AnaptysBio, Inc. (ANAB) 2024年年度報告「NASDAQ」.pdf

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1、UNITED STATESSECURITIES AND EXCHANGE COMMISSIONWashington,D.C.20549_FORM 10-K_ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1934For the fiscal year ended December 31,2024ORTRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1934FOR THE

2、TRANSITION PERIOD FROM TO Commission File Number:001-37985_ANAPTYSBIO,INC.(Exact name of registrant as specified in its charter)_Delaware 20-3828755(State or other jurisdiction of incorporation or organization)(I.R.S.Employer Identification Number)10770 Wateridge Circle,Suite 210San Diego,CA 92121(A

3、ddress of principal executive offices and zip code)(858)362-6295(Registrants telephone number,including area code)_Securities registered pursuant to Section 12(b)of the Act:Title of each classTrading Symbol(s)Name of each exchange on which registeredCommon Stock,$0.001 par valueANABThe Nasdaq Stock

4、Market LLCSecurities 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 or Sect

5、ion 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 preceding 12 months(or for such shorter period that the registrant was required tofile such reports),and(2)ha

6、s been subject to such filing requirements for the past 90 days.Yes No Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T(232.405 of this chapter)during the preceding 12 months(or for

7、such shorterperiod that the registrant was required to submit such files).Yes No Indicate by check mark whether the registrant is a large accelerated filer,an accelerated filer,a non-accelerated filer,a smaller reporting company,or an emerging growth company.See the definitions of“large accelerated

8、filer,”“accelerated filer,”“smaller reporting company,”and“emerging growth company”in Rule 12b-2 of the Exchange Act.Large Accelerated FilerAccelerated FilerNon-accelerated FilerSmaller Reporting CompanyEmerging Growth CompanyIf an emerging growth company,indicate by check mark if the registrant has

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

10、iveness of its internal control over financial reporting under Section 404(b)of the Sarbanes-Oxley Act(15 U.S.C.7262(b)by the registered public accounting firm that prepared or issued its audit report.If securities are registered pursuant to Section 12(b)of the Act,indicate by check mark whether the

11、 financial statements of the registrant included in the filing reflect the correction of an error to previously issued financial statements.Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by any

12、 of the registrants executive officers during the relevant recovery period pursuant to240.10D-1(b).Indicate by check mark whether the registrant is a shell company(as defined in Rule 12b-2 of the Exchange Act).Yes No The aggregate market value of voting common equity held by non-affiliates of the re

13、gistrant was$487,837,306 as of June 30,2024.The number of shares of Registrants Common Stock outstanding was 30,666,781 as of February 24,2025.DOCUMENTS INCORPORATED BY REFERENCEPortions of the registrants Definitive Proxy Statement relating to the 2025 Annual Meeting of Stockholders,scheduled to be

14、 held on June 17,2025,are incorporated by reference into Part III of this Annual Report on Form 10-K to the extent statedherein.The Definitive Proxy Statement will be filed within 120 days of the Registrants fiscal year ended December 31,2024.Except with respect to information specifically incorpora

15、ted by reference in this Form 10-K,the Proxy Statement is notdeemed to be filed as part of this Form 10-K.TABLE OF CONTENTS PagePART I Item 1.Business 2Item 1A.Risk Factors 18Item 1B.Unresolved Staff Comments 49Item 1C.Cybersecurity49Item 2.Properties 50Item 3.Legal Proceedings 50Item 4.Mine Safety

16、Disclosures 50 PART II Item 5.Market for Registrants Common Equity,Related Stockholder Matters and Issuer Purchases of Equity Securities 52Item 6.Reserved 52Item 7.Managements Discussion and Analysis of Financial Condition and Results of Operations 53Item 7A.Quantitative and Qualitative Disclosures

17、About Market Risk 64Item 8.Consolidated Financial Statements and Supplementary Data 66Item 9.Changes in and Disagreements With Accountants on Accounting and Financial Disclosure 95Item 9A.Controls and Procedures 95Item 9B.Other Information 95Item 9C.Disclosure Regarding Foreign Jurisdictions that Pr

18、event Inspections96 PART III Item 10.Directors,Executive Officers and Corporate Governance 96Item 11.Executive Compensation 96Item 12.Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters 96Item 13.Certain Relationships and Related Transactions,and Director I

19、ndependence 96Item 14.Principal Accounting Fees and Services 96 PART IV Item 15.Exhibits,Consolidated Financial Statement Schedules 97Item 16.Form 10-K Summary 100 Signatures 101SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTSThis Annual Report on Form 10-K(“Annual Report”)contains forward-looking

20、statements within the meaning of Section 21E of the Securities Exchange Act of 1934,as amended(the“Exchange Act”),and section 27A of the Securities Act of 1933,as amended(the“Securities Act”).The words“believe,”“may,”“will,”“potentially,”“estimate,”“continue,”“anticipate,”“intend,”“could,”“would,”“p

21、roject,”“plan,”and“expect,”and similar expressions that convey uncertainty of future events or outcomes,are intended to identify forward-looking statements.The forward-looking statements in this report include,among other things,statements about:the success,cost,and timing of our product candidate d

22、evelopment activities and ongoing and planned clinical trials;our plans and ability to develop and commercialize antibodies;the likelihood that the clinical data generated in any study we performed,are performing,or plan to perform in a non-U.S.jurisdiction will be subsequently accepted by the U.S.F

23、ood andDrug Administration(“FDA”)and/or by foreign regulatory authorities outside of the jurisdiction where the study was being performed;the potential benefits and advantages of our product candidates and approaches versus those of our competitors;the success of competing therapies that are or may

24、become available;the timing of and the ability to obtain and maintain regulatory approvals for our product candidates,partnered product candidates and/or product candidates for which we may receiveroyalties;the rate and degree of market acceptance and clinical utility of any approved product candida

25、tes;the size and growth potential of the markets for any approved product candidates,and our ability to serve those markets;regulatory developments in the U.S.and foreign countries;the impact of political,economic or public health events on our business and the United States(“U.S.”)and global econom

26、ies;our ability to attract and retain key scientific or management personnel;general macro-economic factors,including volatility in equity markets,and fluctuations in interest rates and foreign exchange rates;our ability to obtain funding for our operations on favorable terms or at all,including fun

27、ding necessary to complete further development and commercialization of our product candidates;our ability to find a licensing partner for etokimab;the timing and ability of our collaborators to develop and commercialize our partnered product candidates;our use of the net proceeds from our public of

28、ferings and other financing transactions;andour estimates regarding expenses,future revenue,capital requirements,and needs for additional financing.These forward-looking statements are subject to a number of risks,uncertainties,and assumptions,including those described in Item 1A,“Risk Factors,”and

29、elsewhere in this Annual Report.Moreover,we operate in a competitive and rapidly changing environment,and new risks emerge from time to time.It is not possible for our management to predict all risks,nor can we assess theimpact of all factors on our business or the extent to which any factor,or comb

30、ination of factors,may cause actual results to differ materially from those contained in any forward-looking statementswe may make.In light of these risks,uncertainties,and assumptions,the forward-looking events and circumstances discussed in this Annual Report may not occur,and actual results could

31、 differmaterially and adversely from those anticipated or implied in the forward-looking statements.You should not rely upon forward-looking statements as predictions of future events.Although we believe that the expectations reflected in the forward-looking statements are reasonable,wecannot guaran

32、tee that the future results,levels of activity,performance,or events and circumstances reflected in the forward-looking statements will be achieved or occur.We undertake no obligationto update publicly any forward-looking statements to conform these statements to actual results or to changes in our

33、expectations,except as required by law.You should read this Annual Report with the understanding that our actual future results,levels of activity,performance,and events and circumstances may be materially different from whatwe expect.Unless the context indicates otherwise,as used in this Annual Rep

34、ort,the terms“AnaptysBio,”“Anaptys,”“company,”“we,”“us”and“our”refer to AnaptysBio,Inc.,a Delawarecorporation,and its subsidiaries taken as a whole,unless otherwise noted.AnaptysBio is our common law trademark.This Annual Report contains additional trade names,trademarks,and servicemarks ofother com

35、panies,which are the property of their respective owners.We do not intend our use or display of other companies trade names,trademarks,or service marks to imply a relationship with,orendorsement or sponsorship of us by,these other companies.1PART IItem 1.BusinessOverviewWe are a clinical-stage biote

36、chnology company focused on delivering innovative immunology therapeutics for autoimmune and inflammatory diseases.Our pipeline includes our lead program,rosnilimab,a depleter and agonist targeting PD-1+T cells,in a Phase 2b trial for the treatment of moderate-to-severe rheumatoid arthritis(“RA”)and

37、 a Phase 2 trial for the treatment of moderate-to-severe ulcerative colitis(“UC”).We also have other antibodies in our portfolio,including ANB033,a CD122 antagonist in a Phase 1 trial and ANB101,a BDCA2 modulator,entering a Phase 1 trial.We have also discovered multiple therapeutic antibodies licens

38、ed to GlaxoSmithKline,Inc.(“GSK”)in a financial collaboration for immuno-oncology,including a PD-1 antagonist(Jemperli(dostarlimab-gxly)or“Jemperli”)and a TIM-3 antagonist(cobolimab,GSK4069889).We currently recognize revenue from milestones and royalties achieved under our immuno-oncologycollaborati

39、on with GSK.Our Wholly Owned Product Candidate PipelineOur immune cell modulating antibodies treat inflammatory disorders by down regulating immune responses mediated by multiple immune cell types including T cells.We believe thesemolecules have potential applicability across a broad range of autoim

40、mune and inflammatory diseases including dermatology,rheumatology,gastroenterology,respiratory,and neurology therapeuticareas.RosnilimabPD-1,or programmed cell death protein 1,is a co-inhibitory receptor that regulates T cell proliferation,and cytokine secretion.It is expressed preferentially on act

41、ivated T cells,reducing thepotential for off-target activity by rosnilimab.Genetic mutations in the PD-1 pathway are known to be associated with increased susceptibility to human inflammatory diseases which leads us tobelieve that rosnilimab is applicable to diseases where PD-1 co-inhibitory recepto

