aTyr Pharma Inc (LIFE) 2020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 31,2020orTRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 19

2、34For 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 ofincorporation or organization)(I.R.S.EmployerIdentification No.)3545 John Hopkins Court,Suite#250,San Diego,CA 9

3、2121(Address of principal executive offices)(Zip Code)Registrants telephone number,including area code(858)731-8389 Securities 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 shareLIFEThe Nasdaq

4、 Capital Market Securities 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 13 o

5、r 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 15(d)of the Securities Exchange Act of 1934 during the preceding12 months(or for such shorter period that the registrant was required to file such reports),and(2)has b

6、een 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 preceding 12 months(or for suc

7、h 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 growthcompany.See the definitions of“large accelerated file

8、r,”“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 mark if the registrant ha

9、s elected not to use the extended transition period for complying with any new or revised financialaccounting standards provided pursuant to Section 13(a)of the Exchange Act.Indicate by check mark whether the registrant has filed a report on and attestation to its managements assessment of the effec

10、tiveness of its internal control over financialreporting 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.Indicate by check mark whether the registrant is a shell company(as defined in Rule 12b-2 of the Ac

11、t).Yes No The aggregate market value of the registrants common stock held by non-affiliates of the registrant was approximately$25,388,988 based on the closing price of theregistrants common stock on the Nasdaq Capital Market of$4.44 per share on June 30,2020,the last business day of the registrants

12、 most recently completed second quarter.Sharesof 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 valu

13、e$0.001 per share,as of March 19,2021 was 16,011,385.DOCUMENTS INCORPORATED BY REFERENCEPortions of the registrants proxy statement to be filed with the Securities and Exchange Commission(SEC),pursuant to Regulation 14A in connection with the registrants2021 Annual Meeting of Stockholders,which will

14、 be filed subsequent to the date hereof,are incorporated by reference into Part III of this annual report on Form 10-K.Such proxystatement will be filed with the SEC not later than 120 days following the end of the registrants fiscal year ended December 31,2020.ATYR PHARMA,INC.ANNUAL REPORT ON FORM

15、10-KFor the Fiscal Year Ended December 31,2020Table of Contents PageForward-Looking Statements3Summary of Risks Associated with Our Business3 PART I Item 1Business4Item 1ARisk Factors23Item 1BUnresolved Staff Comments55Item 2Properties55Item 3Legal Proceedings55Item 4Mine Safety Disclosures55 PART I

16、I Item 5Market for Registrants Common Equity,Related Stockholder Matters and Issuer Purchases of Equity Securities55Item 6Selected Financial Data56Item 7Managements Discussion and Analysis of Financial Condition and Results of Operations56Item 7AQuantitative and Qualitative Disclosures About Market

17、Risk63Item 8Financial Statements and Supplementary Data64Item 9Changes in and Disagreements With Accountants on Accounting and Financial Disclosure85Item 9AControls and Procedures85Item 9BOther Information85 PART III Item 10Directors,Executive Officers and Corporate Governance86Item 11Executive Comp

18、ensation86Item 12Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters86Item 13Certain Relationships and Related Transactions,and Director Independence86Item 14Principal Accountant Fees and Services86 PART IV Item 15Exhibits and Financial Statement Schedules8

19、7Item 16Form 10-K Summary90 Signatures91 In this Annual Report on Form 10-K(Annual Report),unless the context requires otherwise,aTyr Pharma,“aTyr,”Company,we,our,andus means aTyr Pharma,Inc.and our subsidiary,Pangu BioPharma Limited.The market data and certain other statistical information used in

20、this Annual Report are based on independent industry publications,governmentalpublications,reports by market research firms or other independent sources.Some data are also based on our good faith estimates.Information that is basedon estimates,forecasts,projections,market research or similar methodo

21、logies is inherently subject to uncertainties and actual events or circumstances maydiffer materially from events and circumstances reflected in this information.We own various U.S.federal trademark applications and unregistered trademarks,including our company name.All other trademarks or tradename

22、s referred to in this Annual Report are the property of their respective owners.Solely for convenience,the trademarks and trade names in this AnnualReport are referred to without the symbols and,but such references should not be construed as any indicator that their respective owners will notassert,

23、to the fullest extent under applicable law,their rights thereto.2Forward-Looking StatementsIn addition to historical information,this Annual Report and the information incorporated herein by reference contains forward-looking statementswithin the meaning of Section 27A of the Securities Act of 1933,

24、as amended(the Securities Act)and Section 21E of the Securities Exchange Act of 1934,as amended(the Exchange Act)including statements regarding our business,our financial position,the research and development of biopharmaceuticalproducts,the timing of clinical trial activities and other statements d

25、escribing our goals,expectations,intentions or beliefs.These statements include but arenot limited to statements under the captions“Business”and“Managements Discussion and Analysis of Financial Condition and Results of Operations”,aswell as other sections in this Annual Report.Such statements reflec

26、t 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 thosediscussed in this Annual Report.Factors that could cause or contribu

27、te to such differences include,but are not limited to,those identified in Item 1Aentitled“Risk Factors”beginning on page 23 of this Annual Report,as well as those discussed in our other filings with the Securities and ExchangeCommission(SEC)including our Quarterly Reports on Form 10-Q.As a result,yo

28、u are cautioned not 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.Summary of Risks Associated with Our BusinessBelow is a summary of the prin

29、cipal factors that make an investment in our securities speculative or risky.This summary does not address all of therisks that we face.Additional discussion of the risks summarized in this risk factor summary,and other risks that we face,can be found below under theheading“Risk Factors”and should b

30、e carefully considered,together with other information in this Annual Report and our other filings with the SEC beforemaking investment decisions regarding our securities.Investing in our securities involves substantial risk.The risks described under the heading“Risk Factors”immediately following th

31、is summary maycause us to 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 moresignificant risks we face include the following:We will need to raise additional capital or enter into strategic partnering relati

32、onships to fund our operations.We have incurred significant losses since our inception and anticipate that we will continue to incur significant losses for the foreseeablefuture.We have incurred significant losses since our inception and anticipate that we will continue to incur significant losses f

33、or the foreseeablefuture.We may encounter substantial delays and other challenges in our clinical trials or we may fail to demonstrate safety and efficacy to thesatisfaction of applicable regulatory authorities.If we are unable to successfully complete or otherwise advance clinical development,obtai

34、n regulatory or marketing approval for,orsuccessfully commercialize our therapeutic product candidates,including ATYR1923,or experience significant delays in doing so,ourbusiness will be materially harmed.Our current product candidates and any other product candidates that we may develop from our di

35、scovery engine represent novel therapeuticapproaches,which may cause significant delays or may 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 regulatoryapproval,limit the com

36、mercial profile of an approved label,or result in significant negative consequences following marketing approval,ifany.We depend on our existing collaborations and may depend on collaborations with additional third parties for the development andcommercialization of certain of our product candidates

37、.If our collaborations are not successful,we may not be able to capitalize on the marketpotential 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 intellectualproperty protection is not s

38、ufficiently broad,we may not be able to compete effectively in our markets.Our business could continue to be adversely affected by the effects of the COVID-19 pandemic.Our future success depends on our ability toretain key employees,consultants and advisors and to attract,retain and motivate qualifi

39、ed personnel.3PART IItem 1.Business.We are a biotherapeutics company engaged in the discovery and development of innovative medicines based on novel biological pathways.Wehave concentrated our research and development efforts on a newly discovered area of biology,the extracellular functionality and

40、signaling pathways oftRNA synthetases.Built on more than a decade of foundational science on extracellular tRNA synthetase biology and its effect on immune responses,wehave built a global intellectual property estate directed to a potential pipeline of protein compositions derived from 20 tRNA synth

41、etase genes and theirextracellular targets,such as neuropilin-2(NRP2).Our lead clinical product candidate,ATYR1923,is a selective modulator of NRP2 that downregulates both the innate and adaptive immuneresponses in uncontrolled inflammatory disease states.We are developing ATYR1923 as a potential di

42、sease-modifying therapy for patients with severeinflammatory lung diseases with high unmet medical need.This includes interstitial lung diseases(ILD),a group of rare immune-mediated disorders thatcause progressive fibrosis of the lung,and severe respiratory complications caused by COVID-19.We select

43、ed pulmonary sarcoidosis as our first ILDindication and recently completed enrollment in a Phase 1b/2a multi-center clinical trial.The study has been designed to evaluate the safety,tolerability,steroid-sparing effect and immunogenicity of multiple doses of ATYR1923 and to evaluate established clini

44、cal endpoints and certain biomarkers to assesspreliminary clinical activity of ATYR1923.The results of this study will guide future development of ATYR1923 in pulmonary sarcoidosis and provideinsight for the potential of ATYR1923 in other ILD such as chronic hypersensitivity pneumonitis(CHP)and conn

45、ective tissue disease related ILD(CTD-ILD).In response to the COVID-19 pandemic,we conducted a Phase 2 study in patients with COVID-19 related severe respiratory complications.Thestudy was designed to evaluate the safety and preliminary efficacy of ATYR1923 as compared to placebo through the assessm

46、ent of key clinical outcomemeasures.In early 2021,we reported positive data which showed that the trial met its primary endpoint of safety,demonstrating that a single,intravenous(IV)dose of ATYR1923 was generally safe and well-tolerated in both the 1.0 and 3.0 mg/kg treatment groups,with no drug-rel

47、ated serious adverse events.The study also showed a signal of activity in the 3.0 mg/kg cohort.In addition,patients treated with ATYR1923 demonstrated a trend of overallimprovement in key biomarkers analyzed compared to placebo.In January 2020,we entered into a collaboration and license agreement wi

48、th Kyorin Pharmaceutical Co.,Ltd.(Kyorin)for the development andcommercialization of ATYR1923 for ILD in Japan.Under the agreement(the Kyorin Agreement),Kyorin received an exclusive right to develop andcommercialize ATYR1923 in Japan for all forms of ILD.Under the terms of the Kyorin Agreement,Kyori

