Apellis Pharmaceuticals, Inc. (APLS) 2024年10-K年度報告「NASDAQ」.pdf

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1、 Table of Contents UNITED STATESSECURITIES AND EXCHANGE COMMISSION Washington,D.C.20549 FORM 10-K (Mark One)ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1934 For the fiscal year ended December 31,2024OR TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURIT

2、IES EXCHANGE ACT OF 1934 FOR THE TRANSITION PERIOD FROM TO Commission File Number 001-38276 APELLIS PHARMACEUTICALS,INC.(Exact name of registrant as specified in its charter)DELAWARE27-1537290(State or other jurisdiction ofincorporation or organization)(I.R.S.EmployerIdentification No.)100 Fifth Ave

3、nueWaltham,MA02451(Address of principal executive offices)(Zip Code)Registrants telephone number,including area code:(617)977-5700 Securities registered pursuant to Section 12(b)of the Act:Title of each classTrading Symbol(s)Name of each exchange on which registeredCommon Stock,$0.0001 par value per

4、 shareAPLSNasdaq Global Select Market Securities registered pursuant to Section 12(g)of the Act:None Indicate by check mark if the registrant is a well-known seasoned issuer,as defined in Rule 405 of the Securities Act.YES NO Indicate by check mark if the registrant is not required to file reports p

5、ursuant to Section 13 or 15(d)of the Act.YES NO Indicate by check mark whether the registrant:(1)has filed all reports required to be filed by Section 13 or 15(d)of the Securities Exchange Act of 1934 during the preceding 12 months(or for such shorter period that the registrant was required to file

6、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)during the prece

7、ding 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 an emerging growth company.See the definition

8、s 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 Small reporting company Emerging growth company If an emerging growth company,indicate by check

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

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

11、e by check mark whether the financial statements of the registrant included in the filing reflect the correction of an error to previously issued financial statements.2025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm1/274 Indicate by check mark wh

12、ether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by any of the registrants executive officers during the relevant recovery period pursuant to 240.10D-1(b).Indicate by check mark whether the registrant is a shell company(

13、as defined in Rule 12b-2 of the Exchange Act).YES NO As of June 28,2024,the aggregate market value of the voting and non-voting common equity held by non-affiliates of the registrant,based on the closing price of the shares of common stock on the Nasdaq Global Select Stock Market on such date,was$4.

14、2 billion.2025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm2/274 Table of ContentsThe number of shares of the registrants common stock,par value$0.0001 per share outstanding as of February 19,2025 was 125,515,813.DOCUMENTS INCORPORATED BY REFERENC

15、EThe registrant intends to file a definitive proxy statement pursuant to Regulation 14A in connection with its 2025 Annual Meeting of Stockholders within 120 days of the end of the registrants fiscal year ended December 31,2024.Portions of such proxy statement are incorporated by reference into Part

16、 III of this Annual Report on Form 10-K.2025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm3/274 iTable of Contents Table of Contents PagePART I Item 1.Business5Item 1A.Risk Factors44Item 1B.Unresolved Staff Comments90Item 1C.Cybersecurity90Item 2.P

17、roperties90Item 3.Legal Proceedings91Item 4.Mine Safety Disclosures91 PART II Item 5.Market for Registrants Common Equity,Related Stockholder Matters and Issuer Purchases of Equity Securities92Item 6.Reserved93Item 7.Managements Discussion and Analysis of Financial Condition and Results of Operation

18、s94Item 7A.Quantitative and Qualitative Disclosures About Market Risk107Item 8.Financial Statements and Supplementary Data108Item 9.Changes in and Disagreements with Accountants on Accounting and Financial Disclosure140Item 9A.Controls and Procedures140Item 9B.Other Information142Item 9C.Disclosure

19、Regarding Foreign Jurisdictions that Prevent Inspections142 PART III Item 10.Directors,Executive Officers and Corporate Governance143Item 11.Executive Compensation143Item 12.Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters143Item 13.Certain Relationships

20、 and Related Transactions,and Director Independence143Item 14.Principal Accountant Fees and Services143 PART IV Item 15.Exhibits,Financial Statement Schedules144 2025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm4/274 Table of ContentsSPECIAL NOTE

21、REGARDING FORWARD-LOOKING STATEMENTS AND INDUSTRY DATAThis Annual Report on Form 10-K contains forward-looking statements that involve substantial risks and uncertainties.All statements,other than statements of historical facts,contained in this Annual Report on Form 10-K,including statements regard

22、ing our strategy,future operations,future financial position,future revenue,projected costs,prospects,plans and objectives of management and expected market growth are forward-looking statements.The words“anticipate,”“believe,”“continue,”“could,”“estimate,”“expect,”“intend,”“may,”“plan,”“potential,”

23、“predict,”“project,”“should,”“target,”“would”and similar expressions are intended to identify forward-looking statements,although not all forward-looking statements contain these identifying words.These forward-looking statements include,among other things,statements about:the ongoing commercializat

24、ion of EMPAVELI and SYFOVRE;our plans with respect to our ongoing and planned clinical trials for our product candidates,whether conducted by us or Swedish Orphan Biovitrum AB(Publ),or Sobi,or by any future collaborators,including the timing of initiation,dosing of patients,enrollment and completion

25、 of these trials and expectations regarding the anticipated results from these trials;our sales,marketing and distribution capabilities and strategies,including for the commercialization and manufacturing of EMPAVELI,SYFOVRE and any future products for which we receive marketing approval;the rate an

26、d degree of market acceptance of EMPAVELI,SYFOVRE and any future products for which we receive marketing approval;our ability to identify and develop current and future products or product candidates with significant clinical benefits and commercial potential;the timing of and our ability to obtain

27、and maintain regulatory approvals for our product candidates for current and future treatment indications in the U.S.and other jurisdictions;our current and any future collaborations for the development and commercialization of our current and future product candidates;including our collaborations w

28、ith Sobi and Beam Therapeutics,Inc.;our intellectual property position and strategy;the sufficiency of our cash and cash equivalents and our expected revenues from sales of EMPAVELI and SYFOVRE to fund our projected operating expenses and capital expenditures to profitability;our estimates regarding

29、 expenses,future revenue,capital requirements and needs for additional financing;developments relating to our competitors and our industry;andthe impact of new government laws and regulations(including tax).We may not actually achieve the plans,intentions or expectations disclosed in our forward-loo