42、r function may be insufficient to maintain immune homeostasis.Rosnilimab is an IgG1 antibody that directly targets PD-1+T cells,resulting in their depletion or agonism,broadly impacting pathogenic drivers of autoimmune and inflammatory diseases.AnIgG1 PD-1 agonist acts through three distinct mechani

43、sms;depletion of PD-1 effector T cells,depletion of PD-1 Tfh and Tph cells,and agonism of PD-1 T cells.This drives specificimmunological outcomes in both inflamed tissue and the periphery,such as reduction in T cell proliferation,migration,and cytokine secretion,and reduction of plasma cell generati

44、on andautoantibody levels.Rosnilimab is designed to enable formation of a tight immune synapse by binding to PD-1 on a membrane-proximal epitope,and simultaneously anchoring to an Fc receptor onan opposing cell,supporting crosslinking and excluding activating phosphatases such as CD45.Rosnilimab als

45、o facilitates depletion by bringing effector cells into closer proximity to pathogenicallyactivated PD-1T cells.In in vitro studies,when PD-1+T cells were cocultured in the presence of NK cells,rosnilimab demonstrated potent depletion of PD-1+T cells.In separate in vitro studies,in which T cellswere

46、 stimulated in the presence of only dendritic cells(in the absence of any cells capable of mediating depletion),rosnilimab demonstrated potent agonism properties such as a reduction in PD-1+Tcell proliferation and reduction in secretion of inflammatory cytokines.We announced positive top-line data f

47、rom a healthy volunteer Phase 1 trial of rosnilimab in November 2021.A total of 144 subjects were enrolled in the randomized,double-blind,placebo-controlled healthy volunteer Phase 1 trial,where single ascending dose(“SAD”)cohorts received subcutaneous or intravenous(“IV”)single doses of rosnilimab

48、up to 600mg or placebo,whilemultiple ascending dose(“MAD”)cohorts received four weekly subcutaneous doses of rosnilimab ranging up to 400mg or placebo.Rosnilimab was generally well-tolerated and no dose limitingtoxicities were observed.Rosnilimab demonstrated a favorable pharmacokinetic(“PK”)profile

49、 with an estimated two-week half-life for subcutaneous and IV routes of administration.Full PD-1 receptor occupancy wasobserved rapidly and was maintained for at least 30 days.Potent and sustained reduction was observed in peripheral PD-1+T cells for 30 days,including 90%reduction of PD-1 T cells an

50、d a50%reduction of PD-1+T cells bringing the overall T cell composition to a less activated state,without meaningfully reducing overall T cell numbers.In February 2025,we announced top-line data from rosnilimabs randomized,placebo-controlled,global 424-patient,Phase 2b clinical trial for moderate-to

51、-severe rheumatoid arthritis.Patientswere randomized to receive either 100mg of subcutaneous rosnilimab every four weeks(Q4W),400mg Q4W,600mg every two weeks(Q2W),or placebo.The trial achieved its primary endpoint ofthe mean change from baseline in baseline disease activity score-28 joints(DAS-28)C-

52、Reactive Protein(CRP)score at Week 12 for all three doses of rosnilimab compared to the placebo.Rosnilimab achieved statistical significance in at least one dose and numerical superiority at all doses,including once monthly administration,on key secondary endpoints of ACR20,ACR50and clinical disease

53、 activity index(CDAI)low disease activity(LDA)score at Week 12.Following completion of the Week 14 visit,69%(or 220 of the 318)rosnilimab-treatedhighhighinthigh high2patients who achieved CDAI LDA and continued their assigned treatment in a blinded,all-active treatment period as of the December 10,2

54、024 data cutoff,appeared to show sustained CDAI LDA,ACR50 and ACR70 responses out to end-of-treatment at Week 28.These Phase 2b data to date have demonstrated a favorable safety and tolerability profile.Translational blood biomarker data,across all doses in the Phase 2b trial,showed similar immunolo

55、gical impact with robust on-target pharmacological activity in rosnilimab-treated patientsthat was not observed in patients on placebo.Rosnilimab demonstrated rapid and sustained reduction of approximately 90%PD-1 T cells and approximately 50%of PD-1+T cells,and an increasein total Tregs.Additionall

56、y,an approximate 50%reduction in the mean CRP from baseline was observed in rosnilimab-treated patients through the entire trial period that was not observed in patientson placebo.We are also conducting a randomized placebo-controlled 132-patient,global Phase 2 trial assessing two dose levels of sub

57、cutaneously administered rosnilimab in moderate-to-severe UC.Rosnilimab will be dosed for up to 48 weeks on well-established endpoints including clinical remission on the modified Mayo score(“mMS”),clinical response on the mMS and endoscopicremission.We anticipate reporting top-line data on the prim

58、ary endpoint at Week 12 in the UC trial in the fourth quarter of 2025.ANB033ANB033 targets CD122,the common beta subunit shared by the IL-15 and IL-2 receptors.IL-15 and IL-2 signaling mediate the proliferation and survival of NK cells and certain CD8 T cellsubsets.ANB033 is an antibody designed wit

59、h an affinity to CD122 that inhibits IL-15 and IL-2 signaling through the low affinity IL-2 receptor(comprised of CD122 and the common gammasubunit,CD132)while sparing IL-2 signaling through the high affinity IL-2 receptor(comprised of CD122,CD132 and the alpha receptor subunit for IL-2,CD25)express

60、ed by regulatory T cells.This leads to the potential to achieve and maintain remission of inflammation through the reduction of disease-causing NK cells and certain CD8 T cell subsets,while sparing regulatory T cells.Bypreventing the consumption of IL-2 by pathogenic cells that express the low affin

61、ity IL-2 receptor,circulating levels of IL-2 may increase,potentially enhancing regulatory T cell numbers thatexpress the high affinity IL-2 receptor in the setting of inflammation.We initiated a Phase 1 clinical trial of ANB033 in October 2024.ANB101Blood dendritic cell antigen 2(“BDCA2”)is a molec

62、ule specifically expressed on plasmacytoid dendritic cells(“pDCs”),a class of immune cells which,while found in relatively smallnumbers in healthy individuals,are enriched in patients with a variety of inflammatory diseases,that is critical to the regulation of toll-like receptor signaling and inter

63、feron secretion.pDCs are a keyupstream node in the inflammatory cascade that serve as a bridge between innate and adaptive immunity.They have been shown to be prolific secretors of type I interferons,which drive activation ofa variety of downstream cell types including T cells and monocytes.Together

64、 with their ability to present antigens to the adaptive immune system,this creates a pro-inflammatory environment for theestablishment and perpetuation of autoimmune pathology.BDCA2 has been implicated in the pathophysiology of systemic lupus erythematosus(“SLE”),where there exists mechanistic clini

65、cal proofof concept for pDC modulation.ANB101 is a BDCA2 modulator antibody that targets pDCs and potently inhibits interferon secretion and modulates antigen presentation for the treatment ofautoimmune and inflammatory diseases.We plan to initiate enrollment for a Phase 1 clinical trial in the firs

66、t quarter of 2025.Collaborative ProgramsGSK CollaborationMultiple company-discovered antibody programs have been advanced to preclinical and clinical milestones under our collaborations.Our collaborations include an immuno-oncology-focusedcollaboration with GSK.Under the GSK Agreement,a Biologics Li

67、cense Application(“BLA”)for our most advanced partnered program,which is a PD-1 antagonist antibody called Jemperli(dostarlimab),wasapproved by the FDA in April 2021 for the treatment of advanced or recurrent deficient mismatch repair endometrial cancer(“dMMREC”).In February 2023,the FDA granted ful

68、l approval for thisindication(from an accelerated approval).In addition,in April 2021 the European Medicines Agency(“EMA”)granted conditional marketing authorization in the European Union(“EU”)forJemperli for use in women with mismatch repair deficient(“dMMR”)/microsatellite instability-high(“MSI-H”

69、)recurrent or advanced endometrial cancer who have progressed on or following priortreatment with a platinum containing regimen.A second FDA approval was received in August 2021 for Jemperli in pan-deficient mismatch repair tumors(PdMMRT).In July 2023,the FDAapproved Jemperli in combination with che

70、motherapy for the treatment of adult patients with dMMR MSI-H primary advanced or recurrent endometrial cancer.In December 2023,the EMAapproved,in the EU,Jemperli plus chemotherapy for dMMR/MSI-H primary advanced or recurrent endometrial cancer.In August 2024,the FDA approved Jemperli plus chemother

71、apy for all adultpatients with primary advanced or recurrent endometrial cancer.In January 2025,the EMA approved Jemperli plus chemotherapy for this same indication.high3For the year ended December 31,2024,GSK reported$598.0 million sales for Jemperli,a greater than 200%sales growth when compared to

72、$175.6 million for the year ended December 31,2023.In addition,under the collaboration,GSK is developing dostarlimab in combination with another development program from the GSK Agreement,including cobolimab,a TIM-3 antibody.GSK is conducting a Phase 3 trial,COSTAR Lung,which is a randomized,open la

73、bel 3-arm trial comparing cobolimab plus dostarlimab plus docetaxel to dostarlimab plus docetaxel to docetaxelalone in patients with advanced non-small-cell lung cancer(“NSCLC”)who have progressed on prior anti-PD-(L)1 therapy and chemotherapy with top-line results expected in the first half of 2025

74、.Vanda Pharmaceuticals CollaborationOn January 31,2025,we entered into an Exclusive License Agreement(the“License Agreement”)with Vanda Pharmaceuticals Inc.(“Vanda”)pursuant to which we granted to Vanda anexclusive,global license for the development and commercialization of imsidolimab(IL-36R antago

75、nist mAb),which has completed two registration-enabling global Phase 3 trials,GEMINI-1 andGEMINI-2,evaluating the safety and efficacy of imsidolimab in patients with Generalized Pustular Psoriasis(GPP).Pursuant to the terms of the License Agreement,we will receive an upfront payment of$10.0 million

76、and a$5.0 million payment for existing drug supply.Anaptys is also eligible to receive upto$35.0 million for future regulatory approval and sales milestones in addition to a 10%royalty on net sales.Our Product CandidatesThe following table summarizes certain key information about our wholly owned pr

77、oduct candidates:Our StrategyWe are a clinical-stage biotechnology company focused on delivering innovative immunology therapeutics.Our immune cell modulating antibodies modulate key nodes governing the bodysregulation of autoimmunity and inflammation.Dysregulated immune responses may result in abno

