aTyr Pharma Inc (LIFE) 2024年年度報告「NASDAQ」.pdf

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1、 UNITED STATESSECURITIES AND EXCHANGE COMMISSIONWASHINGTON,D.C.20549 FORM 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 31,2024or TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1

2、934For the transition period from toCommission file number:001-37378 ATYR PHARMA,INC.(Exact name of registrant as specified in its charter)Delaware 20-3435077(State or other jurisdiction of incorporation or organization)(I.R.S.Employer Identification No.)10240 Sorrento Valley Road,Suite 300,San Dieg

3、o,CA 92121(Address of principal executive offices)(Zip Code)Registrants telephone number,including area code:(858)731-8389Securities registered pursuant to Section 12(b)of the Act:Title of each classTrading SymbolName of each exchange on which registeredCommon Stock,par value$0.001 per shareATYRThe

4、Nasdaq Capital MarketSecurities registered pursuant to Section 12(g)of the Act:NoneIndicate by check mark if the registrant is a well-known seasoned issuer,as defined in Rule 405 of the Securities Act.Yes No Indicate by check mark if the registrant is not required to file reports pursuant to Section

5、 13 or Section 15(d)of the Act.Yes No Indicate by check mark whether the registrant(1)has filed all reports required to be filed by Section 13 or Section 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 suc

6、h reports),and(2)has been subject to such filing requirements for the past 90 days.Yes No Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T(232.405 of this chapter)during the precedin

7、g 12 months(or for such shorter period that the registrant was required to submit such files).Yes NoIndicate 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

8、“large accelerated filer,”“accelerated filer,”“smaller reporting 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 ma

9、rk if the registrant has elected not to use the extended transition 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

10、 assessment of the effectiveness of its internal control over financial 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

11、by check mark whether the financial statements of the registrant 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 com

12、pensation received by any of the registrants executive officers 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 registrants voting and non-votin

13、g common equity held by non-affiliates of the registrant was approximately$116,242,729 based on the closing price of the registrants common stock on the Nasdaq Capital Market of$1.56 per share on June 30,2024,the last business day of the registrants most recently completed second fiscal quarter.Shar

14、es of common stock held by each executive officer and director have been excluded from this calculation.This determination of affiliate status may not be conclusive for other purposes.The number of outstanding shares of the registrants common stock,par value$0.001 per share,as of March 7,2025 was 88

15、,858,612.DOCUMENTS INCORPORATED BY REFERENCEPortions of the registrants definitive proxy statement to be filed with the Securities and Exchange Commission(SEC),pursuant to Regulation 14A in connection with the registrants 2025 Annual Meeting of Stockholders,which will be filed subsequent to the date

16、 hereof,are incorporated by reference into Part III of this Annual Report on Form 10-K.Such proxy statement will be filed with the SEC not later than 120 days following the end of the registrants fiscal year ended December 31,2024.2ATYR PHARMA,INC.ANNUAL REPORT ON FORM 10-KFor the Fiscal Year Ended

17、December 31,2024Table of Contents PageForward-Looking Statements3Summary of Risks Associated with Our Business3 PART I Item 1Business4Item 1ARisk Factors23Item 1BUnresolved Staff Comments59Item 1CCybersecurity59Item 2Properties60Item 3Legal Proceedings60Item 4Mine Safety Disclosures 60 PART II Item

18、5Market for Registrants Common Equity,Related Stockholder Matters and Issuer Purchases of Equity Securities61Item 6Reserved61Item 7Managements Discussion and Analysis of Financial Condition and Results of Operations61Item 7AQuantitative and Qualitative Disclosures About Market Risk 68Item 8Financial

19、 Statements and Supplementary Data69Item 9Changes in and Disagreements With Accountants on Accounting and Financial Disclosure91Item 9AControls and Procedures91Item 9BOther Information91Item 9CDisclosure Regarding Foreign Jurisdictions that Prevent Inspections91 PART III Item 10Directors,Executive O

20、fficers and Corporate Governance92Item 11Executive Compensation92Item 12Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters92Item 13Certain Relationships and Related Transactions,and Director Independence92Item 14Principal Accountant Fees and Services92 PAR

21、T IV Item 15Exhibit and Financial Statement Schedules92Item 16Form 10-K Summary95 Signatures 96 3In this Annual Report on Form 10-K(Annual Report),unless the context requires otherwise,“aTyr Pharma,”“aTyr,”“Company,”“we,”“our,”and“us”means aTyr Pharma,Inc.and our subsidiary,Pangu BioPharma Limited.T

22、he market data and certain other statistical information used in this Annual Report are based on independent industry publications,governmental publications,reports by market research firms or other independent sources.Some data are also based on our good faith estimates.Information that is based on

23、 estimates,forecasts,projections,market research or similar methodologies is inherently subject to uncertainties and actual events or circumstances may differ materially from events and circumstances reflected in this information.We own various U.S.federal trademark applications and unregistered tra

24、demarks,including our company name.All other trademarks or trade names referred to in this Annual Report are the property of their respective owners.Solely for convenience,the trademarks and trade names in this Annual Report are referred to without the symbols and,but such references should not be c

25、onstrued as any indicator that their respective owners will not assert,to the fullest extent under applicable law,their rights thereto.Forward-Looking StatementsIn addition to historical information,this Annual Report and the information incorporated herein by reference contains forward-looking stat

26、ements within the meaning of Section 27A of the Securities Act of 1933,as amended(Securities Act),and Section 21E of the Securities Exchange Act of 1934,as amended(Exchange Act),including statements regarding our business,our financial position,the research and development of biopharmaceutical produ

27、cts,the timing of clinical trial activities and other statements describing our goals,expectations,intentions or beliefs.These statements include but are not limited to statements under the captions“Business”and“Managements Discussion and Analysis of Financial Condition and Results of Operations”,as

28、 well as other sections in this Annual Report.Such statements reflect our current views and assumptions and are subject to risks and uncertainties,particularly those inherent in the process of developing and commercializing biopharmaceutical products.Actual results could differ materially from those

29、 discussed in this Annual Report.Factors that could cause or contribute to such differences include,but are not limited to,those identified in Part I,Item 1A“Risk Factors”,as well as those discussed in our other filings with the Securities and Exchange Commission(SEC).As a result,you are cautioned n

30、ot to unduly rely on these forward-looking statements.We disclaim any duty to update any forward-looking statement to reflect events or circumstances that occur after the date on which such statement is made,except as required by law.Risk Factors Summary Below is a summary of the principal factors t

31、hat make an investment in our securities speculative or risky.This summary does not address all of the risks that we face.Additional discussion of the risks summarized in this risk factors summary,and other risks that we face,can be found in Part I,Item 1A“Risk Factors”and should be carefully consid

32、ered,together with other information in this Annual Report and our other filings with the SEC before making investment decisions regarding our securities.Investing in our securities involves substantial risk.The risks described under Part I,Item 1A“Risk Factors”of this Annual Report may cause us to

33、not realize the full benefits of our strengths or may cause us to be unable to successfully execute all or part of our strategy.Some of the more significant risks we face include the following:We may encounter substantial delays and other challenges in our ongoing or planned clinical trials or we ma

34、y fail to demonstrate safety and efficacy to the satisfaction of applicable regulatory authorities;If we are unable to successfully complete or otherwise advance clinical development,obtain regulatory or marketing approval for,or successfully commercialize our therapeutic product candidates,includin

35、g efzofitimod,or experience significant delays in doing so,our business will be materially harmed;There is no established FDA regulatory pathway for approval of a drug in pulmonary sarcoidosis.As a result,our Phase 3 randomized,double-blind,placebo-controlled clinical trial to evaluate the efficacy

36、and safety of efzofitimod in patients with pulmonary sarcoidosis(the EFZO-FIT study),even if successful,may not be sufficient to support FDA approval,which would materially and adversely harm our business;We may face contracted development and manufacturing organization(CDMO)manufacturing stoppages

37、and other CDMO challenges associated with the clinical or commercial manufacture of our product candidates;Our current product candidates and any other product candidates that we may develop from our discovery platform represent novel therapeutic approaches,which may cause significant delays or may

38、not result in any commercially viable drugs;Our therapeutic product candidates may cause undesirable side effects or have other properties that could delay or prevent their regulatory approval,limit the commercial profile of an approved label,or result in significant negative consequences following

39、marketing approval,if any;4We will need to raise additional capital or enter into strategic partnering relationships to fund our operations;We are a pre-commercial biotherapeutics company and have incurred significant losses since our inception and anticipate that we will continue to incur significa

40、nt losses for the foreseeable future;We depend on our existing collaborations and may depend on collaborations with additional third parties for the development and commercialization of certain of our product candidates.If our collaborations are not successful,we may not be able to capitalize on the

41、 market potential of these product candidates;If we are unable to obtain,maintain or protect intellectual property rights related to our product candidates,or if the scope of such intellectual property protection is not sufficiently broad,we may not be able to compete effectively in our markets;Our

42、future success depends on our ability to retain key employees,consultants and advisors and to attract,retain and motivate qualified personnel;Unfavorable macroeconomic conditions could adversely affect our business,financial condition or results of operations;andThe market price of our common stock

43、historically has been highly volatile and is likely to continue to be volatile,and you could lose all or part of your investment.PART IItem 1.Business.We are a clinical stage biotechnology company leveraging evolutionary intelligence to translate tRNA synthetase biology into new therapies for fibros

44、is and inflammation.tRNA synthetases are ancient,essential proteins that have evolved novel domains that regulate diverse pathways extracellularly in humans.Our discovery platform is focused on unlocking hidden therapeutic intervention points by uncovering signaling pathways driven by our proprietar

45、y library of domains derived from all 20 tRNA synthetases.Efzofitimod Our lead therapeutic candidate is efzofitimod,a first-in-class biologic immunomodulator in clinical development for the treatment of interstitial lung disease(ILD),a group of immune-mediated disorders that can cause inflammation a

46、nd fibrosis,or scarring,of the lungs.Efzofitimod is a tRNA synthetase derived therapy that selectively modulates activated myeloid cells through neuropilin-2(NRP2)to resolve aberrant inflammation without immune suppression and potentially prevent the progression of fibrosis.ILDs are predominantly im