30、king statements,and you should not place undue reliance on our forward-looking statements.Actual results or events could differ materially from the plans,intentions and expectations disclosed in the forward-looking statements we make.We have included important factors in the cautionary statements in

31、cluded in this Annual Report on Form 10-K,particularly in the“Risk Factors”section,that could cause actual results or events to differ materially from the forward-looking statements that we make.Our forward-looking statements do not reflect the potential impact of any future acquisitions,mergers,dis

32、positions,collaborations,joint ventures or investments that we may make or enter into.You should read this Annual Report on Form 10-K and the documents that we have filed or incorporated by reference as exhibits to this Annual Report on Form 10-K completely and with the understanding that our actual

33、 future results may be materially different from what we expect.We do not assume any obligation to update any forward-looking statements,whether as a result of new information,future events or otherwise,except as required by applicable law.This Annual Report on Form 10-K includes statistical and oth

34、er industry and market data that we obtained from industry publications and research,surveys and studies conducted by third parties.All of the market data used in this Annual Report on Form 10-K involves a number of assumptions and limitations,and you are cautioned not to give undue weight to such d

35、ata.We believe that the information from these industry publications,surveys and studies is reliable.The industry in which we operate is subject to a high degree of uncertainty and risk due to a variety of important factors,including those described in the section titled“Risk Factors.”These and othe

36、r factors could cause results to differ materially from those expressed in the estimates made by the independent parties and by us.The Apellis,EMPAVELI,SYFOVRE and Apellis Assist names and logos are our trademarks,trade names and service 2025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492

37、422/000095017025029507/apls-20241231.htm5/27412025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm6/274 2Table of Contentsmarks.The other trademarks,trade names and service marks appearing in this Annual Report on Form 10-K are the property of their

38、respective owners.Note Regarding Certain References in this Annual Report on Form 10-KUnless otherwise stated or the context indicates otherwise,all references herein to“Apellis,”“Apellis Pharmaceuticals,Inc.,”“we,”“us,”“our,”“our company,”“the Company”and similar references refer to Apellis Pharmac

39、euticals,Inc.and its wholly owned subsidiaries.In addition,unless otherwise stated or the context indicates otherwise,all references in this Annual Report on Form 10-K to“EMPAVELI(pegcetacoplan)”and“EMPAVELI”refer to systemic pegcetacoplan in the context of the commercially available product in the

40、United States for the treatment of adults with paroxysmal nocturnal hemoglobinuria,or PNH,and references to Aspaveli refer to systemic pegcetacoplan in the context of the commercially available product in the European Union for the treatment of adults with PNH who are anemic after treatment with a C

41、5 inhibitor for at least three months in each case,and references to IC-MPGN refer to primary immune complex membranoproliferative glomerulonephritis,as more fully described herein.Unless otherwise stated or the context indicates otherwise,all references in this Annual Report on Form 10-K to“SYFOVRE

42、(pegcetacoplan injection)”and“SYFOVRE”refer to intravitreal pegcetacoplan in the context of the commercially available product for which we received approval from the U.S.Food and Drug Administration in February 2023 for the treatment of geographic atrophy secondary to age-related macular degenerati

43、on,or GA,and the Therapeutic Goods Administration in Australia in January 2025 for the every-other-month treatment of adult patients with GA with an intact fovea and when central vision is threatened by GA lesion growth.Unless otherwise stated or the context indicates otherwise,all references herein

44、 to“pegcetacoplan”refer to pegcetacoplan in the context of the product candidate for which we are exploring further applications and indications,as more fully described herein.The other trademarks,trade names and service marks appearing in this Annual Report on Form 10-K are the property of their re

45、spective owners.2025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm7/274 Table of ContentsRISK FACTOR SUMMARY Our business is subject to a number of risks that if realized could materially affect our business,financial condition,results of operation

46、s,cash flows and access to liquidity.These risks are discussed more fully in the“Risk Factors”section of this Annual Report on Form 10-K.Our principal risks include the following:We have incurred significant losses since inception,and we may never achieve or maintain profitability.Our net losses wer

47、e$197.9 million,$528.6 million,and$652.2 million for the years ended December 31,2024,2023 and 2022,respectively.We have obtained marketing approval for EMPAVELI for the treatment of paroxysmal nocturnal hemoglobinuria,or PNH,in multiple jurisdictions,and SYFOVRE for the treatment of geographic atro

48、phy secondary to age-related macular degeneration,or GA,in the United States and Australia.Our prospects depend upon the commercial success of SYFOVRE and EMPAVELI.If we are unable to successfully commercialize SYFOVRE and EMPAVELI for their approved indications or develop and obtain marketing appro

49、val for or successfully commercialize pegcetacoplan for C3 glomerulopathy,or C3G,primary immune complex membranoproliferative glomerulonephritis,or IC-MPGN,and other indications,either alone or through a collaboration,or if we experience significant delays in doing so,our business could be harmed.SY

50、FOVRE is currently only approved in the United States and Australia.We cannot be certain that we will be able to obtain regulatory approval for,and successfully commercialize,SYFOVRE in additional jurisdictions.We or others may later discover that EMPAVELI or SYFOVRE is less effective than previousl

51、y believed or causes safety issues that were not previously identified,which could compromise our ability,or that of our collaborators,to market the product.For example,a small number of patients treated with SYFOVRE in the real world have experienced retinal vasculitis,a severe form of intraocular

52、inflammation.A change in the perception of the benefit/risk profile of SYFOVRE may reduce market acceptance of the product and our product revenues may be adversely affected.We expect to continue to incur significant expenses in the course of operating our business.If our cash and cash equivalents,a

53、nd cash generated from sales of EMPAVELI and SYFOVRE,are not sufficient to fund our projected operating plans and capital expenditure requirements to profitability,we will need to obtain additional funding.If we are unable to raise capital when needed,we could be forced to delay,reduce or eliminate

54、product development programs or delay or reduce our commercialization efforts.Patients with PNH who were previously untreated may not start treatment with EMPAVELI or patients who are being treated for PNH with eculizumab,ravulizumab,or iptacopan may not switch to treatment with EMPAVELI.Patients wi

55、th GA may not be diagnosed or seek treatment with SYFOVRE,may elect to be treated with a competitor treatment,or may fail to comply with the treatment regimen over the progression of the disease.If we are not able to maintain our agreements with wholesale distributors,specialty pharmacy providers,th