78、rmal and pathological inflammation in diseases with large and substantially underserved patientpopulations in the therapeutic areas of dermatology,rheumatology,gastroenterology,respiratory and neurology.The key elements of our strategy include:Enabling broad development of our immune cell modulator

79、portfolio.4Generating in vitro and in vivo translational and clinical data to characterize the differentiation of our molecules from in-class competitors and,relative to standard of care,treat patientpopulations most likely to have deeper and/or more durable responses by restoring immune homeostasis

80、.Facilitating the global commercialization of our product candidates while retaining rights in key therapeutic areas and/or commercial markets to enable us to become a fully integrateddiscovery,development and commercial organization.Continuing to leverage our research expertise to generate potentia

81、lly best-in-class antibodies against high-value immunological targets.Maximizing return on equity through execution against a multi-year capital and operating plan,including the potential for future royalty revenues from our GSK immuno-oncologycollaboration and,where actionable,monetizing our legacy

82、 cytokine antagonist programs and enabling further external development and,potentially,commercialization.As described in the section titled“Risk Factors”and elsewhere in this report,the clinical development of drug product candidates is subject to a wide range of risks and uncertainties,any ofwhich

83、 could cause our actual development strategy or timeframes to vary.Antibody OverviewAntibodies are complex proteins naturally generated by the immune system to neutralize foreign pathogens such as bacteria or viruses.B cells,a white blood cell type responsible for thegeneration of antibodies in resp

84、onse to pathogens,secrete billions of antibodies with different specificities into the bloodstream.Antibodies are structurally distinct Y-shaped proteins formed throughthe combination of two long proteins,called heavy chains,and two short proteins,called light chains.Each heavy and light chain pair

85、forms a binding site where the antibody specifically binds itstarget,otherwise known as an antigen,at the Fab domain of the antibody molecule.The specificity of each antibody to a target,and the potency of its binding strength to that target are defined by theamino acid sequences of heavy and light

86、chains in the Fab domain of the antibody molecule.The other end of the antibody,called the Fc domain,is responsible for communication between theantibody and the rest of the immune system.Therapeutic antibodies are typically non-naturally occurring,or recombinant,antibodies specifically developed to

87、 treat human diseases by binding to certain proteins,and thereby modulatingkey biological processes.Therapeutic antibodies are injectable products that are typically dosed subcutaneously or intravenously,unlike synthetic chemistry-based“small molecule”therapeutics thatmay also be administered orally

88、.Therapeutic antibodies have the following key features that we believe make them more predictable than small molecules:Fab Domain.Due to the relatively large size and complex nature of the antibody Fab domain,antibodies generally bind with high specificity to the desired therapeutic target and tend

89、 toexhibit less off-target binding to unrelated proteins,which lowers the risk of unintended biological side effects such as toxicity.Because target proteins are typically larger than antibody Fabdomains,antibodies can be generated against a variety of specific binding epitopes on a given single pro

90、tein,which can alter the functional activity of the protein.For example,antibodiesbinding to unique epitopes on a single target protein can act as antagonists or agonists of the natural target protein function.Fc Domain.The Fc domain of an antibody is the tail region that interacts with cell surface

91、 receptors called Fc receptors and some proteins of the complement system.In humans,there arefive Fc domains referred to as isotypes(IgA,IgD,IgM,IgG,IgE)and numerous Fc receptors expressed on specialized immune cells.Many therapeutic antibodies are subtypes of the IgGisotype and are chosen specifica

92、lly to limit or induce immune system activity for therapeutic purposes.Engagement of Fc domains by specific Fc receptors can modulate biological activity,for example,by clustering the target protein on the cell surface in an immune synapse,leading to modulation of the target protein activity and hen

93、ce altering the function of the cellexpressing the target protein.Specific Fc domain and Fc receptor interactions may also trigger killing of a cell,often referred to as“effector function”of the antibody,via cytotoxicmechanisms depending on the cell type bearing the Fc receptor.In some therapeutic s

94、ettings,mutations can be made to the Fc domain to weaken or entirely abrogate Fc receptor interactions.In creating the most efficacious therapeutic antibody,an appropriate Fc domain is often utilized to avoid or induce immune system activity that contributes to its broader mechanism ofaction.We beli

95、eve that therapeutic antibodies can be significantly de-risked preclinically for specificity,toxicology,pharmacokinetics,and modulation of immune system activity,which isnot generally true for small molecule drugs.Pharmacokinetics and Dosing Frequency.As complex proteins,antibodies are metabolized a

96、nd distributed differently than small molecules.Full length antibodies tend to exhibit serumhalf-lives of seven to 24 days in humans,leading to bi-weekly or monthly dosing as typical practice for therapeutic antibodies.5Potency and Dose Quantities.Antibodies are typically highly potent in binding af

97、finity to their desired target,with binding dissociation constants in the low nanomolar to picomolarrange.Hence,antibodies tend to be dosed at low amounts(less than 1 gram quantities per course of therapy).Our approach to antibody design focuses on discovering and optimizing therapeutic antibodies t

98、ailored to modulate immune function.We use a variety of technologies to optimize the Fabdomain of an antibody in ways that we believe both create a therapeutic antibody with highly potent functional activity and mitigate potential manufacturing liabilities.We also optimize the Fc domain of the antib

99、ody,when needed,to tailor it for specific activity such as reducing Fc receptor interactions or optimizing Fc receptor interactions,in combinationwith the Fab domain of the antibody,to specifically modulate immune cell function,engage effector function that kills specific targeted immune cells,or le

100、verage a combination of both activities.Wefurther optimize the overall antibody through humanization and removal of liabilities that could potentially affect the structure,stability,pharmacology,manufacturability or immunogenicity of theantibody.Optimized antibodies are tested in an extensive suite

101、of immune cell assays,using engineered cell lines,and more relevantly,primary human immune cells from healthy and diseasedindividuals that we believe most accurately recapitulate the conditions in which the antibody will need to have optimal activity in patients.We believe that our approach to antib

102、ody design allows us to effectively tailor antibody discovery to achieve a unique therapeutic benefit.CollaborationsGlaxoSmithKlineIn March 2014,we entered into a Collaboration and Exclusive License Agreement(the“GSK Agreement”)with TESARO,Inc.(“Tesaro”),an oncology-focused biopharmaceutical company

103、now a part of GSK(Tesaro and GSK are hereinafter referred to,collectively,as“GSK”).Currently,under the GSK Agreement,GSK is developing Jemperli(dostarlimab)as a monotherapy forvarious solid tumor indications.In addition,GSK is developing dostarlimab in combination with additional therapies under the

104、 collaboration,including with another development program from theGSK Agreement:cobolimab,a TIM-3 antibody,in 2L NSCLC.In October 2023,Amendment No.5 to the GSK Agreement(the“GSK Amendment No.5”)was agreed by both parties to terminatethe LAG-3 antagonist antibody development program under the GSK Ag

105、reement.In accordance with the GSK Agreement and the GSK Amendment No.5,we have regained full global rights to theLAG-3 antagonist antibody development program.For each remaining development program under the GSK Agreement,we are eligible to receive milestone payments if certain preclinical and clin

106、ical trial events are achieved by GSK,ifcertain U.S.and European regulatory submissions and approvals in multiple indications are achieved,and upon the achievement of specified levels of annual worldwide net sales.We will also beeligible to receive tiered 4-8%royalties related to worldwide net sales

107、 of products developed under the collaboration.On October 23,2020,Amendment No.3 to the GSK Agreement(the“GSKAmendment No.3”)was agreed to by both parties to permit GSK to conduct development and commercialization in combination with any third party molecules of Zejula,an oral,once-daily poly(ADP-ri

108、bose)polymerase(PARP)inhibitor(“Zejula”).Under GSK Amendment No.3,we were granted increased royalties upon sales of Jemperli,equal to 8%of Net Sales(as defined in the GSKAgreement)below$1.0 billion,12%of Net Sales between$1.0 billion and$1.5 billion,20%of Net Sales between$1.5 billion and$2.5 billio

109、n and 25%of Net Sales above$2.5 billion.Unless earlierterminated by either party upon specified circumstances,the GSK Agreement will terminate,with respect to each specific developed product,upon the later of the 12th anniversary of the firstcommercial sale of the product or the expiration of the la

110、st to expire of any patent.In October 2021,we signed a royalty monetization agreement(“Jemperli Royalty Monetization Agreement”)with Sagard Healthcare Royalty Partners,LP(“Sagard”).Under the terms of theJemperli Royalty Monetization Agreement,we received$250.0 million in exchange for royalties and m

111、ilestones payable to us under our GSK collaboration on annual global net sales of Jemperli.Weretained the rights to a$75.0 million sales milestone when Jemperli annual Net Sales exceed$1 billion.In May 2024,we entered into an amendment to the Jemperli Royalty Monetization Agreement,Amendment No.1(th

112、e“Jemperli Amendment”)under which we sold additional receivables toSagard in exchange for$50.0 million.The Jemperli Amendment includes all Jemperli sales,including any product containing Jemperli,whether or not such product constitutes a combinationproduct,and the threshold amounts of aggregate Jemp

113、erli royalties and milestones to be received by Sagard under the Jemperli Amendment is either$600.0 million if received by the end of March31,2031,or$675.0 million if received thereafter.Once either of these thresholds are met,the Jemperli Royalty Monetization Agreement and the Jemperli Amendment wi

114、ll expire,resulting in usregaining all subsequent Jemperli royalties and milestones.As of January 31,2025,Sagard has received a total of$88.8 million in royalties and milestones.For more information see Note 5 Saleof Future Royalties in the accompanying notes to the consolidated financial statements

115、.6The GSK Agreement,as amended,expires when no further payments are due to us,unless earlier terminated.Either party may terminate the GSK Agreement,as amended,in the event of anuncured material breach by the other party.GSK may terminate the GSK Agreement,as amended,at any time upon 90 days prior w

116、ritten notice to us.Intellectual PropertyOur intellectual property is critical to our business and we strive to protect it,including by obtaining and maintaining patent protection in the United States and internationally for productcandidates,novel biological discoveries,epitopes,new therapeutic app