47、mune-mediated disorders that are characterized by chronic inflammation,which can lead to progressive fibrosis of the lung.There are limited treatment options for ILD and there remains a high unmet medical need.Sarcoidosis and systemic sclerosis(SSc,also known as scleroderma)-associated ILD(SSc-ILD)a

48、re two major forms of ILD.The U.S.Food and Drug Administration(FDA)has granted efzofitimod orphan drug designations for the treatment of sarcoidosis and for the treatment of SSc,and Fast Track designations for the treatment of pulmonary sarcoidosis and for the treatment of SSc-ILD.The European Commi

49、ssion(EC)has granted efzofitimod orphan drug designations for the treatment of sarcoidosis and for the treatment of SSc,based on the opinion of the European Medicines Agency(EMA)Committee for Orphan Medicinal Products(COMP).The Pharmaceutical and Medical Devices Agency(PMDA)has granted efzofitimod o

50、rphan drug designation for the treatment of sarcoidosis to Kyorin Pharmaceutical Co.,Ltd.(Kyorin),our partner in Japan.In September 2021,we announced positive results and clinical proof-of-concept from a double-blind,placebo-controlled Phase 1b/2a clinical trial in 37 patients with pulmonary sarcoid

51、osis.The study was designed to evaluate the safety,tolerability,immunogenicity and preliminary efficacy of three doses of intravenous(IV)efzofitimod,1.0,3.0 and 5.0 mg/kg,in the context of a forced steroid taper.Efzofitimod was safe and well-tolerated at all doses administered with no serious drug-r

52、elated adverse events or signal of immunogenicity.Additionally,the study demonstrated consistent dose response for efzofitimod on key efficacy endpoints and improvements compared to placebo,including measures of steroid reduction,lung function,pulmonary sarcoidosis symptom measures and inflammatory

53、biomarkers.These data were subsequently presented at the American Thoracic Society(ATS)International Conference and published in the peer-reviewed journal CHEST during 2022.In October 2024,the same published data for efzofitimod was featured in the Best of CHEST Journals session at the CHEST 2024 An

54、nual Meeting.In February 2022,we met with the FDA in an end-of-Phase 2 meeting to discuss our plans for subsequent clinical development and path to registration for efzofitimod for pulmonary sarcoidosis.Subsequently,we initiated a global pivotal Phase 3 randomized,double-blind,placebo-controlled cli

55、nical trial to evaluate the efficacy and safety of efzofitimod in patients with pulmonary sarcoidosis(the EFZO-FIT study).The EFZO-FIT study is a 52-week study consisting of three parallel cohorts randomized equally to either 3.0 mg/kg or 5.0 mg/kg of efzofitimod or placebo dosed intravenously once

56、a month for a total of 12 doses.We expected the study to enroll up to 264 subjects with pulmonary sarcoidosis at multiple centers in the United States,Europe,Brazil,and Japan.The study design 5incorporates a forced steroid taper.The objective of the study is to evaluate the efficacy and safety of ef

57、zofitimod in patients with pulmonary sarcoidosis.The primary endpoint of the study is steroid reduction.Secondary endpoints include measures of lung function assessed by forced vital capacity(FVC)and health-related quality of life assessments and questionnaires(KSQ lung score).In September 2022,we d

58、osed the first patient in the study.During 2023 and 2024,we have had data and safety monitoring board(DSMB)reviews of our EFZO-FIT study.The DSMB reviews concluded that the study could continue unmodified.In July 2024,we completed enrollment of 268 patients,exceeding target enrollment.Topline data f

59、rom the study are anticipated in the third quarter of 2025.In February 2024,we announced an Individual Patient Expanded Access Program(Individual Patient EAP).The Individual Patient EAP has been initiated based on blinded EFZO-FIT study investigator and patient participant feedback.The program is de

60、signed to allow access for patients who complete the Phase 3 EFZO-FIT study and wish to receive treatment with efzofitimod outside of the clinical trial.The administration of efzofitimod as part of the Individual Patient EAP will occur independent of the EFZO-FIT study protocol,and we,principal inve

61、stigators and patients will remain blinded to the treatment that occurred as part of the EFZO-FIT study.As this Individual Patient EAP will occur independent of the EFZO-FIT study,this program is not an open-label extension(OLE)and no long-term data will be collected by us.Based on the results of th

62、e Phase 1b/2a clinical trial,we believe efzofitimod has potential applications in the treatment of other ILDs,such as chronic hypersensitivity pneumonitis(CHP)and connective tissue disease related ILD(CTD-ILD),including SSc-ILD and rheumatoid arthritis-associated ILD.As such,we designed a focused Ph

63、ase 2 proof-of-concept clinical trial of efzofitimod(the EFZO-CONNECT study)in patients with SSc-ILD.The EFZO-CONNECT study is a randomized,double-blind placebo-controlled proof-of-concept study to evaluate the efficacy,safety and tolerability of efzofitimod in patients with SSc-ILD.This is a 28-wee

64、k study with three parallel cohorts randomized 2:2:1 to either 270 mg or 450 mg of efzofitimod or placebo dosed intravenously monthly for a total of six doses.The study intends to enroll up to 25 patients at multiple centers in the United States.The objective of the study is to evaluate the efficacy

65、 of multiple doses of IV efzofitimod on pulmonary,cutaneous(limited or diffuse)and systemic manifestations in patients with SSc-ILD.The primary endpoint is reduction in FVC.Secondary endpoints include certain measures regarding safety and tolerability.In July 2024,we amended the study to add an OLE

66、to patients.Patients who complete the study and wish to receive ongoing treatment with efzofitimod are eligible to participate in the 24-week OLE.Based on current enrollment projections,we expect to report interim data from the study in the second quarter of 2025.In January 2020,we entered into a co

67、llaboration and license agreement(Kyorin Agreement)with Kyorin for the development and commercialization of efzofitimod for the treatment of ILD in Japan.Under the terms of the Kyorin Agreement,Kyorin received exclusive rights to develop and commercialize efzofitimod in Japan for all forms of ILD,an

68、d is obligated to fund all research,development,regulatory,marketing and commercialization activities in Japan.We are responsible for supplying all drug product for Japan,as well as supporting development activities for efzofitimod.In 2020,Kyorin conducted and funded a Phase 1 clinical trial of efzo

69、fitimod(known as KRP-R120 in Japan).The Phase 1 clinical trial was a placebo-controlled clinical trial to evaluate the safety,pharmacokinetics(PK)and immunogenicity of efzofitimod in 32 healthy Japanese male volunteers.Efzofitimod was observed to be generally well-tolerated with no drug-related seri

70、ous adverse events,and PK findings were consistent with previous studies of efzofitimod.Kyorin is also participating in the EFZO-FIT study as the local sponsor in Japan.In February 2023,Kyorin dosed the first patient in Japan in the EFZO-FIT study which triggered a$10.0 million milestone payment to

71、us.To date,the Kyorin Agreement has generated$20.0 million in upfront and milestone payments to us and we are eligible to receive up to an additional$155.0 million in the aggregate upon achievement of certain development,regulatory and sales milestones,as well as tiered royalties on any net sales in

72、 Japan.Discovery Platform Using efzofitimod as a model,we have developed a process to advance novel tRNA synthetase domains from a concept to therapeutic candidate.This process leverages our early discovery work as well as current scientific understanding of tRNA synthetase evolution,protein structu

73、re,gene splicing and tissue-specific regulation to identify potentially active protein domains.Screening approaches are employed to identify target cells and extracellular receptors for these tRNA synthetase-derived proteins.These cellular systems can then be used in mechanism-of-action studies to e

74、lucidate the role these proteins play in cellular responses and their potential therapeutic utility.We are working to identify new tRNA synthetase based drug candidates through our internal discovery efforts and external collaboration efforts.6Therapeutic Candidate Pipeline Strategy Key elements of

75、our strategy include the following:Advance efzofitimod toward regulatory approval in pulmonary sarcoidosis.Based on the positive results and clinical proof-of-concept from our efzofitimod Phase 1b/2a clinical trial in September 2021,we believe we can expedite development of efzofitimod for pulmonary

76、 sarcoidosis toward regulatory approval.In July 2024,we completed enrollment of the EFZO-FIT study.Topline data from the EFZO-FIT study are anticipated in the third quarter of 2025,and our strategy for the advancement of efzofitimod includes submitting data from the EFZO-FIT study to the FDA,which w

77、e expect to serve as the basis for U.S.regulatory approval.Transition from a clinical stage biotech to a commercial pharmaceutical company.We anticipate that positive topline data from the EFZO-FIT study could be a significant catalyst for potential future commercial development of efzofitimod for p

78、atients with pulmonary sarcoidosis.We have begun pre-commercialization efforts in the U.S.market and intend to expand these efforts with positive topline data.We are focusing our pre-commercialization efforts in marketing,commercial operations and commercial supply,including general and administrati

79、ve support.Develop efzofitimod to address unmet medical needs in other ILDs.In addition,we believe the positive results from our efzofitimod Phase 1b/2a clinical trial,as well as data from numerous preclinical studies we have conducted to date,will give us the opportunity to potentially launch addit

80、ional clinical trials of efzofitimod in other forms of ILD.As part of this strategy,we have initiated and progressed the EFZO-CONNECT study of efzofitimod in patients with SSc-ILD.Build a diverse pipeline of biologics product candidates based on our understanding of extracellular tRNA synthetase bio

81、logy.Utilizing our unique drug discovery approach through internal research efforts and external collaboration efforts,we intend to continue to advance novel tRNA synthetase domains from concept to product candidates in the areas of fibrosis and inflammation.We have advanced two tRNA synthetase prog

82、rams,ATYR0101 and ATYR0750,into preclinical development.We plan to further elucidate the therapeutic potential of these candidates through mechanistic investigations,including in vitro and in vivo preclinical studies.EfzofitimodBackground and Mechanism of Action Efzofitimod is a novel immunomodulato

83、ry Fc fusion protein in development for the treatment of ILD.Efzofitimod is a selective modulator of NRP2 that downregulates innate immune responses at a cellular level in uncontrolled inflammatory disease states to resolve chronic inflammation and prevent subsequent fibrosis.7Efzofitimod is a novel