49、n is obligated to fund all research,development,regulatory,marketing and commercialization activities in Japan.In September 2020,Kyorin began dosing patients in a Phase 1 clinical trial of ATYR1923(known as KRP-R120 in Japan)and completed the last subject visit in December 2020.The Phase 1 clinical

50、trial,which was conducted and funded byKyorin,is a placebo-controlled clinical trial to evaluate the safety,pharmacokinetics(PK)and immunogenicity of ATYR1923 in 32 healthy Japanese malevolunteers.Results from this study are intended to enable Kyorin to initiate patient clinical trials in ILD in Jap

51、an.We received an$8.0 million upfrontpayment in January 2020 and a$2.0 million milestone payment in January 2021 upon completion of enrollment in the Phase 1 clinical trial,and are eligibleto receive up to an additional$165.0 million in the aggregate upon achievement of certain development,regulator

52、y and sales milestones,as well as tieredroyalties ranging from the mid-single digits to mid-teens on net sales in Japan.In conjunction with our clinical development of ATYR1923,we have in parallel been advancing our discovery pipeline of NRP2 antibodies andtRNA synthetases.In November 2020,we declar

53、ed our lead Investigational New Drug(IND)candidate in oncology from our NRP2 antibody program,ATYR2810.ATYR2810 is a fully humanized monoclonal antibody that specifically and functionally blocks the interaction between NRP2 and one of itsprimary ligands,vascular endothelial growth factor(VEGF).ATYR2

54、810 is in preclinical development for the potential treatment of certain aggressivecancers where NRP2 is implicated.NRP2 is highly expressed on certain tumors and increased NRP2 expression is associated with worse outcomes in manycancers,such as overall survival,metastasis and resistance to targeted

55、 therapies.The role of NRP2 and VEGF signaling in the tumor microenvironment andits importance in the progression of certain aggressive cancers is becoming increasingly validated.In March 2020,our subsidiary,Pangu BioPharma Limited(Pangu BioPharma),together with the Hong Kong University of Science a

56、nd Technology(HKUST)was awarded a grant of approximately$750,000 to build a high-throughput platform for the development of bi-specific antibodies.The two-yearproject is being funded by the Hong Kong governments Innovation and Technology Commission under the Partnership Research Program(PRP).The PRP

57、aims to support research and development projects undertaken by companies in collaboration with local universities and public research institutions.Thegrant is expected to fund approximately 50%of the total estimated project cost,and we expect to contribute the remaining 50%.In February 2021,we anno

58、unced two new discovery programs from our tRNA synthetase platform.These programs will investigate thefunctionality of selected fragments of Alanyl-tRNA synthetase(AARS)and Aspartyl-tRNA synthetase(DARS)in immunology,fibrosis and cancer.We arealso advancing our preclinical pipeline of tRNA synthetas

59、es and NRP2 targeting candidates through internal research efforts,industry and academiccollaborations.4The impact of the COVID-19 pandemic has been and will likely continue to be extensive in many aspects of society,which has resulted in and willlikely continue to result in significant disruptions

60、to the global economy,as well as businesses and capital markets around the world.Impacts to ourbusiness have included the delay in enrollment of our Phase 1b/2a clinical trial in patients with pulmonary sarcoidosis and the discontinuation of somepatients in that trial,temporary closures of portions

61、of our facilities and those of our licensees and collaborators,disruptions or restrictions on ouremployees ability to travel and delays in certain research and development activities.Other potential impacts to our business include,but are not limited todisruptions to or delays in other clinical tria

62、ls,third-party manufacturing supply and other operations,the potential diversion of healthcare resources awayfrom the conduct of clinical trials to focus on pandemic concerns,interruptions or delays in the operations of the FDA or other regulatory authorities,andour ability to raise capital and cond

63、uct business development activities.Therapeutic Candidate PipelineStrategyKey elements of our strategy include the following:Develop ATYR1923 to address unmet medical needs within inflammatory lung diseases.We believe that by establishing proof-of-concept inpulmonary sarcoidosis,we can gain insight

64、to the potential of ATYR1923 in other ILD,such as CHP and CTD-ILD.Our resources are devoted tocompleting our ATYR1923 Phase 1b/2a clinical trial and,if that trial is successful,we believe we can expedite development of ATYR1923 for pulmonarysarcoidosis towards regulatory approval.In addition,success

65、 in our ATYR1923 Phase 1b/2a trial and our Kyorin Agreement,could give us the opportunityto potentially launch additional Phase 2 clinical trials for both CHP and CTD-ILD.We plan on leveraging data from our ATYR1923 Phase 2 clinical trial inCOVID-19 patients with severe respiratory complications for

66、 our mechanistic understanding of ATYR1923 and for its application in ILD.Futuredevelopment plans in COVID-19 are being assessed in light of the evolving pandemic and therapeutic landscape and availability of non-dilutive financing.Develop ATYR2810 to address unmet medical needs within certain aggre

67、ssive cancers where NRP2 is implicated and continue to expand ourknowledge on the therapeutic potential of NRP2 antibodies by utilizing our leadership position in this emerging area of biology.NRP2 is a receptor thatplays a key role in lymphatic development and in regulating inflammatory responses.I

68、n many forms of cancer,high NRP2 expression is associated withworse outcomes.These associations may represent new therapeutic drug opportunities,such as ATYR2810.We are currently focused on completing INDenabling studies to allow us to take ATYR2810 into the clinic.We are committed to translating th

69、is area of newly discovered biology to therapeuticapplications,both with our internal research and through academic collaborations.Build a diverse pipeline of biologics based on our understanding of extracellular tRNA synthetase biology.We continue to deepen our expertisein production of biologic pr

70、oduct candidates based on tRNA synthetases with the goal of developing programs5with multiple therapeutic modalities.We have proven this with the announcement of our AARS and DARS discovery programs.Through our internalresearch efforts and both industry and academic collaborators we intend to furthe

71、r our product development efforts in this area.ATYR1923Overview of ATYR1923We are developing ATYR1923 as a potential therapeutic for patients with inflammatory lung diseases.Our primary focus is in ILD,a group ofimmune-mediated fibrotic lung disorders with significant unmet need.ATYR1923 works by se

72、lectively modulating NRP2 to downregulate the innate andadaptive immune responses in uncontrolled inflammatory disease states to resolve inflammation and prevent subsequent fibrosis.Pre-clinically,we havedemonstrated the therapeutic potential of ATYR1923 in a number of preclinical models of lung inj

73、ury,fibrosis and inflammation,both in vitro and inrodents.We have also characterized the pathways by which it exerts its immunomodulatory effects.We announced data from a first-in-human Phase 1clinical trial of ATYR1923 in June 2018.This randomized,double-blind,placebo-controlled study investigated

74、the safety,tolerability,immunogenicity,andPK of intravenous ATYR1923 in 36 healthy volunteers.The results indicate that the drug was generally well-tolerated at all dose levels tested,with nosignificant adverse events and the observed PK profile supports the potential for a once-monthly dosing regim

75、en.A comprehensive review of the preclinical and Phase 1 data in consultation with key opinion leaders led to our selection of pulmonary sarcoidosisas the first clinical indication for ATYR1923,as well as confirmation of the potential of ATYR1923 in other severe inflammatory lung diseases.In Decembe

76、r 2020,we completed the target enrollment of a proof-of-concept Phase 1b/2a clinical trial of ATYR1923 in patients with pulmonarysarcoidosis and expect to report data from this trial in the third quarter of 2021.This Phase 1b/2a study is a multiple-ascending dose,placebo-controlled,first-in-patient

77、study of ATYR1923 that has been designed to evaluate the safety,tolerability,immunogenicity and PK profile of multiple doses ofATYR1923.Secondary endpoints include the evaluation of steroid sparing effect and other established clinical endpoints along with potential biomarkers toassess preliminary a

78、ctivity of ATYR1923.In January 2021,we completed final enrollment in the Phase 1b/2a clinical trial with a total of 37 patientsexceeding the target enrollment of 36 patients.In early 2021 we announced data from a Phase 2 clinical trial of ATYR1923 in hospitalized COVID-19 patients with severe respir

79、atorycomplications.The study met its primary endpoint of safety and tolerability,with no drug-related serious adverse events reported.The study also showed asignal of activity in the 3.0 mg/kg cohort.In addition,patients treated with ATYR1923 demonstrated a trend of overall improvement in key biomar

80、kersanalyzed compared to placebo.In particular,patients treated with ATYR1923 had greater reduction in levels of several inflammatory cytokines andchemokines,including interferon gamma(IFN),interleukin-6(IL-6)and monocyte chemoattractant protein 1(MCP-1).Furthermore,patients treated withATYR1923 als

81、o had a statistically significant reduction in levels of serum amyloid A(SAA),a marker of inflammation and fibrosis that has implications insarcoidosis.Background and Mechanism of ActionATYR1923 is a selective modulator of NRP2 that downregulates the innate and adaptive immune response in uncontroll

82、ed inflammatory diseasestates.The ATYR1923 program was initiated to leverage our knowledge of the extracellular proteins derived from the histidyl-tRNA synthetase(HARS)family to develop a therapeutic which would possess the N-terminal immuno-modulatory activities of HARS.The gene for HARS gives rise

83、 to a number of splice variants,and though most of these have lost their catalytic activity,many retain the N-terminaldomain(HARS amino acids 2-60).This N-terminal domain was appended to HARS during evolutionary development of multicellular organisms and is notessential for protein synthetic activit

84、y,is not generally found in prokaryotic organisms,and is retained with high homology across mammalian species.Alternative splicing of HARS may be differentially regulated during cellular growth and differentiation,unlike the constitutive high level expression of thefull length protein,suggesting tha

85、t these splice variants may play a differential role in growth and cellular development.Recently,significant progress has been made in elucidating the role of extracellular HARS derived proteins,including the identification of aputative cellular receptor of the HARS N-terminal domain through screeni

86、ng via a cell microarray system in which over 4,500 cell surface proteins arerepresented.This screening approach identified two NRP2 isoforms(Neuropilin 2A and 2B)as the only convincing and specific binding partners of theHARS N-terminal domain.Interactions of HARS with NRP2 appear to be specificall