56、ird party payors,pharmacy benefit managers and group purchasing organizations,or maintain our products on formularies,the market opportunity and revenue for our products may be adversely affected.EMPAVELI,SYFOVRE,or any other products that we develop may fail to achieve the degree of market acceptan

57、ce by physicians,patients,third-party payors,and others in the medical community necessary for commercial success,in which case we may not generate significant revenues or become profitable.We face substantial competition,which may result in others discovering,developing or commercializing products

58、before or more successfully than we do.In GA,we face competition from avacincaptad pegol,which the FDA approved for the treatment of GA in August 2023.In PNH,we face competition from eculizumab,ravulizumab and iptacopcan.We also face potential competition in C3G from iptacopan,for which a supplement

59、al new drug application,or sNDA,in C3G was submitted to the FDA in late 2024.We have incurred debt under our financing agreement with Sixth Street Lending Partners to buy out the SFJ Pharmaceuticals development liability.Our business may not generate cash flows from operations in the future that are

60、 sufficient to service our debt and support our growth strategies.If our cash and cash equivalents and cash generated from sales of EMPAVELI and SYFOVRE are not sufficient to fund our projected operating plans and capital expenditure requirements to profitability,we will need to obtain additional fu

61、nding.If we are unable to raise capital when needed,we may be required to adopt one or more alternatives,such as obtaining additional capital on terms that may be onerous or highly dilutive,selling assets,or restructuring debt,and we could be forced to delay,reduce or eliminate product development p

62、rograms,or delay or reduce our commercialization effort.The regulatory approval process is expensive,time consuming and uncertain and may prevent us or our collaborators such as Sobi from obtaining marketing approvals for systemic pegcetacoplan in indications other than PNH,intravitreal pegcetacopla

63、n for indications other than GA or in jurisdictions other than the United States and Australia,or any other product candidate that we develop in any jurisdiction.As a result,we cannot predict when or if,and in which jurisdictions,2025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/0000

64、95017025029507/apls-20241231.htm8/27432025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm9/274 4Table of Contentswe,or our collaborators,will obtain marketing approval for systemic pegcetacoplan in other indications,for intravitreal pegcetacoplan fo

65、r GA in jurisdictions other than the United States and Australia or for any other product candidate that we develop in any jurisdiction.If clinical trials of any of our product candidates fail to satisfactorily demonstrate safety and efficacy to the FDA,the European Medicines Agency,or EMA,and other

66、 regulators,we may incur additional costs or experience delays in completing,or ultimately be unable to complete,the development and commercialization of these product candidates.We contract with third parties for the manufacture,storage and distribution of commercial and clinical supply of EMPAVELI

67、 and SYFOVRE and clinical supply for our product candidates and expect to continue to do so in connection with our development and commercialization efforts.This reliance on third parties increases the risk that we will not have sufficient quantities of EMPAVELI,SYFOVRE,or our product candidates or

68、that such quantities may be acquired at an acceptable cost,which could delay,prevent or impair our development or commercialization efforts.If these third parties do not perform satisfactorily,our development or commercialization efforts could be delayed or impaired.Our prospects for the development

69、 and commercialization of systemic pegcetacoplan outside of the United States will depend in part on the success of our collaboration with Sobi.If we fail to comply with our obligations under our existing and any future intellectual property licenses with third parties,we could lose license rights t

70、hat are important to our business,including our patent license agreements with the University of Pennsylvania under which we license patents with claim that recite a class of compounds generically covering pegcetacoplan,and that specifically recite the active component.2025/5/19 10:0010-Khttps:/www.

71、sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm10/274 Table of ContentsPART IItem 1.Business.OverviewWe are a commercial-stage biopharmaceutical company focused on the discovery,development and commercialization of novel therapeutic compounds to treat diseases with high unme

72、t needs through the inhibition of the complement system,which is an integral component of the immune system.We believe that this approach has the potential to effectively control diseases with high unmet need and that are driven by excessive complement activation.We currently have two marketed drugs

73、 that target C3,the central protein in the complement cascade:SYFOVRE(pegcetacoplan injection),approved by the U.S.Food and Drug Administration,or FDA,in February 2023 for the treatment of geographic atrophy secondary to age-related macular degeneration,or GA;and EMPAVELI(pegcetacoplan),approved by

74、the FDA in May 2021 for the treatment of paroxysmal nocturnal hemoglobinuria,or PNH.We believe SYFOVRE has the potential to be the standard of care for patients with GA,a disease that affects an estimated 1.5 million people in the United States.While we have exclusive,worldwide commercialization rig

75、hts for intravitreal pegcetacoplan,we intend to focus our commercialization efforts in the U.S.and explore international expansion in select markets,including Australia,where we received marketing approval in January 2025.For the year ended December 31,2024 and 2023,we generated$611.9 million and$27

76、5.2 million in U.S.net product revenue from sales of SYFOVRE.We are also developing a next-generation therapy by combining SYFOVRE treatment with APL-3007,which is a small interfering RNA,or siRNA,aimed at comprehensively blocking complement activity in the retina and the choroid.We plan to initiate

77、 a Phase 2 multi-dose trial in patients with GA in the second quarter of 2025.We believe that EMPAVELI has the potential to be a best-in-class treatment for a range of indications with high unmet needs.We have exclusive U.S.commercialization rights for EMPAVELI,and our collaboration partner,Swedish

78、Orphan Biovitrum AB(Publ),or Sobi,has exclusive ex-U.S.commercialization rights for systemic pegcetacoplan outside of the United States.For the years ended December 31,2024 and 2023,we generated$98.1 million and$91.0 million,respectively,in U.S.net product revenue from sales of EMPAVELI for PNH and

79、received$18.4 million and$10.0 million,respectively,in royalties from our collaboration partner,Swedish Orphan Biovitrum AB(Publ),or Sobi,which has exclusive ex-U.S.commercialization rights for systemic pegcetacoplan outside of the United States.The next indications we are pursuing with EMPAVELI are

80、 C3 glomerulopathy,or C3G,and primary immune complex membranoproliferative glomerulonephritis,or IC-MPGN,which together affect an estimated 5,000 people in the United States.We submitted a supplemental new drug application,or sNDA,to the FDA in early 2025,following the positive results from the Phas

