies under development focus on high risk MDS.Among patients with LR MDS,which accounts for approximately 70%of all MDS cases and are less likely to progress to AML,the primary concern is symptomatic anemia.We estimate that the prevalence of LR MDS in the United States and EU5 is between 7
128、5,000 and 80,000 individuals.We believe that activation of wild-type PK in LR MDS patients may improve deficient PK activity in MDS erythrocytes.Current treatment options for LR MDS often require in-Table of Contents7office visits and transfusions,and erythropoiesis stimulating agents and Reblozyl a
129、nd Rytelo are the only approved therapies to treat anemia in a subset of patients.Despite approved therapies in subsets of patients,LR MDS associated anemia remains a disease with a high unmet medical need.Other ProgramsPhenylketonuria(PKU)PKU,is a rare,genetic disease caused by deficiency of the PA
130、H enzyme.Lack of PAH activity leads to the accumulation of phenylalanine and downstream neurocognitive deficits.Patients with PKU are therefore often advised to consume a highly restricted diet in order to minimize phenylalanine intake,which can further reduce patient quality of life.We estimate tha
131、t the prevalence of PKU in the United States and EU5 is between 35,000 and 40,000 individuals.Polycythemia Vera(PV)PV is a rare blood disorder with no disease-modifying treatments that affects approximately 100,000 individuals in the United States.PV is characterized by excessive production of RBCs,
132、which leads to increased blood volume and viscosity,and can result in thrombosis,cardiovascular events,enlarged spleen and death.Phlebotomy,which is the procedure of withdrawing blood,is the current standard of care for patients with PV.PYRUKYND(mitapivat):First-in-Class PK Activator We are developi
133、ng PYRUKYND for the treatment of PK deficiency and other hemolytic anemias such as thalassemia and SCD.PYRUKYND is an orally available small molecule and a potent activator of the wild-type and mutated PK enzymes.PYRUKYND is approved for use by the FDA for the treatment of hemolytic anemia in adults
134、 with PK deficiency in the United States and by the European Commission for the treatment of PK deficiency in adult patients in the EU.Additionally,we received marketing authorization in Great Britain for PYRUKYND for the treatment of PK deficiency in adult patients under the European Commission Dec
135、ision Reliance Procedure.In December 2024,we announced that we submitted an sNDA to the FDA for PYRUKYND for the treatment of adult patients with non-transfusion dependent and transfusion-dependent alpha-or beta-thalassemia,which was accepted with standard review by the FDA and granted a PDUFA goal
136、date of September 7,2025.Also in December 2024,we announced that we submitted an MAA to the EMA and regulatory applications to the Kingdom of Saudi Arabia and United Arab Emirates health authorities for PYRUKYND for the treatment of adult patients with non-transfusion dependent and transfusion-depen
137、dent alpha-or beta-thalassemia.In addition,we are currently evaluating PYRUKYND in clinical trials for the treatment of SCD and in pediatric patients with PK deficiency.We have worldwide development and commercial rights to PYRUKYND.In July 2024,we entered into a distribution agreement with NewBridg
138、e Pharmaceuticals FZ-LLC,or the NewBridge Agreement,pursuant to which we granted NewBridge the right to commercialize PYRUKYND in the GCC region.We expect to fund the future development and commercialization costs related to this program.PYRUKYND has been granted orphan drug designation for the trea
139、tment of PK deficiency by the FDA and the EMA.Additionally,PYRUKYND has received orphan drug designation from the FDA for the treatment of thalassemia and SCD,orphan medicinal product designation from the EMA for the treatment of SCD,and breakthrough medicine designation from the Saudi Food and Drug
140、 Authority for the treatment of thalassemia.We built our commercial infrastructure to support the commercialization of PYRUKYND in adult PK deficiency in the United States,and have expanded this infrastructure to support the potential commercial launch of PYRUKYND in thalassemia in the United States
141、.In connection with our regulatory approvals in the EU and Great Britain,we are currently providing access to PYRUKYND on a free of charge basis for eligible patients in those jurisdictions through a global managed access program.We provide access to PYRUKYND for adult patients with PK deficiency in
142、 other jurisdictions upon request through the global managed access program,on either a free of charge or for charge basis.Our global managed access program has not had a significant impact on our business,financial condition or results of operations.Beyond the global managed access program,we conti
143、nue to evaluate options for the commercialization of PYRUKYND outside of the United States,including through exploring potential partnership opportunities,such as the NewBridge Agreement.We are evaluating PYRUKYND in numerous clinical trials,including the following:An extension study evaluating the
144、long-term safety,tolerability and efficacy of treatment with PYRUKYND in patients from ENERGIZE,our completed phase 3,double-blind,randomized,placebo-controlled multicenter study pivotal trial of PYRUKYND in adults with non-transfusion-dependent alpha-or beta-thalassemia.We announced topline data fo
145、r ENERGIZE in January 2024 and a more detailed analysis of the data in June 2024.A total of 194 patients were enrolled in the study,with 130 randomized to PYRUKYND 100 mg twice-daily,or BID,and 64 randomized to matched placebo.122 patients(93.8%)in the PYRUKYND arm and 62 patients(96.9%)in the place
146、bo arm completed the 24-week double-blind period of the study.The study met the primary endpoint of hemoglobin response,where treatment with PYRUKYND demonstrated a statistically significant increase in hemoglobin response compared to placebo,as Table of Contents842.3%of patients in the PYRUKYND arm
147、 achieved a hemoglobin response,compared to 1.6%of patients in the placebo arm(2-sided p0(95%CI=10.8%to 52.7%).In addition,improvements in changes from baseline for markers of hemolysis(indirect bilirubin,lactate dehydrogenase and haptoglobin)were observed in the mitapivat arm compared to the placeb
148、o arm.In the 20-week double-blind period of the study,a similar proportion of patients had AEs in the mitapivat and placebo arms and there were no discontinuations of study treatment due to AEs or for any reason.The safety results from the trial were consistent with the safety profile for mitapivat
149、previously observed for adult patients with PK deficiency who are not regularly transfused.An extension study evaluating the long-term safety,tolerability and efficacy of treatment with PYRUKYND in patients from ACTIVATE and ACTIVATE-T,our completed pivotal trials of PYRUKYND in not regularly transf
150、used and regularly transfused adult patients with PK deficiency.An extension study evaluating the long-term safety,tolerability and efficacy of treatment with PYRUKYND in patients from DRIVE PK,our completed global phase 2,first-in-patient,open-label safety and efficacy clinical trial of PYRUKYND in
151、 adult,not regularly transfused patients with PK deficiency.Tebapivat:Novel PK ActivatorWe are developing tebapivat,a novel PK activator for the potential treatment of LR MDS and hemolytic anemias.Tebapivat has been granted orphan drug designation for the treatment of MDS by the FDA.We have complete