87、y mediated by the HARS N-terminal domain of HARS,and binding ofthe HARS N-terminal domain of HARS is specific to NRP2 with no observable binding to NRP1,which is the most closely related cell surface receptor.Adomain that is structurally similar to the HARS N-terminal domain(termed the WHEP domain)i

88、s found in other amino-acyl tRNA synthetases,yet these6domains do not exhibit binding to NRP2,indicating this is a highly specific interaction.The discovery of the HARS N-terminal/NRP2 axis represents apreviously unknown mechanism of biological regulation,which may act as a homeostatic regulator of

89、several cellular processes mediated through theneuropilin receptor.The deregulation of these processes may lead to a spectrum of diseases,which could be selectively targeted by modulating the HARSN-terminal/NRP2 axis to address the underlying disease etiology.NRP2 is a pleiotropic co-receptor partic

90、ipating in a broad array of biological pathways including,immunomodulation,lymphangiogenesis,neuronal development and remodeling,cellular growth,migration and differentiation,and cancer development.These biological processes are mediatedthrough a complex interplay of several signaling systems includ

91、ing the semaphorins/plexin receptor family,the VEGF-C/VEGFR3 receptor family,as wellas chemokine ligand 21 driven trafficking and integrin signaling pathways.Growing evidence indicates that NRP2 influences myeloid cell biology such asactivation and recruitment to inflammatory sites.For instance,NRP2

92、 expression on alveolar macrophages regulates airway inflammatory responses toinhaled lipopolysaccharide.ATYR1923 development builds upon our understanding of the biology of the extracellular activity of HARS.This novel molecular entity acts as aselective modulator of NRP2 downregulating the innate

93、and adaptive immune response in inflammatory disease states.ATYR1923 is a fusion proteincomprised of the immuno-modulatory domain of HARS fused to the FC region of a human IgG1 antibody.Preclinical DevelopmentOur preclinical estate of translational animal models were selected to help inform and de-r

94、isk clinical development of ATYR1923.We haveevaluated the biological activity and safety of ATYR1923 across a diverse set of experimental lung disease models,representative of all the major forms ofILD(sarcoidosis,CHP,CTD-ILD and idiopathic pulmonary fibrosis(IPF),as well as in normal animals,lookin

95、g for signals of activity and potentialbiomarkers,while confirming tolerability and a favorable safety profile.In these models,ATYR1923 has significantly reduced histological lung fibrosis and inflammation,restored normal lung function,reduced lungprotein levels of several inflammation and fibrosis-

96、related cytokines and chemokines(e.g.IFN-,MCP-1/CCL2,IL-6)and reduced counts of immune cellsin BAL central to ILD pathology(e.g.neutrophils).These data have been presented in posters at key respiratory conferences over the past few years(e.g.the American Thoracic Society(ATS)International Congress)a

97、nd are available for review on our website.ATYR1923 and NRP2 receptorNRP2 is a pleiotropic cell surface receptor known to be expressed on a number of different immune cell types that plays a key role in regulatinginflammatory responses.ATYR1923 is a fusion protein combining a novel immunomodulatory

98、domain from histidyl-tRNA synthetase(HARS)and ahuman IgG1 Fc.ATYR1923 inhibits cytokines and chemokines involved in the regulation of inflammatory and fibrotic responses and reducesinflammation-dependent fibrosis in animal models of interstitial lung diseases.ATYR1923 has previously demonstrated pot

99、ent immunomodulatoryactivity in vitro and in vivo.We sought to characterize the molecular basis for ATYR1923s immuno-modulatory properties and demonstrated thatATYR1923 specifically and selectively binds to NRP2 on the cell surface.These findings indicate that modulation of the NRP2 signaling pathwa

100、y withATYR1923 could be a novel therapeutic approach to immune-mediated diseases such as pulmonary sarcoidosis.We identified NRP2 as the specific binding partner to ATYR1923,has an emerging role in the regulation of inflammatory responses.Sarcoidosis ischaracterized by the formulation of granulomas,

101、clumps of inflammatory cells,in one or more organs of the body.Little is known about the role of NRP2 inimmune regulation and disease,in particular very little is known about the expression of NRP2 in sarcoidosis patients.We sought to characterize NRP2expression patterns on immune cells implicated i

102、n the pathology of sarcoidosis.Through in vitro and in vivo models,NRP2 was shown to be expressed insamples obtained from lung and skin of sarcoidosis patients and NRP2 expression was detected on key immune cells known to play an important role ininflammation and granuloma formation.These findings h

103、ighlight the potential of ATYR1923 to exert its effect on various immune cells directly related tothe pathology of the target patient population.These data were presented in posters at the ATS International Virtual Meeting in August 2020.Based on our translational biology program,which demonstrated

104、activity across distinct experimental animal models either driven by direct lunginjury or systemic pathology,along with our understanding of the ATYR1923 and NRP2 interaction and the cell types impacted by the mechanism of actionof our drug,we decided to move the program forward into patient clinica

105、l trials in ILD.ILD,Pulmonary Sarcoidosis,and the Role of ImmunologyThe primary target population for ATYR1923 are ILD.ILD are a group of immune-mediated disorders which can cause progressive fibrosis of thelung.There are over 200 different types of ILD,of which the four major forms are:pulmonary sa

106、rcoidosis,CHP,CTD-ILD,and IPF.We have focused ourdevelopment efforts on progressive,immune-mediated forms of ILD,with limited7therapeutic options,that have as the potential to be impacted by ATYR1923.These lung conditions are recognized as having a measurable immune-mediated pathology,involving both

107、 innate and adaptive immune mechanisms that contribute to pathogenesis,and can result in progressive disease leadingto fibrosis and death.The first ILD that we are investigating clinically is pulmonary sarcoidosis.Sarcoidosis is an inflammatory disease of unknown cause,characterized by the formation

108、 of granulomas,clumps of inflammatory cells,in one ormore organs in the body.Sarcoidosis affects people of all ages,with the incidence peaking at 20 to 39 years of age.The disorder usually begins in thelungs,skin or lymph nodes,but can affect almost any organ.Sarcoidosis in the lungs is called pulmo

109、nary sarcoidosis and affects over 90%patients.Estimates of prevalence vary;but generally indicate that approximately 200,000 Americans live with pulmonary sarcoidosis.The prognosis for patientswith pulmonary sarcoidosis ranges from benign and self-limiting to chronic,debilitating fibrotic disease an

110、d mortality.The immunopathogenesis of sarcoidosis is not yet well understood.A leading hypothesis is that granuloma formation involves the interplaybetween antigen,human leukocyte antigen class II molecules,and T-cell receptors:a presumptive sarcoid antigen is engulfed by circulating antigen-present

111、ing cells(APCs;macrophages,dendritic cells)and the subsequent interplay between APCs and CD4+T-cells initiates granuloma formation.Tlymphocyte activation subsequently plays a crucial role in sarcoidosis pathogenesis.For patients with pulmonary sarcoidosis,the primary goal of treatment is to improve

112、the patients symptoms and quality of life,while secondarilymanaging the inflammation associated with the granulomas that could lead to the development of more permanent fibrosis and impairment of pulmonaryfunction.ATYR1923 may provide a therapeutic benefit in pulmonary sarcoidosis by providing an im

113、munomodulatory function to help resolveinflammation.Moreover,the mechanism of action of ATYR1923 in T-cells and macrophages potentially overlaps with the cellular pathology observed inpulmonary sarcoidosis.In preclinical studies,ATYR1923 has been observed to inhibit cytokines involved in regulation

114、of inflammatory and immuneresponses and attenuate T-cell activation,while also modulating macrophage endosome maturation.Related to our mechanistic studies,we have alsodiscovered that NRP2 is up-regulated during activation of myeloid cells including macrophages,dendritic cells and neutrophils,and th

115、at ATYR1923 canbind to NRP2 on these cell types.Furthermore,ATYR1923 has been observed to significantly reduce inflammation-dependent pulmonary fibrosis andimprove respiratory function parameters in bleomycin-induced animal models of ILD,particularly when administered during the inflammatory phase o

116、f thedisease.We believe that by inhibiting the chronic inflammatory response in these patients,ATYR1923 may be able to restore immune balance and preventprogressive fibrosis,thereby providing a safer,potentially more effective alternative to oral corticosteroids and other immunosuppressive therapies

117、 thatcurrently comprise the standard of care for patients with symptomatic pulmonary sarcoidosis.Clinical DevelopmentATYR1923 Phase 1b/2a Clinical Trial Pulmonary SarcoidosisWe initiated a proof-of-concept Phase 1b/2a clinical trial for ATYR1923 in December 2018 following FDA acceptance of our IND a

118、pplication filedin October 2018.The Phase 1b/2a clinical trial is a randomized,double-blind,placebo-controlled multiple-ascending dose,first-in-patient study with IVATYR1923 in 36 patients.The study is being conducted in patients with pulmonary sarcoidosis undergoing an oral corticosteroids(OCS)tape

119、ring 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.We completed enrollment for this trial in December 2020 andexpect to report top line data in the third quarter of 2021.The primary objective of the study is to evaluate safety and tolerability of mu

120、ltiple ascending doses of ATYR1923.Secondary objectives includeassessment of the potential steroid-sparing effects of ATYR1923.In addition,ATYR1923 PK and immunogenicity following multiple dose administrationwill be evaluated.Additional endpoints of interest include the exploratory assessment of the

121、 efficacy of ATYR1923 for the treatment of pulmonarysarcoidosis by evaluating changes over time in:fluorodeoxyglucose-positron emission tomography(FDG-PET)/CT lung imaging;lung function assessedby percent predicted forced vital capacity(FVC%predicted)and diffusing capacity of the lungs for carbon mo

122、noxide;serum biomarkers of interest;health-related quality of life assessments and questionnaires;and measurement of skin lesions(for patients with cutaneous involvement at baseline).This study consists of three staggered dose cohorts.Each cohort will consist of three periods:a screening period,a 20