81、e 3 VALIANT trial investigating systemic pegcetacoplan in adolescent and adult patients with naive and post-transplant recurrence C3G and IC-MPGN that we reported in August 2024.Importantly,the VALIANT study demonstrated positive effects on the three key markers of disease at six months:a 68%reducti

82、on in proteinuria in C3G and IC-MPGN patients compared to placebo(p 0.0001),the primary endpoint.Results were consistent across all subgroups,including disease type,age,and transplant status.Additionally,pegcetacoplan-treated patients achieved stabilization of kidney function(nominal p=0.03),as meas

83、ured by estimated glomerular filtration rate,and a substantial proportion of patients achieved a reduction in C3c staining intensity(nominal p0.0001).Data also demonstrated favorable safety and tolerability results,consistent with pegcetacoplans established profile.Additionally,in February 2025,Sobi

84、 received validation for its indication extension application for C3G and IC-MPGN from the European Medicines Agency,or EMA.We plan to initiate two new Phase 3 clinical trials with EMPAVELI in the second half of 2025 for the treatment of primary focal segmental glomerulosclerosis,or FSGS,and delayed

85、 graft function,or DGF.Both FSGS and DGF are both rare,severe nephrology conditions with no approved therapies and in which complement overactivation plays a significant role.Sobi is also leading the development of systemic pegcetacoplan for hematopoietic stem cell transplantation-associated thrombo

86、tic microangiopathy,or HSCT-TMA,in hematology under the collaboration.Finally,we are developing new product candidates to further advance our pipeline.Through our collaboration with Beam Therapeutics,Inc.,or Beam,we have commenced pre-clinical studies for a treatment targeting the neonatal Fc recept

87、or,orFcRn,which has the potential to be a first-in-class gene editing treatment for future target indications with one-time dosing.We are also developing other programs with our proprietary in-house capabilities.Our Scientific ApproachThe complement system plays a pivotal role in both innate and ada

88、ptive immune systems.Complement proteins are produced primarily by the liver and circulate in the blood and through the bodys tissues.The complement system may be activated through 2025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm11/2745three prin

89、cipal pathways known as the classical,lectin and alternative pathways,each of which requires the C3 protein to enable three 2025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm12/274 6Table of Contentsprincipal immune responses:opsonization,inflammat

90、ion and formation of the membrane attack complex,or MAC.When C3 is activated,C3 fragments,such as C3b,tag cell surfaces in a process called opsonization,which marks the cells for removal from tissues or the bloodstream.Two other fragments,C3a and C5a,are released,contributing to inflammation in the

91、surrounding tissues.Further complement activation causes membrane attack complex formation on cell surfaces,piercing holes and causing cells to lyse,or rupture,and others to depolarize or lose membrane potential and become dysfunctional.The following figure depicts the complement system,its three pr

92、incipal activation pathways and its principal effects:Under conditions of excessive or uncontrolled activation,the complement system is believed to play a key role in the incidence and progression of several autoimmune and inflammatory diseases.In these diseases,the complement system acts directly t

93、hrough cell dysregulation and tissue destruction by the membrane attack complex and indirectly by signaling other elements of the immune system to inappropriately target otherwise healthy tissues.Because the contribution of complement activation to the development and progression of these diseases i

94、s not fully understood,it has been difficult to develop therapeutics that ameliorate the conditions contributing to these diseases by targeting only one of the complement activation pathways.Complement activation and its effects can be inhibited in multiple ways.By targeting complement proteins upst

95、ream of C3,one of the three principal activation pathways can be inhibited.For example,inhibition of factor B or factor D results in inhibition of the alternative pathway,but not the classical or lectin pathways.The complement system can also be inhibited by targeting complement proteins downstream

96、of C3,which results in limited inhibition of complement effects.For example,inhibition of C5 leads to inhibition of the formation of the membrane attack complex and C5a-mediated inflammation but does not affect cell opsonization by C3 fragments or C3a-mediated inflammation.We have designed pegcetaco

97、plan to target complement proteins centrally at the level of C3 and its fragment C3b.We believe that this approach can result in broad inhibition of the complement pathways and has the potential to effectively control complement-dependent diseases.We believe that pegcetacoplan has the potential to b

98、e a best-in-class treatment and may address the limitations of existing treatment options or provide a treatment option where there is none.We are leveraging our expertise in complement immunology to develop new pipeline candidates that may affect different components or pathways within the compleme

99、nt system,whether as independent treatments or as a supplement to the effects of pegcetacoplan.2025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm13/274 7Table of ContentsOur Strategy We aim to become a leading biopharmaceutical company focused on t

100、he discovery,development and commercialization of novel therapeutic compounds to treat diseases in areas such as ophthalmology,rare disease,and neurology through the inhibition of the complement system.To achieve our goals,we are pursuing the following strategies in 2025 with a continued focus on co

101、mpassion and commitment to patients:Transform the treatment of GA with SYFOVRE.Maximize EMPAVELIs impact in rare diseases.Advance our innovative pipeline,leveraging our complement expertise.Our Programs Pegcetacoplan targets C3,the central protein of the complement cascade.Pegcetacoplan is a conjuga

102、te of a compstatin analogue,formulated both for intravitreal administration by injections directly into the eye,and systemic administration by subcutaneous injection,which is an injection into the tissue under the skin.We have developed and are developing pegcetacoplan and other product candidates t

103、hrough various routes of administration.The following table summarizes key information about our products and our clinical programs:2025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm14/274 Table of ContentsOphthalmology We are commercializing SYFOV

104、RE as a monotherapy for patients with GA.Geographic AtrophyGA is a type of AMD.According to the Brightfocus Foundation,over ten million people in the United States have some form of AMD.AMD is a disorder of the central portion of the retina in the eye,known as the macula,which is responsible for cen

105、tral vision and color perception.AMD affects vision in one or both eyes and results in progressive and chronic degeneration of the macula,often resulting in irreversible vision loss.AMD is a disease of aging,typically occurring after the age of 50.In the early stage of the disease,yellow deposits,or

106、 drusen,appear under the retina.Over time,the disease can progress to an intermediate stage where drusen deposits grow larger and other changes reflective of disease progression appear and then to an advanced stage associated with progressive and often severe vision loss which may be characterized a

107、s either GA or wet AMD.GA is characterized by a degenerative process resulting in the progressive loss of retinal cells,which over the course of several years results in blindness.Based on published studies,we estimate that at least five million people worldwide,including approximately 1.5 million p