117、roaches and potential indications,and other inventions that are important to our business.In total,our patent portfolio,includingpatents co-owned with GSK,patents licensed from Centessa Pharmaceuticals(UK)Ltd.,and patents to certain antibody discovery technology consisted of approximately 100 issued

118、 patents and 134pending patent applications as of December 31,2024.For our product candidates,generally we initially pursue patent protection covering compositions of matter including antibody sequences,methods of use,and methods ofproduction.Throughout the development of our product candidates,we s

119、eek to identify additional means of obtaining patent protection that would potentially enhance commercial success.The patent portfolios for our internal programs are outlined below:RosnilimabAs of December 31,2024,we owned 17 patents and pending patent applications in various countries directed to t

120、he antibody sequence of rosnilimab and its variants,methods of use andrelated matters.We intend to prosecute our pending applications,and/or other patent applications claiming priority thereto,and pursue patent issuance and protection in key commercial marketswhere significant product sales may occu

121、r.Patents that have issued or that may issue from or claim priority to our pending applications could provide protection for aspects of this product candidateuntil June 2040.ANB033As of December 31,2024,we owned one pending U.S.provisional patent application and one pending international(PCT)patent

122、application directed to the antibody sequence of ANB033and its variants,methods of use and related matters.We intend to prosecute these patent applications,file additional patent applications claiming priority to these patent applications,and pursue patentissuance,in key commercial markets where sig

123、nificant product sales may occur.Patents that may issue claiming priority to these patent applications could provide protection for aspects of thisproduct candidate until September 2045.ANB101As of December 31,2024,we owned rights to 14 pending patent applications in various countries directed to th

124、e antibody sequence of ANB101 and its variants,methods of use and relatedmatters.We intend to prosecute the pending applications,and/or other patent applications claiming priority thereto,and pursue patent issuance and protection in key commercial markets wheresignificant product sales may occur.Pat

125、ents that may issue from or claim priority to the pending applications could provide protection for aspects of these product candidates until August 2040.ANB032As of December 31,2024,we owned 28 patent applications in various countries,including one international(PCT)patent application,directed to t

126、he antibody sequence of ANB032 and itsvariants,methods of use and related matters.We intend to prosecute the pending patent applications,and/or other patent applications claiming priority thereto,and pursue patent issuance andprotection in key commercial markets where significant product sales may o

127、ccur.Patents that may issue from or claim priority to our pending applications could provide protection for aspects of thisproduct candidate until May 2044.Dostarlimab(GSK4057190)As of December 31,2024,we owned or co-owned 24 patents and patent applications in various countries directed to the antib

128、ody sequence of GSK4057190(dostarlimab),a PD-1 antagonist,and its variants,methods of use and related matters.We intend to prosecute our pending applications,and/or other patent applications claiming priority thereto,and pursue patent issuance andprotection in key commercial markets where significan

129、t product sales may occur.Patents that have issued,or that may issue from or claim priority to our pending applications,could provideprotection for aspects of this product until June 2038.7Cobolimab(GSK4069889)As of December 31,2024,we owned or co-owned 26 patents and patent applications in various

130、countries directed to the antibody sequence of GSK4069889(cobolimab),a TIM-3 antagonist,and its variants,methods of use and related matters.We intend to prosecute our pending applications,and/or other patent applications claiming priority thereto,and pursue patent issuance andprotection in key comme

131、rcial markets where significant product sales may occur.Patents that have issued,or that may issue from or claim priority to our pending applications,could provideprotection for aspects of this product candidate until November 2037.ImsidolimabAs of December 31,2024,we owned 44 patents and patent app

132、lications in various countries directed to the antibody sequence of imsidolimab and its variants,methods of use and relatedmatters.We intend to prosecute our pending applications,and/or other patent applications claiming priority thereto,and pursue patent issuance and protection in key commercial ma

133、rkets wheresignificant product sales may occur.Patents that have issued,or that may issue from or claim priority to our pending applications could provide protection for aspects of this product candidate untilMay 2042.EtokimabAs of December 31,2024,we owned 19 patents and patent applications in vari

134、ous countries directed to the antibody sequence of etokimab and its variants,methods of use and related matters.We intend to prosecute our pending applications,and/or other patent applications claiming priority thereto,and pursue patent issuance and protection in key commercial markets where signifi

135、cantproduct sales may occur.Patents that have issued,or that may issue from or claim priority to our pending applications could provide protection for aspects of this product candidate until January2035.Other Intellectual Property MattersThe patent positions of biotechnology companies like ours are

136、generally uncertain and involve complex legal,scientific and factual questions.In addition,the coverage claimed in a patentapplication can be significantly reduced before the patent is issued,and its scope can be reinterpreted after issuance.Consequently,we may not obtain or maintain adequate patent

137、 protection for anyof our product candidates.We cannot predict whether the patent applications we are currently pursuing will issue as patents in any particular jurisdiction or whether the claims of any issued patentswill provide sufficient proprietary protection from competitors.Any patents that we

138、 hold may be challenged,circumvented or invalidated by third parties.For a more comprehensive discussion of therisks related to our intellectual property,please see“Risk Factors Risks Related to Our Intellectual Property.”The term of individual patents depends upon the legal term of the patents in t

139、he countries in which they are obtained.In most countries in which we file,the patent term is 20 years from theearliest date of filing a non-provisional patent application related to the patent.A U.S.patent also may be accorded a patent term adjustment(“PTA”)under certain circumstances to compensate

140、 fordelays in obtaining the patent from the U.S.Patent and Trademark Office(“USPTO”).In some instances,such a PTA may result in a U.S.patent term extending beyond 20 years from the earliest dateof filing a non-provisional patent application related to the U.S.patent.In addition,the term of a U.S.pat

141、ent that covers an FDA-approved drug may also be eligible for patent term extension,whichpermits patent term restoration as compensation for the patent term lost during the FDA regulatory review process.The Hatch-Waxman Act permits a patent term extension of up to five years beyondthe expiration of

142、the patent.The length of the patent term extension is related to the length of time the drug is under regulatory review.Patent term extension cannot extend the remaining term of apatent beyond a total of 14 years from the date of product approval and only one patent applicable to an approved drug ma

143、y be extended.Similar provisions are available in Europe and other foreignjurisdictions to extend the term of a patent that covers an approved drug.In the future,if and when our products receive FDA approval,we expect to apply for patent term extensions on patentscovering those products.We plan to s

144、eek patent term extensions to any of our issued patents in any jurisdiction where these are available,however there is no guarantee that the applicable authorities,including the FDA in the United States,will agree with our assessment of whether such extensions should be granted,and if granted,the le

145、ngth of such extensions.We also rely on trade secrets relating to our research and development and product candidates and seek to protect and maintain the confidentiality of proprietary information to protect aspectsof our business that are not amenable to,or that we do not consider appropriate for,

146、patent protection.Although we take steps to protect our proprietary information and trade secrets,includingthrough contractual means with our employees and consultants,third parties may independently develop substantially equivalent proprietary information and techniques or otherwise gain access too

147、ur trade secrets or disclose our technology.Thus,we may not be able to meaningfully protect our trade secrets.It is our policy to require our employees,consultants,outside scientific collaborators,sponsored researchers and other advisors to execute confidentiality agreements upon the commencementof

148、employment or consulting relationships with8us.These agreements provide that all confidential information concerning our business or financial affairs developed or made known to the individual during the course of the individuals relationshipwith us is to be kept confidential and not disclosed to th

149、ird parties except in specific circumstances.Our agreements with employees also provide that all inventions conceived by the employee in thecourse of employment with us or from the employees use of our confidential information are our exclusive property.ManufacturingWe must manufacture our product c

150、andidates for clinical trial use in compliance with current good manufacturing practices(“cGMP”).The cGMP regulations include requirements relating toorganization of personnel,buildings and facilities,equipment,control of materials,components and drug product containers and closures,production and p

151、rocess controls,packaging and labelingcontrols,holding and distribution,laboratory controls,records and reports,and returned or salvaged products.The manufacturing facilities for our product candidates must meet cGMP requirementsand global regulatory requirements before any product is approved and w

152、e can manufacture commercial products.Our third party manufacturers will be subject to periodic regulatory inspections offacilities by the FDA and other authorities,including procedures and operations used in the testing and manufacture of our products to assess compliance with applicable regulation

153、s.Our internal manufacturing capabilities include non-cGMP antibody and reagent production using small scale quantities for characterization and in vitro and in vivo preclinical assessment ofproduct candidates.We do not have and we do not currently plan to acquire or develop the facilities or capabi

154、lities to manufacture our product candidates for use in human clinical trials.We rely on third party manufacturers to generate cGMP compliant cell lines and will rely on them to produce cGMP drug substance and drug product required for our clinical trials,and weexpect to continue to rely on third pa

155、rties to manufacture clinical trial drug supplies for the foreseeable future.We also contract with additional third parties for the testing,labeling,packaging,storageand distribution of investigational drug products.We have personnel with significant technical,manufacturing,analytical,quality,includ

156、ing cGMP,and project management experience to oversee ourthird party manufacturers and to manage manufacturing and quality data and information for regulatory compliance purposes.While our contract manufacturers have not yet produced commercially-approved cGMP batches of our product candidates,they

157、have previously manufactured products for other companies in compliance with cGMP and have been previously inspected by regulatoryauthorities for compliance with cGMP standards.Failure to comply with statutory and regulatory requirements subjects a manufacturer to possible legal or regulatory action

158、,including warning letters,the seizure or recall of products,injunctions,consent decrees placing significant restrictions on or suspending manufacturing operations and civil and criminal penalties.These actions could have a material impact on the availabilityof our products.Third party manufacturers

159、 often encounter difficulties involving production yields,quality control and quality assurance,as well as shortages of qualified personnel.CompetitionThe biotechnology and pharmaceutical industries are characterized by continuing technological advancement and significant competition.While we believ

160、e that our product candidates,technology,knowledge,experience and scientific resources provide us with competitive advantages,we face competition from major pharmaceutical and biotechnology companies,academicinstitutions,governmental agencies and public and private research institutions,among others

161、.Any product candidates that we successfully develop and commercialize will compete with existingtherapies and new therapies that may become available in the future.Key product features that would affect our ability to effectively compete with other therapeutics include the efficacy,safety andconven

