Astria Therapeutics Inc (ATXS) 2024年年度報告「NASDAQ」.pdf

《Astria Therapeutics Inc (ATXS) 2024年年度報告「NASDAQ」.pdf》由會員分享，可在線閱讀，更多相關《Astria Therapeutics Inc (ATXS) 2024年年度報告「NASDAQ」.pdf（165頁珍藏版）》請在三個皮匠報告上搜索。

1、Table of ContentsUNITED STATESSECURITIES AND EXCHANGE COMMISSIONWashington,DC 20549FORM 10-K(Mark One)ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1934For the fiscal year ended December 31,2024orTRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCH

2、ANGE ACT OF 1934For the transition period from toCommission File Number:001-37467Astria Therapeutics,Inc.(Exact name of registrant as specified in its charter)Delaware 26-3687168(State or other jurisdiction of incorporation or organization)(IRS Employer Identification No.)22 Boston Wharf Road10th Fl

3、oor Boston,Massachusetts02210(Address of principal executive offices)(Zip Code)Registrants telephone number,including area code(617)349-1971Securities registered pursuant to Section 12(b)of the Act:Title of each class Trading Symbol(s)Name of each exchange on which registeredCommon Stock,$0.001 par

4、value per shareATXSNasdaq Global MarketSecurities registered pursuant to Section 12(g)of the Act:NoneIndicate by check mark if the registrant is a well-known seasoned issuer,as defined in Rule 405 of the Securities Act.Yes NoIndicate by check mark if the registrant is not required to file reports pu

5、rsuant to Section 13 or Section 15(d)of the Act.Yes NoIndicate 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 suchshorter period that the registrant was required to

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

7、receding 12 months(or for such shorter period 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 emerging growth company.See the definitio

8、ns of“large accelerated filer,”“accelerated filer,”“smaller reporting company,”and“emerging growth company”in Rule 12b-2 of the Exchange Act:Large accelerated filer Accelerated filer Non-accelerated filer Smaller reporting company Emerging growth company If an emerging growth company,indicate by che

9、ck mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standardsprovided pursuant to Section 13(a)of the Exchange Act.Indicate by check mark whether the registrant has led a report on and attestation to its managemen

10、ts assessment of the effectiveness of its internal control over nancial reporting under Section 404(b)of the Sarbanes-Oxley Act(15 U.S.C.7262(b)by the registered public accounting rm that prepared or issued its audit report.If securities are registered pursuant to Section 12(b)of the Act,indicate by

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

12、sation received by any of the registrants executive officersduring the relevant recovery period pursuant to 240.10D-1(b).Indicate by check mark whether the registrant is a shell company(as defined in Rule 12b-2 of the Exchange Act).Yes No Aggregate market value of the voting and non-voting common eq

13、uity held by non-affiliates of the registrant,based on the last sale price for such stock on June 28,2024:$370,232,653.As of February 28,2025,there were 56,434,219 shares of the registrants common stock,par value$0.001 per share,outstanding.DOCUMENTS INCORPORATED BY REFERENCEPortions of the registra

14、nts definitive proxy statement relating to its 2025 Annual Meeting of Stockholders are incorporated by reference into Part III of this Annual Report on Form 10-K whereindicated.The registrant intends to file such proxy statement with the U.S.Securities and Exchange Commission within 120 days after t

15、he end of the fiscal year to which this Annual Report on Form 10-K relates.Table of ContentsiTABLE OF CONTENTSPART I Item 1.Business1Item 1A.Risk Factors39Item 1B.Unresolved Staff Comments99Item 1C.Cybersecurity99Item 2.Properties100Item 3.Legal Proceedings100Item 4.Mine Safety Disclosures100PART II

16、Item 5.Market for Registrants Common Equity,Related Stockholder Matters and Issuer Purchases of Equity Securities101Item 6.Reserved101Item 7.Managements Discussion and Analysis of Financial Condition and Results of Operations102Item 7A.Quantitative and Qualitative Disclosures About Market Risk112Ite

17、m 8.Financial Statements and Supplementary Data112Item 9.Changes in and Disagreements With Accountants on Accounting and Financial Disclosure112Item 9A.Controls and Procedures112Item 9B.Other Information113Item 9C:Disclosure Regarding Foreign Jurisdictions that Prevent Inspections113PART IIIItem 10.

18、Directors,Executive Ofcers and Corporate Governance114Item 11.Executive Compensation114Item 12.Security Ownership of Certain Benecial Owners and Management and Related Stockholder Matters114Item 13.Certain Relationships and Related Transactions,and Director Independence114Item 14.Principal Accountan

19、t Fees and Services114PART IVItem 15.Exhibits and Financial Statement Schedules115Item 16.Form 10-K Summary117SIGNATURESTable of ContentsiiSummary of the Material Risks Associated with Our BusinessInvesting in our common stock involves a high degree of risk because our business is subject to numerou

20、s risks and uncertainties.The principal factors and uncertainties that make investing in our common stock risky include,among others:We are entirely dependent on the success of our product candidates,navenibart for the treatment of hereditary angioedema,or HAE,and STAR-0310 for the treatment of atop

21、ic dermatitis,or AD.We cannot give any assurance that we will generatepreclinical,clinical or other data for navenibart or STAR-0310 sufficiently supportive to receive regulatory approval,whichwill be required before either can be commercialized.Interim topline and preliminary data from our clinical

22、 trials that we announce or publish from time to time may change asmore study participant data become available and are subject to audit and verification procedures that could result inmaterial changes in the final data.We will need substantial additional funding.If we are unable to raise capital wh

23、en needed or on acceptable terms,we couldbe forced to delay,reduce or eliminate our product development programs or commercialization efforts.Raising additional capital may cause dilution to our stockholders,restrict our operations or require us to relinquish rights toour technologies or product can

24、didates.We have never generated any revenue from product sales and may never be profitable.We have never obtained marketing approval for a product candidate,and we may be unable to obtain,or may be delayed inobtaining,marketing approval for any future product candidate we may seek to develop.Clinica

25、l trials are costly,time consuming,difficult to enroll and inherently risky,and we may fail to demonstrate safety andefficacy on the timelines that we expect or to the satisfaction of applicable regulatory authorities.We also expect that anylater stage clinical trials we conduct for STAR-0310 will b

26、e larger and more expensive when compared to those we areconducting,and plan to conduct,for navenibart because AD,the indication for which we are developing STAR-0310,is nota rare disease.Navenibart,STAR-0310 or any future product candidates may cause adverse events or undesirable side effects or ha

27、veother unexpected properties that could delay or halt clinical trials,delay or prevent their regulatory approval,limit thecommercial viability of an approved label,or result in significant negative consequences following marketing approval,ifany.We face substantial competition from other pharmaceut

28、ical and biotechnology companies,and our operating results maysuffer if we fail to compete effectively.Product development involves a lengthy and expensive process with an uncertain outcome,and results of earlier preclinicalstudies and clinical trials may not be predictive of future clinical trial r

29、esults.We rely on in-licensed patent and other intellectual property rights for our STAR-0310 program and we may need to obtainlicenses from third parties to other intellectual property rights for the development and commercialization of our STAR-0310 and navenibart programs;if we fail to comply wit

30、h our existing or future obligations under these licenses,or if theselicenses are terminated,we could lose license rights that are important to our business.We rely on third parties to conduct our preclinical studies and clinical trials.If they do not perform satisfactorily,ourbusiness could be sign

31、ificantly harmed.Table of ContentsiiiWe will need to maintain a master cell bank for navenibart,a master cell bank for STAR-0310 and cell lines or banks forany other future biologic candidate that generate sufficient material for preclinical,nonclinical and clinical studies,and alsobuild and maintai

32、n sufficient preclinical,clinical and commercial manufacturing drug substance,drug product and drug-device combination capacity,in each case,through third party manufacturers,for navenibart,STAR-0310 and any otherfuture product candidate that advances into such stages,on the timetables and in a mann

33、er that,in each case,are consistentwith our expected development timetables and financial projections,the failure of which could materially harm ourbusiness and operating results and require us to raise capital sooner than we expect.Our forecasts of cash usage and how long we expect our existing cas

34、h,cash equivalents and short-term investments to fundoperating expenses and capital expenditure requirements may not be accurate and we may therefore use our cash,cashequivalents and short-term investments more rapidly than we expect,which could force us to delay,reduce or eliminate ourproduct devel

35、opment programs or commercialization efforts,if any,and therefore materially harm our operating results,and we could be required to raise capital sooner than we expect.We have incurred significant losses since inception,have a limited operating history on which to assess our business,andanticipate t

36、hat we will continue to incur significant losses for the foreseeable future.If we are unable to obtain and maintain sufficient patent and/or regulatory protection for product candidates,or if the scopeof the patent and/or regulatory protection is not sufficiently broad,our competitors could develop

37、and commercializeproducts similar or identical to ours,and our ability to commercialize such product candidates successfully may beadversely affected.The price of our common stock has been and is likely to continue to be highly volatile,which could result in substantiallosses for our stockholders.Th

38、e summary risk factors described above should be read together with the text of the full risk factors below,in the section entitled“Risk Factors”in Part I,Item 1A of this Annual Report on Form 10-K and the other information set forth in this Annual Report onForm 10-K,including under the heading“Mana

39、gements Discussion and Analysis of Financial Condition and Results of Operations”andour consolidated financial statements and the related notes,as well as in other documents that we file with the Securities and ExchangeCommission.The risks summarized above or described in full below are not the only

40、 risks that we face.Additional risks anduncertainties not precisely known to us,or that we currently deem to be immaterial,may also materially adversely affect our business,financial condition,results of operations and future growth prospects.Table of ContentsivSPECIAL NOTE REGARDING FORWARD-LOOKING

41、 STATEMENTS AND INDUSTRY DATAThis Annual Report on Form 10-K contains forward-looking statements,which reflect our current views with respect to,amongother things,our operations and financial performance,strategy,future financial condition and clinical development programs.Suchforward-looking statem

42、ents are subject to various risks and uncertainties.Accordingly,there are or will be important factors that couldcause actual outcomes or results to differ materially from those indicated in these statements.All statements,other than statements ofhistorical facts,contained in this Annual Report on F

43、orm 10-K,including statements regarding our strategy,future operations,futurefinancial position,future revenue,projected costs,prospects,plans and objectives of management,clinical development programs,regulatory filings and expected market growth are forward-looking statements.The words“anticipate,

44、”“believe,”“continue,”“could,”“estimate,”“expect,”“intend,”“may,”“plan,”“potential,”“predict,”“project,”“should,”“target,”“would”and similar expressions areintended to identify forward-looking statements,although not all forward-looking statements contain these identifying words.Theseforward-looking