108、eople in the United States,are living with GA.The mechanism by which complement activation is upregulated and can damage the retina is poorly understood.However,we believe that the upregulation of complement activation due to immune dysregulation damages retinal cells in two ways.First,retinal cells

109、 are damaged by inflammation caused by increased levels of C3a and C5a.Second,the increased deposition of C3b on the cell surface of retinal cells caused by complement activation,combined with the limited ability of cells to remove C3 activated fragments such as C3b,leads to the accumulation of C3 f

110、ragments on the retinal cells.The presence of C3a and C5a,as well as C3 fragment deposition on retinal cells,activates macrophages and microglia.Macrophages are large white blood cells that form part of the immune system that engulf and digest cells,debris and foreign substances.Macrophages also pla

111、y an important role in modulating other parts of the immune system.Microglia are a type of tissue-residing macrophage located in the brain,spinal cord and retina.Because pegcetacoplan both blocks the production of C3a and C5a and prevents the accumulation of C3 fragments on retinal cells through the

112、 inhibition of C3,we believe that pegcetacoplan may control complement activation in the retinal environment to return it to its quiescent state.We do not believe that selective inhibitors of the alternative pathway,which would only partially block the formation of C3b on the retinal cell surface,or

113、 C5 inhibitors,which cannot prevent C3b deposition on retinal cells,can cause the retinal environment to return to its quiescent state.Benefits of Our Approach We believe SYFOVRE,with its inhibition of complement activation at the level of C3 in the retinal environment,may provide the following bene

114、fits for patients with GA:Prevention or reduction of the rate of retinal cell death,with increasing treatment effects over time.We believe SYFOVRE may mitigate or prevent retinal cell death in GA,leading to a reduction in GA lesion growth over time.In our Phase 3 trials,SYFOVRE showed a slowing of G

115、A progression,with evidence of treatment effects increasing over the 24-month period,and well-demonstrated safety profile following nearly 12,000 injections.Treatment effects observed in two dosing regimens.In our Phase 3 trials,SYFOVRE showed a slowing of GA progression over 24 months in both every

116、-other-month and monthly dosing.The prescribing label for SYFOVRE indicates that the 2025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm15/27482025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm16/2

117、74 Table of Contentsrecommended dose to be administered to each eye is once every 25 to 60 days.This provides physicians with flexibility to determine the appropriate dosing schedule for their individual patients.Potential application to all patients with GA regardless of lesion location.SYFOVRE,by

118、targeting C3,has been designed to inhibit all three principal complement activation pathways and may therefore be effective in a broad patient population.In our Phase 3 trials at 24 months,pegcetacoplan showed a slowing of GA progression in lesions with or without subfoveal involvement.DERBY and OAK

119、S are the only clinical trials to-date that have shown a slowdown in the progression of GA regardless of lesion location.Regulatory Matters In February 2023,the FDA approved intravitreal pegcetacoplan with the brand name SYFOVRE for the treatment of adult patients with GA secondary to AMD and,in Jan

120、uary 2025,the Therapeutic Goods Administration,or TGA,in Australia,approved SYFOVRE for every-other-month treatment of adult patients with GA with an intact fovea where central vision is threatened by lesion growth.We are currently evaluating our regulatory strategy for select jurisdictions outside

121、the United States.In October 2024,we withdrew our marketing authorization application,or MAA,from the European Medicines Agency,or EMA,after the Committee for Medicinal Products for Human Use,or CHMP,adopted a negative opinion following the re-examination of the MAA,despite multiple dissenting votes

122、 by CHMP members.Despite our withdrawal,the European Commission issued a negative decision with respect to our MAA in December 2024.Commercial and Medical Activities for GAWe launched SYFOVRE,the first approved treatment for GA,in the United States in March 2023.SYFOVRE is currently the market-leadi

123、ng treatment for GA,a disease that affects an estimated 1.5 million people in the United States.Our U.S.field sales team has been engaging with eyecare professionals,or ECPs,focusing specifically on retina specialists and treating ophthalmologists.Field teams are focused on SYFOVRE brand messaging,h

124、ighlighting key advantages such as increasing effects over time,its strong clinical profile,and dosing flexibility.We also have a thought leader liaison team,which is focused on building advocacy with key opinion leaders in the retina space,and a strategic account team,which identifies and develops

125、working relationships with key decision makers within targeted private equity groups and large accounts.Our marketing efforts are designed to reach ECPs through digital and print media.We seek to reach patients through direct-to-consumer(TV,print and digital media)disease state education and branded

126、 SYFOVRE messaging encouraging them to see their eye doctor if they have symptoms or a previous diagnosis.Additionally,our efforts have focused on increasing awareness of GA and SYFOVRE with general ophthalmologists and optometrists to ensure GA patients are able to connect with a retina specialist

127、or ophthalmologist who can treat them.We launched a practice finder tool to help physicians and patients identify practices near them that have recently treated GA.Our market access team has been engaging with primary and secondary payers representing a significant percentage of GA patients.We have

128、also established a robust distribution network by partnering with key specialty distributors and specialty pharmacies to maximize product access by retina specialists.Finally,we have a field reimbursement team to educate practices and address access issues to fully support the reimbursement journey

129、for SYFOVRE.ApellisAssist for SYFOVRE is designed to eliminate patient access barriers by providing enrolled individuals with insurance support,financial assistance for eligible patients,and education on the importance of maintaining treatment as prescribed.Additionally,prescribers have the option t

130、o enroll their patients in GAMyWay,our patient services program,for ongoing treatment support and continuous education.Our medical affairs team is engaging with ECPs through our presence at medical meetings and other in-person engagements.Throughout 2024,we participated in key scientific meetings,in

131、cluding the American Academy of Ophthalmology,Retina Society,FLORETINA,and Macula Society.Clinical Development We are currently conducting two post-marketing studies:GALE and GARLAND.Our registrational Phase 3 DERBY and OAKS trials evaluated the efficacy and safety of SYFOVRE in patients with GA sec

132、ondary to AMD.The DERBY and OAKS were initiated in September 2018,and we presented reported 24-month results from our DERBY and OAKS trials in August 2022,following 18-month results presented in March 2022 and 12-month results presented in September 2021.Prior to DERBY and OAKS,we completed the Phas

133、e 2 FILLY trial in August 2017.Post-Marketing Studies 2025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm17/27492025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm18/274 Table of Contents We are cur