123、-week placebo-controlledtreatment period,and a four-week follow-up period ending with final study assessments at Week 24.Within each cohort,12 patients were randomized 2:1to ATYR1923(N=8)or placebo(N=4).Study drug is administered via IV infusion every four weeks for a total of six doses(20 weeks of

124、treatment).TheATYR1923 doses levels being evaluated are 1.0 mg/kg,3.0 mg/kg and 5.0 mg/kg.Starting on Day 15 patients will begin a taper(reduction)in OCSaccording to specific guidelines from their starting dose of 10-25 mg/day of prednisone(or equivalent)to a target dose of 5.0 mg/day,to be complete

125、d on orbefore Day 50.The OCS dose will be tapered through Week 24 and patients will be followed for the remainder of the study to determine their ability tomaintain on this 5.0 mg dose.Optionally,further reductions in the OCS dose to below 5.0 mg/day may be attempted after the Week 16 visit,if deter

126、minedby the investigator to be feasible.Patients who require an increase in OCS dose at any time in the study were to continue to receive blinded study drug andbe followed through to the end of the study.8Cohorts 1 through 3 were enrolled sequentially in a staggered manner.After a minimum of six pat

127、ients of a given cohort received at least three IVinfusions of study drug(ATYR1923 or placebo),cumulative unblinded safety data was reviewed by a data safety monitoring board(DSMB).Enrollment inthe next scheduled(higher dose)cohort began after this review was completed,dose escalation was approved b

128、y the DSMB,and the remaining six patientswere enrolled in the ongoing cohort.Dose escalation continued in this manner until the highest planned dose level of ATYR1923 was reached.In December 2019,we announced the results of a pre-planned,blinded interim analysis of safety and tolerability,the primar

129、y endpoint of our Phase1b/2a clinical trial.Study drug(ATYR1923 or placebo)was observed to be generally well tolerated with no drug-related serious adverse events,consistentwith the earlier Phase 1 study results in healthy volunteers.Adverse events(AEs)were mostly mild or moderate in severity and as

130、sessed by the studyinvestigators as unrelated to study drug.Interim safety data results were from 15 pulmonary sarcoidosis patients who had received a minimum of one doseof blinded study drug(ATYR1923 or placebo).The average age of patients evaluated was approximately 51 years.The patient population

131、 consisted of 53%males and 47%females,of which 73%were Caucasian and 27%were African American.No induction of anti-drug antibodies was observed with repeatdosing of study drug.There were no notable trends for clinical laboratory values or vital signs.In December 2020,we completed enrollment and are

132、now focused on demonstrating activity of ATYR1923 and advancing our trial to provideevidence of the potential of ATYR1923 as a treatment option to improve the lives of patients with pulmonary sarcoidosis.Kyorin AgreementIn January 2020,we entered into the Kyorin Agreement for the development and com

133、mercialization of ATYR1923 for ILD in Japan.Pursuant tothe terms of the Kyorin Agreement,Kyorin received exclusive rights to develop and commercialize ATYR1923 in Japan for all forms of ILD and isobligated to fund all research,development,regulatory,marketing and commercialization activities in Japa

134、n.We are responsible for supplying all drugproduct for Japan,as well as supporting development activities for ATYR1923.In September 2020,Kyorin began dosing of its Phase 1 clinical trial ofATYR1923(known as KRP-R120 in Japan)and completed the last subject visit in December 2020.The Phase 1 trial,whi

135、ch is being conducted and fundedby Kyorin,is a placebo-controlled study to evaluate the safety,PK and immunogenicity of ATYR1923 in 32 healthy Japanese male volunteers.Resultsfrom this clinical trial are intended to enable Kyorin to initiate patient trials in ILD in Japan.We received an$8.0 million

136、upfront payment in January 2020and a$2.0 milestone payment in January 2021 upon completion of enrollment in the Phase 1 clinical trial,and we are eligible to receive up to an additional$165.0 million in the aggregate upon achievement of certain development,regulatory and sales milestones,as well as

137、tiered royalties ranging from the mid-single digits to mid-teens on net sales in Japan.Unless earlier terminated,the term of the Kyorin Agreement continues until the expiration of the royalty obligations.Following the firstanniversary of the effective date of the Kyorin Agreement,Kyorin has the righ

138、t to terminate the agreement for any reason upon 90 days advance writtennotice to the Company.Either party may terminate the Kyorin Agreement in the event that the other party breaches the agreement and fails to cure thebreach,becomes insolvent or challenges certain of the intellectual property righ

139、ts licensed under the agreement.ATYR1923 Phase 1 Clinical Trial Healthy VolunteersIn June 2018,we announced results of our first-in-human Phase 1 clinical trial of ATYR1923 conducted in Australia.This randomized,double-blind,placebo-controlled study evaluated the safety,tolerability,immunogenicity,a

140、nd PK of intravenous(IV)ATYR1923 in healthy volunteers.The Phase1 study enrolled 36 healthy volunteers who were randomized to one of six sequential cohorts and received a single infusion of IV ATYR1923 or placebo.Ascending ATYR1923 doses by cohort ranged from 0.03 mg/kg to 5.0 mg/kg.The results indi

141、cate that the drug was generally well-tolerated at all doselevels tested,with no significant adverse events or induction of anti-drug antibodies observed following ATYR1923 dosing or throughout the one-monthfollow-up period.The PK profile of ATYR1923 following single-dose administration was linear a

142、cross the evaluated dose range.Higher ATYR1923 dosesyielded sustained serum concentrations through the end of the one-month follow-up period that were above the predicted therapeutic threshold,supportingthe potential for a once-monthly dosing regimen.In parallel,as described above we expanded our kn

143、owledge of the therapeutic potential of ATYR1923 by conducting several in vivo and in vitromodels to further elucidate its potential clinical utility.These translational research data,as well as the Phase 1 clinical trial results and discussions with keyopinion leaders,helped to guide our developmen

144、t plans for ATYR1923.In September 2018,we announced pulmonary sarcoidosis as the indication for ournext study.ATYR1923 Phase 2 Clinical Trial COVID-19In response to the COVID-19 pandemic,we are investigating ATYR1923s potential as a treatment for COVID-19 patients with severe respiratorycomplication

145、s.The inflammatory lung injury related to COVID-19 may be similar to that of ILD.By targeting aberrant immune responses,we believe thatATYR1923s mechanism of action has substantial overlap with this disease pathology.In9June 2020,we initiated a Phase 2 randomized,double blind,placebo-controlled clin

146、ical trial of ATYR1923 in hospitalized COVID-19 patients with severerespiratory complications who did not require mechanical ventilation,at hospitals in the U.S and Puerto Rico.Patients enrolled in the trial were randomized1:1:1 to a single IV dose of either 1.0 or 3.0 mg/kg of ATYR1923 or placebo.P

147、atients were followed for 60 days post treatment.The trial was not poweredfor statistical significance and was designed to evaluate the preliminary safety and preliminary efficacy of ATYR1923 as compared to placebo through theassessment of key clinical outcome measures.In October 2020,we completed e

148、nrollment of 32 patients exceeding the target enrollment of 30 patients.In early 2021,we announced positive results and reported that the trial met its primary endpoint of safety in moderate to severe hospitalizedCOVID-19 patients,demonstrating that a single,IV dose of ATYR1923 was generally safe an

149、d well-tolerated in both the 1.0 and 3.0 mg/kg treatmentgroups,with no drug-related serious adverse events.The study demonstrated a signal of activity through clinical improvement in the 3.0 mg/kg treatmentgroup with the assessment of time to recovery,defined as either achieving a WHO ordinal scale

150、score of 3 or hospital discharge with no requirement ofsupplemental oxygen.Patients who received the 3.0 mg/kg dose of ATYR1923 experienced a median time to recovery of 5.5 days compared to six days inthe placebo group.In addition,83%of patients in the 3.0 mg/kg treatment group achieved recovery by

151、Day 6,compared to 56%in the placebo arm.Patients in the 1.0 mg/kg treatment group experienced a median time to recovery of seven days.Biomarker data confirms that at baseline,patients enrolledin the ATYR1923 treatment arms compared to placebo had higher levels of inflammatory cytokines and known COV

152、ID-19 biomarkers including ferritin,D-dimer and C-reactive protein(CRP),indicating a more inflamed patient population in the ATYR1923 treatment arms.Demographic and baseline diseasecharacteristics data included in the results showed that the ATYR1923 treatment groups had more patients over the age o

153、f 65,with severe hypoxia or withmultiple comorbidities compared to placebo,factors associated with a greater risk of COVID-19 complications and worse outcomes.All patients in thestudy received standard of care treatment at the time of enrollment,which included remdesivir and/or dexamethasone.At the

154、Day 60 day follow up,we sawno disability or long-term limitation of activities in patients treated with 3.0 mg/kg treatment group as compared to placebo.In addition,patients treated with ATYR1923 demonstrated a trend of overall improvement in key biomarkers analyzed compare to placebo.Specifically,p

155、atients treated with ATYR1923 demonstrated a trend of overall improvement in 82%(14 of 17)of biomarkers analyzed compared to placebo.In particular,patients treated with ATYR1923 had greater reduction in levels of several inflammatory cytokines and chemokines,including interferongamma(IFN),interleuki

156、n-6(IL-6)and monocyte chemoattractant protein 1(MCP-1).Furthermore,patients treated with ATYR1923 also had a statisticallysignificant reduction in levels of serum amyloid A(SAA),a marker of inflammation and fibrosis that has implications in sarcoidosis.Notably,thecytokines that we saw reduced to the

157、 greatest extent as a result of ATYR1923 treatment in these COVID-19 patients are the same cytokines we have seenATYR1923 downregulate in our animal models.The data provides the first-in-patient mechanistic proof-of-concept for ATYR1923.These findings further demonstrate the potential of ATYR1923 as

158、 a therapeutics for severe inflammatory lung disease,including pulmonarysarcoidosis and other ILD.We plan on leveraging data from our ATYR Phase 2 clinical trial for our ILD programs and will move the program forwardbased upon the competitive landscape and the availability of non-dilutive financing.