45、 statements include but are not limited to those described under the heading“Summary of the Material Risks Associatedwith our Business”and the“Risk Factors”in Part I,Item 1A of this Annual Report on Form 10-K and include,among other things,statements about:our expectations regarding the potential si

46、gnificance of the results from the Phase 1a clinical trial and ALPHA-STAR 1b/2clinical trial of navenibart;our expectations regarding the timing of disclosure of initial safety and efficacy data from the ALPHA-SOLAR trial ofnavenibart;our expectations regarding the timing,nature,goals and results of

47、 the ALPHA-ORBIT Phase 3 clinical trial of navenibart,including the expected timing of release of topline results from such trial,and that favorable results from such trial and theORBIT-EXPANSE long-term trial could support registration of navenibart as a potential treatment for hereditaryangioedema

48、,or HAE;our expectations regarding development and clinical testing of any drug device combination for dosing of navenibart;our expectations about the unmet medical need for HAE,the potential differentiating attributes of navenibart as a potentialtreatment for HAE,along with the potential market imp

49、act of such differentiation,the potential of navenibart to be a best-in-class,market-leading and patient-friendly treatment for HAE,and our vision for navenibart to become the first-choicepreventative treatment for HAE with administration every three or six months with the goal of normalizing the li

50、ves ofpeople living with HAE;the HAE treatment landscape,the product profile of existing HAE therapies and HAE therapies under development,andthe estimated size and anticipated growth of the global HAE market;our expectations to continue to use third party contract manufacturers to meet our nonclini

51、cal,clinical and commercialneeds for navenibart,STAR-0310,and any other development candidate and statements regarding having adequate clinicaland commercial supply of navenibart,any drug device combination of navenibart and STAR-0310;the potential therapeutic benefits and potential attributes of ST

52、AR-0310 and our plans to develop STAR-0310 as atreatment for atopic dermatitis,or AD;our expectations about the anticipated timing of early proof-of-concept data from the Phase 1a clinical trial of STAR-0310;our expectations about the plans and potential design of a STAR-0310 proof-of-concept trial

53、in AD patients;the potential commercial opportunity for STAR-0310 in AD and the likelihood that it can effectively compete in AD,assuming it is approved;the estimated size and anticipated growth of the AD market and the need for treatments for AD;Table of Contentsvthe potential to pursue the develop

54、ment of STAR-0310 in additional indications;our goals and visions for the STAR-0310 program;our expectations regarding our ability to expand our pipeline;the potential benefits of any future acquisition,in-license,collaboration or preclinical development activities;our manufacturing plans,capabiliti

55、es and strategy;our intellectual property position and strategy;our facilities plans and capacity;our management and mitigation of cybersecurity risks;our estimates regarding our cash runway,expenses,future revenue,capital requirements and needs for additional financing,including additional financin

56、g to fund our long-term operations;developments relating to our competitors and our industry;andthe impact of government laws and regulations.We may not actually achieve the plans,intentions or expectations disclosed in our forward-looking statements,and you should notplace undue reliance on our for

57、ward-looking statements.Actual results or events could differ materially from the plans,intentions andexpectations disclosed in the forward-looking statements we make.We have included important factors in the cautionary statementsincluded in this Annual Report on Form 10-K,particularly in the“Risk F

58、actors”in Part I,Item 1A of this Annual Report on Form 10-K,that could cause actual results or events to differ materially from the forward-looking statements that we make.Our forward-lookingstatements do not reflect the potential impact of any future acquisitions,mergers,dispositions,collaborations

59、,joint ventures orinvestments that we may make or enter into.You should read this Annual Report on Form 10-K with the understanding that our actual future results may be materially differentfrom what we expect.We do not assume any obligation to update any forward-looking statement,whether as a resul

60、t of newinformation,future events or otherwise,except as required by law.REFERENCES TO ASTRIAExcept as otherwise indicated herein or as the context otherwise requires,references in this Annual Report on Form 10-K to“Astria,”“the Company,”“we,”“us,”and“our”refer to Astria Therapeutics,Inc.and its con

61、solidated subsidiaries.Table of Contents1PART IItem 1.BusinessOverviewWe are a biopharmaceutical company focused on the discovery,development and commercialization of novel therapeutics forallergic and immunological diseases.Our focus is to develop first-choice therapies that improve the health and

62、outcomes of patients withallergic and immunologic diseases.Our lead product candidate is navenibart,formerly known as STAR-0215,a potential best-in-classmonoclonal antibody inhibitor of plasma kallikrein in clinical development for the treatment of hereditary angioedema,or HAE,a rare,debilitating an

63、d potentially life-threatening disease.We believe that navenibart has the potential to be the market-leading and mostpatient-friendly chronic treatment option for HAE,based on proof-of-concept data in HAE patients and the existing HAE treatmentlandscape.Our second product candidate is STAR-0310,a mo

64、noclonal antibody OX40 antagonist that is in clinical development for thetreatment of atopic dermatitis,or AD,an immune disorder associated with loss of skin barrier function and itching.We believe that withboth of these programs,we are advancing a pipeline of products with meaningfully differentiat

65、ed profiles based on validatedmechanisms.NavenibartThe treatment options for patients with HAE have improved in recent years,however,there is remaining unmet medical need and theglobal market for HAE therapy is strong and growing.The goal for navenibart is to develop a best-in-class monoclonal antib

66、ody inhibitorof plasma kallikrein able to provide long-acting,effective attack prevention for HAE.Our vision for navenibart is to lead the HAEmarket and become the first-choice preventative treatment for HAE with administration every three and six months with the goal ofnormalizing the lives of peop

67、le living with HAE.Targeted plasma kallikrein inhibition can prevent HAE attacks by suppressing thepathway that generates bradykinin and causes excessive swelling.Navenibart is currently in clinical development and the U.S.Food andDrug Administration,or FDA,has granted Fast Track and Orphan Drug des

68、ignations to navenibart for the treatment of HAE.TheEuropean Commission has granted Orphan Medicinal Product Designation to navenibart for the treatment of HAE.In February 2025,we initiated a Phase 3 trial of navenibart called ALPHA-ORBIT.This global,randomized,double-blind,placebo-controlled trial

69、is evaluating the efficacy and safety of navenibart over a 6-month treatment period in up to 135 adults and 10 adolescents(open-label),with Type 1 or Type 2 HAE.Adult patients will be randomized to receive one of three navenibart dose arms:1)an initial600 mg dose followed by 300 mg every 3 months(Q3

70、M),2)600 mg every six months(Q6M),3)600 mg Q3M,or placebo;adolescentswill receive an initial 600 mg dose followed by 300 mg Q3M.The dose arms support the potential to provide patient-centered dosingflexibility to people with HAE.The primary endpoint is time-normalized monthly HAE attacks at 6 months

71、,and a key secondaryendpoint includes the proportion of participants who are attack-free at 6 months.After 6 months,patients may be eligible to enterORBIT-EXPANSE,a long-term trial,in which all patients will be treated with navenibart(open-label)and which will include a patient-centered flexible dos

72、ing period.The navenibart Phase 3 program will consist of the ALPHA-ORBIT Phase 3 trial and ORBIT-EXPANSE,which are designed to support registration globally.Top-line results from the ALPHA-ORBIT trial are anticipated in early2027.In addition,to ease the administration of navenibart,we are developin

73、g both autoinjector and pre-filled syringe drug devicecombinations.In February 2023,we initiated a Phase 1b/2 trial of navenibart called ALPHA-STAR,or Astria Long-acting Prophylaxis forHereditary Angioedema:STAR-0215.This global,multi-center,open-label,single and multiple dose proof-of-concept clini

74、cal trial inpeople with HAE evaluated safety,tolerability,HAE attack rate reduction,pharmacokinetics,or PK,pharmacodynamics,or PD,andquality of life in patients three and six months after subcutaneous navenibart administration.We reported initial proof-of-concept data inHAE patients in March 2024.Ta

75、rget enrollment of 16 patients was achieved with all doses administered and we reported final resultsfrom ALPHA-STAR target enrollment in December 2024 which were as follows:Cohort 1 evaluated a single 450 mg dose(n=4).The results for the cohort measured over 6 months were averages of:a 91%reduction

76、 in monthly attack rate;a 96%reduction in moderate and severe attacks;anda 94%reduction in acute rescue medication use;with50%of patients being attack-free through 3 months of follow-up,and 25%being attack-free through 6 months of follow-up.Table of Contents2Cohort 2 evaluated a 600 mg dose followed

77、 by a 300 mg dose three months later,on Day 84(n=6).The results for the cohortmeasured over 6 months were averages of:a 95%reduction in monthly attack rate;a 95%reduction in moderate and severe attacks;anda 94%reduction in acute rescue medication use;with67%of patients being attack-free.Cohort 3 rec

78、eived a 600 mg dose followed by a 600 mg dose one month later,on Day 28(n=6).The results for the cohort measuredover 6 months were averages of:a 92%reduction in monthly attack rate;a 96%reduction in moderate and severe attacks;anda 91%reduction in acute rescue medication use;with67%of patients being

79、 attack-free.Navenibart was generally well-tolerated with no serious treatment-emergent adverse events,or TEAEs,and no discontinuations.There were four non-severe and quickly resolved treatment-related TEAEs:one case of dizziness,one transient injection site reaction(rash),one case of injection site

80、 erythema,and one case of injection site pruritus.There were no injection site reactions of pain.In October 2024,we presented new quality of life data from initial results from ALPHA-STAR at the American College of AllergyAsthma and Immunology(ACAAI)demonstrating that navenibart induced rapid improv

81、ements in quality of life in HAE patients.By day28 after navenibart administration,80%of participants achieved clinically meaningful improvements.Enrollment in ALPHA-STAR was expanded and a total of 29 patients were enrolled in the trial in order to accelerate the collectionof data to support potent

82、ial regulatory filings and future approvals.ALPHA-SOLAR,a long-term open-label trial assessing the long-term safety and efficacy of navenibart,is ongoing.All of the 29patients from ALPHA-STAR have entered ALPHA-SOLAR.Participants are being assigned to receive navenibart in one of two dosingregimens:

83、either 300mg Q3M or 600mg Q6M.We expect to report initial safety and efficacy data from ALPHA-SOLAR in mid-2025.STAR-0310We believe that OX40 inhibition has the potential to treat AD and other diseases.The current treatment options in AD areinsufficient to address the needs of many patients,and stan

84、dard of care treatments include steroids and topical medications which cantreat symptoms but do not address the underlying disease.Our goal for STAR-0310 is to reduce disease activity,relapse rate,andtreatment burden for patients with moderate-to-severe AD.STAR-0310 was engineered with YTE half-life