134、rently conducting a 36-month,open-label extension study(GALE)to evaluate the long-term safety and efficacy of intravitreal pegcetacoplan in patients with GA secondary to AMD.The objectives of the study are to evaluate the long-term incidence and severity of ocular and systemic treatment emergent adv

135、erse events as well as change in the total area of GA lesions as measured by fundus autofluorescence.Approximately 800 patients enrolled into the GALE extension study.In February 2025,we presented data from GALE following four years of continuous treatment with SYFOVRE.Results showed that SYFOVRE co

136、ntinued to demonstrate increasing treatment effects over time.We are currently conducting a 36-month,open label,Phase 4 study(GARLAND)to evaluate the safety,tolerability and treatment patterns of SYFOVRE in patients over the age of 60 with GA in a clinical practice setting.Secondary endpoints includ

137、e GA progression,changes in drusen over time and the ability of physicians to determine GA lesion location.Approximately 234 patients have been enrolled into the GARLAND study.Phase 3 Clinical TrialsOur Phase 3 clinical program in GA consisted of two prospective,multicenter,randomized,double-masked,

138、sham-injection controlled trials(DERBY and OAKS)conducted at more than 200 sites worldwide to assess the efficacy and safety of multiple intravitreal injections of pegcetacoplan in patients with GA.We enrolled 621 patients in DERBY and 637 patients in OAKS.Patients in each Phase 3 trial received a d

139、ose of 15 mg of pegcetacoplan injected intravitreally in a 0.1 cc volume,monthly or every other month for 24 months.In the sham-injection cohorts,patients received a simulated injection.As with our Phase 2 FILLY clinical trial,the primary endpoint of each trial was the change in total area of GA les

140、ions in the study eye compared to sham.The measurements of change in lesion size were analyzed at 12 months,18 months,and 24 months.Patients who develop new onset exudation in the study eye continued to be treated with pegcetacoplan along with anti-VEGF injections,the current standard of care for we

141、t AMD.We completed the primary analysis for the 24-month treatment period in August 2022.Monthly and every-other-month,or EOM,treatment with SYFOVRE showed increased effects over time.In OAKS,monthly and EOM treatment with SYFOVRE reduced GA lesion growth by 22%(p0.0001)and 18%(p=0.0002),respectivel

142、y.In DERBY,monthly and EOM treatment with SYFOVRE reduced GA lesion growth by 19%(p=0.0004)and 16%(p=0.0030),respectively.All p-values are nominal and were calculated using the same methodologies as the 12-month primary endpoint analysis.Between months 18-24,the pegcetacoplan treatment effect accele

143、rated compared to previous six-month periods,with robust reductions of GA lesion growth versus sham(all p-values are nominal).The increased effects were driven by a greater slowing of lesion growth by pegcetacoplan and not by an increase in the lesion growth rate in the sham group,which was highly c

144、onsistent over each of the four six-month intervals(1.0+/-0.05 mm2).DERBY:36%monthly,p0.0001;29%EOM,p=0.0002OAKS:24%monthly,p=0.0080;25%EOM,p=0.0007 Additionally,the reduction of GA lesion growth in lesions without subfoveal involvement(28%monthly;28%EOM)was comparable to the reduction in lesions wi

145、th subfoveal involvement(34%monthly;28%EOM)in the combined studies between months 18-24.SYFOVRE was well-tolerated in both DERBY and OAKS,generally consistent with longer-term exposure to intravitreal injections.The most common adverse reactions(5%)reported in patients receiving SYFOVRE in these stu

146、dies were ocular discomfort,neovascular AMD,vitreous floaters,and conjunctival hemorrhage.Rates of ischemic optic neuropathy events were higher in the monthly group as compared to the every-other-month and sham groups(1.7%of patients treated monthly,0.2%of patients treated EOM and 0.0%of patients as

147、signed to sham).Rates of endophthalmitis and intraocular inflammation were generally in line with those reported in studies of other intravitreal therapies.No events of occlusive or non-occlusive vasculitis or retinitis were observed over 24 months.We used a liquid formulation of pegcetacoplan in ou

148、r Phase 3 trials instead of the freeze-dried formulation that we used in the Phase 2 FILLY trial,which we believe may reduce the incidence of endophthalmitis.SYFOVRE and APL-30072025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm19/274102025/5/19 10

149、:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm20/274 Table of ContentsIn January 2025,we shared Phase 1 data with APL-3007,our siRNA,in healthy volunteers showing greater than 90%knockdown of C3 as measured by the remaining levels of protein in the blood.B

150、ased on the results of this study,we are now developing a next generation treatment for GA by combining SYFOVRE plus APL-3007,which we believe may comprehensively block complement activity in the retina and the choroid.We believe that with less C3 present in the eye following administration with APL

151、-3007,there may be a greater degree of efficacy contribution from SYFOVRE.We expect to initiate a Phase 2 study with SYFOVRE and APL-3007 in GA patients in the second quarter of 2025.Product DevelopmentWe are developing a single package for SYFOVRE,or co-pack,that will contain SYFOVRE vials packaged

152、 with the necessary ancillaries for its administration.We expect that the co-pack will standardize administration of SYFOVRE and provide physicians with a more convenient way to store and handle the drug and ancillaries.The co-pack will also streamline both distribution operations and receipt by cus

153、tomers.We anticipate the supply of the co-pack to be available in the first half of 2026.We are also developing a single dose,sterilized prefilled syringe for SYFOVRE.We believe the prefilled syringe will provide physicians with a new way to administer SYFOVRE that requires fewer steps compared to t

154、he current administration.Rare Diseases EMPAVELI in PNHWe launched EMPAVELI in the United States for patients with PNH following its approval by the FDA in May 2021.We believe that EMPAVELI elevated the standard of care for patients with PNH.We generated net product revenue from sales of EMPAVELI of

155、$98.1 million during the year ended December 31,2024.Systemic pegcetacoplan was subsequently approved by the European Commission,the United Kingdom,Canada,Japan,Saudi Arabia and Australia.Paroxysmal Nocturnal Hemoglobinuria(PNH)PNH is a rare,chronic,debilitating blood disorder that is most frequentl

156、y acquired in early adulthood and usually continues throughout the life of the patient.Some of the prominent symptoms of PNH include severe anemia,a condition that results from having too few red blood cells,severe abdominal pain,severe headaches,back pain,excessive weakness,fatigue and recurrent in