84、 molecular entity comprised of a human 59 amino acid protein fused to the Fc region of human immunoglobulin 1(IgG1).It acts as an extracellular immunomodulator.The amino acid sequence of the active moiety corresponds identically to the extracellularly active immunomodulatory domain of histidyl-tRNA

85、synthetase(HARS)amino acids 2 to 60(HARS 2-60).The gene for HARS gives rise to a number of splice variants,and though most of these have lost their catalytic activity,they all retain the N-terminal domain(HARS amino acids 1-60).This N-terminal domain,non-essential for the enzymes protein synthesis a

86、ctivity that is required in all living organisms,was appended to HARS during the evolutionary development of multicellular organisms and retained with high sequence identity across mammalian species,but is not found in lower organisms.One splice variant(SV9),which encodes only the N-terminal domain

87、of the protein,is enriched in human lung tissue.Expression of this HARS splice variant is increased following inflammatory cytokine stimulation(interferon gamma(IFN-g)and TNF alpha(TNF-a),two key players in the initiation of lung inflammation and fibrosis)followed by subsequent secretion,indicating

88、it is being regulated in response to local inflammation.Furthermore,HARS,specifically the N-terminal domain,is targeted by autoantibodies in a rare autoimmune disorder(known as anti-Jo-1 syndrome).Anti-Jo-1 syndrome is characterized by extensive activation and migration of immune cells into lung and

89、 muscle and is classically associated with the triad of ILD,myositis,and arthritis.It is hypothesized that the sequestration of HARS may play a causal role through disruption of its homeostatic immune-regulatory effects.NRP2 was identified as the sole binding partner for efzofitimod through screenin

90、g via a cell microarray system in which over 4,500 cell surface proteins are represented.This screening approach identified two NRP2 isoforms(Neuropilin 2A and 2B)as the only convincing and specific binding partners of efzofitimod.The binding site was confirmed to be within the“turn”of the helix-tur

91、n-helix structure of the HARS N-terminal domain comprised within efzofitimod.Binding of efzofitimod is specific to NRP2 with no observable cross-reactivity to NRP1,which is the most closely related cell surface receptor in both protein sequence and structure.A domain that is structurally similar(but

92、 divergent in protein sequence)to the HARS N-terminal domain(termed the WHEP domain)is found in other amino-acyl tRNA synthetases,yet these domains do not exhibit binding to NRP2,indicating this is a highly specific interaction.Interestingly,binding of efzofitimod occurs in a manner distinct from th

93、e more well-characterized ligands of NRP2 including VEGF and semaphorin 3F(SEMA3F),and does not interfere with NRP2 dimerization with their co-receptors.Thus,the HARS N-terminus appears to be a newly discovered ligand for NRP2,as opposed to an antagonist.The discovery of the HARS N-terminus/NRP2 sig

94、naling axis represents a previously unknown mechanism of biological regulation,in which this novel ligand of NRP2 may act as a homeostatic regulator of aberrant immune responses.NRP2 is a cell surface receptor that is present on multiple immune cell types,including certain myeloid cells and subsets

95、of T-cells.NRP2 expression is often upregulated upon inflammatory insult or stimulation.Growing evidence indicates that NRP2 predominantly influences myeloid cell biology such as activation and recruitment to inflammatory sites.For instance,NRP2 expression on alveolar macrophages regulates airway in

96、flammatory responses to inhaled lipopolysaccharide.In sarcoidosis,NRP2 expression has been shown to be localized within the sarcoid granulomas,highly expressed in Langhans giant cells which are myeloid in nature.Efzofitimod has been shown to significantly reduce lung inflammation and fibrosis,reduce

97、 immune cell trafficking to the lung and improve respiratory function parameters in multiple animal models of lung fibrosis.Furthermore,efzofitimod has demonstrated consistent downregulatory effects on inflammatory and pro-fibrotic cytokines and chemokines in both animal disease models and human cli

98、nical trials.Efzofitimod appears to primarily impact interleukin-6(IL-6),TNF-?,IFN-?,MCP-1 and IP-10,markers that have been implicated in the pathology of ILD.Preclinical DevelopmentOur preclinical estate of translational animal models was selected to help inform and de-risk clinical development of

99、efzofitimod.We have evaluated the biological activity and safety of efzofitimod across a diverse set of experimental fibrotic lung disease models,representative of the four major forms of ILD(sarcoidosis,CHP,CTD-ILD and idiopathic pulmonary fibrosis(IPF),as well as in normal animals,looking for sign

100、als of activity and potential biomarkers,while confirming tolerability and a favorable safety profile.In these models,efzofitimod has significantly reduced histological lung fibrosis and inflammation,restored normal lung function,reduced lung protein levels of several inflammation and fibrosis-relat

101、ed cytokines and chemokines(e.g.IFN-,MCP-1/CCL2,IL-6)and reduced counts of immune cells in bronchoalveolar lavage(BAL)central to ILD pathology(e.g.,neutrophils).These data have been presented in posters at key respiratory conferences over the past several years(e.g.the ATS International Congress)and

102、 are available for review on our website.8Efzofitimod and NRP2 receptor NRP2 is known to be expressed on a number of different immune cell types that play a key role in regulating inflammatory responses.Efzofitimod is a fusion protein combining a novel immunomodulatory domain from HARS and a human I

103、gG1 Fc.Efzofitimod inhibits cytokines and chemokines involved in the regulation of inflammatory and fibrotic responses and reduces inflammation and fibrosis in animal models of ILD.Efzofitimod has previously demonstrated potent immunomodulatory activity in vitro and in vivo.We sought to characterize

104、 the molecular basis for efzofitimods immunomodulatory properties and demonstrated that efzofitimod specifically and selectively binds to NRP2 on the cell surface.These findings indicate that modulation of the NRP2 signaling pathway with efzofitimod could be a novel therapeutic approach to immune-me

105、diated and fibrotic diseases such as pulmonary sarcoidosis.Sarcoidosis is characterized by the formulation of granulomas,clumps of inflammatory cells found in one or more organs of the body and denoted by the presence of Langhans giant cells which are myeloid in nature.NRP2 was shown to be expressed

106、 in samples obtained from lung and skin of sarcoidosis patients with high NRP2 expression detected on key immune cells known to play an important role in inflammation and granuloma formation,including the Langhans giant cells.In work carried out in collaboration with Dr.Elliot Crousers laboratory at

107、 The Ohio State University utilizing an established ex vivo assay of granuloma formation,it was demonstrated that an efzofitimod analog containing the identical immunomodulatory HARS domain exhibited statistically significant reduction of granuloma formation generated from sarcoid peripheral blood m

108、ononuclear cells(PBMCs).Given the importance of granulomas in the pathology and progression of pulmonary sarcoidosis and the known ability of efzofitimod to disrupt inflammatory responses,we hypothesize that efzofitimod may play a role in regulating sarcoid granuloma formation.These findings highlig

109、ht the potential of efzofitimod to exert its effect on various immune cells directly related to the pathology of the target patient population.These data were presented in posters at the ATS International Virtual Meeting in 2020 and the European Society International Congress in 2021.As an extension

110、 of this work,a highly selective and sensitive antibody was developed for immunohistochemical detection of the target receptor for efzofitimod,NRP2,in patient tissue samples.Development and characterization of the antibody,as well as detection of NRP2 on key immune cells in granulomas of sarcoidosis

111、 patient lung and skin biopsy samples was highlighted in a poster presentation at the European Respiratory Society(ERS)International Congress 2022 in Barcelona,Spain.SSc-ILD is an autoimmune disease characterized by chronic inflammation and fibrosis with common involvement of the skin and lungs.As i

112、n sarcoidosis,myeloid cells are centrally involved in driving this cycle of chronic inflammation and fibrosis in SSc-ILD.One aspect of this is the production by these cells of inflammatory cytokines,including IL-6.Based on our translational biology program,which demonstrated activity across distinct

113、 experimental animal models either driven by direct lung injury or systemic pathology,along with our understanding of efzofitimods mechanism of action,we decided to move the program forward into patient clinical trials in ILD.ILD and the Role of Immunology The current primary target population for e

114、fzofitimod is ILD,a group of predominantly immune-mediated disorders which can cause progressive fibrosis of the lung.There are over 200 different types of ILD,of which the four major forms are:pulmonary sarcoidosis,CHP,CTD-ILD,and IPF.These four types comprise roughly 80%of the total ILD population

115、.We have focused our development efforts on progressive,immune-mediated forms of ILD,with limited therapeutic options,where we believe efzofitimod can have disease modifying effects.These lung conditions are recognized as having a measurable immune-mediated pathology,involving both innate and adapti

116、ve immune mechanisms that contribute to pathogenesis,and can result in progressive disease leading to fibrosis and death.Pulmonary Sarcoidosis Sarcoidosis is an inflammatory disease of unknown cause,characterized by the formation of granulomas,clumps of inflammatory cells in one or more organs in th

117、e body.Sarcoidosis affects people of all ages,with the incidence peaking at 30-50 years of age.The disorder can occur in almost any organ,but primarily affects the lungs.Sarcoidosis in the lungs is called pulmonary sarcoidosis and occurs in over 90%of sarcoidosis patients.Approximately 200,000 Ameri

118、cans are currently living with sarcoidosis.The prognosis for patients with pulmonary sarcoidosis ranges from benign and self-limiting to chronic,debilitating fibrotic disease and death.The immunopathogenesis of sarcoidosis is not yet well understood,but a hallmark of the disease is the presence of g

119、ranulomas,or clumps of immune cells.Granulomas consist of epithelioid cells,lymphocytes(both T and B cells)and myeloid cells,with macrophages and multinucleated giant cells(formed by fusion of macrophages),both of myeloid origin,playing a central role in their formation and persistence.A leading hyp

120、othesis is that granuloma formation involves the interplay between antigen,human leukocyte antigen class II molecules,and T-cell receptors:a presumptive sarcoid antigen is engulfed by circulating antigen-presenting cells(APCs;macrophages,dendritic cells)and the subsequent interplay between APCs and

121、CD4+T-cells initiates granuloma formation.This process is accompanied by the release of inflammatory cytokines such as MCP-1,IL-6,IFN-g and TNF-a from myeloid cells.9For patients with pulmonary sarcoidosis,the primary goal of treatment is to improve quality of life and avoid damage to organs.Efzofit