85、 extension technology toenable infrequent dosing.As a potential long-acting OX40 inhibitor,STAR-0310 aims to address the need for a safe,effective,andinfrequently administered AD treatment.In January 2025,we announced the initiation of our Phase 1a trial of STAR-0310 in healthy subjects.The Phase 1a

86、 randomized,double-blind,placebo-controlled single ascending dose trial is evaluating the safety,tolerability,PK,and immunogenicity of STAR-0310in approximately 40 healthy adult participants.We anticipate early proof-of-concept results from the trial in the third quarter of 2025.In May 2024,we share

87、d preclinical results for STAR-0310 at the European Academy of Allergy and Clinical Immunology(EAACI)conference.STAR-0310 exhibited a long mean half-life of 26 days in cynomolgus monkeys compared to a half-life of 10-14 days for atypical non-half-life-extended IgG antibody.There was also an approxim

88、ately 8-fold increase in binding affinity to human OX40observed for STAR-0310 compared to telazorlimab,an earlier generation antibody prior to affinity maturation without half-lifeextension.Preclinical results demonstrated significantly less antibody-dependent cellular cytotoxicity,or ADCC,potential

89、 with STAR-0310 compared to rocatinlimab,an anti-OX40 monoclonal antibody in Phase 3 development by Amgen,Inc.,with comparable potency.Having less ADCC in the context of robust potency could potentially result in a favorable safety profile and potentially wider therapeuticwindow for STAR-0310.We bel

90、ieve these preclinical results support the potential for STAR-0310 to have the best-in-class OX40inhibitor profile.Table of Contents3Assuming positive results from the Phase 1a clinical trial,we are planning a proof-of-concept clinical trial of STAR-0310 in patientswith AD.The goals of the proof-of-

91、concept trial would be to demonstrate initial efficacy in AD as well as show differentiation in safetyand tolerability and the potential for a reduced treatment burden as a result of extended half-life as compared to existing therapies.Our Product CandidatesNavenibartNavenibart is a monoclonal antib

92、ody that was designed to inhibit plasma kallikrein for the treatment of HAE.Plasma kallikrein is acritical component of the plasma contact system,which causes pathologic vascular permeability in Type I and Type II HAE.Navenibartis a humanized monoclonal antibody that was developed through a hybridom

93、a screening and antibody optimization process.Followinghumanization and optimization for affinity and overall properties,the antibody was modified to increase its plasma half-life.This processresulted in navenibart,a humanized monoclonal antibody having the following desirable features:high affinity

94、 and kallikrein inhibitoryactivity,selectivity for plasma kallikrein compared to prekallikrein,reduced chemistry,manufacturing and controls or,CMC,liabilitiesand long plasma half-life.Based on these characteristics,preclinical experiments,clinical trial results with navenibart,and the HAEmarket land

95、scape,we believe that navenibart has the potential to be a best-in-class and the most patient-friendly monoclonal antibodyinhibitor of plasma kallikrein that could combine the benefits of infrequent dosing with the inhibition of attacks over long periods of timeand low risk of injection pain while m

96、aintaining high levels of efficacy.We have established clinical proof of concept with our Phase1b/2 ALPHA-STAR trial in people with HAE,and we believe that we can develop a differentiated,best-in-class new preventativetherapy for HAE with a well-understood monoclonal antibody modality to provide pat

97、ients with improved outcomes and quality of life.Overview of HAEHAE is a rare,autosomal dominant genetic disorder.The disease is characterized by recurrent,unpredictable,debilitating andpotentially life-threatening edema in the skin,abdomen and airway.The vast majority of HAE cases(Type I and Type I

98、I)are caused bydefects in the C1 esterase inhibitor gene.Deficiencies in the C1 esterase inhibitor gene result in overproduction of bradykinin,a keymediator of vasodilation and angioedema.In several other types of HAE,which are a small minority of cases,other mutations(e.g.,inthe Factor XII gene)can

99、 cause HAE.The estimated prevalence of Type I and Type II HAE range from 1 in 10,000 to 1 in 50,000 withfewer than 8,000 patients in the United States and 15,000 patients in Europe with HAE.There are active and knowledgeable HAE patientadvocacy organizations in the United States and internationally.

100、Patients with HAE are typically diagnosed by the age of 20 with the average age of disease onset around 11.The severity andfrequency of swelling attacks is highly variable even between family members.The Role of Plasma Kallikrein in Hereditary AngioedemaPlasma kallikrein is an enzyme that cleaves hi

101、gh molecular weight kininogen,or HMWK,to release bradykinin.Normally,circulating C1 esterase inhibitor,or C1INH,limits the activation of plasma kallikrein from its precursor prekallikrein,and therebyprevents the release of excess bradykinin from the cleavage of HMWK by plasma kallikrein.In HAE assoc

102、iated with C1INH deficiency,plasma kallikrein is hyperactive,resulting in excessive bradykinin release.Bradykinin activates the bradykinin receptor,or B2R,inendothelial cells,resulting in increased vascular permeability and release of fluid into subcutaneous tissue spaces,or angioedema.Thus,unchecke

103、d plasma kallikrein activity is a critical component that causes pathologic vascular permeability and vasodilation in HAE,leading to excessive tissue swelling,a primary clinical symptom.Unaddressed Market OpportunityThere are two treatment approaches to managing the unpredictable and recurrent edema

104、 attacks typically experienced by people withHAE.On-demand treatments are administered at the onset of an attack to reduce the severity and duration of the attack,and preventativetreatments,which is the treatment approach that we are pursuing with navenibart,are taken chronically to reduce the frequ

105、ency andseverity of future attacks.The HAE treatment market is substantial and growing.We estimate that the HAE market was 2.8 billiondollars in 2023 and that it has potential to grow to 5.4 billion dollars by 2030.This growth is predicted based on patients being diagnosedearlier,more patients takin

106、g treatments to prevent HAE attacks,as well as expansion of available therapies in more geographic regions.In the United States,the FDA has approved four therapies for on-demand treatment of HAE:BERINERT(C1 esterase inhibitorhuman),FIRAZYR(icatibant injection),KALBITOR(ecallantide)and RUCONEST(C1 es

107、terase inhibitor recombinant).Forlong-term preventative treatment of HAE,the FDA has approved the following four therapies:CINRYZE(C1 esterase inhibitorhuman),HAEGARDA(C1 esterase inhibitor subcutaneous human),TAKHZYRO(lanadelumab-flyo)and ORLADEYO(berotralstat).Table of Contents4With the exception

108、of KALBITOR,these therapies are also approved and commercially available outside of the United States.Theapproved preventative therapies have provided HAE patients with treatment options but have limitations in dosing frequency,side effectsand/or efficacy.CINRYZE and HAEGARDA are administered twice

109、a week;CINRYZE by IV infusion and HAEGARDA by SCinjection.TAKHZYRO is dosed every two weeks by SC injection.Dosing every four weeks may be considered in some patients.Withthese injectable therapies,patients have reported a desire for less burdensome administration.ORLADEYO is an oral capsule taken d

110、ailywith food,and data from its approved label,while not comparative data,suggest a lower percentage reduction in attack rate than otheravailable therapies.Historically,androgens and antifibrinolytic treatments have also been used as preventative treatment but they areassociated with side effects su

111、ch as hypertension,acne,hirsutism,rashes,amenorrhea,liver enzyme elevations and increased risk ofthrombosis and their overall use has been declining with the availability of more-tolerable,HAE-specific therapies.Although there hasbeen progress with recent innovation in therapies for HAE and,as descr

112、ibed in the section entitled“Competition”in this Businesssection,there are a significant number of product candidates for HAE in clinical and preclinical development,we believe that there isremaining unmet medical need for potent and long duration of action preventative therapies to provide patients

113、 with lower burden oftreatment and improved outcomes and quality of life.Market research with U.S.physicians and HAE patients has shown strong interestin a product with the potential profile of navenibart.Clinical Trial Results and Development PlansWe initiated a Phase 1a clinical trial of navenibar

114、t in August 2022 and we announced initial results in December 2022.We presentedadditional preliminary results from the trial in February 2023 and further results were shared at the American College of Allergy,Asthma,and Immunology Conference in November 2023.Final results from the trial were shared

115、at the American Academy of Allergy,Asthma,and Immunology Conference in February 2024.This Phase 1a randomized,double-blind,placebo-controlled single ascendingdose clinical trial evaluated the safety,PK and PD of navenibart at a single U.S.center.Forty-one healthy subjects received a single doseof na

116、venibart or placebo in four cohorts of 100mg,300mg,600mg,and 1200mg administered by SC injection or a fifth cohort of 600mgor placebo administered by IV injection.Navenibart was well-tolerated at all dose levels,with no serious adverse events ordiscontinuations due to an adverse event,and low risk o

117、f injection pain.Navenibart demonstrated rapid and sustained drug levels withdose-dependent PK.Navenibart achieved potentially therapeutic levels in less than one day after single doses greater than 100mg andshowed an estimated half-life of up to 109 days.PK modeling of potential once-every-three-mo

118、nth and once-every-six-month clinicaldose regimens over one to two years indicate navenibart has the potential for PK coverage that would confer HAE attack prevention.PDdata showed statistically significant inhibition of Factor XIIa-induced plasma kallikrein activity compared to levels prior to dosi

119、ng,observed using two different assay formats.The percentage inhibition of plasma kallikrein observed was consistent with clinical activityfor doses greater than 300mg.Treatment-emergent ADAs were observed in eleven subjects from completed cohorts,all first observed onor after 140 or more days after

120、 the single dose of navenibart.ADAs were determined not to affect the PK or PD of navenibart.These results support navenibarts target profile as a long-acting plasma kallikrein inhibitor and supported advancing navenibart toour Phase 1b/2 ALPHA-STAR trial,which we initiated in February 2023.This glo

121、bal,multi-center,open-label,single and multiple doseproof-of-concept clinical trial in people with HAE evaluated safety,tolerability,HAE attack rate,PK,PD,and quality of life in patients.Efficacy was assessed at three and six months after last navenibart administration.The trial had three cohorts,wh

122、ich all began with aneight week run-in period to assess baseline attack rate.Cohort 1 received a 450mg single dose of navenibart,Cohort 2 received an initial600mg dose followed by a 300mg dose on Day 84,to simulate a potential three-month dosing regimen with maintenance doses of 300mgevery three mon

123、ths.Cohort 3 received an initial 600mg dose,followed by a second 600mg dose 28 days later,to simulate a potential six-month dosing regimen with maintenance doses of 600mg every six months.All doses were administered subcutaneously and all patientsin the trial were followed for six months after the l