162、ience of our products and the ease of use and effectiveness of any companion diagnostics.The level of generic competition and the availability of reimbursement from government and otherthird party payors will also significantly affect the pricing and competitiveness of our products.Our competitors a

163、lso may obtain FDA or other regulatory approval for their products more rapidly thanwe may obtain approval for ours,which could result in our competitors establishing a strong market position before we are able to enter the market.Many of the companies against which we may compete have significantly

164、 greater financial resources and expertise in research and development,manufacturing,preclinical testing,conductingclinical trials,obtaining regulatory approvals and marketing approved products than we do.Smaller or early-stage companies may also prove to be significant competitors,particularly thro

165、ughcollaborative arrangements with large and established companies.These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishingclinical trial sites and patient registration for clinical trials,as well as in acquiring technologies c

166、omplementary to,or necessary for,our programs.Specifically,there are several companies developing or marketing treatments that may be approved for the same indications and/or diseases as our product candidates,including majorpharmaceutical companies.9For our PD-1 agonist antibody program,our competi

167、tors include other PD-1 agonist antibodies GS-0151(Gilead)in Phase 1b development for the treatment of rheumatoid arthritis,and a PD-1 agonist antibody(Boehringer Ingelheim)in Phase 1 development.Our commercial-stage competitors in moderate-to-severe rheumatoid arthritis include monoclonal antibodie

168、s targeting anti-TNF(Humira;Abbvie),IL-6(Actemra;Roche and Kevzara;Regeneron),CD-80/86(Orencia;BMS),CD-20(Rituxan;Roche),and janus kinase inhibitors(Rinvoq;AbbVie,Olumiant;Eli Lilly,andXeljanz;Pfizer).Commercial-stage competitors in moderate-to-severe ulcerative colitis include monoclonal antibodies

169、 targeting anti-TNF(Humira;Abbvie and Remicade;Johnson&Johnson),anti-47(Entyvio;Takeda),anti-IL-23(Stelara;Johnson&Johnson,Omvoh;Eli Lilly,Tremfya;Johnson and Johnson,and Skyrizi;AbbVie)and S1P inhibitors(Zeposia;Bristol Myers Squibb andVelsipity;Pfizer)and janus kinase inhibitors(Rinvoq;AbbVie,and

170、Xeljanz;Pfizer)as well as monoclonal antibodies targeting anti-TL1A(PRA023;Merck,RVT-3101;Roche and duvakitug;Teva/Sanofi)in Phase 2 and 3 development.For our anti-CD122 antagonist antibody program,our clinical competitors include other anti-CD122 antagonist antibodies,auremolimab(Incyte),in Phase 1

171、 development for the treatment ofvitiligo and FB-102(Forte Bioscience)in Phase 1b development for the treatment of celiac disease,and three anti-IL-15 monoclonal antibodies,AMG 714(Amgen),currently in Phase 2 developmentfor the treatment of celiac disease,CALY-002(Novartis),currently in Phase 1b dev

172、elopment for the treatment of celiac disease and eosinophilic esophagitis,and TEV-408(Teva),currently in Phase1b development for the treatment of celiac disease and vitiligo.For our anti-BDCA2 program,our competitors include another anti-BDCA2 antibody,litifilimab(Biogen)in Phase 3 development for S

173、LE and CLE,and an anti-ILT7 antibody,daxdilimab(Amgen)in Phase 2 development for dermatomyositis or anti-synthetase inflammatory myositis,and discoid lupus erythematosus.Government Regulation and Product ApprovalGovernment authorities in the United States,at the federal,state and local level,and in

174、other countries and jurisdictions,including the EU,extensively regulate,among other things,theresearch,development,testing,manufacture,quality control,approval,packaging,storage,recordkeeping,labeling,advertising,promotion,distribution,marketing,post-approval monitoring andreporting,and import and e

175、xport of pharmaceutical products.The processes for obtaining regulatory approvals in the United States and in foreign countries and jurisdictions,along with subsequentcompliance with applicable statutes and regulations and other regulatory authorities,require the expenditure of substantial time and

176、financial resources.FDA approval processIn the United States,pharmaceutical products are subject to extensive regulation by the FDA.The Federal Food,Drug,and Cosmetic Act(“FDC Act”),and other federal and state statutes andregulations,govern,among other things,the research,development,testing,manufac

177、ture,storage,recordkeeping,approval,labeling,promotion and marketing,distribution,post-approval monitoringand reporting,sampling,and import and export of pharmaceutical products.Biological products used for the prevention,treatment,or cure of a disease or condition of a human being are subject toreg

178、ulation under the FDC Act,except the section of the FDC Act which governs the approval of new drug applications(“NDAs”).Biological products are approved for marketing under provisions ofthe Public Health Service Act(“PHSA”),via a BLA.However,the application process and requirements for approval of B

179、LAs are similar to those for NDAs,and biologics are associated with similarapproval risks and costs as drugs.Failure to comply with applicable U.S.requirements may subject a company to a variety of administrative or judicial sanctions,such as clinical hold,FDA refusal toapprove pending NDAs or BLAs,

180、warning or untitled letters,product recalls,product seizures,total or partial suspension of production or distribution,injunctions,fines,civil penalties,and criminalprosecution.Biological product development for a new product or certain changes to an approved product in the United States typically i

181、nvolves preclinical laboratory and animal tests,the submission tothe FDA of an investigational new drug application(“IND”),which must become effective before clinical testing may commence in the United States,and adequate and well-controlled clinical trialsto establish the safety and effectiveness o

182、f the drug for each indication for which FDA approval is sought.Satisfaction of FDA premarket approval requirements typically takes many years and theactual time required may vary substantially based upon the type,complexity,and novelty of the product or disease.Preclinical tests include laboratory

183、evaluation of product chemistry,formulation,and toxicity,as well as animal trials to assess the characteristics and potential safety and efficacy of theproduct.The conduct of the preclinical tests must comply with federal regulations and requirements,including good laboratory practices(“GLPs”).The r

184、esults of preclinical testing are submitted tothe FDA as part of an IND along with other information,including information about product chemistry,manufacturing and controls,and a proposed clinical trial protocol.Long term preclinical tests,such as animal tests of reproductive toxicity and carcinoge

185、nicity,may continue after the IND is submitted.A 30-day waiting period after the submission of each IND is required prior to thecommencement of clinical testing in humans.If the FDA has neither commented on nor questioned the IND within this 30-day period,the clinical trial proposed in the IND may b

186、egin.Clinical trialsinvolve the administration of the investigational biologic to healthy volunteers or patients under the supervision of a10qualified investigator.Clinical trials must be conducted:(i)in compliance with federal regulations;(ii)in compliance with good clinical practices(“GCPs”),an in

187、ternational standard meant to protectthe rights and health of patients and to define the roles of clinical trial sponsors,administrators,and monitors;as well as(iii)under protocols detailing the objectives of the trial,the parameters to beused in monitoring safety,and the effectiveness criteria to b

188、e evaluated.Each protocol involving testing on U.S.patients and subsequent protocol amendments must be submitted to the FDA as part ofthe IND.The FDA may order the temporary,or permanent,discontinuation of a clinical trial at any time,or impose other sanctions if it believes that the clinical trial

189、either is not being conducted inaccordance with FDA requirements or presents an unacceptable risk to the clinical trial patients.The trial protocol and informed consent information for patients in clinical trials must also besubmitted to an institutional review board(“IRB”)for approval.An IRB may al

190、so require the clinical trial at the site to be halted,either temporarily or permanently,for failure to comply with theIRBs requirements,or may impose other conditions.Clinical trials to support BLAs for marketing approval are typically conducted in three sequential phases,but the phases may overlap

191、.In Phase 1,the initial introduction of the biologic intohealthy human subjects or patients,the product is tested to assess metabolism,pharmacokinetics,pharmacological actions,side effects associated with increasing doses,and,if possible,earlyevidence on effectiveness.Phase 2 usually involves clinic

192、al trials in a limited patient population to determine the effectiveness of the drug or biologic for a particular indication,dosage tolerance,andoptimal dosage,and to identify common adverse effects and safety risks.If a compound demonstrates evidence of effectiveness and an acceptable safety profil

193、e in Phase 2 evaluations,Phase 3clinical trials are undertaken to obtain the additional information about clinical efficacy and safety in a larger number of patients,typically at geographically dispersed clinical trial sites,to permit theFDA to evaluate the overall benefit risk relationship of the d

194、rug or biologic and to provide adequate information for the labeling of the product.In most cases,the FDA requires two adequate andwell-controlled Phase 3 clinical trials to demonstrate the efficacy of the biologic.A single Phase 3 clinical trial may be sufficient in rare instances,including(i)where

195、 the clinical trial is a largemulticenter clinical trial demonstrating internal consistency and a statistically persuasive finding of a clinically meaningful effect on mortality,irreversible morbidity or prevention of a disease with apotentially serious outcome and confirmation of the result in a se

196、cond clinical trial would be practically or ethically impossible or(ii)when in conjunction with other confirmatory evidence.After completion of the required clinical testing,a BLA is prepared and submitted to the FDA.FDA approval of the BLA is required before marketing of the product may begin in th

197、e UnitedStates.The BLA must include the results of all preclinical,clinical,and other testing and a compilation of data relating to the products pharmacology,chemistry,manufacture,and controls.The costof preparing and submitting a BLA is substantial.The submission of most BLAs is additionally subjec

198、t to a substantial application user fee,and the applicant under an approved BLA is also subject toannual product and establishment user fees.These fees are typically increased annually.The FDA has 60 days from its receipt of a BLA to determine whether the application will be accepted forfiling based

199、 on the agencys threshold determination that it is sufficiently complete to permit substantive review.Once the submission is filed,the FDA begins an in-depth review.The FDA hasagreed to certain performance goals in the review of BLAs.Most such applications for standard review biologic products are r

200、eviewed within 10 months of the date the BLA is filed with the FDA;most applications for priority review biologics are reviewed within six months of the date the BLA is filed with the FDA.Priority review can be applied to a biologic that the FDA determines has thepotential to treat a serious or life

201、-threatening condition and,if approved,would be a significant improvement in safety or effectiveness compared to available therapies.The review process for bothstandard and priority review may be extended by the FDA for three additional months to consider certain late-submitted information or inform