122、imod may provide a therapeutic benefit in pulmonary sarcoidosis by resolving chronic inflammation,alleviating symptoms such as cough and shortness of breath and preventing disease progression towards fibrosis and permanent organ damage.Efzofitimod may also improve patient quality of life by allowing

123、 patients to reduce or completely avoid the need for oral corticosteroids(OCS),which are associated with debilitating side effects when used chronically.Efzofitimod targets the immune cells,primarily of myeloid lineage(monocytes,macrophages and dendritic cells),that drive the cellular pathology obse

124、rved in pulmonary sarcoidosis.In preclinical studies,efzofitimod has been observed to inhibit cytokines involved in regulation of inflammatory and immune responses,modulating the reaction of myeloid cells at the sites of inflammation and attenuating T-cell activation.We have also discovered that efz

125、ofitimods receptor target NRP2 is up-regulated during differentiation and activation of myeloid cells including macrophages,dendritic cells and neutrophils.Furthermore,efzofitimod has been observed to significantly reduce lung inflammation and fibrosis and improve respiratory function parameters in

126、bleomycin-induced animal models of ILD.We believe that by inhibiting the chronic inflammatory response in these patients,efzofitimod may be able to restore immune balance and prevent progressive fibrosis,without toxicity associated with current treatment options,thereby providing a safer,potentially

127、 more effective alternative to OCS and other immunosuppressive therapies that currently comprise the standard of care for patients with symptomatic pulmonary sarcoidosis.Systemic Sclerosis Systemic sclerosis(SSc,or scleroderma)is a chronic,progressive,autoimmune disease characterized by inflammation

128、 and fibrosis of connective tissues throughout the body,including the skin and other internal organs.SSc that occurs in the lungs is called SSc-ILD.It is estimated that approximately 100,000 people in the U.S.are affected by SSc and over 50%may develop ILD.SSc-ILD is caused by chronic inflammation i

129、n the lungs and,if left untreated,can result in scarring,or fibrosis,that causes permanent loss of lung function.ILD is the primary cause of death in patients with SSc.Current treatment options are limited.They mainly focus on slowing lung function decline,do not improve patient symptoms and are ass

130、ociated with significant toxicity.New treatments are needed that can stabilize or improve lung function and improve patient quality of life.Efzofitimod has been shown to reduce lung and skin fibrosis in an animal model of SSc.Certain cytokines central to the immune pathology of SSc-ILD,including IL-

131、6 and MCP-1,were also downregulated in both animal models of ILD and in humans in an adjacent ILD,pulmonary sarcoidosis,in our Phase 1b/2a study.Furthermore,NRP2 is expressed in the skin of patients with SSc.This data in both animal and human systems,along with our current understanding of the role

132、of efzofitimods target receptor NRP2 and the manner with which this novel ligand can modulate the immune response at the sites of inflammation,suggest it is a promising therapeutic candidate for SSc-ILD.Clinical DevelopmentEfzofitimod Phase 3 Clinical Trial Pulmonary SarcoidosisWe are conducting the

133、 EFZO-FIT study,which is a global Phase 3,multicenter,randomized,double-blind,placebo-controlled study to evaluate the efficacy and safety of IV efzofitimod 3.0 mg/kg and 5.0 mg/kg versus placebo in patients with symptomatic pulmonary sarcoidosis.It is a 52-week study with patients receiving either

134、efzofitimod or placebo once a month for a total of 12 doses.The study enrolled 268 adults with histologically confirmed pulmonary sarcoidosis receiving stable treatment with OCS,with or without immunosuppressant therapy,at centers throughout the United States,Europe,Brazil and Japan.The study incorp

135、orates a forced steroid taper.The objective of the study is to evaluate the efficacy and safety of efzofitimod in patients with pulmonary sarcoidosis.The primary endpoint of the study is steroid reduction.Secondary endpoints include measures of lung function assessed by FVC and health-related qualit

136、y of life assessments and questionnaires(KSQ lung score).This study consists of three periods:a screening period,a 48-week placebo-controlled treatment period with the primary endpoint being measured at week 48,and a four-week follow-up period.Within the study,patients will be randomized 1:1:1 to ef

137、zofitimod 3.0 mg/kg(N=88),efzofitimod 5.0 mg/kg(N=88)or placebo(N=88).Study drug is administered via IV infusion every four weeks for a total of 12 doses(48 weeks of treatment).Starting on Day 15 patients begin a taper(reduction)in OCS according to specific guidelines from their starting dose of 7.5

138、-25 mg/day of prednisone(or equivalent)to a target dose of 0.0 mg/day.Patients will be followed for the remainder of the study to determine their ability to remain off of OCS.Patients who require an increase in OCS dose at any time in the study will continue to receive blinded study drug and be foll

139、owed through to the end of the study.In September 2022,we dosed the first patient in this study.Additionally,during 2023 and 2024,we had DSMB reviews of our EFZO-FIT study.Following each DSMB review,the DSMB concluded that the study could continue unmodified.In July 2024,we completed enrollment of 2

140、68 patients,exceeding target enrollment of 264 patients.Topline data from the study are anticipated in the third quarter of 2025.In February 2024,we announced an Individual Patient EAP.The Individual Patient EAP has been initiated based on blinded EFZO-FIT study investigator and patient participant

141、feedback.The program is designed to allow access for patients who complete the 10Phase 3 EFZO-FIT study and wish to receive treatment with efzofitimod outside of the clinical trial.The administration of efzofitimod as part of the Individual Patient EAP will occur independent of the EFZO-FIT study pr

142、otocol,and we,principal investigators and patients will remain blinded to the treatment that occurred as part of the EFZO-FIT study.As this Individual Patient EAP will occur independent of the EFZO-FIT study,this program is not an OLE and no long-term data will be collected by us.Efzofitimod Phase 1

143、b/2a Clinical Trial Pulmonary SarcoidosisWe designed a proof-of-concept Phase 1b/2a clinical trial for efzofitimod in patients with pulmonary sarcoidosis.The Phase 1b/2a clinical trial was a randomized,double-blind,placebo-controlled multiple-ascending dose,first-in-patient study with IV efzofitimod

144、 in 37 patients.The study was conducted in patients with pulmonary sarcoidosis undergoing an OCS tapering regimen,in three cohorts of 12 patients each,at dose levels of 1.0 mg/kg,3.0 mg/kg and 5.0 mg/kg.The primary objective of the study was to evaluate safety and tolerability of multiple ascending

145、doses of efzofitimod.Secondary objectives included assessment of the potential steroid-sparing effects of efzofitimod.In addition,efzofitimods PK and immunogenicity following multiple dose administration were evaluated.Additional endpoints of interest included the exploratory assessment of the effic

146、acy of efzofitimod for the treatment of pulmonary sarcoidosis by evaluating changes over time in:lung function assessed by forced vital capacity(FVC)and diffusing capacity of the lungs for carbon monoxide(DLCO);health-related quality of life assessments and questionnaires;and serum biomarkers of int

147、erest.This study consisted of three staggered dose cohorts.Each cohort consisted of three periods:a screening period,a 20-week placebo-controlled treatment period,and a four-week follow-up period ending with final study assessments at Week 24.Within each cohort,12 patients were randomized 2:1 to efz

148、ofitimod(N=8)or placebo(N=4).Study drug was administered via IV infusion every four weeks for a total of six doses(20 weeks of treatment).The efzofitimod doses levels being evaluated were 1 mg/kg,3 mg/kg and 5 mg/kg.Starting on Day 15 patients began a taper(reduction)in OCS according to specific gui

149、delines from their starting dose of 10-25 mg/day of prednisone(or equivalent)to a target dose of 5.0 mg/day,to be completed on or before Day 50.The OCS dose was tapered through Week 24 and patients were followed for the remainder of the study to determine their ability to maintain on this 5 mg dose.

150、Optionally,further reductions in the OCS dose to below 5.0 mg/day may be attempted after the Week 16 visit,if determined by the investigator to be feasible.Patients who required an increase in OCS dose at any time in the study were to continue to receive blinded study drug and be followed through to

151、 the end of the study.In September 2021,we announced positive results and clinical proof-of-concept from the Phase 1b/2a clinical trial in 37 patients with pulmonary sarcoidosis.These data were subsequently presented at the ATS International Conference and published in the peer reviewed journal CHES

152、T in 2022.Efzofitimod was safe and well-tolerated at all doses with no drug-related serious adverse events or signal of immunogenicity.Additionally,the study demonstrated consistent dose response for efzofitimod on key efficacy endpoints and improvements compared to placebo,including measures of ste

153、roid reduction,lung function,sarcoidosis symptom measures and inflammatory biomarkers.Key safety and clinical efficacy findings for efzofitimod from the study include:Safe and well-tolerated at all doses:No dose-relationship with most common adverse events associated with underlying disease;No drug-

154、related serious adverse events;andNo signal of immunogenicity.Dose response and consistent positive findings across key efficacy endpoints:Steroid reduction of 58%overall from baseline and 22%relative reduction compared to placebo in steroid usage post taper in the 5.0 mg/kg treatment group;Complete

155、 steroid taper to 0 mg achieved and maintained for 33%of patients in the 5.0 mg/kg treatment group compared to no patients in any other group;Absolute improvement in FVC as a measure of lung function at week 24 of 3.3%in the 5.0 mg/kg treatment group compared to placebo,with an improvement in FVC of

156、 2.5%,considered clinically meaningful;Clinically meaningful improvement over placebo observed for dyspnea(shortness of breath),cough,fatigue and the Kings Sarcoidosis Scores for Lung and General Health in 5.0 mg/kg treatment group;Dose dependent trends of improvement in key inflammatory biomarkers

157、compared to placebo including IL-6,MCP-1,IFN-,IP-10 and TNF-?as well as key sarcoidosis markers including ACE,IL-2Ra and SAA with tightest control in the 5.0 mg/kg treatment group;and 11FDG-PET-CT was not evaluable due to incomplete data primarily caused by operational issues related to the COVID-19

158、 pandemic.We have published additional analyses of data from this study.The study demonstrated consistent dose response for efzofitimod on key efficacy endpoints and improvements compared to placebo,including measures of steroid reduction,lung function,pulmonary sarcoidosis symptom measures and infl