124、ast dose administered.We reported initial proof-of-concept data in HAE patients in theMarch 2024,and final results from the target enrollment in December 2024,which showed rapid onset of robust and durable efficacy,favorable safety and tolerability,and PK and PD consistent with sustained plasma kall

125、ikrein inhibition for both Q3M and Q6Madministration.Final results from the target enrollment included reduction in mean monthly attack rate of 90-95%and up to a 67%attack-free rate over 6 months.Enrollment in ALPHA-STAR was expanded and a total of 29 patients were enrolled in the trial in order to

126、accelerate the collectionof data to support potential regulatory filings and future approvals.ALPHA-SOLAR,a long-term open-label trial assessing the long-term safety and efficacy of navenibart,is ongoing.All of the 29patients from ALPHA-STAR have entered ALPHA-SOLAR.Participants are being assigned t

127、o receive navenibart in one of two dosingregimens:either 300mg Q3M or 600mg Q6M.We expect to report initial safety and efficacy data from ALPHA-SOLAR in mid-2025.Table of Contents5In February 2025,we initiated a Phase 3 trial of navenibart called ALPHA-ORBIT.This global,randomized,double-blind,place

128、bo-controlled trial is evaluating the efficacy and safety of navenibart over a 6-month treatment period in up to 135 adults and 10 adolescents(open-label),with Type 1 or Type 2 HAE.Adult patients will be randomized to receive one of three navenibart dose arms:1)an initial600 mg dose followed by 300

129、mg every 3 months(Q3M),2)600 mg every six months(Q6M),3)600 mg Q3M,or placebo;adolescentswill receive an initial 600 mg dose followed by 300 mg Q3M.The dose arms support the potential to provide patient-centered dosingflexibility to people with HAE.The primary endpoint is time-normalized monthly HAE

130、 attacks at 6 months,and a key secondaryendpoint includes the proportion of participants who are attack-free at 6 months.After 6 months,patients may be eligible to enterORBIT-EXPANSE,a long-term trial,in which all patients will be treated with navenibart(open-label)and which will include a patient-c

131、entered flexible dosing period.The navenibart Phase 3 program will consist of the ALPHA-ORBIT Phase 3 trial and ORBIT-EXPANSE,which are designed to support registration globally.Top-line results from the ALPHA-ORBIT trial are anticipated in early2027.In addition,to ease the administration of navenib

132、art,we are developing both autoinjector and pre-filled syringe drug devicecombinations.STAR-0310STAR-0310 is a monoclonal antibody OX40 antagonist incorporating YTE half-life extension technology that we are developing asa potential best-in-class treatment for AD as well as potentially for other all

133、ergic and immunological diseases.STAR-0310 is currently inclinical development.We licensed the rights to STAR-0310 under a license agreement,or the Ichnos License Agreement,that we enteredinto with Ichnos Sciences SA and Ichnos Sciences Inc.,or collectively Ichnos,in October 2023,pursuant to which I

134、chnos granted to usan exclusive(even as to Ichnos and its affiliates),worldwide,and sublicensable right and license to certain patent rights and relatedknow-how,or collectively the Licensed Intellectual Property,to develop,manufacture,and commercialize Ichnos proprietary OX40portfolio,which includes

135、 STAR-0310.Ichnos has also agreed not to develop or commercialize any product that directly modulates theOX40 receptor.Overview of Atopic DermatitisAD is an immune disorder associated with loss of skin barrier function and itching.AD is caused by diverse mechanisms,spanningthe spectrum of T cell-dri

136、ven pathology.Approximately 90%of patients develop the disease within the first 5 years of life.AD isestimated to affect approximately 5%of the adult population in the United States,approximately half of which cases are reported to bemoderate or severe.AD is a chronic disease and current treatment o

137、ptions are insufficient to address the needs of many patients.Standardof care treatments include steroids and topical medications,which can treat symptoms but do not address the underlying disease.Role of OX40 in Atopic DermatitisOX40 is a receptor expressed on activated T cells that can target mult

138、iple effector T cell pathways with the potential for broadimpact on the inflammatory cascade.Th1,Th2,and Th17/22 signaling can all contribute to AD.OX40 is upstream of Th1,Th2,andTh17/22 signaling and inhibition of OX40 could reduce the activity of this broad group of Th cells that are known to cont

139、ribute to thedisease.Our goal for STAR-0310 is to reduce disease activity,relapse rate,and treatment burden for patients with moderate and severe AD inorder to help normalize their lives.STAR-0310 was engineered with YTE half-life extension technology to enable infrequent dosing.Asa potential long-a

140、cting OX40 inhibitor,STAR-0310 aims to address the need for a safe,effective,and infrequently administered ADtreatment.By targeting OX40,STAR-0310 is designed to address a wide range of T cells involved in the heterogenous AD pathology,providing the potential for better efficacy and a broader addres

141、sable patient population.Preclinical results support the potential for STAR-0310 to have the best-in-class OX40 inhibitor profile.By design,there issignificantly less ADCC with STAR-0310 compared to rocatinlimab,an afucosylated anti-OX40 monoclonal antibody currently in Phase3 clinical development b

142、y Amgen,Inc.Reduced ADCC has the potential for a more favorable safety profile and potentially widertherapeutic window for STAR-0310,which we believe provides the potential to drive more efficacy.STAR-0310 exhibits a long meanhalf-life of 26 days in cynomolgus monkeys,compared to 10-14 days in a typ

143、ical non-half-life extended IgG1 antibody,and hascomparable potency to rocatinlimab.Table of Contents6Unaddressed Market OpportunityWhile there are available treatment options in AD,there remains unmet need for a therapy that is safe and effective for a broadpatient population,with a low treatment b

144、urden.Standard of care includes systemic steroids and topical medications,which can treatsymptoms but do not address underlying disease.Moderate-to-severe patients who do not respond to topical prescription therapiestypically turn to biologics as their next option,and,subsequently,to Janus kinase,or

145、 JAK,inhibitors.We estimate that the moderate-to-severe AD treatment market was approximately$7 billion in 2022 and that it has the potential to grow to$26 billion by 2030 likely dueto an increase in drug-treatment rates,especially with availability of new therapies and growth in biologics-treated p

146、atients owing todermatologists increasing comfort with biologics.Four biologics have been approved by the FDA for the treatment of AD:DUPIXENT(dupilumab),ADBRY(tralokinumab-ldrm),EBLGYSS(lebrikizumab)and NEMLUVIO(nemolizumab)all of which are administered subcutaneously every two or fourweeks and wor

147、k by targeting the Th2 inflammatory pathway(IL-4/13,IL-13,and IL-31).Due to the heterogenicity of AD,there aremany patients using these approved biologics who do not respond to treatment or experience limited efficacy.In addition,the FDA hasapproved two oral JAK inhibitors for the treatment of AD:RI

148、NVOQ(upadacitinib)and CIBINQOTM(abrocitinib),and in theEuropean Union OLUMIANT(baricitinib),another JAK inhibitor,is also approved for the treatment of AD.While these JAK inhibitorstend to have better efficacy than the approved biologics,they require daily oral administration and there are significa

149、nt safety concerns,including a boxed warning,associated with JAK inhibitors.Inhibiting OX40 could target multiple effector T cell pathways,and therefore has the potential to reduce the activity of a broadergroup of Th cells that are known to contribute to AD and potentially induce higher rates of cl

150、inical responses in more patients thancurrently available biologics.Additionally,OX40 inhibition has the potential to be disease modifying.Although there has been progresswith recent innovation in therapies for AD and,as described in the section entitled“Competition”in this Business section,there ar

151、e asignificant number of product candidates for AD in clinical development,we believe that there is remaining unmet medical need fortherapies with efficacy across a broader range of AD patients and a longer duration of action to provide patients with a lower treatmentburden and improved outcomes and

152、 quality of life.Development PlansWe shared preclinical profile results in May 2024 and received IND clearance from the FDA for STAR-0310 for the treatment of ADin December 2024.We initiated a Phase 1a clinical trial of STAR-0310 in healthy subjects in January 2025 and expect early proof ofconcept r

153、esults in the third quarter of 2025,including PK and PD data and early signals on safety and tolerability.Assuming positiveresults from the Phase 1a clinical trial,we are planning a proof-of-concept clinical trial of STAR-0310 in patients with AD.We also see an opportunity to explore the potential o

154、f STAR-0310 in additional allergic and immunological indications.CompetitionThe development and commercialization of new drug products is highly competitive.If we successfully develop and commercializeany of our product candidates,we and any future collaborators will face significant competition fro

155、m major pharmaceutical companies,specialty pharmaceutical companies and biotechnology companies worldwide.Many of the entities developing and marketing existingand potentially competing products have significantly greater financial resources and expertise than we do in research and development,manuf

156、acturing,preclinical testing,conducting clinical trials,obtaining regulatory approvals and commercialization.Even if we are ableto successfully develop and commercialize a product,our commercial opportunity will be reduced or eliminated if our competitorsdevelop and commercialize products that are m

157、ore effective,have fewer side effects,are more convenient or are less expensive than ourproduct.NavenibartWe are developing navenibart for the potential preventative treatment of HAE.The key competitive factors affecting the success ofnavenibart,if approved,are likely to be its efficacy,safety,dosin

158、g frequency,method of administration,convenience,price and theavailability of coverage and reimbursement from government and other third-party payors.In particular,we believe that the competitiveposition of navenibart will depend in part on whether it is approved for dosing once every three months,o

159、nce every six months,or both,and whether we are able to obtain commercial approval of dosing with an autoinjector and pre-filled syringe for ease of administration.Table of Contents7In the United States,the FDA has approved four therapies for on-demand treatment of HAE:BERINERT,FIRAZYR,KALBITORand R

160、UCONEST.For long-term preventative treatment of HAE,the FDA has also approved four therapies:CINRYZE,HAEGARDA,TAKHZYRO and ORLADEYO.There are four main manufacturers of therapies for HAE:CSL Behring(BERINERT andHAEGARDA),Takeda(FIRAZYR,KALBITOR,CINRYZE and TAKHZYRO),Pharming(RUCONEST)and BioCryst(OR

161、LADEYO).With the exception of KALBITOR,these therapies are also approved and commercially available outside of the United States(HAEGARDA is marketed as BERINERT SC outside of the United States).Historically,androgens and antifibrinolytic treatments havealso been used as preventative treatment for H