152、d a phase 1 clinical trial evaluating tebapivat in healthy volunteers and patients with SCD,and we expect to dose the first patient in a phase 2 clinical trial of tebapivat in adult patients with SCD in mid-2025.We also initiated a phase 2a clinical trial of tebapivat in adults with LR MDS in the th
153、ird quarter of 2022,and the trial has completed enrollment with 22 patients,including 12 patients classified as non-transfused and 10 patients classified as low transfusion burden.Patients received 5 mg of tebapivat once daily for up to 16 weeks.The two primary endpoints of the trial were transfusio
154、n independence(for patients classified as low transfusion burden),defined as transfusion-free for eight consecutive weeks during the 16-week treatment period,and hemoglobin response,defined as a 1.5 g/dL increase from baseline in the average hemoglobin concentration measured from week 8 through week
155、 16.In November 2023,we announced that we achieved clinical proof-of-concept in the phase 2a portion of the trial.We observed that four of the 10 patients with low transfusion burden achieved the transfusion independence endpoint,and one of the 22 patients achieved the hemoglobin response endpoint i
156、n the 16-week treatment period.The safety profile observed was consistent with data reported in the healthy volunteer study of tebapivat.19 patients elected to enroll in the extension period for up to 156 weeks.We evaluated the phase 2a trial results and assessed the impact of those results on the p
157、hase 2b portion of the protocol,and based on the data generated in the phase 2a portion of the trial,we plan to increase the dosage levels evaluated in the phase 2b portion of the trial,which we initiated in the third quarter of 2024.We expect to complete enrollment in this phase 2b trial in late 20
158、25.Other ProgramsIn addition to the aforementioned development programs,we are developing AG-181,a PAH stabilizer for the potential treatment of PKU,for which we filed an IND in December 2023.We initiated a phase 1 clinical trial of AG-181 in healthy volunteers in the first quarter of 2024.Also,in J
159、uly 2023,we entered into a license agreement with Alnylam for the development and commercialization of products containing or comprised of an siRNA preclinical development candidate discovered by Alnylam and targeting the TMPRSS6 gene,and we have begun preclinical development of a product candidate,
160、AG-236,for the potential treatment of patients with PV.We expect to file an investigational new drug application,or IND,with the FDA for AG-236 for the treatment of PV in mid-2025.Intellectual PropertyOur commercial success depends in part on our ability to obtain and maintain proprietary or intelle
161、ctual property protection for our product candidates and our core technologies,including novel biomarker and diagnostic discoveries,and other know-how,to operate without infringing on the proprietary rights of others and to prevent others from infringing on our proprietary or intellectual property r
162、ights.Our policy is to seek to protect our proprietary and intellectual property position by,among other methods,filing United States and foreign patent applications related to our proprietary technology,inventions and improvements that are important to the development and implementation of our busi
163、ness.We also rely on confidential information,know-how,in-licensing opportunities and continuing technological innovation to develop and maintain our proprietary and intellectual property position.We may also choose to rely on trade secrets to protect certain aspects of our business that are not sui
164、table or appropriate for patent protection.Table of Contents11We file,or may collaborate with third parties to file,patent applications directed to our key products and product candidates,including PYRUKYND,tebapivat and AG-181,in addition to related compounds and potential back-up compounds,in an e
165、ffort to establish intellectual property positions to protect these new chemical entities and methods of using these compounds in the treatment of diseases,as well as formulations,solid state forms,and manufacturing processes for these compounds.We may also seek patent protection for certain biomark
166、ers that may be useful in identifying the appropriate patient population for therapies with our product candidates.PK activator program The patent portfolio for our PK activator program contains issued patents and pending patent applications directed to compositions of matter for PYRUKYND,as well as
167、 to related compounds,various solid state forms of PYRUKYND,compositions of matter for additional PKR activators,such as tebapivat,as well as various solid state forms,methods of use and methods of manufacture for tebapivat and other novel compounds.As of February 1,2025,we owned 17 issued United St
168、ates patents and 434 issued foreign patents,and have pending patent applications in the United States and in various foreign jurisdictions.The patents that have issued or may issue for PYRUKYND will have a statutory expiration date of at least 2030 to 2042,and the patents that have issued or may iss
169、ue for tebapivat will have a statutory expiration date of at least 2038 to 2045.Patent term adjustments or patent term extensions could result in later expiration dates.In some cases,the term of a United States patent can be shortened by the filing of a terminal disclaimer which operates to reduce t
170、he term of a patent to that of an earlier expiring patent.We have issued patents and pending patent applications pertaining to our products/product candidates in our PK activator program in a number of foreign jurisdictions,including Argentina,Australia,Austria,Belgium,Brazil,Canada,China,the Czech
171、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 process,during which the sco
172、pe of the claims initially submitted for examination can be significantly narrowed by the time they issue,if they issue at all.We expect this could be the case with respect to some of our pending patent applications referred to above.We are also currently involved in adversarial proceedings before t
173、he European Patent Office.Two of the European patents in our PYRUKYND portfolio,neither being the primary compound patent,have been challenged in opposition proceedings.PAH stabilizer program The patent portfolio for our PAH stabilizer program contains issued patents and pending patent applications
174、directed to compositions of matter and methods of use for AG-181 and other novel PAH stabilizers.As of February 1,2025,we owned one issued United States patent and two issued foreign patents and have pending patent applications in the United States and in various foreign jurisdictions.The patents th
175、at have issued or may issue for our PAH stabilizer program will have a statutory expiration date of at least 2043 to 2044.Patent term adjustments or patent term extensions could result in later expiration dates.In some cases,the term of a United States patent can be shortened by the filing of a term
176、inal disclaimer which operates to reduce the term of a patent to that of an earlier expiring patent.We have issued patents and pending patent applications pertaining to our products/product candidates in our PAH stabilizer program in a number of foreign jurisdictions,including Argentina,Australia,Br
177、azil,Canada,China,Europe,Japan,Lebanon,Mexico,Eurasia,Saudi Arabia,and Taiwan.Prosecution is a lengthy process,during which the scope of the claims initially submitted for examination can be significantly narrowed by the time they issue,if they issue at all.We expect this could be the case with resp