202、ation intended to clarify information already provided inthe submission.The FDA may also refer applications for novel biologic products,or biologic products that present difficult questions of safety or efficacy,to an advisory committeetypically a panel thatincludes clinicians and other expertsfor r

203、eview,evaluation,and a recommendation as to whether the application should be approved.The FDA is not bound by the recommendation of an advisorycommittee,but it generally follows such recommendations.Before approving a BLA,the FDA will typically inspect one or more clinical sites to assure complianc

204、e with GCP.Additionally,the FDAwill inspect the facility or the facilities at which the biologic product is manufactured.The FDA will not approve the product unless compliance with cGMP is satisfactory and the BLA contains datathat provide substantial evidence that the biologic is safe,pure,potent a

205、nd effective in the indication studied.After the FDA evaluates the BLA and the manufacturing facilities,it issues either an approval letter or a complete response letter.A complete response letter generally outlines thedeficiencies in the submission and may require substantial additional testing,or

206、information,in order for the FDA to reconsider the application.If,or when,those deficiencies have been addressed tothe FDAs satisfaction in a resubmission of the BLA,the FDA will issue an approval letter.The FDA has committed to reviewing such resubmissions in two or six months depending on the type

207、 ofinformation included.An approval letter authorizes commercial marketing of the biologic with specific prescribing information for specific indications.As a condition of BLA approval,the FDA mayrequire a risk evaluation and mitigation strategy(“REMS”)to help ensure that the benefits of the biologi

208、c outweigh the potential risks.REMS can include medication guides,communication plans forhealth care11professionals,and elements to assure safe use(“ETASU”).ETASU can include,but are not limited to,special training or certification for prescribing or dispensing,dispensing only under certaincircumsta

209、nces,special monitoring,and the use of patient registries.The requirement for a REMS can materially affect the potential market and profitability of the product.Moreover,productapproval may require substantial post-approval testing and surveillance to monitor the products safety or efficacy.Once gra

210、nted,product approvals may be withdrawn if compliance with regulatory standards is not maintained or problems are identified following initial marketing.Changes to some of theconditions established in an approved application,including changes in indications,labeling,or manufacturing processes or fac

211、ilities,require submission and FDA approval of a new BLA or BLAsupplement before the change can be implemented.A BLA supplement for a new indication typically requires clinical data similar to that in the original application,and the FDA uses the sameprocedures and actions in reviewing BLA supplemen

212、ts as it does in reviewing BLAs.Foreign clinical studies to support an INDThe FDA will accept as support for an IND a well-designed,well-conducted,non-IND foreign clinical study if it was conducted in accordance with GCP and the FDA is able to validate thedata from the study through an onsite inspec

213、tion,if necessary.A sponsor or applicant who wishes to rely on a non-IND foreign clinical study to support an IND must submit the following supportinginformation to the FDA to demonstrate that the study conformed to GCP:the investigators qualifications;a description of the research facilities;a deta

214、iled summary of the protocol and study results and,if requested,case records or additional background data;a description of the drug substance and drug product,including the components,formulation,specifications,and,if available,the bioavailability of the drug product;information showing that the st

215、udy is adequate and well controlled;the name and address of the independent ethics committee that reviewed the study and a statement that the independent ethics committee meets the required definition;a summary of the independent ethics committees decision to approve or modify and approve the study,

216、or to provide a favorable opinion;a description of how informed consent was obtained;a description of what incentives,if any,were provided to subjects to participate;a description of how the sponsors monitored the study and ensured that the study was consistent with the protocol;a description of how

217、 investigators were trained to comply with GCP and to conduct the study in accordance with the study protocol;anda statement on whether written commitments by investigators to comply with GCP and the protocol were obtained.Disclosure of clinical trial informationSponsors of clinical trials of FDA-re

218、gulated products,including biological products,are required to register and disclose certain clinical trial information.Information related to the product,patient population,phase of investigation,trial sites and investigators,and other aspects of the clinical trial is then made public as part of th

219、e registration.Sponsors are also obligated to discuss theresults of their clinical trials after completion.Disclosure of the results of these clinical trials can be delayed in certain circumstances for up to two years after the date of completion of the clinicaltrial.Competitors may use this publicl

220、y available information to gain knowledge regarding the progress of development programs.Pediatric informationUnder the Pediatric Research Equity Act(“PREA”),NDAs or BLAs or supplements to NDAs or BLAs must contain data to assess the safety and effectiveness of the biological product for theclaimed

221、indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the biological product is safe and effective.The FDAmay grant full or partial waivers,or deferrals,for submission of data.Unless otherwise required by regulation,t

222、he PREA does not apply to any biological product for an indication for which OrphanDrug Designation has been granted.12The Best Pharmaceuticals for Children Act(“BPCA”)provides sponsors of NDAs with an additional six-month period of market exclusivity for all unexpired patent or non-patent exclusivi

223、tyon all forms of the drug containing the active moiety if the sponsor submits results of pediatric studies specifically requested by the FDA under BPCA within required timeframes.The BPCAprovides sponsors of BLAs an additional six-month extension for all unexpired non-patent market exclusivity on a

224、ll forms of the biological containing the active moiety pursuant to the BPCA if theconditions under the BPCA are met.Additional controls for biologicsTo help reduce the increased risk of the introduction of adventitious agents,the PHSA emphasizes the importance of manufacturing controls for products

225、 whose attributes cannot be preciselydefined.The PHSA also provides authority to the FDA to immediately suspend licenses in situations where there exists a danger to public health,to prepare or procure products in the event ofshortages and critical public health needs,and to authorize the creation a

226、nd enforcement of regulations to prevent the introduction or spread of communicable diseases in the United States andbetween states.After a BLA is approved,the product may also be subject to official lot release as a condition of approval.As part of the manufacturing process,the manufacturer is requ

227、ired to performcertain tests on each lot of the product before it is released for distribution.If the product is subject to official release by the FDA,the manufacturer submits samples of each lot of product to the FDAtogether with a release protocol showing a summary of the history of manufacture o

228、f the lot and the results of all of the manufacturers tests performed on the lot.The FDA may also perform certainconfirmatory tests on lots of some products,such as viral vaccines,before releasing the lots for distribution by the manufacturer.In addition,the FDA conducts laboratory research related

229、to the regulatory standards on the safety,purity,potency,and effectiveness of biological products.As with drugs,after approval ofbiologics,manufacturers must address any safety issues that arise,are subject to recalls or a halt in manufacturing,and are subject to periodic inspection after approval.P

230、atent term restorationAfter approval,owners of relevant drug or biologic patents may apply for up to a five year patent extension.The allowable patent term extension is calculated as half of the drugs testingphasethe time between IND application and NDA or BLA submissionand all of the review phaseth

231、e time between NDA or BLA submission and approval up to a maximum of five years.Thetime can be shortened if FDA determines that the applicant did not pursue approval with due diligence.The total patent term after the extension may not exceed 14 years from the date of marketingapproval.For patents th

232、at might expire during the application phase,the patent owner may request an interim patent extension.An interim patent extension increases the patent term by one year andmay be renewed up to four times.For each interim patent extension granted,the post-approval patent extension is reduced by one ye

233、ar.The director of the USPTO must determine that approval of thedrug covered by the patent for which a patent extension is being sought is likely.Interim patent extensions are not available for a drug or biologic for which an NDA or BLA has not been submitted.BiosimilarsThe Biologics Price Competiti

234、on and Innovation Act of 2009(“BPCIA”)created an abbreviated approval pathway for biological products shown to be highly similar to or interchangeablewith an FDA licensed reference biological product.Biosimilarity sufficient to reference a prior FDA-approved product requires that there be no differe

235、nces in conditions of use,route ofadministration,dosage form,and strength,and no clinically meaningful differences between the biological product and the reference product in terms of safety,purity,and potency.Biosimilarity mustbe shown through analytical trials,animal trials,and a clinical trial or

236、 trials,unless the Secretary of the U.S.Department of Health and Human Services(“HHS”)waives a required element.Abiosimilar product may be deemed interchangeable with a prior approved product if it meets the higher hurdle of demonstrating that it can be expected to produce the same clinical results

237、as thereference product and,for products administered multiple times,the biologic and the reference biologic may be switched after one has been previously administered without increasing safety risks orrisks of diminished efficacy relative to exclusive use of the reference biologic.The first biosimi

238、lar was approved by the FDA in 2015,and the first interchangeable product was approved in 2021.A reference biologic is granted 12 years of exclusivity from the time of first licensure of the reference product,and no application for a biosimilar can be submitted for four years from thedate of licensu

239、re of the reference product.The first biologic product submitted under the abbreviated approval pathway that is determined to be interchangeable with the reference product hasexclusivity against a finding of interchangeability for other biologics for the same condition of use for the lesser of(i)one

240、 year after first commercial marketing of the first interchangeable biosimilar,(ii)18 months after the first interchangeable biosimilar is approved if there is no patent challenge,(iii)18 months after resolution of a lawsuit over the patents of the reference biologic in favor of thefirst interchange

241、able biosimilar applicant,or(iv)42 months after the first interchangeable biosimilars application has been approved if a patent lawsuit is ongoing within the 42-month period.13Post-approval requirementsOnce a BLA is approved,a product will be subject to certain post-approval requirements.For instanc

242、e,the FDA closely regulates the post-approval marketing and promotion of biologics,including standards and regulations for direct-to-consumer advertising,off-label promotion,industry-sponsored scientific and educational activities and promotional activities involving the internet.Biologics may be ma

243、rketed only for the approved indications and in accordance with the provisions of the approved labeling.Changes to some of the conditions established in an approvedapplication,including changes in indications,labeling,or manufacturing processes or facilities,may require a submission to and approval

244、by the FDA before the change can be implemented.A BLAsupplement for a new indication typically requires clinical data similar to that in the original application and similar procedures and actions in reviewing BLA or supplements as in reviewing BLAs.Adverse event reporting and submission of periodic

245、 reports are required following FDA approval of a BLA.The FDA also may require post-marketing testing,known as Phase 4 testing,REMS,and surveillance to monitor the effects of an approved product,or the FDA may place conditions on an approval that could restrict the distribution or use of the product