162、AE,however their use is declining with the availability of more-tolerable,HAE-specifictherapies.On-demand and preventative HAE therapies target one of three primary mechanisms.BERINERT,HAEGARDA,RUCONEST andCINRYZE are C1 Esterase Inhibitors(CI-INH)replacement therapies.FIRAZYR is a B2-receptor,or B2

163、R,antagonist,and KALBITOR,TAKHZYRO and ORLADEYO target plasma kallikrein.TAKHZYRO is a monoclonal antibody and ORLADEYO is a small moleculeinhibitor.On-demand therapies are taken as needed;BERINERT and RUCONEST are IV infusions approved for adult and pediatric patients,FIRAZYR is an SC injection,app

164、roved for adults 18 and older,and KALBITOR is a series of three SC injections,approved for patients12 years and older.KALBITOR must be administered by a healthcare professional to monitor for the risk of anaphylactic reactions.Preventative therapies are taken chronically.CINRYZE is an IV infusion an

165、d HAEGARDA is an SC injection;both are administeredtwice a week and are approved for adult and pediatric patients 6 years and older.TAKHZYRO is an SC injection generally administeredevery two weeks;however,dosing every four weeks may be considered in some patients.TAKHZYRO is approved for patients 2

166、 yearsand older.ORLADEYO is an oral capsule taken once daily with food for patients 12 years and older.Given that TAKHZYRO is an approvedmonoclonal antibody inhibitor of plasma kallikrein,if navenibart is approved,we expect that it will compete most directly withTAKHZYRO.TAKHZYRO is the current glob

167、al market leader of HAE preventative treatments.We are aware of additional programs in development for HAE,which are focused largely on preventative approaches.For example,CSL Behrings garadacimab,a factor XIIa-inhibitory monoclonal antibody,or FXIIa mAb,has completed Phase 3 development forpreventa

168、tive treatment and submitted regulatory applications for marketing approval in regions including the United States.Garadacimabis approved in the European Union,Australia and the United Kingdom under the brand name ANDEMBRY.Ionis Pharmaceuticals,Inc.sdonidalorsen,an antisense inhibitor of prekallikre

169、in synthesis has also completed Phase 3 development for preventative treatment andhas a PDUFA date set for August 21,2025.Pharvaris is developing two oral treatments,deucrictibant IR(immediate release)anddeucrictibant XR(extended release).Deucrictibant is a small molecule inhibitor of B2R.Deucrictib

170、ant IR is in Phase 3 development foron-demand treatment.Based on a proof-of-concept Phase 2 trial with deucrictibant IR for preventative treatment,Pharvaris has initiateda Phase 3 trial for deucrictibant XR for preventative treatment.KalVista Pharmaceuticals,Inc.has an oral small molecule plasmakall

171、ikrein inhibitor sebetralstat for on-demand treatment of HAE that has completed Phase 3 development and has a PDUFA date set forJune 17,2025(the Phase 2 trial for KVD824 for preventative treatment was terminated).Intellia Therapeutics has initiated a Phase 3 trialfor NTLA-2002,a CRISPR knockout of t

172、he prekallikrein gene KLKB1.ADARx Pharmaceuticals,Inc.is conducting a Phase 2a trial forADX-324,a prekallikrein siRNA inhibitor.Argo Biopharmaceutical Co.,Ltd.is in Phase 1 development for PKK/BW-20805,an siRNAinhibitor.Preclinical development programs for preventative treatment include KalVistas or

173、al FXIIa inhibitor and RactigenTherapeutics C1-INH gene(SERPING1)RNA activating program(RAG-12).STAR-0310We are developing STAR-0310 for the treatment of moderate-to-severe AD.The key competitive factors affecting the success ofSTAR-0310,if approved,are likely to be its safety and tolerability,effic

174、acy,frequency of dosing,method of administration,convenience,price,and the availability of coverage and reimbursement from government and other third-party payors.In the United States,the FDAhas approved two oral JAK inhibitors for the treatment of AD:RINVOQ and CIBINQO,and in the European Union OLU

175、MIANT is alsoapproved for the treatment of AD.Additionally,the FDA has approved four biologics for the treatment of AD:DUPIXENT,ADBRY,EBGLYSS,and NEMLUVIO.Standard of care also includes systemic steroids and topical medications which can treat symptoms but donot address underlying disease.Moderate-t

176、o-severe patients who do not respond to topical prescription therapies typically turn tobiologics as their next option,and,subsequently,to JAK inhibitors.Table of Contents8Both DUPIXENT and ADBRY are administered subcutaneously every two weeks,and work by targeting the Th2 inflammatorypathway(IL-4/1

177、3,and IL-13,respectively).EBGLYSS and NEMLUVIO are administered subcutaneously every two or four weeks,andwork by targeting the Th2 inflammatory pathway(IL-13 and IL-31,respectively).RINVOQ and CIBINQO require daily oraladministration and are only available to patients who do not sufficiently respon

178、d to systemic therapies including biologics.While theseJAK inhibitors tend to have better efficacy than the approved biologics,there are significant safety concerns including a boxed warningassociated with JAK inhibitors.We are aware of additional programs in development for AD,which are focused lar

179、gely on biologic approaches.There are othercompanies that have product candidates in early-stage development for moderate-to-severe AD,including Nektar Therapeutics(rezpegaldesleukin),Pfizer(PF-07275315 and PF-07264660),LEO Pharma(temtokibart,LEO 152020),Akesobio(AK120),ConnectBiopharma(rademikibart

180、),Biosion(bosakitug),Apogee Therapeutics(APG777),InnoCare Pharma(ICP-332),Kymera Therapeutics(KTK-474),GSK(GSK1070806),UCB(UCB9741 and UCB1381),Union Therapeutics(orismilast),J&J(JNJ-7528 and JNJ-5939),Celldex Therapeutics(barzolvolimab),Evommune(EVO301 and EVO756),Eli Lilly(ucenprubart),Sanofi(SAR4

181、44656)and Opsidio(OpSCF).Additionally,a new class of biologics is in clinical development targeting OX40,the same target as for STAR-0310.Amlitelimab(Sanofi)is an anti-OX40 ligand(OX40L)antibody that has started a Phase 3 trial.Rocatinlimab(Amgen)is an afucosylated OX40receptor(OX40R)antibody curren

182、tly in Phase 3 trials in AD.IMG-007(Inmagene)is an OX40 receptor(OX40R)antibody that hascompleted a proof-of-concept trial in AD.APG990(Apogee)is an anti-OX40 ligand antibody currently in a Phase 1a trial in AD.ABCL575(AbCellera)is an anti-OX40 ligand antibody that is in preclinical development.Inte

183、llectual PropertyWe strive to protect the proprietary technologies that we believe are important to our business.This includes plans to pursue andmaintain patent protection intended to cover the composition of matter of navenibart and STAR-0310,their methods of use,and otherrelated technologies and

184、inventions that are important to our business.In addition to seeking patent protection,we also rely on tradesecrets to protect aspects of our business that are not amenable to,or that we do not consider appropriate for,patent protection.Our commercial success depends in part upon our ability to obta

185、in and maintain patent and other proprietary protection forcommercially important technologies,inventions and know-how related to our business,defend and enforce our intellectual propertyrights,in particular,our patent rights,preserve the confidentiality of our trade secrets and operate without infr

186、inging valid andenforceable intellectual property rights of others.Navenibart ProgramAs of December 31,2024,we own five patent families directed to navenibart.The first patent family is directed to the compositionof matter of our product candidate navenibart and its use in treating various plasma ka

187、llikrein associated disorders including HAE.Thisfamily includes applications filed in North America(such as Canada,the U.S.,and Mexico),South America(such as Argentina andBrazil),Europe,Asia(such as China,Japan,and Korea),the Middle East(such as Israel,Saudi Arabia,United Arab Emirates,andKuwait),an

188、d Australia.These applications,if granted,would expire in 2042,assuming all maintenance fees are paid.Depending uponthe circumstances,additional patent term may be available in certain jurisdictions,e.g.,the U.S.,Japan,and Europe,via patent termextensions or supplementary protection certificates,alt

189、hough only patents directed to navenibart may be extended.In the second patent family,we own one International(PCT)patent application directed to methods of treating various plasma-kallikrein associated disorders,including HAE,with specific dosing regimens of navenibart.Any national or regional stag

190、e applicationsderived from this PCT application,if filed and granted,would expire in 2043,assuming all maintenance fees are paid and without takinga potential patent term extension into account.In a third patent family,we own one International(PCT)patent application and one U.S.patent application di

191、rected to methods oftreating hereditary angioedema with navenibart.Any national or regional stage applications derived from this PCT application,if filedand granted,would expire in 2044,assuming all maintenance fees are paid.If the U.S.application is granted,it would expire in 2043,assuming all main

192、tenance fees are paid and without taking a potential patent term extension into account.Table of Contents9In the fourth patent family,we own one U.S.provisional patent application directed to pharmaceutical formulations of navenibart.Any non-provisional patent applications claiming priority to this

193、provisional application,if filed and granted,would expire in 2045,assuming all maintenance fees are paid and without taking a potential patent term extension into account.In a fifth patent family,we own one U.S.provisional patent application directed to methods of treating hereditary angioedema with

194、navenibart.Any non-provisional patent applications claiming priority to this provisional application,if filed and granted,would expire in2045,assuming all maintenance fees are paid and without taking a potential patent term extension into account.Anti-OX40 ProgramIn our anti-OX40 program,we have in-

195、licensed from and co-own with Ichnos one International(PCT)patent application directed tothe composition of matter of our product candidate STAR-0310 and its use in treating AD and other disorders.Any national or regionalstage applications derived from this PCT application,if filed and granted would

196、 expire in 2044,assuming all maintenance fees are paid.Depending upon the circumstances,additional patent term may be available in certain jurisdictions,e.g.,the U.S.,Japan,and Europe,viapatent term extensions,although only patents directed to STAR-0310 may be extended.In addition,we have also in-li

197、censed five patent families from Ichnos directed to telazorlimab and telazorlimab-containingformulations,and their use.In particular,we have in-licensed one patent family directed to the telazorlimab composition of matter and itsuse with patents granted in North America(such as Canada,the U.S.,and M

198、exico),Europe(such as Germany,France,Italy,Spain,Switzerland,and the UK),Asia(such as China,Japan,and Korea),and Australia.These patents are expected to expire in 2032,assumingall maintenance fees are paid.In the remaining patent families,we have in-licensed three pending U.S.patent applications and

199、 threepending European patent applications directed to telazorlimab uses and formulations,which if granted will expire from 2039 to 2040.The patent positions for biopharmaceutical companies like us are generally uncertain and can involve complex legal,scientific andfactual issues.In addition,the cov