178、ect to some of our pending patent applications referred to above.Patent TermThe term of individual patents depends upon the legal term for patents in the countries in which they are obtained.In most countries,including the United States,the patent term is 20 years from the earliest filing date of a
179、non-provisional patent application,although term extensions may be available.In the United States,a patents term may be lengthened by patent term adjustment,which compensates a patentee for administrative delays by the United States Patent and Trademark Office,or USPTO,in examining and granting a pa
180、tent or may be shortened if a patent is terminally disclaimed over an earlier filed patent.The term of a patent that covers a drug or biological product may also be eligible for patent term extension when FDA approval is granted,provided statutory and regulatory requirements are met.The extension of
181、 the term of foreign patents varies,in accordance with local law.Although certain of the patents granted by the regulatory authorities of the EU may expire at specific dates,the terms of patents granted in certain European countries may extend beyond such EU patent expiration date if we were to obta
182、in a supplementary protection certificate.In addition,because of the extensive time required for clinical development and regulatory review of a product candidate we may develop,it is possible that,before any of our product candidates can be commercialized,any related patent may expire or remain in
183、force for only a short period following commercialization,thereby reducing any advantage of any such patent.In the future,if and when our product candidates receive approval by the FDA or foreign regulatory authorities,we expect to apply for patent term extensions on issued patents covering those pr
184、oducts,depending upon the length of the clinical trials for Table of Contents12each product candidate and other factors.There can be no assurance that any of our pending patent applications will be issued or that we will benefit from any patent term extension or favorable adjustment to the term of a
185、ny of our patents.Additional ConsiderationsAs with other biotechnology and pharmaceutical companies,our ability to maintain and solidify our proprietary and intellectual property position for our product,product candidates and technologies will depend on our success in obtaining effective patent cla
186、ims and enforcing those claims if granted.However,patent applications that we may file or license from third parties may not result in the issuance of patents.We also cannot predict the breadth of claims that may be allowed or enforced in our patents.Any issued patents that we may receive in the fut
187、ure may be challenged,invalidated or circumvented.For example,a third party can challenge the patentability of one or more of the claims of an issued patent in a post-grant proceeding before the USPTO or a foreign patent office such as the European Patent Office,which can result in the loss of certa
188、in claims or the loss of an entire patent.In addition,it is possible that a third party has filed a patent application in the United States,or abroad,that claims the same technology or chemical structures that are claimed in our own patent applications or patents.In such cases,we may have to partici
189、pate 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.In addition to patent protection,we also rely upon unpatented confidential information,including confidential technical information,know-how a
190、nd continuing technological innovation to develop and maintain our competitive position.We seek to protect our proprietary information,in part,by using confidentiality agreements with our collaborators,third-party service providers,scientific advisors,employees and consultants,and by invention assig
191、nment agreements with our employees.We also have agreements requiring assignment of inventions with selected consultants,scientific advisors and collaborators.The confidentiality agreements are designed to protect our proprietary information and,in the case of agreements or clauses requiring inventi
192、on assignment,to grant us ownership of technologies that are developed through a relationship with a third party.Nevertheless,confidential information and know-how can be difficult to protect.In particular,we anticipate that at least some of our technical information and know-how will,over time,beco
193、me known within the industry through independent development,the publication of journal articles,and the movement of personnel skilled in the art from academic to industry scientific positions.CompetitionThe pharmaceutical and biotechnology industries are characterized by rapidly advancing technolog
194、ies,intense competition and a strong emphasis on proprietary products.While we believe that our technology,development experience and scientific knowledge provide us with competitive advantages,we face potential competition from many different sources,including major pharmaceutical,specialty pharmac
195、eutical and biotechnology companies,academic institutions and governmental agencies,and public and private research institutions.PYRUKYND and any product candidates that we successfully develop and commercialize will compete with existing therapies and new therapies that may become available in the
196、future.We compete in pharmaceutical,biotechnology and other related markets that address rare diseases,particularly hemolytic anemias,PKU and PV.There are other companies working to develop rare disease therapies,including divisions of large pharmaceutical companies and biotechnology companies of va
197、rious sizes.Our competitors include but are not limited to:BioMarin Pharmaceutical,Inc.,or BioMarin;bluebird bio,Inc.,or bluebird;Bristol-Myers Squibb Company,or BMS;CRISPR Therapeutics AG,or CRISPR;Emmaus Life Sciences,Inc.,or Emmaus;Fulcrum Therapeutics,Inc.,or Fulcrum;Geron Corporation,or Geron;I
198、ncyte Corporation,or Incyte;Ionis Pharmaceuticals,Inc.,or Ionis;Merck&Co.,Inc.,or Merck;Novartis International AG,or Novartis;Novo Nordisk A/S,or Novo;Otsuka Pharmaceutical Co.,Ltd.,or Otsuka;Pfizer,Inc.,or Pfizer;PharmaEssentia USA Corporation,or PharmaEssentia;Protagonist Therapeutics,Inc.,or Prot
199、agonist,in collaboration with Takeda,Pharmaceutical Company Limited,or Takeda;PTC Therapeutics,Inc.,or PTC;Rocket Pharmaceuticals,Inc.,or Rocket Pharma;Silence Therapeutics plc,or Silence;Takeda;and Vertex Pharmaceuticals Incorporated,or Vertex.The most common methods for treating patients with rare
200、 diseases include dietary restriction,dietary supplementation or replacement,treatment of symptoms and complications,gene therapy,blood transfusions,phlebotomies,stem cell transplant and ERTs and there are several marketed therapies available for treating patients with hemolytic anemias,PKU and PV.F
201、or example,recently approved treatments for thalassemia,SCD,LR MDS,PKU and PV include Reblozyl from Merck/BMS(formerly Acceleron/BMS);Revlimid from BMS;Zynteglo and Lyfgenia from bluebird;Adakveo from Novartis;Casgevy from Vertex/CRISPR;Kuvan and Palynziq from BioMarin;Endari from Emmaus;Besremi fro
202、m PharmaEssentia;Jakafi from Incyte;and Rytelo from Geron.While our product and product candidates may compete with existing medicines and other therapies,to the extent they are ultimately used in combination with or as an adjunct to these therapies,our product or product candidates may not be compe