159、ATYR2810Overview of ATYR2810ATYR2810 is the first IND candidate to arise from our internal research program designing monoclonal antibodies to selectively target the NRP2receptor and its associated signaling pathways.ATYR2810 is a fully humanized monoclonal antibody that specifically and functionall

160、y blocks theinteraction between NRP2 and one of its primary ligands,VEGF.ATYR2810 is currently in preclinical development for cancer.NRP2 is highly expressed in certain tumors,the lymphatic system and on key immune cells implicated in cancer progression.Increased NRP2expression is associated with ne

161、gative outcomes in many cancers,including resistance to targeted therapies,metastasis and worsened overall survival.Therole of NRP2 and VEGF signaling in the tumor microenvironment and its importance in the progression of certain aggressive cancers,such as breastcancer,renal cell carcinoma and lung

162、cancer,is becoming increasingly validated.Preclinical DevelopmentPreclinical data suggest that ATYR2810 could be effective against certain types of solid tumors,including highly aggressive tumors such as triple-negative breast cancer.There is a growing body of evidence that expression of NRP2 is enr

163、iched in treatment-resistant,dedifferentiated cancer cellsexpressing mesenchymal markers.Furthermore,NRP2/VEGF signaling is implicated in enhanced tumor metastasis promoted by the process of epithelial-to-mesenchymal transition in breast cancer.ATYR2810 blocks binding of VEGF to NRP2 and had demonst

164、rated tumor inhibitory effects and increasedsensitivity to chemotherapy in human-derived organoids and other in vitro models of triple-negative breast cancer.These findings suggest that targeting theNRP2/VEGF pathway may be an effective therapeutic strategy for breast cancer and potentially other ag

165、gressive solid tumors where many patients remainunresponsive to currently available treatments.10ATYR2810 is currently undergoing IND-enabling studies.Our Discovery EnginesNRP2 BiologyWe are actively working on NRP2 receptor biology pathways of interest to select additional product candidates for pr

166、eclinical and clinicalinvestigation in a variety of disease settings through efforts internally,as well as with collaborators in academia.NRP2 is a pleiotropic cell surface receptor that was originally identified based on its role in axon guidance during neuronal development,andsubsequently shown to

167、 be important in the development of the lymphatic and immune system.Importantly,NRP2 can bind to multiple ligands and co-receptors to influence these multiple functional roles,including interaction with type 3 semaphorins and plexins to impact neural development,and alsoforms of vascular endothelial

168、 growth factor,especially VEGF-C which is involved in lymphogenesis.Recent evidence suggests that there are high levels of NRP2 expression found on multiple immune cell types,which may play important roles inmigration,antigen presentation,phagocytosis and cell-to-cell interactions.NRP2 is expressed

169、in various cells of the immune system such as B cells,T-cells,NK cells,neutrophils,dendritic cells and macrophages,including alveolar macrophages.It plays an important role in the regulation of immune cellactivation and migration including endosome maturation,the modulation of autophagy and efferocy

170、tosis.This suggests that NRP2 may be an importantregulator of biological responses in a number of different disease settings with potential for therapeutic intervention.We are collaborating with leading academic groups working on these pathways and we are excited to contribute to advancing the under

171、standing ofNRP2 biology and how it may play a role in certain diseases.We continue to research the ways in which NRP2 utilizes common mechanisms,includingVEGFs and semaphorins,to regulate diverse pathways.We believe our growing evidence base of data on the functions of NRP2 will allow us to select a

172、nddevelop additional novel product candidates for various diseases with unmet need.tRNA Synthetase BiologyExtracellular tRNA synthetase biology represents a novel set of potential physiological modulators and therapeutic targets.Using ATYR1923 as a model,we have developed a process to advance novel

173、tRNA synthetase domains from a concept to clinical productcandidate.This process leverages our early discovery work as well as current scientific understanding of tRNA synthetase protein structure,gene splicingand tissue-specific regulation to identify potentially active protein domains.Screening ap

174、proaches are employed to identify target cells and extracellularreceptors for these tRNA synthetase-derived proteins.These cellular systems can then be used in mechanism-of-action studies to elucidate the role theseproteins play in cellular responses and their potential therapeutic utility.We are wo

175、rking to identify new tRNA synthetase based drug candidates throughour internal discovery efforts as well as industry and academic collaborations.AARS/DARSIn February 2021,we announced two new discovery programs from our tRNA synthetase platform.These programs will investigate thefunctionality of se

176、lected fragments of AARS and DARS in immunology,fibrosis and cancer.Initial experiments will be designed to explore the role ofAARS and DARS fragments on natural killer cell biology while also exploring activities related to newly identified receptor candidates for thesefragments.These discovery pro

177、grams were the result of a research collaboration and option agreement with CSL Behring which was terminated in February2021.Hong Kong University of Science and TechnologyIn October 2007,we formed our Hong Kong subsidiary,Pangu BioPharma to support our basic and translational research in tRNA synthe

178、tasebiology.We hold 98%of the outstanding shares of Pangu BioPharma,and a subsidiary of HKUST holds the remaining outstanding shares.PanguBioPharma originally collaborated with HKUST on the discovery and development of aminoacyl tRNA synthetase protein therapeutics.Beginning in July2008,Pangu BioPha

179、rma,in collaboration with HKUST,entered into a series of three research grant agreements with the Government of the Hong KongSpecial Administrative Region to carry out research in the discovery and development of tRNA synthetase biology.Following the completion of theresearch grants,Pangu BioPharma

180、funded research with respect to development of aminoacyl tRNA synthetase protein therapeutics pursuant to annual jointresearch agreements.As a result of work performed under these agreements,HKUST researchers with support from Pangu BioPharma were instrumental indiscovering a splice variant of HARS

181、that liberates the smaller,active HARS amino acid 2-60 from the full-length tRNA synthetase11and has been shown to modulate the immune system.To date,researchers at HKUST have discovered over 200 novel compositions that are covered inissued patents and have published six articles detailing their res

182、earch in peer-reviewed scientific journals.In March 2020,we announced that Pangu BioPharma,together with HKUST,was awarded a grant of approximately$750,000 to build a high-throughput platform for the development of bi-specific antibodies.Initially this research will focus on diseases,including cance

183、r,in which NRP2overexpression is strongly implicated.A bi-specific antibody approach presents a further differentiated opportunity to elucidate the therapeutic potential ofNRP2 and its co-receptors as drug targets.The fact that NRP2 interacts directly with various co-receptor molecules,including cer

184、tain plexins,integrins andchemokine receptors like CCR7,makes it a prime target for bi-specific antibodies that can target both receptors simultaneously and modulate the activity ofthese signaling complexes.The two-year project is being funded by the Hong Kong Governments Innovation and Technology C

185、ommission under thePartnership Research Program.The grant is expected to fund approximately 50%of the total estimated project cost,and we expect to contribute theremaining 50%.In April 2020,we entered a research grant agreement with HKUST and the Hong Kong Special Administrative Region for this gran

186、t(the“Grant Agreement”).Pangu BioPharma is the sole beneficial owner of all resulting intellectual property rights from the research performed under these agreements,subject to the right of HKUSTs subsidiary to use certain background intellectual property of HKUST in conducting the research and,in t

187、he event PanguBioPharma applies for individual funding of any work under the research programs,compliance with the terms and conditions of any written agreementcovering ownership of such funded works.In addition,the Grant Agreement requires the completion of the research project for the assignment o

188、fintellectual property rights.We are also party to a license agreement with Pangu BioPharma,pursuant to which Pangu BioPharma has granted us an exclusive,royalty-bearinglicense(with a right to sublicense)in and to certain of Pangu BioPharmas solely and jointly owned patent rights and know-how to res

189、earch,develop,manufacture,use,import,export,distribute,offer for sale,sell and have sold products incorporating such patent rights and know-how for any therapeutic,prognostic or diagnostic use throughout the world.CompetitionThe biotechnology and pharmaceutical industries are intensely competitive.W

190、e will face competition with respect to our current product candidatesand any other therapeutics we may develop or commercialize in the future,from pharmaceutical companies,biotechnology companies,universities andother research institutions.Our competitors may have substantially greater financial,te

191、chnical and other resources,such as larger research and developmentstaff and established marketing,sales and manufacturing organizations.Additional mergers and acquisitions in the biotechnology and pharmaceuticalindustries may result in even more resources being concentrated in our competitors.Compe

192、tition may increase further as a result of advances in thecommercial 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

193、 or less costly than any product candidate that we may develop.Although we believe we are the only company engaged in the discovery and development of therapeutics based on novel functions of tRNAsynthetases and NRP2 receptor biology,we are aware of other companies that could compete with our clinic

194、al stage product candidate,ATYR1923,for thetreatment of pulmonary sarcoidosis,other ILD and other severe inflammatory lung diseases as described below.ATYR1923For patients with pulmonary sarcoidosis,the primary goal of treatment is typically to improve the patients quality of life,while secondarilym

195、anaging the inflammation that could lead to the development of more permanent fibrosis and impairment of pulmonary function.Currently,the only FDAapproved therapies for the treatment of sarcoidosis are prednisone,a generic corticosteroid,and H.P.Acthar Gel,a repository corticotropin injectionmarkete

196、d globally by Mallinckrodt plc,which was approved in 1952 and is not widely used by physicians due to toxicity and cost issues.The consensusstandard of care for pulmonary sarcoidosis is immune-modulatory therapy.First line treatment is typically with OCS that act mainly by suppressinginflammatory ge

197、nes.OCS therapy has been shown to stabilize or improve disease symptoms in some patients,although relapse commonly occurs onceOCS therapy is tapered or discontinued.Long-term OCS use is associated with significant side effects including substantial weight gain,development ofinsulin resistance,osteop

198、orosis,and risk of infection.Alternatives,such as cytotoxic immunosuppressive agents(e.g.methotrexate)have been used assteroid-sparing agents,however,these therapies can also have significant side effects and toxicities,including malignancies.Patients who have progressivedisease despite OCS or other