200、erage claimed in a patent application can be significantly reduced before a patent is issued,and itsscope can be reinterpreted and even challenged after issuance.As a result,we cannot guarantee that our navenibart and STAR-0310product candidates will be protected or remain protectable by enforceable

201、 patents,even if issued.We cannot predict whether the patentapplications we are currently pursuing will issue as granted patents in any particular jurisdiction or whether the claims of any grantedpatent will provide sufficient proprietary protection from competitors.Any patents that we hold may be c

202、hallenged,circumvented orinvalidated by third parties.The term of individual patents depends upon the legal term of the patents in the countries in which they areobtained.In most countries where we may elect to file,the patent term is 20 years from the earliest date of filing a non-provisional paten

203、tapplication.In the United States,a patents term may be lengthened by patent term adjustment,which compensates a patentee foradministrative delays by the United States Patent and Trademark Office,or USPTO,in granting a patent.A United States patent termmay be shortened,if a patent is terminally disc

204、laimed by its owner,over another patent.In the United States,the term of a patent covering an FDA-approved drug may be eligible for a patent term extension under TheDrug Price Competition and Patent Term Restoration Act of 1984,or the Hatch-Waxman Act,as compensation for the loss of patent termdurin

205、g the FDA regulatory review process.The period of extension may be up to five years beyond the expiration of the patent,butcannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval.Only one patent among thoseeligible for an extension may be extended.Si

206、milar provisions are available in Europe,Japan,and in certain other jurisdictions to extendthe term of a patent that covers an approved drug.It is possible that an issued United States patent covering navenibart or STAR-0310may be entitled to a patent term extension.If either of our navenibart or ST

207、AR-0310 product candidates receives FDA approval,weintend to apply for a patent term extension,if available,to extend the term of the patent that covers the approved product candidate.Wealso intend to seek patent term extensions in any jurisdictions where they are available.However,there is no guara

208、ntee that the applicableauthorities,including the USPTO or FDA,will agree with our assessment of whether such extensions should be granted,and even ifgranted,the length of such extensions.In addition to patent protection,we may rely on other forms of regulatory and legislative non-patent exclusivity

209、 protection that aretypically triggered by marketing approval of a product.In the United States,these include orphan drug exclusivity,pediatric exclusivity,new chemical entity exclusivity and,for biologics such as navenibart and STAR-0310,reference product exclusivity.The EuropeanUnion,which we refe

210、r to as the European Union or EU,and many other key markets outside the United States have comparable forms ofsuch exclusivity.However,there is no guarantee that we will obtain any of these forms of exclusivity protection for navenibart,STAR-0310 or any future product candidate.Table of Contents10We

211、 also rely on trade secret protection for our proprietary information that is not amenable to,or that we do not consider appropriatefor,patent protection,including,for example,certain aspects of our manufacturing processes.However,trade secrets can be difficult toprotect.Although we take steps to pr

212、otect our proprietary information,including restricting access to our premises and our confidentialinformation,as well as entering into agreements with our employees,consultants,advisors,contract research organizations,contractmanufacturing organizations and potential collaborators,third parties may

213、 independently develop the same or similar proprietaryinformation or may otherwise gain access to our proprietary information.As a result,we may be unable to meaningfully protect our tradesecrets and proprietary information.Manufacturing and SupplyWe do not own or operate manufacturing facilities.We

214、 currently rely on third-party manufacturers and suppliers to make,package,label and distribute navenibart and STAR-0310.We expect to continue to do so to meet our nonclinical,clinical and commercial needsfor navenibart,STAR-0310,and any other development candidate.We are developing a drug device co

215、mbination product for navenibartand will need to rely on third-party contract manufacturers to manufacture any drug device combination product for navenibart or anyother product candidate.We currently have no plans to build our own clinical or commercial scale manufacturing capabilities and havehire

216、d qualified individuals with significant development and manufacturing experience to oversee our relationships with our contractdevelopment and manufacturing partners.Our third-party manufacturers are required to manufacture navenibart,STAR-0310,any drugdevice combination product and any future prod

217、uct candidates under current good manufacturing practices,or cGMPs,and otherapplicable laws and regulations.We have also adopted good inventory management and warehousing practices to minimize supply chainrisks related to the manufacture of navenibart and STAR-0310.Human CapitalAs of December 31,202

218、4,we had 78 full-time employees,45 of whom were primarily engaged in research and developmentactivities.A total of 16 of our full-time employees have Ph.D.degrees.None of our employees are represented by a labor union and webelieve our relations with our employees are good.Our human capital resource

219、s objectives include,as applicable,identifying,recruiting,retaining,incentivizing and integrating ourexisting and additional employees.Our cash compensation,which consists of base salary and annual bonuses based upon bonus targets,are market-based and are designed to attract,retain and motivate our

220、employees.The principal purposes of our equity incentive plans arealso to attract,retain and motivate employees,selected consultants and the members of our board of directors through the granting ofstock-based compensation awards,which have solely consisted of stock options,and to align such awards

221、with the interests of ourstockholders.We provide a comprehensive benefits package to help employees manage health,well-being,finances,and life outside ofwork,including health insurance,dental and vision insurance,life insurance,short-term and long-term disability insurance,paid sickleave,a 401(k)pla

222、n,including a matching contribution,a health savings account program,and paid vacation time.We take pride in our people and work to create an inclusive environment where diversity is seen as a benefit and our differences areappreciated.We consider our people to be one of our biggest assets and belie

223、ve that our investment in them through developmentopportunities,engagement,and retention is critical to our success.Government Regulation and Product ApprovalGovernment authorities in the United States,at the federal,state and local level,and in other countries and jurisdictions,includingthe Europea

224、n Union,extensively regulate,among other things,the research,development,testing,manufacture,quality control,approval,packaging,storage,recordkeeping,labeling,advertising,promotion,distribution,marketing,sales,pricing,reimbursement,post-approvalmonitoring and reporting,and import and export of drugs

225、 and biologics.The processes for obtaining regulatory approvals in the UnitedStates and in foreign countries and jurisdictions,along with subsequent compliance with applicable statutes and regulations and otherregulatory authorities,require the expenditure of substantial time and financial resources

226、.The regulatory requirements applicable toproduct development,approval and marketing are subject to change,and regulations and administrative guidance often are revised orreinterpreted by government agencies in ways that may have a significant impact on our business.Table of Contents11Review and App

227、roval of Drugs and Biologics in the United StatesIn the United States,the FDA approves and regulates drug products under the Federal Food,Drug,and Cosmetic Act,or FDCA,andrelated regulations.Biological products,or biologics,are licensed for marketing under the Public Health Service Act,or PHSA,andsu

228、bject to regulation under the FDCA and related regulations.A company,institution,or organization which takes responsibility for theinitiation and management of a clinical development program for such products is referred to as a sponsor.A sponsor seeking approval tomarket and distribute a new drug o

229、r biological product in the United States must typically secure the following:completion of preclinical laboratory tests in compliance with the FDAs good laboratory practice,or GLP,regulations;design of a clinical protocol and submission to the FDA of an IND which must take effect before human clini

230、cal trials maybegin;approval by an independent institutional review board,or IRB,representing each clinical site before each clinical trial maybe initiated;performance of adequate and well-controlled human clinical trials in accordance with good clinical practices,or GCPs,toestablish the safety and

231、efficacy of the proposed drug product for each proposed indication;submission to the FDA of a new drug application,or NDA,for a drug candidate product and a biologics licenseapplication,or BLA,for a biological product requesting marketing for one or more proposed indications;review of the request fo

232、r approval by an FDA advisory committee,where appropriate or if applicable;completion of one or more FDA inspections of the manufacturing facility or facilities at which the product,or componentsthereof,are produced to assess compliance with cGMP requirements to assure the products identity,strength

233、,quality andpurity;completion of FDA audits of clinical trial sites to assure compliance with GCPs and the integrity of the clinical data;payment of application and program fees pursuant to the Prescription Drug User Fee Act,or PDUFA;FDA approval of the NDA or BLA authorizing marketing of the drug o

234、r biological product for particular indications in theUnited States;andcompliance with any post-approval requirements,including the potential requirement to implement a Risk Evaluation andMitigation Strategy,or REMS,and the potential requirement to conduct post-approval studies.Preclinical StudiesBe

235、fore a sponsor begins testing a compound with potential therapeutic value in humans,the product candidate enters the preclinicaltesting stage.Preclinical studies include laboratory evaluation of the purity and stability of the manufactured substance or activepharmaceutical ingredient and the formula

236、ted product,as well as in vitro and animal studies to assess the safety and activity of theproduct candidate for initial testing in humans and to establish a rationale for therapeutic use.These studies are typically referred to asIND-enabling studies.The conduct of preclinical studies is subject to

237、federal regulations and requirements,including GLP regulationsand standards and the United States Department of Agricultures Animal Welfare Act,if applicable.Some long-term preclinical testing,such as animal tests of reproductive adverse events and carcinogenicity,and long-term toxicity studies,may

238、continue after the IND issubmitted.With passage of the FDAs Modernization Act 2.0 in December 2022,Congress eliminated provisions in both the FDCA and thePHSA that required animal testing in support of an NDA or BLA.While animal testing may still be conducted,the FDA was authorizedto rely on alterna

239、tive non-clinical tests,including cell-based assays,microphysiological systems,or bioprinted or computer models.Table of Contents12The IND and IRB ProcessesAn IND is a request for FDA authorization to administer an investigational product candidate to humans.Such authorization must besecured prior t

240、o interstate shipment and administration of any new drug or biologic that is not the subject of an approved NDA or BLA.In support of a request for an IND,sponsors must submit a protocol for each clinical trial and any subsequent protocol amendments mustbe submitted to the FDA as part of the IND.In a

241、ddition,the results of the preclinical tests,together with manufacturing information,analytical data,any available clinical data or literature and plans for clinical trials,among other things,are submitted to the FDA as partof an IND.The FDA requires a 30-day waiting period after the filing of each

242、IND before clinical trials may begin.This waiting period isdesigned to allow the FDA to review the IND to assure the safety and rights of patients and to help assure that the quality of theinvestigation will be adequate to permit an evaluation of the drugs effectiveness and safety and of the biologi

243、cal products safety,purityand potency.At any time during this 30-day period,the FDA may raise concerns or questions about the conduct of the trials as outlinedin the IND and impose a clinical hold or partial clinical hold.In this case,the IND sponsor and the FDA must resolve any outstandingconcerns

244、before clinical trials can begin.Following commencement of a clinical trial under an IND,the FDA may also place a clinical hold or partial clinical hold on thattrial.Clinical holds are imposed by the FDA whenever there is concern for patient safety and may be a result of new data,findings,ordevelopm