159、ammatory biomarkers.These data were presented at the American Thoracic Society(ATS)International Conference and published in the peer-reviewed journal CHEST during 2022.In October 2024,the same published data for efzofitimod was featured in the Best of CHEST Journals session at the CHEST 2024 Annual

160、 Meeting.Efzofitimod Phase 2 Clinical Trial SSc-ILDDuring 2023,we initiated the EFZO-CONNECT study,a Phase 2 study of efzofitimod in patients with SSc-ILD.The EFZO-CONNECT study is a Phase 2 randomized,double-blind placebo-controlled proof-of-concept study to evaluate the efficacy,safety and tolerab

161、ility of efzofitimod in patients with SSc-ILD.The study is a 28-week study with three parallel cohorts randomized 2:2:1 to either 270 mg or 450 mg of efzofitimod or placebo dosed IV monthly for a total of six doses.The study intends to enroll up to 25 patients at multiple centers in the United State

162、s.The objective of the study is to evaluate the efficacy of multiple doses of IV efzofitimod on pulmonary,cutaneous(limited or diffuse)and systemic manifestations in patients with SSc-ILD.The primary endpoint is reduction of FVC.Secondary endpoints include certain measures regarding safety and toler

163、ability.In July 2024,we amended the study to add an OLE to patients.Patients who complete the study and wish to receive ongoing treatment with efzofitimod are eligible to participate in the 24-week OLE.Based on current enrollment projections,we expect to report interim data from the study in the sec

164、ond quarter of 2025.Efzofitimod Phase 2 Clinical Trial COVID-19 with Severe Respiratory Complications In response to the COVID-19 pandemic,we conducted a Phase 2 clinical trial of efzofitimod in patients with COVID-19 related severe respiratory complications.The study was designed to evaluate the sa

165、fety and preliminary efficacy of efzofitimod compared to placebo through the assessment of key clinical outcome measures.In early 2021,we reported positive data which showed that the trial met its primary endpoint of safety,demonstrating that a single,IV dose of efzofitimod was observed to be genera

166、lly safe and well-tolerated in both the 1.0 and 3.0 mg/kg treatment groups.The study also showed a signal of activity in the 3.0 mg/kg cohort.In addition,patients treated with efzofitimod demonstrated a trend of overall improvement in key biomarkers analyzed compared to placebo.We are leveraging the

167、se data for our mechanistic understanding of efzofitimod and for its application in ILD.Efzofitimod Phase 1 Clinical Trial Healthy VolunteersIn June 2018,we announced results of our first-in-human Phase 1 clinical trial of efzofitimod conducted in Australia.This randomized,double-blind,placebo-contr

168、olled study evaluated the safety,tolerability,immunogenicity,and PK of IV efzofitimod in healthy volunteers.The Phase 1 clinical trial enrolled 36 healthy volunteers who were randomized to one of six sequential cohorts and received a single infusion of IV efzofitimod or placebo.Ascending efzofitimod

169、 doses by cohort ranged from 0.03 mg/kg to 5.0 mg/kg.The results indicate that the drug was observed to be generally well-tolerated at all dose levels tested,with no significant adverse events or induction of anti-drug antibodies observed following efzofitimod dosing or throughout the one-month foll

170、ow-up period.The PK profile of efzofitimod following single-dose administration was linear across the evaluated dose range.Higher efzofitimod doses yielded sustained serum concentrations through the end of the one-month follow-up period that were above the predicted therapeutic threshold,supporting

171、the potential for a once-monthly dosing regimen.Kyorin AgreementIn January 2020,we entered into the Kyorin Agreement for the development and commercialization of efzofitimod for the treatment of ILD in Japan.Under the terms of the Kyorin Agreement,Kyorin received exclusive rights to develop and comm

172、ercialize efzofitimod in Japan for all forms of ILD and is obligated to fund all research,development,regulatory,marketing and commercialization activities in Japan.We are responsible for supplying alldrug product for Japan,as well as supporting development activities for efzofitimod.In 2020,Kyorin

173、conducted and funded a Phase 1 clinical trial of efzofitimod(known as KRP-R120 in Japan).The Phase 1 trial was a placebo-controlled study to evaluate the safety,PK and immunogenicity of efzofitimod in 32 healthy Japanese male volunteers.Efzofitimod was observed to be generally well-tolerated with no

174、 drug-related serious adverse events,and PK findings were consistent with previous studies of efzofitimod.Kyorin is also participating in the EFZO-FIT study as the local sponsor in Japan.In February 2023,Kyorin dosed the first patient in Japan in the EFZO-FIT study which triggered a$10.0 million mil

175、estone payment to us.To date,the KyorinAgreement has generated$20.0 million in upfront and milestone payments to us and we are eligible to receive up to an additional$155.0 million in the aggregate upon achievement of certain development,regulatory and sales milestones,as well as tiered royalties on

176、 any net sales in Japan.12Unless earlier terminated,the term of the Kyorin Agreement continues until the expiration of the royalty obligations.Either party may terminate the Kyorin Agreement in the event that the other party breaches the agreement and fails to cure the breach,becomes insolvent or ch

177、allenges certain of the intellectual property rights licensed under the agreement.Our Discovery Platform tRNA Synthetase Biology Extracellular tRNA synthetase biology represents a novel set of potential physiological modulators and therapeutic targets.Using efzofitimod as a model,we have developed a

178、 process to advance novel tRNA synthetase domains from a concept to therapeutic candidate.This process leverages our early discovery work as well as current scientific understanding of tRNA synthetase evolution,protein structure,gene splicing and tissue-specific regulation to identify potentially ac

179、tive protein domains.Screening approaches are employed to identify target cells and extracellular receptors for these tRNA synthetase-derived proteins.These cellular systems can then be used in mechanism-of-action studies to elucidate the role these proteins play in cellular responses and their pote

180、ntial therapeutic utility.We are working to identify new tRNA synthetase based drug candidates through our internal discovery efforts and intend to continue to advance our product development efforts within our tRNA synthetase biology platform.tRNA Synthetase CandidatesUtilizing our novel approach,w

181、e have identified target receptors for domains of two additional tRNA synthetases,gaining insights into their potential biological activity in immunology and fibrosis.These fragments form the basis of our additional pipeline candidates.We plan to further elucidate the therapeutic potential of these

182、candidates through mechanistic investigations,including in vitro and in vivo preclinical studies.ATYR0101ATYR0101 is a fusion protein derived from a domain of aspartyl-tRNA synthetase(DARS).ATYR0101 binds directly to latent-transforming growth factor beta-binding protein 1(LTBP1),which regulates tra

183、nsforming growth factor beta(TGF),which is at the apex of fibrotic signaling.Derived from a naturally occurring tRNA synthetase,ATYR0101 interacts with LTBP1 in a unique way that presents a differentiated approach to targeting fibrosis.Early data suggest ATYR0101 exerts its antifibrotic effects by i

184、nducing apoptosis of myofibroblasts in a TGF dependent manner.We believe ATYR0101 may have broad therapeutic applications in multiple fibrotic diseases,such as pulmonary fibrosis,SSc,liver fibrosis and kidney fibrosis.ATYR0750ATYR0750 is a fusion protein derived from a domain of alanyl-tRNA syntheta

185、se(AARS).ATYR0750 is a novel ligand to fibroblast growth factor receptor 4(FGFR4),which is involved in many cellular processes,including cell proliferation,differentiation,and tissue repair.FGFR4 is known to play a role in diseases related to inflammation and fibrosis,particularly in the liver.As a

186、novel ligand,ATYR0750 interacts with FGFR4 in a differentiated way to other approaches targeting the receptor,which may lead to improved therapeutic benefit.Competition The biotechnology and pharmaceutical industries are intensely competitive.We will face competition with respect to our current prod

187、uct candidates and any other therapeutics we may develop or commercialize in the future,from pharmaceutical companies,biotechnology companies,universities and other research institutions.Our competitors may have substantially greater financial,technical and other resources,such as larger research an

188、d development staff and established marketing,sales and manufacturing organizations.Additional mergers and acquisitions in the biotechnology and pharmaceutical industries may result in even more resources being concentrated in our competitors.Competition may increase further as a result of advances

189、in the commercial applicability of technologies and greater availability of capital for investment in these industries.Our competitors may succeed in developing,acquiring or licensing on an exclusive basis,drug products that are more effective,safer or less costly than any product candidate that we

190、may develop.Although we believe we are the only company engaged in the discovery and development of therapeutics based on novel functions of tRNA synthetases,we are aware of other companies that could compete with our product candidates as described below.Efzofitimod Our lead indication for efzofiti

191、mod is pulmonary sarcoidosis.For patients with pulmonary sarcoidosis,the primary goal of treatment is to improve the patients quality of life and avoid danger to organs,such as development of scarring or fibrosis caused by chronic inflammation.Currently,the only FDA-approved therapies for the treatm

192、ent of sarcoidosis are glucocorticoids approved by the 13FDA in the 1950s,prior to current regulatory standards.The consensus standard of care for pulmonary sarcoidosis is immunomodulatory therapy.First line treatment is typically with OCS that act mainly by suppressing inflammatory genes.OCS therap

193、y has been shown to stabilize or improve disease symptomsin some patients,although relapse commonly occurs once OCS therapy is tapered or discontinued.Long-term OCS use is associated with significant side effects including substantial weight gain,development of insulin resistance,osteoporosis,and ri

194、sk of infection.Alternatives,such as cytotoxic immunosuppressive agents(e.g.,methotrexate)have been used as steroid-sparing agents,however,these therapies can also have significant side effects and toxicities,including serious infections and liver toxicity.Patients who have progressive disease despi

195、te OCS or other immunosuppressive therapy are sometimes given biologic immunomodulators,such as the tumor necrosis factor(TNF)inhibitors infliximab or adalimumab.These therapies are not approved by the FDA or other regulatory agencies for the treatment of sarcoidosis,and are also associated with ser

196、ious potential side effects,including malignancy.The efficacy of these agents in sarcoidosis has not been well established clinically.Given the known toxicities of long-term OCS,immunosuppressive and immunomodulatory biologic therapeutic regimens,treatment of patients with sarcoidosis is limited to

197、those who are symptomatic and whose disease is considered active.The presence of granulomas from sarcoidosis define the disease as active,and granulomatous inflammation is the major cause of fibrosis in pulmonary sarcoidosis.Studies to date have not clearly demonstrated that OCS or other immunomodul