199、 immunosuppressive therapy are sometimes given biologic immunomodulators,such as the TNF inhibitors infliximab oradalimumab.These therapies are not approved by the FDA or other regulatory agencies for the treatment of sarcoidosis,and hence providers may facereimbursement challenges if they decide to

200、 use these treatments.The clinical efficacy of these agents has not been well established and they are associatedwith toxicity when used chronically.Given the known toxicities of long-term OCS,immunosuppressive and immunomodulatory biologic therapeuticregimens,treatment of patients with sarcoidosis

201、is limited to those who are symptomatic and whose disease is considered active.The12presence of granulomas from sarcoidosis define the disease as active,and granulomatous inflammation is the major cause of fibrosis in pulmonarysarcoidosis.Studies to date have not clearly demonstrated that OCS or oth

202、er immunomodulatory therapies prevent disease progression or formation offibrosis.We believe there remains a substantial unmet need for safer,more effective therapies for sarcoidosis that could reduce or replace the requirementfor long-term OCS therapy.If ATYR1923 is successful for the treatment of

203、pulmonary sarcoidosis,we believe it may have applications in other ILDindications and potentially in other severe forms of lung inflammation.Immunosuppressive therapy has traditionally been used to treat most ILD despitelittle evidence demonstrating safety or efficacy in these indications.The except

204、ion is a specific form of ILD,IPF,where immunosuppressive treatment wasdemonstrated to be harmful in clinical trials.We are aware of two FDA approved products with indications for the treatment of a subset of ILD indications.Esbriet(pirfenidone),a pyridine marketed globally by F.Hoffmann-La Roche Lt

205、d.,Shionogi&Co.,Ltd.and ILDONG Pharmaceutical Co.,Ltd.,wasapproved by FDA in 2014 for the treatment of IPF and in 2021 was granted priority review from the FDA for the treatment of adults with unclassifiableILD.Ofev(nintedanib),a small molecule tyrosine-kinase inhibitor marketed globally by Boehring

206、er Ingelheim International GmbH,was approved by FDAin 2014 for the treatment of IPF.In 2019 Ofev received FDA approval for slowing the rate of decline in pulmonary function in patients with systemicsclerosis-associated ILD(SSc-ILD)and in 2020 the approval was further expanded to include patients wit

207、h chronic fibrosis ILD with a progressivephenotype.These therapies have been demonstrated to slow decline in lung function as measured by FVC in controlled clinical studies but are associated withsignificant side effects,continued symptoms,and progressive disease in the majority of patients.There ar

208、e a number of companies engaged in the clinicaldevelopment of potential treatments for various forms of ILD,including Boehringer Ingelheim International GmbH,F.Hoffmann-La Roche Ltd,NovartisPharmaceuticals Corporation,Bristol-Myers Squibb Company,FibroGen Inc.,Galapagos NV,Gilead Sciences,Inc.,Plian

209、t Therapeutics,Inc.andMallinckrodt plc among others;however,most development activity is focused on IPF,with limited activity in other major forms of ILD.In addition to competition we may face in ILD,there is a significant effort across the pharmaceutical and biotech industries to address the ongoin

210、gCOVID-19 pandemic.Many companies have developed,are developing,or are testing in clinical trials,new and repurposed treatments for COVID-19patients.Particular focus has been given to vaccines,anti-viral drugs and immunomodulators.ATYR1923,as an immunomodulator,will compete withgeneric treatments,su

211、ch as the corticosteroid,dexamethasone as well as established products such as Actemra(tocilizumab),currently marketed fordifferent indications by F.Hoffmann-La Roche Ltd.Sales and MarketingWe intend,where strategically appropriate,to build the commercial infrastructure necessary to effectively supp

212、ort the commercialization of ourproduct candidates,if and when we believe a regulatory approval of the first of such product candidates in a particular geographic market appearsimminent.We may elect to utilize strategic partners,distributors,or contract sales forces to assist in the commercializatio

213、n of our products in selectedgeographic locations or for particular indications.For example,we have licensed the rights to Kyorin to develop and commercialize ATYR1923 in Japan.Additional capabilities important to the marketing of therapeutics include the management of key stakeholders such as manag

214、ed care organizations,group-purchasing organizations,specialty pharmacies,and government accounts.To develop the appropriate commercial infrastructure,we will have toinvest significant amounts of financial and management resources,some of which will be committed prior to any confirmation that any of

215、 our productcandidates will be approved.ManufacturingWe currently contract with third parties for the manufacturing and testing of our product candidates for preclinical studies and clinical trials andintend to do so in the future.We do not own or operate manufacturing or testing facilities for the

216、clinical or commercial production of our productcandidates.We currently have no plans to build our own clinical or commercial scale manufacturing capabilities.The use of contracted development andmanufacturing organizations(CDMOs),and contract research organizations(CROs),is cost-efficient and has e

217、liminated the need for our direct investmentin manufacturing facilities and additional resources early in development.Although we rely on CDMOs and CROs,we have personnel with extensivebiologics development and manufacturing experience to oversee such CDMOs and CROs.ATYR1923 is a fusion protein that

218、 is expressed in recombinant E.coli by expression in inclusion bodies and refolding to recreate the nativestructure.We have worked with CDMOs in the United States and internationally on the development and current Good Manufacturing Practices(cGMP)for the successful production of ATYR1923 preclinica

219、l and clinical drug substance and drug product.We contracted with CROs to conduct labeling,storage and distribution of ATYR1923 to clinical sites.To date,our CDMOs and CROs have met our manufacturing requirements for clinical development and we expect that our current CDMOs andCROs are capable of pr

220、oviding sufficient quantities of our product candidates to meet our anticipated clinical development needs.However,are currentlyexperiencing delays due to the COVID pandemic in the delivery of key raw materials which are essential for the production of ATYR1923,the result ofwhich may cause delays an

221、d shortfalls in our ability to manufacture sufficient ATYR1923,and other clinical candidates,to meet our projected clinicaldevelopment needs.13Patents and Proprietary RightsWe strive to protect the proprietary technologies that we believe are important to our business,including seeking and maintaini

222、ng patent protectionintended to cover the composition of matter of our product candidates,their methods of use,related technology and other inventions that are important toour business.We own,or have exclusive licenses to,over 220 issued patents or allowed patent applications with predicted expirati

223、on dates ranging from2026 to 2034.In addition to patent protection,we also rely on trade secrets and careful monitoring of our proprietary information to protect aspects of ourbusiness that are not amenable to,or that we do not consider appropriate for,patent protection.Our success will depend signi

224、ficantly on our ability to obtain and maintain patent and other proprietary protection for commercially importanttechnology,inventions and know-how related to our business,defend and enforce our patents,maintain our licenses to use intellectual property owned bythird parties,preserve the confidentia

225、lity of our trade secrets and operate without infringing the valid and enforceable patents and other proprietary rights ofthird parties.We also rely on know-how,continuing technological innovation and in-licensing opportunities to develop,strengthen,and maintain ourproprietary position in the field

226、of extracellular tRNA synthetase biology,their receptors and associated signaling pathways,including,for example,antibody therapeutics to NRP2.A third party may hold intellectual property,including patent rights,which is important or necessary to the development of our products.It may benecessary fo

227、r us to use the patented or proprietary technology of third parties to commercialize our products,in which case we would be required to obtaina license from these third parties on commercially reasonable terms,or our business could be harmed,possibly materially.We plan to continue to expand our inte

228、llectual property estate by filing patent applications directed to new methods of treatment,therapeutics andadditional new product forms thereof with new therapeutic or pharmacokinetic properties.Specifically,we seek patent protection in the United States andinternationally for novel compositions of

229、 matter covering our protein therapeutics,antibody therapeutics,next generation product forms and the use ofthese compositions in a variety of therapies.The patent positions of biopharmaceutical companies like us are generally uncertain and involve complex legal,scientific and factual questions.Inad

230、dition,the coverage claimed in a patent application can be significantly reduced before the patent is issued,and its scope can be reinterpreted afterissuance.Consequently,we do not know whether any of our product candidates will be protectable or remain protected by enforceable patents.We cannotpred

231、ict whether the patent applications we are currently pursuing will issue as patents in any particular jurisdiction or whether the claims of any issuedpatents will provide sufficient proprietary protection from competitors.Any patents that we hold may be challenged,circumvented or invalidated by thir

232、dparties.Because patent applications in the United States and certain other jurisdictions are maintained in secrecy for 18 months,and since publication ofdiscoveries in the scientific or patent literature often lags behind actual discoveries,we cannot be certain of the priority of inventions covered

233、 by pendingpatent 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 proceedings,such as oppositions,that challenge prio

234、rity ofinvention or other features of patentability.Such proceedings could result in us incurring substantial costs,even if the eventual outcome is favorable to us.ATYR1923Our ATYR1923 patent portfolio is comprised of a number of patent families related to derivatives of HARS,including the HARS amin

235、o 2-60,related splice variants,combinations with other therapeutics,and next-generation product forms with modified therapeutic activity or pharmacokineticcharacteristics.As of March 2021,our ATYR1923 patent portfolio includes a patent family that is jointly owned by us and our 98%owned subsidiary,P

236、angu BioPharma,and includes issued patents,in the United States,Australia,Canada,China,Europe,Japan and Hong Kong,and pending patentapplications in the United States.The U.S.patents are expected to expire between 2030 and 2031,absent any patent term extension for regulatory delays,and the ex-U.S.pat

237、ents,and patents that issue from these patent applications,if any,are expected to expire in 2030,absent any patent term extension.The ATYR1923 patent portfolio includes another patent family jointly owned by us and Pangu BioPharma,which includes patent applicationsdirected to related splice variants

238、 of HARS.This patent family includes issued patents in the United States,Australia,China,Japan,New Zealand andHong Kong.A patent application is allowed/pending in the United States and Canada.The issued patents and any patents that issue from these patentapplications,if any,are expected to expire in