245、ents in clinical,nonclinical,and/or CMCs.A clinical hold is an order issued by the FDA to the sponsor to delay a proposedclinical trial or to suspend an ongoing trial.A partial clinical hold is a delay or suspension of only part of the clinical work requestedunder the IND.For example,a specific prot

246、ocol or part of a protocol is not allowed to proceed,while other protocols may do so.Nomore than 30 days after imposition of a clinical hold or partial clinical hold,the FDA will provide the sponsor a written explanation ofthe basis for the hold.Following issuance of a clinical hold or partial clini

247、cal hold,a trial may only resume after the FDA has notified thesponsor that the trial may proceed.The FDA will base that determination on information provided by the sponsor correcting thedeficiencies previously cited or otherwise satisfying the FDA that the trial can proceed.The FDAs primary object

248、ives in reviewing an IND are to assure the safety and rights of patients and to help assure that the qualityof the investigation will be adequate to permit an evaluation of the drugs effectiveness and safety and of the biological products safety,purity and potency.Additionally,some trials are overse

249、en by an independent group of qualified experts organized by the trial sponsor,known as a data safety monitoring board committee.This group provides authorization for whether a trial may move forward atdesignated check points based on access that only the group maintains to available data from the t

250、rial.Suspension or termination ofdevelopment during any phase of clinical trials can occur if it is determined that the participants or patients are being exposed to anunacceptable health risk.Once an IND application takes effect,the sponsor of the IND may amend the application as needed to ensure t

251、hat the clinical trialsare conducted according to protocols included in the IND.The FDA has indicated that sponsors are expected to submit amendments fornew protocols or changes to existing protocols before implementation of the respective changes.New studies may begin,however,whenthe sponsor has su

252、bmitted the change to the FDA for its review and the new protocol or changes to the existing protocol have beenapproved by the IRB with the responsibility for review and approval of the studies.In addition to the foregoing IND requirements,an IRB representing each institution participating in the cl

253、inical trial must review andapprove the plan for any clinical trial before it commences at that institution,and the IRB must conduct continuing review and reapprovethe trial at least annually.The IRB must review and approve,among other things,the trial protocol and informed consent information tobe

254、provided to trial subjects.An IRB must operate in compliance with FDA regulations.An IRB can suspend or terminate approval of aclinical trial at its institution,or an institution it represents,if the clinical trial is not being conducted in accordance with the IRBsrequirements or if the product cand

255、idate has been associated with unexpected serious harm to patients.Additionally,some trials are overseen by a Data Monitoring Committee,an independent group of qualified experts organized by thetrial sponsor.This group provides authorization for whether or not a trial may move forward at designated

256、check points based on accessthat only the group maintains to available data from the trial.Suspension or termination of development during any phase of clinicaltrials can occur if it is determined that the participants or patients are being exposed to an unacceptable health risk.Other reasons forsus

257、pension or termination may be made by us based on evolving business objectives and/or competitive climate.Expanded Access to an Investigational Drug for Treatment UseExpanded access,sometimes called“compassionate use,”is the use of investigational new drug products outside of clinical trials totreat

258、 patients with serious or immediately life-threatening diseases or conditions when there are no comparable or satisfactoryTable of Contents13alternative treatment options.FDA regulations allow access to investigational drugs under an IND by the company or the treatingphysician for treatment purposes

259、 on a case-by-case basis for:individual patients(single-patient INDs for treatment in emergency settingsand non-emergency settings);intermediate-size patient populations;and larger populations for use of the drug under a treatment protocol.When considering an IND for expanded access to an investigat

260、ional product with the purpose of treating a patient or a group ofpatients,the sponsor and treating physicians or investigators will determine suitability when all of the following criteria apply:patient(s)have a serious or immediately life-threatening disease or condition,and there is no comparable

261、 or satisfactory alternativetherapy to diagnose,monitor,or treat the disease or condition;the potential patient benefit justifies the potential risks of the treatment andthe potential risks are not unreasonable in the context or condition to be treated;and the expanded use of the investigational dru

262、g for therequested treatment will not interfere with the initiation,conduct,or completion of clinical trials that could support marketing approval ofthe product or otherwise compromise the potential development of the product.There is no obligation for a sponsor to make its drug products available f

263、or expanded access;however,as required by the21st Century Cures Act,or Cures Act,passed in 2016,sponsors are required to make policies for evaluating and responding to requestsfor expanded access for patients publicly available upon the earlier of initiation of a Phase 2 or Phase 3 clinical trial,or

264、 15 days after theinvestigational drug or biologic receives designation as a breakthrough therapy,fast track product,or regenerative medicine advancedtherapy.In May 2018,the Right to Try Act was signed into law.The law,among other things,provides a federal framework for certainpatients to access cer

265、tain investigational new drug products that have completed a phase 1 clinical trial and that are undergoinginvestigation for FDA approval.Under certain circumstances,eligible patients can seek treatment without enrolling in clinical trials andwithout obtaining FDA permission under the FDA expanded a

266、ccess program.There is no obligation for a drug manufacturer to make itsdrug products available to eligible patients,but the manufacturer must develop an internal policy and respond to patient requestsaccording to that policy.Human Clinical Studies in Support of an NDA or BLAClinical trials involve

267、the administration of the investigational product to human subjects under the supervision of qualifiedinvestigators in accordance with GCP requirements,which include,among other things,the requirement that all research subjectsprovide their informed consent in writing before their participation in a

268、ny clinical trial.Clinical trials are conducted under written trialprotocols detailing,among other things,the inclusion and exclusion criteria,the objectives of the trial,the parameters to be used inmonitoring safety and the effectiveness criteria to be evaluated.Each protocol,and any subsequent mat

269、erial amendment to the protocol,must be submitted to the FDA as part of the IND,and progress reports detailing the status of the clinical trials must be submitted to theFDA annually.The clinical investigation of an investigational drug or biological product is generally divided into four phases.Alth

270、oughthe phases are usually conducted sequentially,they may overlap or be combined.The four phases of an investigation are as follows:Phase 1.Phase 1 studies include the initial introduction of an investigational new drug or biological product into humans.These studies are designed to evaluate the sa

271、fety,dosage tolerance,metabolism and pharmacologic actions of theinvestigational drug or biological product in humans,the side effects associated with increasing doses,and if possible,togain early evidence on effectiveness.Phase 2.Phase 2 includes the controlled clinical trials conducted to prelimin

272、arily or further evaluate the effectiveness ofthe investigational drug or biological product for a particular indication(s)in patients with the disease or condition undertrial,to determine dosage tolerance and optimal dosage,and to identify possible adverse side effects and safety risksassociated wi

273、th the drug or biological product.Phase 2 clinical trials are typically well-controlled,closely monitored,andconducted in a limited patient population.Phase 3.Phase 3 clinical trials are generally controlled clinical trials conducted in an expanded patient populationgenerally at geographically dispe

274、rsed clinical trial sites.They are performed after preliminary evidence suggestingeffectiveness of the drug or biological product has been obtained,and are intended to further evaluate dosage,clinicaleffectiveness and safety,to establish the overall benefit-risk relationship of the investigational d

275、rug or biological product,and to provide an adequate basis for product approval.Phase 4.Post-approval studies may be conducted after initial marketing approval.These studies are used to gain additionalexperience from the treatment of patients in the intended therapeutic indication.A clinical trial m

276、ay combine the elements of more than one phase and the FDA often requires more than one Phase 3 trial to supportmarketing approval of a product candidate.A companys designation of a clinical trial as being of a particular phase is not necessarilyTable of Contents14indicative that the study will be s

277、ufficient to satisfy the FDA requirements of that phase because this determination cannot be made untilthe protocol and data have been submitted to and reviewed by the FDA.Moreover,as noted above,a pivotal trial is a clinical trial that isbelieved to satisfy FDA requirements for the evaluation of a

278、product candidates safety and efficacy such that it can be used,alone orwith other pivotal or non-pivotal trials,to support regulatory approval.Generally,pivotal trials are Phase 3 trials,but they may be Phase2 trials if the design provides a well-controlled and reliable assessment of clinical benef

279、it,particularly in an area of unmet medical need.In December 2022,with the passage of the Food and Drug Omnibus Reform Act,or FDORA,Congress required sponsors todevelop and submit a diversity action plan for each Phase 3 clinical trial or any other“pivotal study”of a new drug or biological product.T

280、hese plans are meant to encourage the enrollment of more diverse patient populations in late-stage clinical trials of FDA-regulatedproducts.Specifically,actions plans must include the sponsors goals for enrollment,the underlying rationale for those goals,and anexplanation of how the sponsor intends

281、to meet them.In addition to these requirements,the legislation directs the FDA to issue newguidance on diversity action plans,or DAPs.In June 2024,as mandated by FDORA,the FDA issued draft guidance outlining the generalrequirements for DAPs.Unlike most guidance documents issued by the FDA,the DAP gu

282、idance when finalized will have the force oflaw because FDORA specifically dictates that the form and manner for submission of DAPs are specified in FDA guidance.On January27,2025,in response to an Executive Order issued by President Trump on January 21,2025,on Diversity,Equity and Inclusionprograms

283、,the FDA removed this draft guidance from its website.The implications of this action are not yet known.In June 2023,the FDA issued draft guidance with updated recommendations for GCPs aimed at modernizing the design and conductof clinical trials.The updates are intended to help pave the way for mor

284、e efficient clinical trials to facilitate the development of medicalproducts.The draft guidance was adopted from the International Council for Harmonisations recently updated E6(R3)draft guidelinethat was developed to enable the incorporation of rapidly developing technological and methodological in

285、novations into the clinical trialenterprise.In addition,the FDA issued draft guidance outlining recommendations for the implementation of decentralized clinical trials.Clinical Studies Outside the United States in Support of FDA ApprovalSponsors frequently conduct clinical trials at sites outside th

286、e United States.When a foreign clinical study is conducted under anIND,all IND requirements must be met unless waived.When a foreign clinical study is not conducted under an IND,the sponsor mustensure that the study complies with certain regulatory requirements of the FDA in order to use the study a

287、s support for an IND orapplication for marketing approval.Specifically,the studies must be conducted in accordance with GCP,including undergoing reviewand receiving approval by an independent ethics committee and seeking and receiving informed consent from subjects.GCPrequirements encompass both eth

288、ical and data integrity standards for clinical studies.The FDAs regulations are intended to help ensurethe protection of human subjects enrolled in non-IND foreign clinical studies,as well as the quality and integrity of the resulting data.They further help ensure that non-IND foreign studies are co