203、titive with them.In addition to currently marketed therapies,there are also several products that are either small molecules,biologics,ERTs or gene therapies in various stages of development to treat hemolytic anemias,PKU and PV.For example,Rocket Pharma is conducting a clinical trial of a gene ther
204、apy targeting PK deficiency;Novo is developing etavopivat(a PKR activator)for the treatment of hemolytic anemias,including SCD;Pfizer is developing inclacumab and osivelotor(GBT-601)for the treatment of SCD;Fulcrum is developing Table of Contents13pociredir(FTX-6058)in SCD;Takeda is developing TAK-2
205、26 for the treatment of anemia in LR MDS;a number of companies,including PTC and Otsuka are developing therapies to treat PKU;and a number of companies,including Silence,Protagonist with Takeda,Italfarmaco S.p.A.,Disc Medicine,Inc.,Merck&Co.,Inc.,and Ionis are developing therapies to treat PV.These
206、products may provide efficacy,safety,convenience and other benefits not provided by current marketed therapies or the current standards of care.As a result,they may provide competition for any of our product or product candidates for which we obtain market approval.Many of our competitors may have s
207、ignificantly greater financial resources and expertise in research and development,manufacturing,preclinical testing,conducting clinical trials,obtaining regulatory approvals and globally marketing approved medicines than we do.Mergers and acquisitions in the pharmaceutical,biotechnology and diagnos
208、tic industries may result in even more resources being concentrated among a smaller number of our competitors.These competitors also compete with us in recruiting and retaining qualified scientific and management personnel,and establishing clinical trial sites and patient registration for clinical t
209、rials,as well as in acquiring or in-licensing technologies complementary to,or necessary for,our programs.Smaller or early-stage companies may also prove to be significant competitors,particularly through collaborative arrangements with large and established companies.The key competitive factors aff
210、ecting the success of PYRUKYND and any of our product candidates that we develop,if approved,are likely to be their efficacy,safety,convenience,price,the level of generic competition and the availability of reimbursement from government and other third-party payors.Our commercial opportunity could b
211、e reduced or eliminated if our competitors develop and commercialize medicines that are safer,more effective,have fewer or less severe side effects,are more convenient or are less expensive than any medicines that we may develop.Our competitors also may obtain FDA or other regulatory approval for th
212、eir medicines more rapidly than we may obtain approval for ours,which could result in our competitors establishing a strong market position before we are able to enter the market.In addition,our ability to compete may be affected in many cases by insurers or other third-party payors seeking to encou
213、rage the use of generic or other branded medicines.There are generic medicines currently on the market for indications that we are pursuing,and additional medicines are expected to become available on a generic basis over the coming years.We expect that PYRUKYND and any of our product candidates tha
214、t may receive marketing approval in the future will be priced at a significant premium over competitive generic medicines.Manufacturing and Supply ChainPYRUKYND,tebapivat,and AG-181 are organic compounds of low molecular weight,generally called small molecules,and are dosed orally.Our siRNA program,
215、AG-236,targeting the TMPRSS6 gene is an oligonucleotide intended for use as a sterile parenteral administration.Each can be manufactured in reliable and reproducible synthetic processes from readily available starting materials.The chemistries are amenable to scale-up and do not require unusual equi
216、pment in the manufacturing process.We expect to continue to develop product 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 in-house manufacturing or supply chain related facilities.We current
217、ly,and expect to continue to,rely on third parties for the manufacture and supply of our clinical and preclinical product candidates,as well as for commercial manufacture of PYRUKYND and any product for which we may receive marketing approval in the future.We conduct extensive prequalification progr
218、ams to ensure the compliance,quality and reliability of third-party manufacturing and supply operations.To date,we have obtained materials for PYRUKYND,tebapivat,AG-181 and AG-236 for our ongoing and planned clinical testing and ongoing preclinical testing from third-party manufacturers.We have long
219、-term commercial manufacture and supply agreements in place for PYRUKYND,and we obtain our supplies from these manufacturers on a purchase order basis.Due to the volatility of the supply networks globally,we have gained regulatory approval for redundant supply of raw materials and active pharmaceuti
220、cal ingredient,or API,for PYRUKYND,and have an ongoing program to ensure this risk mitigation remains effective,including establishing safety stocks.We do not currently have arrangements in place for redundant supply for drug product,but maintain a multi-faceted safety stock program.As we have done
221、for PYRUKYND,we intend to identify and qualify additional manufacturing and supply related services for our other product candidates.Government Regulation and Product ApprovalsGovernment authorities in the United States,at the federal,state and local level,and in other countries and jurisdictions,in
222、cluding the EU,extensively regulate,among other things,the research,development,testing,manufacture,pricing,quality control,approval,packaging,storage,recordkeeping,labeling,advertising,promotion,distribution,marketing,post-approval monitoring and reporting,and import and export of biopharmaceutical
223、 products.The processes for obtaining marketing approvals in the United States and in foreign countries and jurisdictions,along with compliance with applicable statutes and regulations and other regulatory authorities,require the expenditure of substantial time and financial resources.Table of Conte
224、nts14Approval and Regulation of Drugs in the United StatesIn the United States,drug products are regulated under the Federal Food,Drug and Cosmetic Act,or FDCA,and applicable implementing regulations and guidance.A company,institution,or organization responsible for initiating and managing a clinica
225、l development program for such products,and for their regulatory approval,is typically referred to as a sponsor.A sponsor seeking approval to market and distribute a new drug in the United States generally must satisfactorily complete each of the following steps before the product candidate will be
226、approved by the FDA:preclinical testing including laboratory tests,animal studies and formulation studies which must be performed in accordance 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
227、 testing,which must become effective before human clinical trials may begin;approval by an independent institutional review board,or IRB,representing each clinical site before each clinical trial may be initiated;performance of adequate and well-controlled human clinical trials to establish the safe
228、ty and efficacy of the product candidate for each proposed indication,in accordance with current good clinical practices,or GCP;preparation and submission to the FDA of an NDA,or a sNDA for a change to a previously approved drug product,which submissions include not only the results of the clinical