198、atory therapies prevent disease progression or formation of fibrosis.We believe there remains a substantial unmet need for safer,more effective therapies for sarcoidosis that could reduce or replace the requirement for long-term OCS or other immunosuppressive therapy.To our knowledge,efzofitimod is

199、the most advanced drug candidate currently in development for the treatment of pulmonary sarcoidosis.Our second indication for efzofitimod is SSc-ILD.SSc-ILD is very difficult to treat,with limited options.Few randomized studies have been conducted,and first line standard of care remains off-label i

200、mmunosuppressive agents,whose impact is modest and associated with significant side effects including malignancies.Despite not being approved for SSc-ILD,the immunosuppressants mycophenolate mofetil and cyclophosphamide are typically used as first-line treatment.Two products were recently approved f

201、or the treatment of SSc-ILD.Ofev(nintedanib)marketed globally by Boehringer Ingelheim International GmbH,received FDA approval in 2019 for slowing the rate of decline in pulmonary function in patients with SSc-ILD.Actemra(tocilizumab)marketed globally by F.Hoffmann-La Roche Ltd.and Chugai Pharmaceut

202、ical Co Ltd.,was approved by the FDA in 2021 for slowing the rate of decline in pulmonary function in adult patients with SSc-ILD.These therapies have demonstrated the ability to slow decline in lung function as measured by FVC in controlled clinical studies but did not improve underlying systemic d

203、isease in these trials and are associated with significant side effects.Rituximab,a biologic immunosuppressant targeting B-cells,is also used,but there is little clinical evidence supporting its efficacy in this indication.If efzofitimod is successful for the treatment of pulmonary sarcoidosis and S

204、Sc-ILD,we believe it may have applications in other ILD indications and potentially in other severe immune disorders.Based on analyses from independent consultants that we have engaged and our own modeling,we estimate that there is a$2-5 billion global market opportunity in pulmonary sarcoidosis and

205、 SSc-ILD.There are a number of companies engaged in the clinical development of potential new treatments for ILD,including Boehringer Ingelheim International GmbH,F.Hoffman-La Roche Ltd.,Merck&Co.,Sanofi-Aventis LLC,and GSK plc,among others.Sales and Marketing We intend,where strategically appropria

206、te,to build the commercial infrastructure necessary to effectively support the commercialization of our product candidates,if and when we believe a regulatory approval of the first of such product candidates in a particular geographic market appears imminent.We may elect to utilize strategic partner

207、s,distributors,or contract sales forces to assist in the commercialization of our product candidates in selected geographic locations or for particular indications.For example,we have licensed the rights to Kyorin to develop and commercialize efzofitimod in Japan.To develop the appropriate commercia

208、l infrastructure to prepare our products and markets for commercial entry,and to support the engagement and management of key stakeholders,we will have to invest significant amounts of financial and management resources,some of which will be committed prior to any confirmation that any of our produc

209、t candidates will be approved.Manufacturing We currently contract with third parties for the manufacturing and testing of our product candidates,including efzofitimod,to support preclinical studies and clinical trials,and we intend to do so in the future.We do not own or operate manufacturing or tes

210、ting facilities for the clinical or commercial production of our product candidates.We currently have no plans to build our own clinical or commercial scale manufacturing capabilities.The use of CDMOs is cost-efficient and has eliminated the need for our direct investment in manufacturing facilities

211、 and additional resources early in development.Although we rely on CDMOs,we employ personnel with extensive biologics development and manufacturing experience to oversee such CDMOs.Efzofitimod is a fusion protein that is expressed in recombinant E.coli.We have worked with CDMOs in the United States

212、and internationally on the development and manufacture of products using current Good Manufacturing Practices(cGMP)to produce drug 14substance and drug product to support preclinical and clinical development.We have also contracted with CDMOs to conduct the labeling,storage and distribution of our d

213、rug product candidates to clinical sites.To date,our CDMOs have met our manufacturing and testing requirements for clinical development and we expect that our current supply chain is capable of providing sufficient quantities of our product candidates to meet our anticipated clinical development nee

214、ds.Currently we have sufficient efzofitimod on hand to meet our projected needs for the EFZO-FIT(and related Individual Patient EAP)and EFZO-CONNECT studies.Additionally,during 2023,the CDMO that we engaged during late 2021 completed its first and second full,commercial-scale bulk drug substance GMP

215、 runs.Quality release testing was completed and all release specifications were met,supporting the CDMOs ability to produce bulk drug substance of efzofitimod for commercial purposes if we receive regulatory approval for efzofitimod.During 2024,we initiated preparatory work with the CDMO on process

216、performance qualification batches that will be required as part of our potential BLA submission for efzofitimod.During the first quarter of 2025,the first of three upstream batches did not meet process performance qualification specifications,and will need to be replaced.The replacement batch has be

217、en scheduled with our CDMO.The deviation of this first batch was due to operational errors at the CDMO and not related to the underlying process nor the drug substance.We believe this deviation should not impact the timing of our potential BLA submission.However,future operational errors in these ba

218、tches could negatively impact the timing of our potential BLA submission and could require significant additional funding.We will also need to demonstrate that the drug substance manufactured by this CDMO is comparable in quality,safety and potency to the drug substance manufactured by our previous

219、CDMO,which is currently being used in the EFZO-FIT and EFZO-CONNECT studies.We have completed a comparability study and are awaiting regulatory feedback.Patents and Proprietary Rights We strive to protect the proprietary technologies that we believe are important to our business,including seeking an

220、d maintaining patent protection intended to cover the composition of matter of our product candidates,their methods of use,related technology and other inventions that are important to our business.We own,or have exclusive licenses to,over 300 issued patents or allowed patent applications with predi

221、cted expiration dates ranging from 2026 to 2034.In addition to patent protection,we also rely on trade secrets and careful monitoring of our proprietary information to protect aspects of our business that are not amenable to,or that we do not consider appropriate for,patent protection.Our success wi

222、ll depend significantly on our ability to obtain and maintain patent and other proprietary protection for commercially important technology,inventions and know-how related to our business,defend and enforce our patents,maintain our licenses to use intellectual property owned by third parties,preserv

223、e the confidentiality of our trade secrets and operate without infringing the valid and enforceable patents and other proprietary rights of third parties.We also rely on know-how,continuing technological innovation and in-licensing opportunities to develop,strengthen,and maintain our proprietary pos

224、ition in the field of extracellular tRNA synthetase biology,their receptors and associated signaling pathways,including,for example,antibody diagnostics and therapeutics to NRP2.A third party may hold intellectual property,including patent rights,which is important or necessary to the development of

225、 our products.It may be necessary for us to use the patented or proprietary technology of third parties to commercialize our products,in which case we would be required to obtain a license from these third parties on commercially reasonable terms,or our business could be harmed,possibly materially.W

226、e plan to continue to expand our intellectual property estate by filing patent applications directed to new methods of treatment,therapeutics and additional new product forms thereof with new therapeutic or pharmacokinetic properties.Specifically,we seek patent protection in the United States and in

227、ternationally for novel compositions of matter covering our protein therapeutics,antibody therapeutics,next generation product forms and the use of these compositions in a variety of therapies.The patent positions of biopharmaceutical companies like us are generally uncertain and involve complex leg

228、al,scientific and factual questions.In addition,the coverage claimed in a patent application can be significantly reduced before the patent is issued,and its scope can be reinterpreted after issuance.Consequently,we do not know whether any of our product candidates will be protectable or remain prot

229、ected by enforceable patents.We cannot predict whether the patent applications we are currently pursuing will issue as patents in any particular jurisdiction or whether the claims of any issued patents will provide sufficient proprietary protection from competitors.Any patents that we hold may be ch

230、allenged,circumvented or invalidated by third parties.Because patent applications in the United States and certain other jurisdictions are maintained in secrecy for 18 months,and since publication of discoveries in the scientific or patent literature often lags behind actual discoveries,we cannot be

231、 certain of the priority of inventions covered by pending patent applications.Moreover,we may have to participate in interference proceedings declared by the United States Patent and Trademark Office(USPTO),or a foreign patent office to determine priority of invention or in post-grant challenge proc

232、eedings,such as oppositions,that challenge priority of invention or other features of patentability.Such proceedings could result in us incurring substantial costs,even if the eventual outcome is favorable to us.15Efzofitimod Our efzofitimod patent portfolio is comprised of a number of patent famili

233、es related to derivatives of HARS,including the HARS amino 1-60,related splice variants,combinations with other therapeutics,and next-generation product forms with modified therapeutic activity or pharmacokinetic characteristics.Our efzofitimod patent portfolio includes a patent family that is joint

234、ly owned by us and our 98%owned subsidiary,Pangu BioPharma,andincludes issued patents in the United States,Australia,Canada,China,Europe,Hong Kong and Japan,and pending patent applications in the United States.The U.S.patents are expected to expire between 2030 and 2031,absent any patent term extens

235、ion for regulatory delays,and the ex-U.S.patents,and patents that issue from these patent applications,if any,are expected to expire in 2030,absent any patent term extension.The efzofitimod patent portfolio includes another patent family jointly owned by us and Pangu BioPharma,which includes patent

236、applications directed to related splice variants of HARS.This patent family includes issued patents in the United States,Australia,Canada,China,Europe,Hong Kong,Japan and New Zealand.The issued patents are expected to expire in 2031,absent any patent term extension.Also included within the efzofitim

237、od patent portfolio are issued patents and pending patent applications directed to specific product forms of efzofitimod,and other HARS splice variants,including patent families directed to Fc fusion proteins,and combinations for treating lung inflammation,among other indications.One family directed

238、 to specific Fc fusion proteins includes issued or allowed patents in the United States,Australia,Canada,Europe,Hong Kong,India and Japan,and pending patent applications in the United States and Japan.A patent family directed to combination therapies includes issued patents in the United States,Euro

239、pe and Hong Kong and pending patent applications in the United States,Australia,Canada and Japan.If issued,the patents that derive from the patent applications are predicted to expire between 2034 and 2038,absent any patent term extensions.tRNA SynthetasesOur pipeline of extracellular tRNA synthetas