157、fections.If not treated,PNH results in the death of approximately 35%of affected individuals within five years of diagnosis and 50%of affected individuals within ten years of diagnosis,primarily due to the formation of life-threatening blood clots inside the blood vessels,or thrombosis.Based on prev

158、alence data published in an abstract in a peer-reviewed journal,we estimate that there are approximately 4,700 patients with PNH in the United States and approximately 15,000 patients with PNH worldwide.PNH is caused by the presence of mutant stem cells in the bone marrow that lack important protein

159、s on their surface that protect against activation of the complement system.In patients with PNH,an autoimmune response targets and eliminates normal stem cells,enabling mutant cells to become dominant in the bone marrow.These mutant stem cells lead to mutant platelets and red blood cells that,unlik

160、e normal cells,are overly susceptible to activation or destruction by the complement system.Mutant platelets,activated by the membrane attack complex,increase the risk of thrombosis,which is the leading cause of mortality in patients with PNH.Mutant red blood cells are susceptible to destruction by

161、intravascular and extravascular hemolysis.Intravascular hemolysis,which involves the destruction of blood cells within the blood vessels,is caused by the formation of the membrane attack complex on the surface of red blood cells causing them to rupture.Intravascular hemolysis causes severe anemia an

162、d contributes to the risk of thrombosis.Extravascular hemolysis,which involves the destruction of blood cells outside the blood vessels,is caused by C3-related opsonization on red blood cells leading to removal of the cells from the blood stream by the liver and the spleen.Extravascular hemolysis fu

163、rther contributes to severe anemia and transfusion dependency in patients with PNH.CommercializationOur sales efforts are focused on the health care professionals,or HCPs,and key treatment centers,who have patients that continue to experience breakthrough hemolysis,have persistently low hemoglobin,h

164、igh fatigue,and require transfusions despite being on C5 inhibitors.Our market access team is engaging with primary and secondary payers representing a significant percentage of PNH patients.Our discussions with primary and secondary payers have yielded positive feedback on the clinical profile of p

165、egcetacoplan and resulted in EMPAVELI being added to several positive formulary positions.We implemented a limited distribution specialty 2025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm21/274112025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar

166、/data/1492422/000095017025029507/apls-20241231.htm22/274 Table of Contentspharmacy model,which we believe provided patients with a consistent,positive experience at the time of treatment initiation and long-term assistance to the extent needed.We also have Apellis Assist,a patient-focused program sp

167、ecifically designed to assist patients with onboarding,product training and ongoing support with pegcetacoplan treatment,and we have built a care educator team to connect directly with PNH patients and their caregivers to provide education and training on the use of pegcetacoplan.Our medical affairs

168、 team is engaging with physicians through our presence at medical meetings and other in-person engagements.In December 2024,we participated in the American Hematology Society,or ASH,annual meeting.Sobi will conduct medical affairs activities for systemic pegcetacoplan outside the United States.Devel

169、opmentIn June 2018,we initiated the Phase 3 PEGASUS trial in patients.The PEGASUS trial was an 80-patient randomized head-to-head trial comparing systemic pegcetacoplan monotherapy to eculizumab monotherapy in patients with PNH currently on treatment with eculizumab who have a hemoglobin level of le

170、ss than 10.5 g/dL,regardless of eculizumab dose or transfusion history.The primary efficacy endpoint of the trial was the change in hemoglobin level from baseline at week 16.We initiated the Phase 3 PRINCE trial in September 2019.The PRINCE trial was a 54-patient randomized,multicenter,open-label tr

171、ial to evaluate the efficacy of systemic pegcetacoplan in treatment-nave PNH patients.The primary endpoints were avoidance of a greater than 1 g/dL decrease in hemoglobin level from baseline in the absence of transfusion through week 26 and reduction in LDH level from baseline to week 26,in patients

172、 with PNH who are currently not being treated with complement inhibitors.In January 2020,we announced top-line data from the PEGASUS trial that showed that systemic pegcetacoplan met the primary efficacy endpoint,demonstrating superiority to eculizumab with a statistically significant improvement in

173、 adjusted means of 3.8 g/dL of hemoglobin at week 16(p 0.0001).In May 2021,we reported top-line results from PRINCE demonstrating statistical superiority on the co-primary endpoints of hemoglobin stabilization and reduction in LDH compared to standard of care,which did not include complement inhibit

174、ors,at week 26.In both the PEGASUS and PRINCE trials,the safety profile of systemic pegcetacoplan was comparable to eculizumab and consistent with previously reported data.In all trials of pegcetacoplan administered systemically by subcutaneous injection,we have monitored the safety of our targeting

175、 of C3 closely.Individuals who lack functional levels of C3 or C5 have been shown to be susceptible to infection by certain bacterial species,including Neisseria meningitidis in C5-deficient individuals and Neisseria meningitidis,Streptococcus pneumoniae and Haemophilus influenzae in C3-deficient in

176、dividuals.As a result,we vaccinate patients in these trials against these three pathogens,which we believe minimizes the risk of infection.No unexpected safety concerns have been observed in patients in the clinical or post-marketing settings.EMPAVELI in NephrologyC3G glomerulopathy,or C3G,and prima

177、ry immune complex membranoproliferative glomerulonephritis,or IC-MPGN,are rare,debilitating kidney diseases that affect an estimated 5,000 people in the United States,for which no therapies are currently approved.Symptoms of these diseases include blood in the urine,dark foamy urine due to the prese

178、nce of protein,swelling,and high blood pressure.Approximately 50%of people living with C3G and IC-MPGN ultimately suffer kidney failure within five to 10 years of diagnosis.Although IC-MPGN is considered a distinct disease from C3G,the underlying cause and progression of the two diseases are remarka

179、bly similar and include overactivation of the complement cascade,with excessive accumulation of C3 breakdown products in the kidney causing inflammation and damage to the organ.Since pegcetacoplan is designed to prevent C3 activation,we believe it has the potential to prevent further deposition of C

180、3 activation products in the glomeruli,which may protect the kidney from further injury.Regulatory Matters and Clinical Development We submitted a sNDA to the FDA in early 2025 following the positive results from the Phase 3 VALIANT trial investigating EMPAVELI in adolescent and adult patients with