239、 2031,absent any patent term extension.Also included within the ATYR1923 patent portfolio are issued patents and pending patent applications directed to specific product forms ofATYR1923,and other HARS splice variants,including patent families directed to FC fusion proteins,and combinations for trea

240、ting lung inflammation,among other indications.One family directed to specific FC fusion proteins includes issued patents in Australia,the United States,Europe,Hong Kong,and Japan,and pending applications in the United States,Canada,14China,Hong Kong,India,and Japan.If issued,the patents that derive

241、 from the patent applications are predicted to expire between 2034 and 2038,absentany patent term extensions.ATYR2810We filed two US patent applications and corresponding international patent applications under the PCT that are directed to our first generation ofdomain-specific anti-neuropilin 2(NRP

242、2)antibodies,including affinity-matured and humanized antibodies.Certain of the anti-NRP2 antibodies displaypreferential functional activity on the VEGF and semaphorin pathways,and form one element of a multilayered approach to develop an anti-NRP2antibody IP portfolio.tRNA SynthetaseOur pipeline of

243、 extracellular tRNA synthetase proteins is covered by a series of patent families,which are directed to all 20 human cytosolic tRNAsynthetases.Numerous patents are issued in the United States and elsewhere,including issued U.S.patents directed to specific therapeutic proteincompositions,the correspo

244、nding protein polynucleotide sequences,and certain antibody compositions to specific splice variants.These cases are jointlyowned by us and Pangu BioPharma,and include issued patents and/or pending applications in the United States,Australia,Canada,Europe,China andJapan.Patents that issue from these

245、 applications,if any,would be expected to expire in 2031,absent any patent term extension.Additional patentapplications have also been separately filed on GARS(Glycyl-tRNA synthetase),DARS,YARS(tyrosyl-tRNA synthetase),and other tRNA synthetases,and any patents issuing from these patent applications

246、 are expected to expire between 2026 and 2030,absent any patent term extension.In addition,we areactively expanding our patent portfolio directed to antibodies to NRP2,including therapeutic compositions,methods of use and diagnostic uses.Currentlythe anti-NRP2 patent portfolio includes two patent fa

247、milies directed to murine humanized antibody therapeutics.Any patents issuing from these patentapplications are expected to expire between 2039 and 2040,absent any patent term extension.The term of individual patents depends upon the legal term of the patents in the countries in which they are obtai

248、ned.In most countries in which wefile,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 States,the patent term of a patent that covers a drug approved by the FDA,may also be eligible for patent ter

249、m extension,whichpermits patent term restoration as compensation for the patent term lost during the FDA regulatory review process.The Hatch-Waxman Act permits apatent term extension of up to five years beyond the expiration of the patent.The length of the patent term extension is related to the len

250、gth of time the drugis 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 andonly one patent applicable to an approved drug may be extended.Similar provisions are available in Europe and other non-United

251、States jurisdictions toextend 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 applyfor patent term extensions on patents covering those products.We intend to seek patent term extensions to any of our issued pat

252、ents in any jurisdictionwhere these are available,however there is no guarantee that the applicable authorities,including the FDA in the United States,will agree with ourassessment of whether such extensions should be granted,and even if granted,the length of such extensions.We also rely on trade se

253、cret protection for our confidential and proprietary information.Although we take steps to protect our proprietaryinformation and trade secrets,including through contractual means with our employees and consultants,third parties may independently developsubstantially equivalent proprietary informati

254、on and techniques or otherwise gain access to our trade secrets or disclose our technology.Thus,we may notbe able to meaningfully protect our trade secrets.It is our policy to require our employees,consultants,outside scientific collaborators,sponsoredresearchers and other advisors to execute confid

255、entiality agreements upon the commencement of employment or consulting relationships with us.Theseagreements provide that all confidential information concerning our business or financial affairs developed or made known to the individual during thecourse of the individuals relationship with us is to

256、 be kept confidential and not disclosed to third parties except in specific circumstances.In the case ofemployees,the agreements provide that all inventions conceived by the individual,and which are related to our current or planned business or research anddevelopment or made during normal working h

257、ours,on our premises or using our equipment or proprietary information,are our exclusive property.Government RegulationGovernment authorities in the United States,including federal,state,and local authorities,and in other countries,extensively regulate,among otherthings,the manufacturing,research an

258、d clinical development,marketing,labeling and packaging,storage,distribution,post-approval monitoring andreporting,advertising and promotion,and export and import of biological products,such as those we are developing.Pricing of such products is alsosubject to regulation in many countries.The proces

259、s of obtaining regulatory approvals and the subsequent compliance with appropriate federal,state,local,and foreign statutes and regulations require the expenditure of substantial time and financial resources.15U.S.Government RegulationIn the United States,the FDA regulates biologics under the Federa

260、l Food,Drug,and Cosmetic Act and the Public Health Service Act and theirimplementing regulations.FDA approval is required before any new unapproved biologic or dosage form,including a new use of a previously approvedbiologic,can be marketed in the United States.Biologics are also subject to other fe

261、deral,state,and local statutes and regulations.If we fail to comply withapplicable FDA or other requirements at any time during the product development process,clinical testing,approval process or after approval,we maybecome subject to administrative or judicial sanctions.These sanctions could inclu

262、de the FDAs refusal to approve pending applications,license suspensionor revocation,untitled or warning letters,product recalls,product seizures,total or partial suspension of production or distribution,injunctions,fines,civilpenalties or criminal prosecution.Any FDA enforcement action could have a

263、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:completion of extensive preclinical laboratory tests and preclinical animal studies,performed in accordance with the good laboratory practicer

264、egulations,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 by an independent institutional review board(IRB)or ethics committee representing each clinical site before each clinical trial maybe i

265、nitiated;performance of adequate and well-controlled human clinical trials to establish the safety and efficacy of the product candidate for eachproposed indication and conducted in accordance with good clinical practice(GCP)requirements;preparation of and submission to the FDA of a biologics licens

266、e application(BLA)after completion of all pivotal clinical trials;potential review of the product application by an FDA advisory committee,where appropriate and if applicable;a determination by the FDA within 60 days of its receipt of a BLA to file the application for review;satisfactory completion

267、of an FDA pre-approval inspection of the manufacturing facilities where the proposed product is produced to assesscompliance with cGMP;potential FDA audit of the clinical trial sites that generated the data in support of the BLA;and FDA review and approval of a BLA prior to any commercial marketing

268、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 we cannot be certain that anyapprovals for our product candidates will be granted on a timely basis,if at all.An IND is a request for aut

269、horization from the FDA to administer an investigational new drug or biologic product to humans in clinical trials.TheIND submission includes the general investigational plan and the protocol(s)for human trials.The IND also includes results of preclinical testing,including animal and in vitro studie

270、s,to assess the toxicology,PK,pharmacology,and pharmacodynamic characteristics of the product;chemistry,manufacturing,and controls information;and any available human data or literature to support the use of the investigational new drug.An IND mustbecome effective before human clinical trials may be

271、gin.An IND will automatically become effective 30 days after receipt by the FDA,unless before thattime the FDA raises concerns or questions related to the proposed clinical trials.In such a case,the IND may be placed on clinical hold and the INDsponsor and the FDA must resolve any outstanding concer

272、ns or questions before clinical trials can begin.Accordingly,submission of an IND may or maynot result in the FDA allowing clinical trials to commence.The FDA may impose a clinical hold at any time during a clinical trial and may impose a partialclinical hold that would apply certain limits to the t

273、rial,for example,imposing dosage limitations or restricting the time frame of the trial.Clinical TrialsClinical trials involve the administration of the investigational new drug to human subjects under the supervision of qualified investigators inaccordance with GCPs which include the requirement th

274、at all research subjects provide their informed consent for their participation in any clinical trial.Clinical trials are conducted under protocols detailing,among other things,the objectives of the study,the parameters to be used in monitoring safety,andthe efficacy criteria to be evaluated.A proto

275、col for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of theIND.Additionally,approval must also be obtained from each clinical trial sites IRB before the trials may be initiated,and the IRB must monitor the trialuntil it is completed.There are also r

276、equirements governing the reporting of ongoing clinical trials and clinical trial results to public registries.16The clinical investigation of a drug is generally divided into three phases.Although the phases are usually conducted sequentially,they may overlapor be combined.Phase 1.The drug is initi

277、ally introduced into a relatively small number of healthy human subjects or patients with the target disease orcondition.These studies are designed to evaluate the safety,dosage tolerance,metabolism and pharmacologic actions of the investigationalnew drug in humans,the side effects associated with i

278、ncreasing doses,and if possible,to gain early evidence on effectiveness.Phase 2.The drug is administered to a limited patient population to evaluate dosage tolerance and optimal dosage,identify possible adverseside effects and safety risks,and preliminarily evaluate efficacy.Multiple Phase 2 clinica

279、l trials may be conducted by the sponsor to obtaininformation prior to beginning larger and more costly Phase 3 clinical trials.Phase 3.The drug is administered to an expanded patient population,generally at geographically dispersed clinical trial sites to generateenough data to evaluate dosage,clin

280、ical effectiveness and safety,and establish the overall benefit-risk relationship of the investigational newdrug product.A well-controlled,statistically robust Phase 3 trial may be designed to deliver the data that regulatory authorities will use todecide whether or not to approve,and,if approved,ho

281、w 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 for a product candidate on the sponsors agreement to conduct additional clinical trialsafter approval.In other cases,a sponsor may voluntarily conduct additional cli

282、nical trials after approval to gain more information about the drug.Suchpost-approval studies are typically referred to as Phase 4 clinical trials.Failure to exhibit due diligence with regard to conducting Phase 4 clinical trials thatthe FDA requires as a condition of approval could result in FDA wi

283、thdrawing approval for the product.A clinical trial sponsor must submit written IND safety reports to the FDA and the investigators for serious and unexpected adverse reactions,anyclinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or in

284、vestigators brochure,or any findingsfrom other studies or animal or in vitro testing that suggest a significant risk in humans exposed to the product candidate within 15 calendar days after thesponsor determines that the information qualifies for reporting.The sponsor also must notify the FDA of any