246、.In addition,qualitycontrol,biological product manufacture,packaging,and labeling procedures must continue to conform to cGMPs after approval.Biologic manufacturers and certain of their subcontractors arerequired to register their establishments with the FDA and certain state agencies.Registration w

247、ith the FDA subjects entities to periodic unannounced inspections by the FDA,during which theagency inspects manufacturing facilities to assess compliance with cGMPs.Accordingly,manufacturers must continue to expend time,money,and effort in the areas of production and quality-controlto maintain comp

248、liance with cGMPs.Regulatory authorities may withdraw product approvals or request product recalls if a company fails to comply with regulatory standards,if it encountersproblems following initial marketing,or if previously unrecognized problems are subsequently discovered.In addition,biological pro

249、duct manufacturers in the U.S.must comply with applicableprovisions of the Drug Supply Chain Security Act and provide and receive product tracing information,maintain appropriate licenses,ensure they only work with other properly licensed entities andhave procedures in place to identify and properly

250、 handle suspect and illegitimate products.Other U.S.health care laws and compliance requirementsIn the United States,our activities are potentially subject to regulation by various federal,state and local authorities in addition to the FDA,including but not limited to,the Centers forMedicare and Med

251、icaid Services(“CMS”),other divisions of the HHS(such as the Office of Inspector General),the U.S.Department of Justice(“DOJ”),and individual U.S.Attorney offices withinthe DOJ,and state and local governments.For example,sales,marketing and scientific/educational grant programs may have to comply wi

252、th the anti-fraud and abuse provisions of the Social SecurityAct,anti-kickback statutes,false claims laws,the privacy and security provisions of the Health Insurance Portability and Accountability Act(“HIPAA”),and similar state laws,each as amended,asapplicable.The federal Anti-Kickback Statute proh

253、ibits,among other things,any person or entity,from knowingly and willfully offering,paying,soliciting or receiving any remuneration,directly orindirectly,overtly or covertly,in cash or in kind,to induce or in return for purchasing,leasing,ordering or arranging for the purchase,lease or order of any

254、item or service reimbursable underMedicare,Medicaid or other federal health care programs.The term remuneration has been interpreted broadly to include anything of value.The Anti-Kickback Statute has been interpreted to applyto arrangements between pharmaceutical manufacturers on one hand and prescr

255、ibers,purchasers,and formulary managers on the other.There are a number of statutory exceptions and regulatory safeharbors protecting some common activities from prosecution.The exceptions and safe harbors are drawn narrowly and practices that involve remuneration that may be alleged to be intended

256、toinduce prescribing,purchasing or recommending may be subject to scrutiny if they do not qualify for an exception or safe harbor.Failure to meet all of the requirements of a particular applicablestatutory exception or regulatory safe harbor does not make the conduct per se illegal under the Anti-Ki

257、ckback Statute.Instead,the legality of the arrangement will be evaluated on a case-by-casebasis based on a cumulative review of all of its facts and circumstances.Our practices may not in all cases meet all of the criteria for protection under a statutory exception or regulatory safe harbor.Addition

258、ally,the intent standard under the Anti-Kickback Statute was amended by the Patient Protection and Affordable Care Act(“ACA”)to a stricter standard such that a person or entityno longer needs to have actual knowledge of the statute or specific intent to violate it in order to have committed a violat

259、ion.In addition,the ACA codified case law that a claim including items orservices resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal False Claims Act(discussed below).The civil monetary penalties statute imposes penalti

260、es against any person or entity that,among other things,is determined to have presented or caused to be presented a claim to a federalhealth program that the person knows or should know is for an item or service that was not provided as claimed or is false or fraudulent.14Federal false claims and fa

261、lse statement laws,including the federal False Claims Act,prohibit,among other things,any person or entity from knowingly presenting,or causing to be presented,a false or fraudulent claim for payment to,or approval by,the federal health care programs,including Medicare and Medicaid,or knowingly maki

262、ng,using,or causing to be made or used a falserecord or statement material to a false or fraudulent claim to the federal government.As a result of a modification made by the Fraud Enforcement and Recovery Act of 2009,a claim includes“anyrequest or demand”for money or property presented to the U.S.go

263、vernment.Recently,several pharmaceutical and other health care companies have been prosecuted under these laws for allegedlyproviding free product to customers with the expectation that the customers would bill federal programs for the product.Other companies have been prosecuted for causing false c

264、laims to besubmitted because of the companies marketing of the product for unapproved,and thus generally non-reimbursable,uses.HIPAA created additional federal criminal statutes that prohibit,among other things,knowingly and willfully executing,or attempting to execute,a scheme to defraud or to obta

265、in,by meansof false or fraudulent pretenses,representations or promises,any money or property owned by,or under the control or custody of,any health care benefit program,including private third party payors,willfully obstructing a criminal investigation of a health care offense,and knowingly and wil

266、lfully falsifying,concealing or covering up by trick,scheme or device,a material fact or making anymaterially false,fictitious or fraudulent statement in connection with the delivery of or payment for health care benefits,items or services.Like the Anti-Kickback Statute,the ACA amended theintent sta

267、ndard for certain health care fraud statutes under HIPAA such that a person or entity no longer needs to have actual knowledge of the statute or specific intent to violate it in order to havecommitted a violation.Also,many states have similar fraud and abuse statutes or regulations that apply to ite

268、ms and services reimbursed under Medicaid and other state programs,or,in several states,applyregardless of the payor.Additionally,to the extent that our product is sold in a foreign country,we may be subject to similar foreign laws.We may be subject to data privacy and security regulations by both t

269、he federal government and the states in which we conduct our business.HIPAA,as amended by the Health InformationTechnology for Economic and Clinical Health Act(“HITECH”),and its implementing regulations,imposes requirements relating to the privacy,security and transmission of individually identifiab

270、lehealth information.Among other things,HITECH makes HIPAAs privacy and security standards directly applicable to business associates,independent contractors or agents of covered entities thatreceive or obtain protected health information in connection with providing a service on behalf of a covered

271、 entity.HITECH also created four new tiers of civil monetary penalties,amended HIPAAto make civil and criminal penalties directly applicable to business associates,and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforceHIPAA and se

272、ek attorneys fees and costs associated with pursuing federal civil actions.In addition,many state laws govern the privacy and security of health information in specified circumstances,many of which differ from each other in significant ways and may not have the same effect,thus complicating complian

273、ce efforts.Additionally,the federal Physician Payments Sunshine Act within the ACA,and its implementing regulations,require that certain manufacturers of drugs,devices,biological and medicalsupplies for which payment is available under Medicare,Medicaid or the Childrens Health Insurance Program(with

274、 certain exceptions)report annually to CMS information related to certainpayments or other transfers of value made or distributed to physicians and teaching hospitals,or to entities or individuals at the request of,or designated on behalf of,the physicians and teachinghospitals and to report annuall

275、y certain ownership and investment interests held by physicians and their immediate family members.Moreover,the Drug Supply Chain Security Act imposes newobligations on manufacturers of pharmaceutical products related to product tracking and tracing.Legislative and regulatory proposals have been mad

276、e to expand post-approval requirements andrestrict sales and promotional activities for pharmaceutical products.In order to distribute products commercially,we must comply with state laws that require the registration of manufacturers and wholesale distributors of drug and biological products in ast

277、ate,including,in certain states,manufacturers and distributors who ship products into the state even if such manufacturers or distributors have no place of business within the state.Some states alsoimpose requirements on manufacturers and distributors to establish the pedigree of product in the chai

278、n of distribution,including some states that require manufacturers and others to adopt newtechnology capable of tracking and tracing product as it moves through the distribution chain.Several states have enacted legislation requiring pharmaceutical and biotechnology companies toestablish marketing c

279、ompliance programs,file periodic reports with the state,make periodic public disclosures on sales,marketing,pricing,clinical trials and other activities,and/or register their salesrepresentatives,as well as to prohibit pharmacies and other health care entities from providing certain physician prescr

280、ibing data to pharmaceutical and biotechnology companies for use in sales andmarketing,and to prohibit certain other sales and marketing practices.All of our activities are potentially subject to federal and state consumer protection and unfair competition laws.If our operations are found to be in v

281、iolation of any of the federal and state health care laws described above or any other governmental regulations that apply to us,we may be subject topenalties,including without limitation,civil,criminal and/or administrative penalties,damages,fines,disgorgement,exclusion from participation in govern

282、ment programs,such as Medicare andMedicaid,injunctions,private“qui tam”actions brought by individual whistleblowers in the name of the15government,or refusal to allow us to enter into government contracts,contractual damages,reputational harm,administrative burdens,diminished profits and future earn

283、ings,and the curtailment orrestructuring of our operations,any of which could adversely affect our ability to operate our business and our results of operations.Coverage,pricing and reimbursementSignificant uncertainty exists as to the coverage and reimbursement status of any product candidates for

284、which we obtain regulatory approval.In the United States and markets in othercountries,sales of any products for which we receive regulatory approval for commercial sale will depend,in part,on the extent to which third-party payors provide coverage,and establish adequatereimbursement levels for such

285、 products.In the United States,third party payors include federal and state health care programs,private managed care providers,health insurers and otherorganizations.The process for determining whether a third party payor will provide coverage for a product may be separate from the process for sett

286、ing the price of a product or for establishing thereimbursement rate that such a payor will pay for the product.Third party payors may limit coverage to specific products on an approved list,also known as a formulary,which might not include allof the FDA-approved products for a particular indication

287、.Third party payors are increasingly challenging the price,examining the medical necessity and reviewing the cost-effectiveness of medicalproducts,therapies and services,in addition to questioning their safety and efficacy.We may need to conduct expensive pharmacoeconomic studies in order to demonst

288、rate the medical necessity andcost-effectiveness of our products,in addition to the costs required to obtain the FDA approvals.Our product candidates may not be considered medically necessary or cost-effective.A payorsdecision to provide coverage for a product does not imply that an adequate reimbur

289、sement rate will be approved.Further,one payors determination to provide coverage for a product does not assurethat other payors will also provide coverage for the product.Adequate third party reimbursement may not be available to enable us to maintain price levels sufficient to realize an appropria

290、te return onour investment in product development.Different pricing and reimbursement schemes exist in other countries.In the EU,governments influence the price of pharmaceutical products through their pricing and reimbursement rulesand control of national health care systems that fund a large part