229、trials,but also,detailed information on the chemistry,manufacture and quality controls for the product candidate and proposed labeling for one or more proposed indication(s);review of the product candidate by an FDA advisory committee,where appropriate or if applicable;satisfactory completion of FDA
230、 inspection of the manufacturing facility or facilities,including those of third parties,at which the product candidate or components thereof are manufactured to assess compliance with current good manufacturing practices,or cGMP,requirements and to assure that the facilities,methods and controls ar
231、e adequate to preserve the products identity,strength,quality and purity;satisfactory completion of any FDA audits of the non-clinical and clinical trial sites to assure compliance with GCP and the integrity of clinical data in support of the NDA;payment of user fees pursuant to PDUFA;approval of an
232、 NDA for the new drug product authorizing marketing of the new drug product for particular indications in the United States;andcompliance with any post-approval requirements,including the potential requirement to implement risk evaluation and mitigation strategies,or REMS,and the potential requireme
233、nt 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 the preclinical testing stage.Preclinical tests include laboratory evaluations of product chemist
234、ry,formulation and stability and other studies to evaluate,among other things,the toxicity of the product candidate.The conduct of the preclinical tests and formulation of the compounds for testing must comply with federal regulations and requirements,including GLP regulations and standards,and the
235、United States Department of Agricultures Animal Welfare Act,if applicable.The results of the preclinical tests,together with manufacturing information and analytical data,are submitted to the FDA as part of an IND and are typically referred to as IND-enabling studies.Some long-term preclinical testi
236、ng,such as animal tests of reproductive adverse events and carcinogenicity,and long-term toxicity studies,may continue after the IND is submitted.With passage of the FDAs Modernization Act 2.0 in December 2022,Congress eliminated provisions in both the FDCA and the Public Health Service Act,or PHSA,
237、that required animal testing in support of an NDA.While animal testing may still be conducted,the FDA was authorized to rely on alternative non-clinical tests,including cell-based assays,microphysiological systems or bioprinted or computer models.Table of Contents15The IND and IRB ProcessesAn IND is
238、 an exemption from the FDCA that allows an unapproved product candidate to be shipped in interstate commerce for use 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 sh
239、ipment and administration of any product candidate that is not the subject of an approved NDA.In addition to reviewing an IND to assure the safety and rights of patients,the FDA also focuses on the quality of the investigation and whether it will be adequate to permit an evaluation of the drugs safe
240、ty and efficacy.In support of a request for an IND,sponsors must submit a protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of the IND.The FDA requires a 30-day waiting period after the filing of each IND before clinical trials may begin.Thi
241、s waiting period is designed to allow the FDA to review the IND to determine whether human research subjects will be exposed to unreasonable health risks.At any time during this 30-day period,or thereafter,the FDA may raise concerns or questions about the conduct of the trials as outlined in the IND
242、 and impose a clinical or partial clinical hold.In this case,the IND sponsor and the FDA must resolve any outstanding concerns before clinical trials can begin.Following commencement of a clinical trial under an IND,the FDA may also place a clinical or partial clinical hold on that trial.A clinical
243、hold is an order issued by the FDA to the sponsor to delay a proposed clinical trial or to suspend an ongoing 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 is not allowed
244、to proceed,while other protocols may do so.No more than 30 days after imposition of a clinical hold or partial clinical hold,the FDA will provide the sponsor a written explanation of the basis for the hold.Following issuance of a clinical or partial clinical hold,an investigation may only resume aft
245、er the FDA has notified the sponsor that the investigation may proceed.The FDA will base that determination on information provided by the sponsor correcting the deficiencies previously cited or otherwise satisfying the FDA that the investigation can proceed.A sponsor may choose,but is not required,
246、to conduct a foreign clinical trial under an IND.When a foreign clinical trial is conducted under an IND,all FDA IND requirements must be met unless waived.When a foreign clinical trial is not conducted under an IND,the sponsor must ensure that the study complies with certain regulatory requirements
247、,including GCP requirements,of the FDA to use the study as support for an IND or application for marketing approval.The GCP requirements encompass both ethical and data integrity standards for clinical studies.The FDAs regulations are intended to help ensure the protection of human subjects enrolled
248、 in non-IND foreign clinical studies,as well as the quality and integrity of the resulting data.They further help ensure that non-IND foreign studies are conducted in a manner comparable to that required for IND studies.In addition to the foregoing IND requirements,an IRB representing each instituti
249、on participating in the clinical trial must review and approve the plan for any clinical trial before it commences at that institution,and the IRB must conduct continuing review and reapprove the study at least annually.The IRB must review and approve,among other things,the study protocol and inform
250、ed consent information to be provided to study subjects.An IRB must operate in compliance with FDA regulations.An IRB can suspend or terminate approval of a clinical trial at its institution,or an institution it represents,if the clinical trial is not being conducted in accordance with the IRBs requ
251、irements or if the product candidate has been associated with unexpected serious harm to patients.Additionally,some trials are overseen by an independent group of qualified experts organized by the trial sponsor,known as a data monitoring committee,or DMC.The DMC provides authorization as to whether
252、 or not a trial may move forward at designated check points based on access that only the DMC maintains to available data from the study.Suspension or termination of development during any phase of clinical trials can occur if it is determined that the participants or patients are being exposed to a
253、n unacceptable health risk.Other reasons for suspension or termination may be made based on evolving business objectives and/or competitive climate.Reporting Clinical Trial ResultsUnder the PHSA,sponsors of certain clinical trials of certain FDA-regulated products,including prescription drugs and bi
254、ologics,are required to register and disclose certain clinical trial information on a public registry(clinicaltrials.gov)maintained by the National Institutes of Health.Information related to the product,patient population,phase of investigation,study sites and investigators and other aspects of the