285、 unexpected fatal or life-threatening suspectedadverse reaction within seven calendar days after the sponsors initial receipt of the information.The FDA,the IRB,or the clinical trial sponsor maysuspend or terminate a clinical trial at any time on various grounds,including a finding that the research

286、 subjects are being exposed to an unacceptablehealth risk.Additionally,some clinical trials are overseen by an independent group of qualified experts organized by the clinical trial sponsor,known as adata safety monitoring board or committee.This group provides authorization for whether or not a tri

287、al may move forward at designated check points basedon access to certain data from the trial.We may also suspend or terminate a clinical trial based on evolving business objectives or competitive climate.BLA SubmissionAssuming successful completion of all required testing in accordance with all appl

288、icable regulatory requirements,detailed information about theinvestigational biologic product is submitted to the FDA in the form of a BLA requesting approval to market the product for one or more indications.ATYR1923,ATYR2810 and our other potential product candidates are proteins that will be regu

289、lated as biological products subject to the BLA marketingpathway.Under federal law,the submission of most BLAs is subject to an application user fee,and the sponsor of an approved BLA is also subject to anannual prescription drug product program fee.These fees typically increase annually.Application

290、s for orphan drug products are exempted from the BLAuser fees,unless the application includes an indication for other than a rare disease or condition.A BLA must include all relevant data available from pertinent preclinical studies and clinical trials,including negative or ambiguous results as well

291、as positive findings,together with detailed information relating to the products chemistry,manufacturing,controls,and proposed labeling,among otherthings.To support marketing approval,the data submitted must be sufficient in quality and quantity to establish the safety and effectiveness of theinvest

292、igational new drug product to the satisfaction of the FDA.FDA approval of a BLA must be obtained before a biologic may be marketed in the UnitedStates.Before approving a BLA,the FDA typically will conduct a pre-approval inspection of the facility or facilities where the product is manufactured.The F

293、DA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirementsand adequate to assure consistent production of the product within required specifications.Additionally,before approving a BLA,the FDA will typicallyinspect

294、 one or more clinical sites to assure compliance with GCP.Additionally,the FDA may refer any NDA or BLA,including applications for novel biologic candidates which present difficult questions of safetyor efficacy,to an advisory committee.Typically,an advisory committee is a panel of independent exper

295、ts,including clinicians and other scientific experts,that reviews,evaluates and provides a recommendation as to whether the application should be approved and under what conditions.The FDA is not boundby the recommendations of an advisory committee,but it considers such recommendations carefully whe

296、n making decisions.17The FDAs Decision on a BLAThe FDA evaluates a BLA to determine whether the data demonstrate that the biologic is safe,pure,and potent,or effective.After the FDAevaluates the BLA and conducts inspections of manufacturing facilities where the product will be produced,it may issue

297、an approval letter or a CompleteResponse Letter(CRL).An approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications.ACRL indicates that the review cycle of the application is complete and the application is not ready for approval.A CRL g

298、enerally outlines the deficienciesin the submission and may require substantial additional testing or information in order for the FDA to reconsider the application.A CRL may requireadditional clinical data or an additional pivotal Phase 3 clinical trial(s),or other significant,expensive and time-co

299、nsuming requirements related to clinicaltrials,preclinical studies or manufacturing.Even with the submission of this additional information,however,the FDA may ultimately decide that the BLAdoes not satisfy the criteria for approval and issue a denial.The FDA could also approve the BLA with a Risk E

300、valuation and Mitigation Strategy plan to mitigate risks associated with the product,whichcould include medication guides,physician communication plans,or elements to assure safe use,such as restricted distribution methods,patient registriesand other risk minimization tools.The FDA may also conditio

301、n approval on,among other things,changes to proposed labeling,development of adequatecontrols and specifications,or a commitment to conduct one or more post-market studies or clinical trials.Such post-market testing may include Phase 4clinical trials and surveillance to further assess and monitor th

302、e products safety and effectiveness after commercialization.Also,new governmentrequirements,including those resulting from new legislation,may be established,or the FDAs policies may change,which could delay or preventregulatory approval of our products under development.Expedited Review and Acceler

303、ated Approval ProgramsA sponsor may seek approval of its product candidate under programs designed to accelerate FDAs review and approval of NDAs and BLAs.Forexample,fast track designation may be granted to a drug or biologic intended for treatment of a serious or life-threatening disease or conditi

304、on that haspotential to address unmet medical needs for the disease or condition by providing a therapy where none exists or a therapy that may be potentially superiorto existing therapy based on efficacy or safety factors.The key benefits of fast track designation are more frequent interactions wit

305、h the FDA duringdevelopment and testing and eligibility for priority review.The FDA may also review sections of the NDA or BLA for a fast track product on a rollingbasis before the complete application is submitted,if the sponsor and the FDA agree on a schedule for the submission of the application

306、sections,and thesponsor pays any required user fees upon submission of the first section of the application.Based on results of the Phase 3 clinical trial(s)submitted in aBLA,the FDA may grant the BLA a priority review designation,which sets the target date for FDA action on the application at six m

307、onths after the FDAaccepts the application for filing.Priority review is granted where there is evidence that the proposed product would be a significant improvement in thesafety or effectiveness of the treatment,diagnosis,or prevention of a serious condition.If criteria are not met for priority rev

308、iew,the application is subjectto the standard FDA review period of ten months after FDA accepts the application for filing.Priority review designation does not change thescientific/medical standard for approval or the quality of evidence necessary to support approval.Fast track designation may be wi

309、thdrawn by the sponsoror rescinded by the FDA if the designation is no longer 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 topredict clinical benefit or,

310、on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality,that is reasonably likely to predict aneffect on irreversible morbidity or mortality or other clinical benefit,taking into account the severity,rarity,or prevalence of the condition and theavailability or la

311、ck of alternative treatments.Drugs and biologics granted accelerated approval must meet the same statutory standards for safety andeffectiveness as those granted traditional approval.Post-marketing trials or completion of ongoing trials after marketing approval are generally required toverify the dr

312、ugs clinical benefit in relationship to the surrogate endpoint or ultimate outcome in relationship to the clinical benefit.In addition,a sponsormay 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

313、treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvementover existing therapies on one or more clinically significant endpoints,such as substantial treatment effects observed early in clinical developme

314、nt.If sodesignated,the FDA shall act to expedite the development and review of the products marketing application,including by meeting with the sponsorthroughout the products development,providing timely advice to the sponsor to ensure that the development program to gather preclinical and clinical

315、datais as efficient as practicable,involving senior managers and experienced review staff in a cross-disciplinary review,and assigning a cross-disciplinaryproject lead for the FDA review team to facilitate an efficient review of the development program and to serve as a scientific liaison between th

316、e reviewteam and the sponsor.Post-Approval RequirementsDrugs manufactured or distributed pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA,including,amongother things,requirements relating to recordkeeping,periodic reporting,product sampling and distribution,adv

317、ertising and promotion and reporting ofadverse experiences with the product.After approval,most changes to the approved18product,such as adding new indications or other labeling claims or some changes to the manufacturing process,are subject to prior FDA review andapproval.Drug manufacturers are sub

318、ject to periodic unannounced inspections by the FDA and state 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 thefuture on third parties for the production

319、 of commercial quantities.Future FDA and state inspections may identify compliance issues at our facilities or atthe facilities of our contract manufacturers that may disrupt production or distribution,or require substantial resources to correct.In addition,discovery ofpreviously unknown problems wi

320、th a product or the failure to comply with applicable requirements may result in restrictions on a product,manufacturer orholder of an approved BLA,including withdrawal or recall of the product from the market or other voluntary,FDA-initiated or judicial action that coulddelay or prohibit further ma

321、rketing,or result in the imposition of post-market studies 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 onlyfor the approved indications and in accordance with the provisio

322、ns of the approved label.The FDA and other agencies actively enforce the laws andregulations prohibiting the promotion of off-label uses,and a company that is found to have improperly promoted off-label uses may be subject tosignificant liability.Orphan Designation and ExclusivityThe FDA may grant o

323、rphan drug designation to drugs intended to treat a rare disease or condition that affects fewer than 200,000 individuals in theUnited 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 developingand making a d

324、rug for this type of disease or condition will be recovered from sales in the United States.Orphan drug designation must be requested beforesubmitting an NDA or BLA.After the FDA grants orphan drug designation,the identity of the therapeutic agent and its potential orphan use are disclosedpublicly b

325、y the FDA.Orphan drug designation does not convey any advantage in or shorten the duration of the regulatory review and approval process,but it entitles aparty to financial incentives such as opportunities for grant funding towards clinical trial costs,tax advantages,and user-fee waivers.In addition

326、,if aproduct is the first to receive FDA approval for the indication for which it has orphan designation,the product is entitled to orphan drug exclusivity,whichmeans 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 l

327、imitedcircumstances,such as a showing of clinical superiority over the product with orphan exclusivity.Orphan drug exclusivity,however,also could block theapproval 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

328、indication or disease.Pediatric Trials 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 thesafety and effectiveness of an investigational drug or biologic product for the claimed indications in all rel

329、evant pediatric populations and to support dosingand administration for each pediatric subpopulation for which the drug is safe and effective.A sponsor who is planning to submit a marketing applicationfor a drug product that includes a new active ingredient,new indication,new dosage form,new dosing

330、regimen or new route of administration must submitan initial Pediatric Study Plan(PSP)within sixty days of an end-of-phase 2 meeting or,if there is no such meeting,as early as practicable before theinitiation of the Phase 3 or Phase 2/3 clinical trial.The initial PSP must include an outline of the p

331、ediatric study or studies that 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

332、of the requirement to provide data from pediatric studies along withsupporting information.The FDA may,on its own initiative or at the request of the applicant,grant deferrals for submission of some or all pediatric datauntil after approval of the product for use in adults or full or partial waivers

333、 if certain criteria are met.The FDA and the sponsor must reach agreement onthe 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 datacollected from preclinical studies,early phase clinical trials,and/or other clinical development programs.The requirements for pediatric data do not applyto any drug or biolo