240、e proteins is covered by a series of patent families,which are directed to all 20 human cytosolic tRNA synthetases.Numerous patents are issued in the United States and elsewhere,including issued U.S.patents directed to specific therapeutic protein compositions,the corresponding protein polynucleotid

241、e sequences,and certain antibody compositions to specific splice variants.These cases are jointly owned by us and Pangu BioPharma,and include issued patents and/or pending applications in the United States,Australia,Canada,Europe,China and Japan.Patents that issue from these applications,if any,woul

242、d be expected to expire in 2031,absent any patent term extension.Additional patent applications have also been separately filed(or are in preparation)on the splice variants,and optimized sequences derived from GARS(Glycyl-tRNA synthetase),DARS,YARS(tyrosyl-tRNA synthetase),and other tRNA synthetases

243、,and any patents issuing from these patent applications are expected to expire between 2026 and 2030,absent any patent term extension.A separate provisional application has been filed on specific DARS mutants,and any patents issuing from this patent application are expected to expire in 2045.The ter

244、m of individual patents depends upon the legal term of the patents in the countries in which they are obtained.In most countries in which we file,the patent term is generally 20 years from the earliest date of filing the non-provisional patent application from which the patent issued.In the United S

245、tates,the patent term of a patent that covers a drug approved by the FDA,may also be eligible for patent term extension,which permits patent term restoration as compensation for the patent term lost during the FDA regulatory review process.The Hatch-Waxman Act permits a patent term extension of up t

246、o five years beyond the expiration of the patent.The length of the patent term extension is related to the length of time the drug is under regulatory review.Patent extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval and only one patent

247、 applicable to an approved drug may be extended.Similar provisions are available in Europe and other non-United States jurisdictions to extend the term of a patent that covers an approved drug.In the future,if and when our pharmaceutical products receive FDA approval,we expect to apply for patent te

248、rm extensions on patents covering those products.We intend to seek patent term extensions to any of our issued patents in any jurisdiction where these are available,however there is no guarantee that the applicable authorities,including the FDA in the United States,will agree with our assessment of

249、whether such extensions should be granted,and even if granted,the length of such extensions.We also rely on trade secret protection for our confidential and proprietary information.Although we take steps to protect our proprietary information and trade secrets,including through contractual means wit

250、h our employees and consultants,third parties may independently develop substantially equivalent proprietary information and techniques or otherwise gain access to our trade secrets or disclose our technology.Thus,we may not be able to meaningfully protect our trade secrets.It is our policy to requi

251、re our employees,consultants,outside scientific collaborators,sponsored researchers and other advisors to execute confidentiality agreements upon the commencement of employment or consulting relationships with us.These agreements provide that all confidential information concerning our business or f

252、inancial affairs developed or made known to the individual during the course of the individuals relationship with us is to be kept confidential and not disclosed to third parties except in specific circumstances.In the case of employees,the agreements provide that all inventions conceived by the ind

253、ividual,and which are related to our current or planned business or research 16and development or made during normal working hours,on our premises or using our equipment or proprietary information,are our exclusive property.Government Regulation Government authorities in the United States,including

254、federal,state,and local authorities,and in other countries,extensively regulate,among other things,the manufacturing,research and clinical development,marketing,labeling and packaging,storage,distribution,post-approval monitoring and reporting,advertising and promotion,and export and import of biolo

255、gical products,such as those we are developing.Pricing of such products is also subject to regulation in many countries.The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal,state,local,and foreign statutes and regulations require the expenditure of sub

256、stantial time and financial resources.U.S.Government Regulation In the United States,the FDA regulates biologics under the Federal Food,Drug,and Cosmetic Act and the Public Health Service Act and their implementing regulations.FDA approval is required before any new unapproved biologic or dosage for

257、m,including a new use of a previously approved biologic,can be marketed in the United States.Biologics are also subject to other federal,state,and local statutes and regulations.If we fail to comply with applicable FDA or other requirements at any time during the product development process,clinical

258、 testing,approval process or after approval,we may become subject to administrative or judicial sanctions.These sanctions could include the FDAs refusal to approve pending applications,license suspension or revocation,untitled or warning letters,product recalls,product seizures,total or partial susp

259、ension of production or distribution,injunctions,fines,civil penalties or criminal prosecution.Any FDA enforcement action could have a material adverse effect on us.The process required by the FDA before product candidates may be marketed in the United States generally involves the following:complet

260、ion of extensive preclinical laboratory tests and preclinical animal studies,performed in accordance with the good laboratory practice regulations,where applicable;submission to the FDA of an IND which must become effective before human clinical trials may begin and must be updated annually;approval

261、 by an independent institutional review board(IRB)or ethics committee representing each clinical site before each clinical trial may be initiated;performance of adequate and well-controlled human clinical trials to establish the safety and efficacy of the product candidate for each proposed indicati

262、on and conducted in accordance with good clinical practice(GCP)requirements;preparation of and submission to the FDA of a biologics license application(BLA)after completion of all pivotal clinical trials;potential review of the product application by an FDA advisory committee,where appropriate and i

263、f applicable;a determination by the FDA within 60 days of its receipt of a BLA to file the application for review;satisfactory completion of an FDA pre-approval inspection of the manufacturing facilities where the proposed product is produced to assess compliance with cGMP;potential FDA audit of the

264、 clinical trial sites that generated the data in support of the BLA;andFDA review and approval of a BLA prior to any commercial marketing or sale of the product in the United States.The preclinical and clinical testing and approval process requires substantial time,effort,and financial resources,and

265、 we cannot be certain that any approvals for our product candidates will be granted on a timely basis,if at all.An IND is a request for authorization from the FDA to administer an investigational new drug or biologic product to humans in clinical trials.The IND submission includes the general invest

266、igational plan and the protocol(s)for human trials.The IND also includes results of preclinical testing,including animal and in vitro studies,to assess the toxicology,PK,pharmacology,and pharmacodynamic characteristics of the product;chemistry,manufacturing,and controls information;and any available

267、 human data or literature to support the use of the investigational new drug.An IND must become effective before human clinical trials may begin.An IND will automatically become effective 30 days after receipt by the FDA,unless before that time the FDA raises concerns or questions related to the pro

268、posed clinical trials.In such a case,the IND may be placed on clinical hold and the IND sponsor and the FDA must resolve any outstanding concerns or questions before clinical trials can begin.Accordingly,submission of an IND may or may not result in the FDA allowing clinical trials to commence.The F

269、DA may impose a clinical hold at any time during a clinical trial and may impose a 17partial clinical hold that would apply certain limits to the trial,for example,imposing dosage limitations or restricting the timeframe of the trial.Clinical TrialsClinical trials involve the administration of the i

270、nvestigational new drug to human subjects under the supervision of qualified investigators in accordance with GCPs which include the requirement that all research subjects provide their informed consent for their participation in any clinical trial.Clinical trials are conducted under protocols detai

271、ling,among other things,the objectives of the study,the parameters to be used in monitoring safety,and the efficacy criteria to be evaluated.A protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of the IND.Additionally,approval must also be ob

272、tained from each clinical trial sites IRB before the clinical trials may be initiated,and the IRB must monitor the trial until it is completed.There are also requirements governing the reporting of ongoing clinical trials and clinical trial results to public registries.The clinical investigation of

273、a drug is generally divided into three phases.Although the phases are usually conducted sequentially,they may overlap or be combined.Phase 1.The drug is initially introduced into a relatively small number of healthy human subjects or patients with the target disease or condition.These studies are de

274、signed to evaluate the safety,dosage tolerance,metabolism and pharmacologic actions of the investigational new drug in humans,the side effects associated with increasing doses,and if possible,to gain early evidence on effectiveness.Phase 2.The drug is administered to a limited patient population to

275、evaluate dosage tolerance and optimal dosage,identify possible adverse side effects and safety risks,and preliminarily evaluate efficacy.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 3.Th

276、e drug is administered to an expanded patient population,generally at geographically dispersed clinical trial sites to generate enough data to evaluate dosage,clinical effectiveness and safety,and establish the overall benefit-risk relationship of the investigational new drug product.A well-controll

277、ed,statistically robust Phase 3 trial may be designed to deliver the data that regulatory authorities will use to decide whether or not to approve,and,if approved,how to appropriately label a drug:such Phase 3 studies are referred to as“pivotal.”In some cases,the FDA may condition approval of a BLA

278、for a product candidate on the sponsors agreement to conduct additional clinical trials after approval.In other cases,a sponsor may voluntarily conduct additional clinical trials after approval to gain more information about the drug.Such post-approval studies are typically referred to as Phase 4 cl

279、inical trials.Failure to exhibit due diligence with regard to conducting Phase 4 clinical trials that the FDA requires as a condition of approval could result in FDA withdrawing approval for the product.A clinical trial sponsor must submit written IND safety reports to the FDA and the investigators

280、for serious and unexpected adverse reactions,any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigators brochure,or any findings from other studies or animal or in vitro testing that suggest a significant risk in humans exp

281、osed to the product candidate within 15 calendar days after the sponsor determines that the information qualifies for reporting.The sponsor also must notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction within seven calendar days after the sponsors initial receipt of

282、 the information.The FDA,the IRB,or the clinical trial sponsor may suspend or terminate a clinical trial at any time on various grounds,including a finding that the research subjects are being exposed to an unacceptable health risk.Additionally,some clinical trials are overseen by an independent gro

283、up of qualified experts organized by the clinical trial sponsor,known as a data safety monitoring board or committee.This group provides authorization for whether or not a trial may move forward at designated check points based on access to certain data from the trial.We may also suspend or terminat

284、e a clinical trial based on evolving business objectives or competitive climate.BLA SubmissionAssuming successful completion of all required testing in accordance with all applicable regulatory requirements,detailed information about the investigational biologic product is submitted to the FDA in th

285、e form of a BLA requesting approval to market the product for one or more indications.Efzofitimod and our other potential product candidates are proteins that will be regulated as biological products subject to the BLA marketing pathway.Under federal law,the submission of most BLAs is subject to an

286、application user fee,and the sponsor of an approved BLA is also subject to an annual prescription drug product program fee.These fees typically increase annually.Applications for orphan drug products are exempted from the BLA user fees,unless the application includes an indication for other than a r