289、nducted in a manner comparable to that required for IND studies.The acceptance by the FDA of study data from clinical trials conducted outside the United States in support of U.S.approval may besubject to certain conditions or may not be accepted at all.In cases where data from foreign clinical tria

290、ls are intended to serve as the solebasis for marketing approval in the United States,the FDA will generally not approve the application on the basis of foreign data aloneunless(i)the data are applicable to the U.S.population and U.S.medical practice;(ii)the trials were performed by clinical investi

291、gatorsof recognized competence and pursuant to GCP regulations;and(iii)the data may be considered valid without the need for an on-siteinspection by the FDA,or if the FDA considers such inspection to be necessary,the FDA is able to validate the data through an on-siteinspection or other appropriate

292、means.In addition,even where the foreign study data are not intended to serve as the sole basis for approval,the FDA will not accept thedata as support for an application for marketing approval unless the study is well-designed and well-conducted in accordance with GCPrequirements and the FDA is abl

293、e to validate the data from the study through an onsite inspection if deemed necessary.Many foreignregulatory authorities have similar approval requirements.In addition,such foreign trials are subject to the applicable local laws of theforeign jurisdictions where the trials are conducted.Reporting C

294、linical Trial ResultsUnder the PHSA,sponsors of clinical trials of certain FDA-regulated products,including prescription drugs and biologics,arerequired to register and disclose certain clinical trial information on a public registry(clinicaltrials.gov)maintained by the U.S.NationalInstitutes of Hea

295、lth,or the NIH.In particular,information related to the product,patient population,phase of investigation,trial sites andinvestigators and other aspects of the clinical trial is made public as part of the registration of the clinical trial.Although sponsors arealso obligated to disclose the results

296、of their clinical trials after completion,disclosure of the results can be delayed in some casesTable of Contents15for up to two years after the date of completion of the trial.The NIHs Final Rule on registration and reporting requirements for clinicaltrials became effective in 2017.The PHSA grants

297、the Secretary of Health and Human Services the authority to issue a notice of noncompliance to a responsibleparty for failure to submit clinical trial information as required.The responsible party,however,is allowed 30 days to correct thenoncompliance and submit the required information.As of Decemb

298、er 19,2024,the FDA has issued six notices of non-compliance,thereby signaling the governments willingness to begin enforcing these requirements against non-compliant clinical trial sponsors.While these notices of non-compliance did not result in civil monetary penalties,the failure to submit clinica

299、l trial information toclinicaltrials.gov is a prohibited act under the FDCA with violations subject to potential civil monetary penalties of up to$10,000 foreach day the violation continues.Violations may also result in injunctions and/or criminal prosecution or disqualification from federalgrants.I

300、nteractions with the FDA During the Clinical Development ProgramFollowing the clearance of an IND and the commencement of clinical trials,the sponsor will continue to have interactions with theFDA.A development safety update report detailing the results of clinical trials must be submitted annually

301、within 60 days of theanniversary dates that the IND went into effect.In addition,IND safety reports must be submitted to the FDA for any of the following:serious and unexpected suspected adverse reactions;findings from other studies or animal or in vitro testing that suggest a significant riskin hum

302、ans exposed to the product candidate;and any clinically important increase in the occurrence of a serious suspected adversereaction over that listed in the protocol or investigator brochure.Sponsors are also given opportunities to meet with the FDA at certain points in the clinical development progr

303、am.Specifically,thereare five types of meetings that occur between sponsors and the FDA.Type A meetings are those that are necessary for an otherwisestalled product development program to proceed or to address an important safety issue.Type B meetings include pre-IND and pre-NDAmeetings as well as e

304、nd of phase meetings.A Type C meeting is any meeting other than a Type A or Type B meeting regarding thedevelopment and review of a product candidate,including,for example,meetings to facilitate early consultations on the use of abiomarker as a new surrogate endpoint that has never been previously u

305、sed as the primary basis for product approval in the proposedcontext of use.A Type D meeting is focused on a narrow set of issues(should be limited to no more than two focused topics)and shouldnot require input from more than three disciplines or divisions.Finally,INTERACT meetings are intended for

306、novel products anddevelopment programs that present unique challenges in the early development of an investigational product.At the conclusion of these meetings,the FDA will typically provide its responses to questions posed by the sponsor regarding theclinical development program.The FDA will not i

307、ndicate whether an NDA or BLA will be approved,but it will provide guidance to thesponsor on various questions,including whether an application should be submitted in the first place on the basis of the studies and dataproposed by the sponsor.The agency may also generally express support for the spo

308、nsors approach in the clinical development programbut indicate that questions concerning whether the data support approval will be subject to review by the agency following its acceptancefor filing of the NDA or BLA.The FDA has indicated that its responses,as conveyed in meeting minutes and advice l

309、etters,only constitute mere recommendationsand/or advice made to a sponsor and,as such,sponsors are not bound by such recommendations and/or advice.Nonetheless,from apractical perspective,a sponsors failure to follow the FDAs recommendations for design of a clinical program may put the program atsig

310、nificant risk of failure.Manufacturing and Other Regulatory RequirementsConcurrent with clinical trials,companies often complete additional animal studies and must also develop additional informationabout the chemistry and physical characteristics of the candidate product as well as finalize a proce

311、ss for manufacturing the product incommercial quantities in accordance with cGMP requirements.The manufacturing process must be capable of consistently producingquality batches of the drug candidate and,among other things,must develop methods for testing the identity,strength,quality,purity,andpoten

312、cy of the final drug.Additionally,appropriate packaging must be selected and tested and stability studies must be conducted todemonstrate that the drug candidate does not undergo unacceptable deterioration over its shelf life.Table of Contents16Specifically,the FDAs regulations require that pharmace

313、utical products be manufactured in specific approved facilities and inaccordance with cGMPs.The cGMP regulations include requirements relating to organization of personnel,buildings and facilities,equipment,control of components and product containers and closures,production and process controls,pac

314、kaging and labeling controls,holding and distribution,laboratory controls,records and reports and returned or salvaged products.Manufacturers and other entitiesinvolved in the manufacture and distribution of approved pharmaceuticals are required to register their establishments with the FDA andsome

315、state agencies,and they are subject to periodic unannounced inspections by the FDA for compliance with cGMPs and otherrequirements.The PREVENT Pandemics Act,which was enacted in December 2022,clarifies that foreign drug manufacturingestablishments are subject to registration and listing requirements

316、 even if a drug undergoes further manufacture,preparation,propagation,compounding,or processing at a separate establishment outside the United States prior to being imported or offered forimport into the United States.Inspections must follow a“risk-based schedule”that may result in certain establish

317、ments being inspected more frequently.Manufacturers may also have to provide,on request,electronic or physical records regarding their establishments.Delaying,denying,limiting,or refusing inspection by the FDA may lead to a product being deemed to be adulterated.Changes to the manufacturing process,

318、specifications or container closure system for an approved product are strictly regulated and often require prior FDA approval beforebeing implemented.The FDAs regulations also require,among other things,the investigation and correction of any deviations fromcGMP and the imposition of reporting and

319、documentation requirements upon the sponsor and any third-party manufacturers involved inproducing the approved product.Pediatric StudiesUnder the Pediatric Research Equity Act of 2003,or PREA,an application or supplement thereto must contain data that are adequateto assess the safety and effectiven

320、ess of the product for the claimed indications in all relevant pediatric subpopulations,and to supportdosing and administration for each pediatric subpopulation for which the product is safe and effective.Generally,a sponsor must submitan initial pediatric study plan before the date on which the spo

321、nsor submits the required data and no later than either 60 days after thedate of the end-of-phase 2 meeting or such other time as agreed upon between FDA and the sponsor.Those plans must contain an outlineof the proposed pediatric study or studies the sponsor plans to conduct,including study objecti

322、ves and design,any deferral or waiverrequests and other information required by regulation.The sponsor,the FDA,and the FDAs internal review committee must then reviewthe information submitted,consult with each other and agree upon a final plan.The FDA or the sponsor may request an amendment tothe pl

323、an at any time.For investigational products intended to treat a serious or life-threatening disease or condition,the FDA must,upon the request of asponsor,meet to discuss preparation of the initial pediatric study plan or to discuss deferral or waiver of pediatric assessments.Inaddition,the FDA will

324、 meet early in the development process to discuss pediatric study plans with sponsors,and the FDA must meetwith sponsors by no later than the end-of-phase 1 meeting for serious or life-threatening diseases and by no later than ninety days afterthe FDAs receipt of the study plan.The FDA may,on its ow

325、n initiative or at the request of the sponsor,grant deferrals for submission of some or all pediatric data untilafter approval of the product for use in adults,or full or partial waivers from the pediatric data requirements.A deferral may be grantedfor several reasons,including a finding that the pr

326、oduct or therapeutic candidate is ready for approval for use in adults before pediatrictrials are complete or that additional safety or effectiveness data needs to be collected before the pediatric trials begin.Pursuant to theFood and Drug Administration Safety and Innovation Act of 2012,or FDASIA,t

327、he FDA must send a PREA Non-Compliance letter tosponsors who have failed to submit their pediatric assessments required under PREA,have failed to seek or obtain a deferral or deferralextension or have failed to request approval for a required pediatric formulation.FDASIA further requires the FDA to

328、publicly post thePREA Non-Compliance letter and sponsors response.Unless otherwise required by regulation,the pediatric data requirements do not apply to products with orphan designation,althoughFDA has recently taken steps to limit what it considers abuse of this statutory exemption in PREA by anno

329、uncing that it does not intendto grant any additional orphan drug designations for rare pediatric subpopulations of what is otherwise a common disease.The FDA alsomaintains a list of diseases that are exempt from PREA requirements due to low prevalence of disease in the pediatric population.In May20

330、23,the FDA issued draft guidance that further describes the pediatric study requirements under PREA.Table of Contents17Submission and Review of an NDA or BLA by the FDAIn order to obtain approval to market a drug or biological product in the United States,a marketing application must be submitted to

331、the FDA that provides data establishing the safety and effectiveness of the proposed drug product for the proposed indication,and thesafety,purity and potency of the biological product for its intended indication.The application must include all relevant data availablefrom pertinent preclinical and

332、clinical trials,including negative or ambiguous results as well as positive findings,together with detailedinformation relating to the products CMCs and proposed labeling,among other things.Data can come from company-sponsored clinicaltrials intended to test the safety and effectiveness of a use of

333、a product,or from a number of alternative sources,including studiesinitiated by investigators.To support marketing approval,the data submitted must be sufficient in quality and quantity to establish thesafety and effectiveness of the investigational drug product and the safety,purity and potency of the biological product to the satisfactionof the FDA.The application is the vehicle through which sp