291、of the cost of those products to consumers.Some jurisdictions operate positive and negative list systems under which products mayonly be marketed once a reimbursement price has been agreed.To obtain reimbursement or pricing approval,some of these countries may require the completion of clinical tria

292、ls that compare thecost effectiveness of a particular product candidate to currently available therapies.Other member states allow companies to fix their own prices for medicines,but monitor and control companyprofits.The downward pressure on health care costs has become intense.As a result,increasi

293、ngly high barriers are being erected to the entry of new products.In addition,in some countries,cross-border imports from low-priced markets exert a commercial pressure on pricing within a country.The marketability of any product candidates for which we receive regulatory approval for commercial sal

294、e may suffer if the government and third party payors fail to provide adequatecoverage and reimbursement.In addition,emphasis on managed care in the United States has increased and we expect will continue to increase the pressure on health care pricing.Coverage policiesand third party reimbursement

295、rates may change at any time.Even if favorable coverage and reimbursement status is attained for one or more products for which we receive regulatory approval,lessfavorable coverage policies and reimbursement rates may be implemented in the future.Healthcare reformHealthcare reforms that have been a

296、dopted,and that may be adopted in the future,could result in further reductions in coverage and levels of reimbursement for pharmaceutical products,increases in rebates payable under U.S.government rebate programs and additional downward pressure on pharmaceutical product prices.Healthcare reform in

297、itiatives culminated in the enactment ofthe Inflation Reduction Act(“IRA”),which,among other things,allows the HHS to negotiate the selling price of certain drugs and biologics that CMS reimburses under Medicare Part B and Part D,although only high-expenditure single-source drugs that have been appr

298、oved for at least 7 years(11 years for biologics)can be selected by CMS for negotiation,with the negotiated price taking effecttwo years after the selection year.For 2026,the first year in which negotiated prices become effective,CMS selected 10 high-cost Medicare Part D products in 2023,negotiation

299、s began in 2024,andthe negotiated maximum fair price for each product has been announced.CMS has selected 15 additional Medicare Part D drugs for negotiated maximum fair pricing in 2027.For 2028,an additional15 drugs,which may be covered under either Medicare Part B or Part D,will be selected,and fo

300、r 2029 and subsequent years,20 Part B or Part D drugs will be selected.Negotiations for MedicarePart D products begin in 2024 with the negotiated price taking effect in 2026,and negotiations for Medicare Part B products begin in 2026 with the negotiated price taking effect in 2028.In August2023,HHS

301、announced the ten Medicare Part D drugs and biologics that it selected for negotiations,and by October 1,2023,each manufacturer of the selected drugs signed a manufacturer agreementto participate in the negotiations.HHS announced the negotiated maximum fair prices on August 15,2024,and this price ca

302、p,which cannot exceed a statutory ceiling price,will come into effect onJanuary 1,2026.Beginning in January 2023 for Medicare Part B and October 2022 for Medicare Part D,the IRA will also penalize drug manufacturers that increase prices of Medicare Part B andPart D drugs at a rate greater than the r

303、ate of inflation and in November 2024,CMS finalized regulations pertaining to these inflation rebates.The IRA permits the Secretary of HHS to implementmany of these16provisions through guidance,as opposed to regulation,for the initial years.Manufacturers that fail to comply with the IRA may be subje

304、ct to various penalties,including civil monetary penalties.TheIRA also extends enhanced subsidies for individuals purchasing health insurance coverage in ACA marketplaces through plan year 2025.These provisions began taking effect progressively startingin 2023,although they may be subject to legal c

305、hallenges.For example,the provisions related to the negotiation of selling prices of high-expenditure single-source drugs and biologics have beenchallenged in multiple lawsuits.Thus,while it is unclear how the IRA will be implemented,it will likely have a significant impact on the pharmaceutical ind

306、ustry and the pricing of our products andproduct candidates.It is unclear to what extent other statutory,regulatory,and administrative initiatives will be enacted and implemented in the future.We expect that additional state and federal healthcare reform measures will be adopted in the future.The Fo

307、reign Corrupt Practices ActThe Foreign Corrupt Practices Act(“FCPA”),prohibits any U.S.individual or business from paying,offering,or authorizing payment or offering of anything of value,directly or indirectly,toany foreign official,political party or candidate for the purpose of influencing any act

308、 or decision of the foreign entity in order to assist the individual or business in obtaining or retainingbusiness.The FCPA also obligates companies whose securities are listed in the United States to comply with accounting provisions requiring us to maintain books and records that accurately andfai

309、rly reflect all transactions of the corporation,including international subsidiaries,and to devise and maintain an adequate system of internal accounting controls for international operations.Additional regulationIn addition to the foregoing,we are also subject to numerous federal,state and local la

310、ws relating to such matters as safe working conditions,manufacturing practices,environmentalprotection,fire hazard control,and disposal of hazardous or potentially hazardous substances,including the Occupational Safety and Health Act,the Resource Conservancy and Recovery Act and theToxic Substances

311、Control Act.These and other laws govern our use,handling and disposal of various biological,chemical and radioactive substances used in,and wastes generated by,ouroperations.If our operations result in contamination of the environment or expose individuals to hazardous substances,we could be liable

312、for damages and governmental fines.We believe that we arein material compliance with applicable environmental laws and that continued compliance therewith will not have a material adverse effect on our business.We cannot predict,however,how changesin these laws may affect our future operations.Europ

313、e/rest of world government regulationIn addition to regulations in the United States,we will be subject to a variety of regulations in other jurisdictions governing,among other things,clinical trials and any commercial sales anddistribution of our products.Whether or not we obtain FDA approval of a

314、product,we must obtain the requisite approvals from regulatory authorities in foreign countries prior to the commencementof clinical trials or marketing of the product in those countries.Certain countries outside of the United States have a similar process that requires the submission of a clinical

315、trial application muchlike the IND prior to the commencement of human clinical trials.In the United Kingdom(“UK”)and countries in the EU,for example,a Clinical Trial Authorisation(“CTA”)must be submitted toeach countrys national health authority and an independent ethics committee,much like the FDA

316、and IRB,respectively.Once the CTA is approved in accordance with a countrys requirements,clinical trial development may proceed.Because biologically sourced raw materials are subject to unique contamination risks,their use may be restricted in some countries.The requirements andprocess governing the

317、 conduct of clinical trials,product licensing,pricing and reimbursement vary from country to country.In all cases,the clinical trials are conducted in accordance with GCP andthe applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.To obt

318、ain regulatory approval of an investigational drug or biological product under EU and UK regulatory systems,we must submit a marketing authorization application.The applicationused to file the BLA in the United States is similar to that required in the EU and the UK,with the exception of,among other

319、 things,country-specific document requirements.For other countriesoutside of the EU and the UK,such as countries in Eastern Europe,Latin America or Asia,the requirements governing the conduct of clinical trials,product licensing,pricing and reimbursement varyfrom country to country.In all cases,agai

320、n,the clinical trials are conducted in accordance with GCP and the applicable regulatory requirements and the ethical principles that have their origin in theDeclaration of Helsinki.If we or our potential collaborators fail to comply with applicable foreign regulatory requirements,we may be subject

321、to,among other things,fines,suspension or withdrawal of regulatoryapprovals,product recalls,seizure of products,operating restrictions and criminal prosecution.17Employees and Human Capital ResourcesAs of December 31,2024,we had 136 employees.Of these employees,102 were primarily engaged in research

322、 and development activities and 40 held a doctorate degree such as an M.D.,Ph.D.,or PharmD.None of our employees are represented by a labor union or covered by collective bargaining agreements.We have never experienced a work stoppage and believe that we havegood employee relations.We view our diver

323、se employee population and our culture as key to our success.Our company culture prioritizes learning,supports growth and empowers us to reach new heights.We recruitemployees with the skills and training relevant to succeed and thrive in their functional responsibilities.We assess the likelihood tha

324、t a particular candidate will contribute to the Companys overallgoals,and beyond their specifically assigned tasks.Depending on the position,our recruitment reach can be local as well as national.We provide competitive compensation and benefits that aretailored specifically to the needs and requests

325、 of our employees.Corporate InformationWe were incorporated under the laws of the State of Delaware in November 2005.Our principal executive offices are located at 10770 Wateridge Circle,Suite 210,San Diego,California92121,and our telephone number is(858)362-6295.Our website address is .The informat

326、ion contained on,or that can be accessed through,our website is not part of,and is notincorporated by reference into,this report.Available InformationWe file Annual Reports on Form 10-K,Quarterly Reports on Form 10-Q,Current Reports on Form 8-K and other information with the Securities and Exchange

327、Commission(“SEC”).Ourfilings with the SEC are available free of charge on the SECs website at www.sec.gov and on our website under the“Investors”tab as soon as reasonably practicable after we electronically file suchmaterial with,or furnish it to,the SEC.Item 1A.Risk FactorsInvesting in our common s

328、tock involves a high degree of risk.You should carefully consider the risks described below,as well as the other information in this report,including ourconsolidated financial statements and the related notes and“Managements Discussion and Analysis of Financial Condition and Results of Operations,”b

329、efore deciding whether to invest in ourcommon stock.The occurrence of any of the events or developments described below could harm our business,financial condition,results of operations,and growth prospects.In such an event,themarket price of our common stock could decline,and you may lose all or pa

330、rt of your investment.Summary of Risk FactorsAn investment in our common stock involves various risks,and prospective investors are urged to carefully consider the matters discussed in the section titled“Risk Factors”prior to makingan investment in our common stock.These risks include,but are not li

331、mited to,the following:Our product candidates in development may fail or suffer delays that adversely affect their commercial viability.Results from our initial clinical trials may not be representative of theresults we will experience in later clinical trials.If we or our collaborators are unable t

332、o complete development of or commercialize our product candidates or experience significantdelays in doing so,our business will be materially harmed.Our ongoing and planned clinical trials or those of our collaborators may reveal significant adverse events,toxicities or other side effects and may re

333、sult in a safety profile that couldinhibit regulatory approval or market acceptance of any of our product candidates.We and/or our collaborators may be unable to obtain,or may be delayed in obtaining,required regulatory approvals in the United States or in foreign jurisdictions,which wouldmaterially impair our ability to commercialize and generate revenue from our product candidates.Even if our pr