255、 clinical trial is made public as part of the registration of the clinical trial.The PHSA grants the Secretary of Health and Human Services,or HHS,the authority to issue a notice of noncompliance to a responsible party to failure to submit clinical trial information as required.The responsible party
256、,however,is allowed 30 days to correct the noncompliance and submit the required information.As of December 19,2024,the FDA has issued six notices of non-compliance,signaling the governments willingness to enforce these requirements against non-compliant clinical trial sponsors.While these notices o
257、f non-compliance did not result in civil monetary penalties,the failure to submit clinical trial information to clinicaltrials.gov is a prohibited act under the FDCA with violations subject to potential civil monetary penalties of up to$10,000 for each day the violation continues.Violations may also
258、 result in injunctions and/or criminal prosecution or disqualification from federal grants.Table of Contents16Expanded Access to an Investigational Drug for Treatment Use Expanded access,sometimes called“compassionate use,”is the use of investigational new drug products outside of clinical trials to
259、 treat patients with serious or immediately life-threatening diseases or conditions when there are no comparable or satisfactory alternative treatment options.The rules and regulations related to expanded access are intended to improve access to investigational drugs for patients who may benefit fro
260、m investigational therapies.FDA regulations allow access to investigational 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 setting
261、s);intermediate-size patient populations;and larger populations for use of the drug under a treatment protocol or Treatment IND Application.While there is no obligation to make investigational products available for expanded access,sponsors are required to make policies for evaluating and responding
262、 to requests for expanded access publicly available upon the earlier of initiation of a Phase 2 or Phase 3 clinical trial,or 15 days after the drug or biologic receives designation as a breakthrough therapy,fast track product,or regenerative medicine advanced therapy.In addition,the Right to Try Act
263、,among other things,provides a federal framework for certain patients to access certain investigational new drug products that have completed a Phase 1 clinical trial and are undergoing investigation for FDA approval.Under certain circumstances,eligible patients can seek treatment without enrolling
264、in clinical trials and without obtaining FDA permission under the FDA expanded access program.There is no obligation for a drug manufacturer to make its drug products available to eligible patients as a result of the Right to Try Act,but the manufacturer must develop an internal policy and respond t
265、o patient requests according to that policy.Human Clinical Trials in Support of an NDAClinical trials involve the administration of the investigational product candidate to human subjects under the supervision of a qualified investigator in accordance with GCP requirements which include,among other
266、things,the requirement that all research subjects provide their informed consent in writing before their participation in any clinical trial.Clinical trials are conducted under written clinical trial protocols detailing,among other things,the objectives of the study,inclusion and exclusion criteria,
267、the parameters to be used in monitoring safety and the effectiveness criteria to be 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
268、 candidate for safety,including AEs,dose tolerance,absorption,metabolism,distribution,excretion and pharmacodynamics in healthy humans or in patients.During Phase 1 clinical trials,information about the investigational drug products pharmacokinetics and pharmacological effects may be obtained to per
269、mit the design of well-controlled and scientifically valid Phase 2 clinical trials.Phase 2 clinical trials are generally conducted to identify possible AEs and safety risks,evaluate the efficacy of the product candidate for specific targeted indications,and determine dose tolerance and optimal dosag
270、e.Multiple Phase 2 clinical trials may be conducted by the sponsor 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 th
271、e Phase 2 clinical trials demonstrate that a dose range of the product candidate is potentially effective and has an acceptable safety profile.Phase 3 clinical trials are undertaken within an expanded patient population to further evaluate dosage,provide substantial evidence of clinical efficacy,and
272、 further test for safety in an expanded and diverse patient population at multiple,geographically dispersed clinical trial sites.The FDA may require more than one Phase 3 clinical trial to support approval of a product candidate.A well-controlled,statistically robust Phase 3 clinical trial may be de
273、signed to deliver the data that regulatory authorities will use to decide whether or not to approve,and,if approved,how to appropriately label a drug;such Phase 3 clinical trials are referred to as“pivotal.”A Phase 2 clinical trial can be a“pivotal”trial if the design provides a well-controlled and
274、reliable assessment of clinical benefit,particularly in an area of unmet medical need.A companys designation of the phase of a trial is not necessarily indicative that the trial will be sufficient to satisfy the FDA requirements of that phase.In December 2022,with the passage of the Food and Drug Om
275、nibus Reform Act,or FDORA,Congress required sponsors to develop and submit a diversity action plan for each Phase 3 clinical trial or any other“pivotal study”of a new drug or biological product.These plans are meant to encourage the enrollment of more diverse patient populations in late-stage clinic
276、al trials of FDA-regulated products.Specifically,action plans must include the sponsors goals for enrollment,the underlying rationale for those goals,and an explanation of how the sponsor intends to meet them.In addition to these requirements,the legislation directs the FDA to issue new guidance on
277、diversity action plans.In June 2024,the FDA issued draft guidance outlining the general requirements for diversity action plans.Unlike most guidance documents issued by the FDA,the diversity action plan guidance,when finalized,will have the force of the law because FDORA specifically dictates that t
278、he form and manner for submission of diversity action plans are specified in FDA guidance.In January 2025,in response to an executive Table of Contents17order issued by President Trump on Diversity,Equity and Inclusion programs,the FDA removed this draft guidance from its website.The implications of
279、 this action are not yet known.In June 2023,the FDA issued draft guidance with updated recommendations for GCPs aimed at modernizing the design and conduct of clinical trials.The updates are intended to help pave the way for more efficient clinical trials to facilitate the development of medical pro
280、ducts.The draft guidance is adopted from the International Council for Harmonisations recently updated E6(R3)draft guideline that was developed to enable the incorporation of rapidly developing technological and methodological innovations into the clinical trial enterprise.In addition,the FDA issued
281、 draft guidance outlining recommendations for the implementation of decentralized clinical trials.In some cases,the FDA may approve an NDA for a product candidate but require the sponsor to conduct additional clinical trials to further assess the product candidates safety and effectiveness after app