287、are disease or condition.18A BLA must include all relevant data available from pertinent preclinical studies and clinical trials,including negative or ambiguous results as well as positive findings,together with detailed information relating to the products chemistry,manufacturing,controls,and propo

288、sed labeling,among other things.To support marketing approval,the data submitted must be sufficient in quality and quantity to establish the safety and effectiveness of the investigational new drug product to the satisfaction of the FDA.FDA approval of a BLA must be obtained before a biologic may be

289、 marketed in the United States.Before approving a BLA,the FDA typically will conduct a pre-approval inspection of the facility or facilities where the product is manufactured.The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in complianc

290、e with cGMP requirements and adequate to assure consistent production of the product within required specifications.Additionally,before approving a BLA,the FDA will typically inspect one or more clinical sites to assure compliance with GCP.Additionally,the FDA may refer any NDA or BLA,including appl

291、ications for novel biologic candidates or drug candidates which present difficult questions of safety or efficacy,to an advisory committee.Typically,an advisory committee is a panel of independent experts,including clinicians and other scientific experts,that reviews,evaluates and provides a recomme

292、ndation 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 carefully when making decisions.The FDAs Decision on a BLA The FDA evaluates a BLA to determine whether the da

293、ta demonstrate that the biologic is safe,pure,and potent,or effective.After the FDA evaluates the BLA and conducts inspections of manufacturing facilities where the product will be produced,it may issue an approval letter or a Complete Response Letter(CRL).An approval letter authorizes commercial ma

294、rketing of the drug with specific prescribing information for specific indications.A CRL indicates that the review cycle of the application is complete and the application is not ready for approval.A CRL generally outlines the deficiencies in the submission and may require substantial additional tes

295、ting or information in order for the FDA to reconsider the application.A CRL may require additional clinical data or an additional pivotal Phase 3 clinical trial(s),or other significant,expensive and time-consuming requirements related to clinical trials,preclinical studies or manufacturing.Even wit

296、h the submission of this additional information,however,the FDA may ultimately decide that the BLA does not satisfy the criteria for approval and issue a denial.The FDA could also approve the BLA with a Risk Evaluation and Mitigation Strategy plan to mitigate risks associated with the product,which

297、could include medication guides,physician communication plans,or elements to assure safe use,such as restricted distribution methods,patient registries and other risk minimization tools.The FDA may also condition approval on,among other things,changes to proposed labeling,development of adequate con

298、trols and specifications,or a commitment to conduct one or more post-market studies or clinical trials.Such post-market testing may include Phase 4 clinical trials and surveillance to further assess and monitor the products safety and effectiveness after commercialization.Also,new government require

299、ments,including those resulting from new legislation,may be established,or the FDAs policies may change,which could delay or prevent regulatory approval of our products under development.Expedited Review and Accelerated Approval ProgramsA sponsor may seek approval of its product candidate under prog

300、rams designed to accelerate FDAs review and approval of NDAs and BLAs.For example,Fast Track designation may be granted to a drug or biologic intended for treatment of a serious or life-threatening disease or condition that has potential to address unmet medical needs for the disease or condition by

301、 providing a therapy where none exists or a therapy that may be potentially superior to existing therapy based on efficacy or safety factors.The key benefits of Fast Track designation are more frequent interactions with the FDA during development and testing and eligibility for priority review.The F

302、DA may also review sections of the NDA or BLA for a Fast Track product on a rolling basis before the complete application is submitted,if the sponsor and the FDA agree on a schedule for the submission of the application sections,and the sponsor pays any required user fees upon submission of the firs

303、t section of the application.Based on results of the Phase 3 clinical trial(s)submitted in a BLA,the FDA may grant the BLA a priority review designation,which sets the target date for FDA action on the application at six months after the FDA accepts the application for filing.Priority review is gran

304、ted where there is evidence that the proposed product would be a significant improvement in the safety or effectiveness of the treatment,diagnosis,or prevention of a serious condition.If criteria are not met for priority review,the application is subject to the standard FDA review period of ten mont

305、hs after FDA accepts the application for filing.Priority review designation does not change the scientific/medical standard for approval or the quality of evidence necessary to support approval.Fast Track designation may be withdrawn by the sponsor or rescinded by the FDA if the designation is no lo

306、nger supported by data emerging in the clinical trial process.Under the accelerated approval program,the FDA may approve a BLA on the basis of either a surrogate endpoint that is reasonably likely to predict clinical benefit or,on a clinical endpoint that can be measured earlier than irreversible mo

307、rbidity or mortality,that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit,taking into account the severity,rarity,or prevalence of the condition and the availability or lack of alternative treatments.Drugs and biologics granted 19accelerated

308、 approval must meet the same statutory standards for safety and effectiveness as those granted traditional approval.Post-marketing trials or completion of ongoing trials after marketing approval are generally required to verify the drugs clinical benefit in relationship to the surrogate endpoint or

309、ultimate outcome in relationship to the clinical benefit.In addition,a sponsor may seek FDA designation of its product candidate as a breakthrough therapy if the drug is intended,alone or in combination with one or more other drugs,to treat a serious or life-threatening disease or condition and prel

310、iminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints,such as substantial treatment effects observed early in clinical development.If so designated,the FDA shall act to expedite the developmen

311、t and review of the products marketing application,including by meeting with the sponsor throughout the products development,providing timely advice to the sponsor to ensure that the development program to gather preclinical and clinical data is as efficient as practicable,involving senior managers

312、and experienced review staff in a cross-disciplinary review,and assigning a cross-disciplinary project lead for the FDA review team to facilitate an efficient review of the development program and to serve as a scientific liaison between the review team and the sponsor.Post-Approval RequirementsDrug

313、s manufactured or distributed pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA,including,among other things,requirements relating to recordkeeping,periodic reporting,product sampling and distribution,advertising and promotion and reporting of adverse experience

314、s with the product.After approval,most changes to the approved product,such as adding new indications or other labeling claims or some changes to the manufacturing process,are subject to prior FDA review and approval.Drug manufacturers are subject to periodic unannounced inspections by the FDA and s

315、tate agencies for compliance with cGMP requirements.We rely,and expect to continue to rely,on third parties for the production of clinical quantities of our product candidates,and expect to rely in the future on third parties for the production of commercial quantities.Future FDA and state inspectio

316、ns may identify compliance issues at our facilities or at the facilities of our contract manufacturers that may disrupt production or distribution,or require substantial resources to correct.In addition,discovery of previously unknown problems with a product or the failure to comply with applicable

317、requirements may result in restrictions on a product,manufacturer or holder of an approved BLA,including withdrawal or recall of the product from the market or other voluntary,FDA-initiated or judicial action that could delay or prohibit further marketing,or result in the imposition of post-market s

318、tudies or trials to assess new safety risks.The FDA strictly regulates marketing,labeling,advertising,and promotion of products that are placed on the market.Drugs may be promoted only for the approved indications and in accordance with the provisions of the approved label.The FDA and other agencies

319、 actively enforce the laws and regulations prohibiting the promotion of off-label uses,and a company that is found to have improperly promoted off-label uses may be subject to significant liability.Orphan Designation and Exclusivity The FDA may grant orphan drug designation to drugs intended to trea

320、t a rare disease or condition that affects fewer than 200,000 individuals in the United States,or if it affects more than 200,000 individuals in the United States and for which there is no reasonable expectation that the cost of developing and making a drug for this type of disease or condition will

321、 be recovered from sales in the United States.Orphan drug designation must be requested before submitting an NDA or BLA.After the FDA grants orphan drug designation,the identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA.Orphan drug designation does not c

322、onvey any advantage in or shorten the duration of the regulatory review and approval process,but it entitles a party to financial incentives such as opportunities for grant funding towards clinical trial costs,tax advantages,and user-fee waivers.In addition,if a product is the first to receive FDA a

323、pproval for the indication for which it has orphan designation,the product is entitled to orphan drug exclusivity,which means the FDA may not approve any other application to market the same drug for the same indication for a period of seven years,except in limited circumstances,such as a showing of

324、 clinical superiority over the product with orphan exclusivity.Orphan drug exclusivity,however,also could block the approval of one of our products for seven years if a competitor obtains approval of the same drug as defined by the FDA for treatment of the same indication or disease.Pediatric Trials

325、 and ExclusivityUnder the Pediatric Research Equity Act of 2003,as amended,BLAs or supplement to a BLA must contain data that are adequate to assess the safety and effectiveness of an investigational drug or biologic product for the claimed indications in all relevant pediatric populations and to su

326、pport dosing and administration for each pediatric subpopulation for which the drug is safe and effective.A sponsor who is planning to submit a marketing application for a drug product that includes a new active ingredient,new indication,new dosage form,new dosing regimen or new route of administrat

327、ion must submit an initial Pediatric Study Plan(PSP)within sixty days of an 20end-of-phase 2 meeting or,if there is no such meeting,as early as practicable before the initiation of the Phase 3 or Phase 2/3 clinical trial.The initial PSP must include an outline of the pediatric study or studies that

328、the sponsor plans to conduct,including study objectives and design,age groups,relevant endpoints and statistical approach,or a justification for not including such detailed information,and any request for a deferral of pediatric assessments or a full or partial waiver of the requirement to provide d

329、ata from pediatric studies along with supporting information.The FDA may,on its own initiative or at the request of the applicant,grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults or full or partial waivers if certain criteria are met.

330、The FDA and the sponsor must reach agreement on the PSP.A sponsor can submit amendments to an agreed-upon initial PSP at any time if changes to the pediatric plan need to be considered based on data collected from preclinical studies,early phase clinical trials,and/or other clinical development prog

331、rams.The requirements for pediatric data do not apply to any drug or biologic for an indication for which orphan designation has been granted,except under certain circumstances.Pediatric exclusivity is another type of non-patent exclusivity in the United States and,if granted,provides for the attach

332、ment of an additional six months of marketing protection to the term of any existing regulatory exclusivity,including orphan exclusivity.This six-month exclusivity may be granted if a BLA sponsor submits pediatric data that fairly respond to a written request from the FDA for such data.Rest of World

333、 Government Regulation In addition to regulations in the United States,we will be subject to a variety of regulations in other jurisdictions governing,among other things,clinical trials and any commercial sales and distribution of our products.The cost of establishing a regulatory compliance system for numerous varying jurisdictions can be very significant.Although many of the issues discussed abo