282、roval.Such post-approval trials are typically referred to as Phase 4 clinical trials.These trials are used to gain additional experience from the treatment of a larger number of patients in the intended treatment group and to further document a clinical benefit in the case of drugs approved under ac
283、celerated approval regulations.Failure to exhibit due diligence with regard to conducting Phase 4 clinical trials could result in withdrawal of approval for products.Progress reports detailing the results of clinical trials must be submitted annually to the FDA within 60 days of the anniversary date
284、 that the IND went into effect and more frequently if serious AEs occur.These reports must include a development safety update report.In addition,IND safety reports must be submitted to the FDA for any of the following:serious and unexpected suspected adverse reactions;findings from other studies or
285、 animal or in vitro testing that suggest a significant risk in humans exposed to the product;and any clinically important increase in the case of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.Phase 1,Phase 2 and Phase 3 clinical trials may not be comp
286、leted successfully within any specified period,or at all.The FDA will typically inspect one or more clinical sites to assure compliance with GCP and the integrity of the clinical data submitted.Interactions with the FDA During the Clinical Development ProgramFollowing the clearance of an IND and the
287、 commencement of clinical trials,a sponsor will continue to have interactions with the FDA and the sponsor may meet with the FDA at certain points in the clinical development program.Specifically,sponsors may meet with the FDA prior to the submission of an IND,or a pre-IND meeting,at the end of Phas
288、e 2 clinical trial,or an EOP2 meeting,and before an NDA is submitted,or a pre-NDA meeting.Meetings at other times may also be requested.These meetings provide an opportunity for the sponsor to share information about the data gathered to date with the FDA and for the FDA to provide advice on the nex
289、t phase of development.There are five types of meetings that occur between sponsors and the FDA.Type A meetings are those necessary for an otherwise stalled product development program to proceed or to address an important safety issue.Type B meetings include pre-IND and pre-NDA meetings as well as
290、end of phase meetings,such as EOP2 meetings.A Type C meeting is any meeting other than a Type A or Type B meeting regarding the development and review of a product,including,for example,meetings to facilitate early consultations on the use of a biomarker as a new surrogate endpoint that has never be
291、en previously used as the primary basis for product approval in the proposed context of use.A Type D meeting is focused on a narrow set of issues(typically limited to no more than two focused topics)and should not require input from more than three disciplines or divisions.Finally,INitial Targeted E
292、ngagement for Regulatory Advice on CBER products,or INTERACT,meetings are intended for novel products and development programs that present unique challenges in the early development of an investigational product.Such meetings may be conducted in person,via teleconference/videoconference,or written
293、response only with minutes reflecting the questions that the sponsor posed to the FDA and the FDAs responses.The FDA has indicated that its responses,as conveyed in meeting minutes and advice letters,only constitute mere recommendations and/or advice made to a sponsor and,as such,sponsors are not bo
294、und by such recommendations and/or advice.Nonetheless,from a practical perspective,a sponsors failure to follow the FDAs recommendations for design of a clinical program may put the program at significant risk of failure.In September 2023,the FDA issued draft guidance outlining the terms of such mee
295、tings in more detail.Pediatric StudiesUnder the Pediatric Research Equity Act of 2003,or PREA,an NDA or supplement thereto must contain data that are adequate to assess the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations,and to support dos
296、ing and administration for each pediatric subpopulation for which the product is safe and effective.Sponsors must also submit pediatric study plans prior to the assessment data.Those plans must contain an outline of the proposed pediatric study or studies the sponsor plans to conduct,including study
297、 objectives and design,any deferral or waiver requests and other information required by regulation.The sponsor,the FDA,and the FDAs internal review committee must then review the information submitted,consult with each other and agree upon a final plan.The FDA or the sponsor may request an amendmen
298、t to the plan at any time.Table of Contents18For drugs intended to treat a serious or life-threatening disease or condition,the FDA must,upon the request of a sponsor,meet to discuss preparation of the initial pediatric study plan or to discuss deferral or waiver of pediatric assessments.In addition
299、,the FDA will meet early in the development process to discuss pediatric study plans with sponsors,and the FDA must meet with sponsors by no later than the end-of-phase 1 meeting for serious or life-threatening diseases and by no later than ninety(90)days after the FDAs receipt of the study plan.The
300、 FDA may,on its own initiative or at the request of the sponsor,grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults,or full or partial waivers from the pediatric data requirements.A deferral may be granted for several reasons,including a
301、 finding that the product or therapeutic candidate is ready for approval for use in adults before pediatric trials are complete or that additional safety or effectiveness data needs to be collected before the pediatric trials begin.The law requires the FDA to send a PREA Non-Compliance letter to spo
302、nsors who have failed to submit their pediatric assessments required under PREA,have failed to seek or obtain a deferral or deferral extension or have failed to request approval for a required pediatric formulation.Unless otherwise required by regulation,the pediatric data requirements do not apply
303、to products with orphan designation,although the FDA has recently taken steps to limit what it considers abuse of this statutory exemption in PREA by announcing that it does not intend to grant any additional orphan drug designations for rare pediatric subpopulations of what is otherwise a common di
304、sease.The FDA maintains a list of diseases that are exempt from the requirements of the PREA.In May 2023,the FDA issued new draft guidance that further describes the pediatric study requirements under PREA.Filing and Review of an NDA To obtain approval to market a drug product in the United States,a
305、 marketing application must be submitted to the FDA that provides sufficient data establishing the safety and efficacy of the proposed drug product for its intended indication.The application must include all relevant data available from pertinent preclinical and clinical trials,including negative o
306、r ambiguous results as well as positive findings,together with detailed information relating to the products chemistry,manufacturing,controls and proposed labeling,among other things.Data can come from company-sponsored clinical trials intended to test the safety and effectiveness of a product use,o
307、r from alternative sources,including studies initiated by investigators.To support marketing approval,the data submitted must be sufficient in quality and quantity to establish the safety and efficacy of the drug product to the satisfaction of the FDA.The NDA is a vehicle through which sponsors form
308、ally propose that the FDA approve a new product for marketing and sale in the United States for one or more indications.Every new drug product candidate must be the subject of an approved NDA before it may be commercialized in the United States.Under federal law,the submission of most NDAs is subjec
309、t to an application user fee,which for federal fiscal year 2025 is approximately$4.31 million.The sponsor of an approved NDA is also subject to an annual program fee,which for fiscal year 2025 is$403,889 per product.Certain exceptions and waivers are available for some of these fees,such as an excep
310、tion from the application fee for products with orphan designation and a waiver for certain small businesses.Following submission of an NDA,the FDA conducts a preliminary review of the application generally within 60 calendar days of its receipt and must inform the sponsor at that time or before whe
311、ther the application is sufficiently complete to permit substantive review.In the event that the FDA determines that an application does not satisfy this standard,it will issue a Refusal to File determination to the sponsor.In this event,the application must be resubmitted with the additional inform
312、ation.The resubmitted application is also subject to review before the FDA accepts it for filing.Once the submission is accepted for filing,the FDA begins an in-depth substantive review.Under the goals and policies agreed to by the FDA under the PDUFA,applications seeking approval of New Molecular E
313、ntities,or NMEs,are meant to be reviewed within ten months from the date on which the FDA accepts the application for filing.The review process and the PDUFA goal date may be extended by the FDA for three additional months to consider new information or clarification provided by the sponsor to addre
314、ss an outstanding deficiency identified by the FDA following the original submission.A sponsor is required to submit a sNDA if it wishes to make a change to a product that has already been approved under an NDA.Such changes may include a revision of the labeling for the approved product,addition of
315、a new indication,a change in the dosage,strength or formulation of the drug product,or a modification of the manner in which the drug is manufactured.Under the timelines established pursuant to PDUFA,the standard review time for an sNDA is generally 10 months from receipt of the application by the F
316、DA.Before approving an application,the FDA typically will inspect the facility or facilities where the product is or will be manufactured.These pre-approval inspections may cover all facilities associated with an NDA submission,including component manufacturing,finished product manufacturing and con
317、trol testing laboratories.The FDA will not approve an application unless it determines that the manufacturing processes and facilities comply with cGMP requirements and are adequate to assure consistent production of the product within required specifications.Under the FDA Reauthorization Act of 201
318、7,the FDA must implement a protocol to expedite review of responses to inspection reports pertaining to certain Table of Contents19applications,including applications for products in shortage or those for which approval is dependent on remediation of conditions identified in the inspection report.Mo
319、reover,the FDA will review a sponsors financial relationship with the principal investigators who conducted the clinical trials in support of the NDA.That is because,under certain circumstances,principal investigators at a clinical trial site may also serve as scientific advisors or consultants to a
320、 sponsor and receive compensation in connection with such services.Depending on the level of that compensation and any other financial interest a principal investigator may have in a sponsor,the sponsor may be required to report these relationships to the FDA.The FDA will then evaluate that financia
321、l relationship and determine whether it creates a conflict of interest or otherwise affects the interpretation of the trial or the integrity of the data generated at the principal investigators clinical trial site.If so,the FDA may exclude data from the clinical trial site in connection with its det
322、ermination of safety and efficacy of the investigational product.In addition,as a condition of approval,the FDA may require a sponsor to develop a REMS.REMS use risk minimization strategies beyond the professional labeling to ensure that the benefits of the product outweigh the potential risks.REMS
323、could include medication guides,communication plans for health care professionals,and elements to assure safe use,including special training or certification for prescribing or dispensing,dispensing only under certain circumstances,special monitoring and the use of patent registries.To determine whe
324、ther a REMS is needed,the FDA will consider the size of the population likely to use the product,seriousness of the disease,expected benefit of the product,expected duration of treatment,seriousness of known or potential adverse events and whether the product is an NME.The FDA may refer an applicati
325、on for a novel product which presents difficult questions of safety or efficacy to an advisory committee 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
326、 recommendation as to whether the application should be approved and under what conditions.The FDA is not bound by the recommendations of an advisory committee,but it considers such recommendations when making decisions.Fast Track,Breakthrough Therapy,Priority Review and Regenerative Advanced Therap
327、y DesignationsThe FDA is authorized to designate certain products for expedited review if they are intended to address an unmet medical need in the treatment of a serious or life-threatening disease or condition.These programs are called Fast Track designation,Breakthrough Therapy designation,priori
328、ty review designation and regenerative advanced therapy designation.Fast Track Designation.The FDA may designate a product for Fast Track review if it is intended,either alone or in combination with one or more other products,for the treatment of a serious or life-threatening disease or condition,an
329、d it demonstrates the potential to address unmet medical needs for such a 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 Track products application before the application is complete.This rolling
330、review process may be available if the FDA determines,after preliminary evaluation of clinical data submitted by the sponsor,that a Fast Track product may be effective.However,the FDAs time period goal for reviewing a Fast Track application does not begin until the last section of the application is
331、 submitted.In addition,the Fast Track designation may be withdrawn by the FDA if the FDA believes 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,either
332、 alone or in combination with one or more other products,to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.The FDA ma
333、y take certain actions with respect to Breakthrough Therapies,including:holding meetings with the sponsor throughout the development process;providing timely advice to the product sponsor regarding development and approval;involving more senior staff in the review process;assigning a cross-disciplinary project lead for the review team;and taking other steps to design the clinical trials in an effi
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