181、naive and post-transplant recurrence C3G and IC-MPGN.EMPAVELI received orphan drug designation from the FDA for the treatment of C3G in December 2018.In February 2025,Sobi received EMA validation for its indication extension application for C3G and primary IC-MPGN in the European Union.In August 202

182、4,we announced positive results from our VALIANT study,a randomized,placebo-controlled,double-blinded,multi-center Phase 3 trial in 124 patients who are 12 years of age and older with C3G or primary IC-MPGN.The VALIANT study demonstrated positive effects on the three key markers of disease at Week 2

183、6:a 68%reduction in proteinuria in pegcetacoplan-treated patients compared to placebo(p0.0001),the primary endpoint.Results were consistent across all subgroups,including 2025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm23/27412disease type,age,an

184、d transplant status.Additionally,pegcetacoplan-treated patients achieved stabilization of kidney function(nominal p=0.03),as 2025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm24/274 Table of Contentsmeasured by estimated glomerular filtration rate,

185、and a substantial proportion of patients achieved a reduction in C3c staining intensity(nominal p0.0001).Pegcetacoplan also demonstrated favorable safety and tolerability results,consistent with its established profile.In October 2023,we announced positive results from our NOBLE trial,a randomized,p

186、lacebo-controlled Phase 2 trial in post-transplant recurrence of C3G and IC-MPGN.Specifically,at 12 weeks,80%of patients showed a reduction in C3c staining by one or more orders of magnitude of intensity from baseline,the primary endpoint,and 40%of patients showed zero staining intensity,indicating

187、that C3c deposits were cleared.Patients also showed improvements across key clinical measures,including a mean reduction in proteinuria,and stabilized kidney function.There were no discontinuations due to treatment-emergent adverse events.In October 2020,we reported data from the DISCOVERY trial in

188、five C3G patients treated with systemic pegcetacoplan for 48 weeks.In those patients,mean(SE)proteinuria decreased from 3.48(0.82)mg/mg at baseline to 0.93(0.27)mg/mg at week 48,a decrease of 73.3%,as measured by 24-hour uPCR.Importantly,this reduction in proteinuria was accompanied by a correspondi

189、ng increase in mean serum albumin.Since albumin is the most abundant protein in serum,its level increases when urinary protein losses are reduced.Other biomarkers improved,including an observed increase in mean serum C3 and stabilization of renal function,as measured by mean serum creatinine.No seri

190、ous or severe adverse events were reported,and pegcetacoplan was well tolerated overall.We plan to initiate two pivotal studies with EMPAVELI in FSGS and DGF in the second half of 2025.Complement plays a significant role in both diseases,and there are currently no FDA-approved therapies.FSGS is a ra

191、re kidney disease that causes scarring in the glomeruli and,similar to C3G and IC-MPGN,results in end stage kidney disease within 5-10 years for approximately half of patients.There are an estimated 13,000 primary FSGS patients in the United States.DGF is a complication in kidney transplantation whe

192、re the transplanted kidney fails to function and typically requires dialysis within the first week of transplant.This negatively affects the long-term survival of the kidney and overall patient outcomes.In 2023,there were an estimated 21,000 transplants in the U.S.using deceased donor kidneys,of whi

193、ch DGF occurred in 30-35%of them.EMPAVELI in Other IndicationsHematopoietic stem cell transplantation thrombotic microangiopathy,or HSCT-TMA,is rare blood disease that can be a fatal complication of a bone marrow transplant or HSCT.In HSCT-TMA,microscopic blood clots form in small blood vessels,lead

194、ing to organ damage.The kidneys are commonly affected,although any organ may be involved.HSCT-TMA occurs in up to 40%of HSCT recipients;every year,there are approximately 9,000 allogeneic transplants in the United States.Excessive complement activation is a high-risk feature in patients with HSCT-TM

195、A,and C3 is believed to play a critical role in TMA based on proinflammatory and procoagulant properties of C3a and C3b.In early 2022,Sobi dosed the first patient in the Phase 2 clinical trial of systemic pegcetacoplan in patients with HSCT-TMA.The Phase 2 trial is an open label,single arm,multicent

196、er trial evaluating the pharmacokinetics,efficacy and safety and tolerability of pegcetacoplan in approximately 12 patients with HSCT-TMA.Sobi expects to report top-line on this study in mid-2025.Beam Research CollaborationIn June 2021,we entered into an exclusive five-year research collaboration wi

197、th Beam focused on the use of Beams proprietary base editing technology to discover new treatments for complement-driven diseases.Under the collaboration agreement,we are collaborating on up to six research programs focused on C3 and other complement targets in the eye,liver and brain.We have commen

198、ced pre-clinical studies for a FcRn treatment,which has the potential to be a first-in-class gene editing treatment for future target indications with one-time dosing.Collaboration and License Agreement with Sobi On October 27,2020,we and our subsidiaries,Apellis International GmbH(f/k/a Apellis Swi

199、tzerland GmbH)and APL DEL Holdings,LLC,entered into a Collaboration and License Agreement(the“Sobi collaboration agreement”)with Sobi,concerning the development and commercialization of pegcetacoplan and specified other structurally and functionally similar compstatin analogues or derivatives for us

200、e systemically or for local non-ophthalmological administration(collectively referred to as the“Licensed Products”).Under the Sobi collaboration agreement,we granted Sobi an exclusive(subject to certain retained rights of the Company),sublicensable license of certain patent rights and know-how to de

201、velop and commercialize Licensed Products in all countries outside of the United States.We retain the right to commercialize Licensed Products in the United States and,subject to specified limitations,to develop Licensed Products worldwide for commercialization in the United States.2025/5/19 10:0010

202、-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm25/274132025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm26/274 Table of ContentsUnder the Sobi collaboration agreement,we and Sobi agreed to collaborate to devel

203、op Licensed Products for certain indications,including PNH,C3G,IC-MPGN and HSCT-TMA,and any other indications subsequently agreed upon by the parties,for commercialization by or on behalf of us in the United States and by or on behalf of Sobi outside of the United States.If the parties do not agree

204、to jointly pursue any development activities for the Licensed Products,the party proposing to pursue such activities may conduct such activities at its sole expense(with the non-proposing party having the right to obtain rights to the data generated by such development activities by paying a specifi

205、ed percentage of that expense),subject to agreed-upon exceptions that limit each partys unilateral development rights.We and Sobi have formed several governance committees to oversee the development and manufacture,and to review and discuss the commercialization,of Licensed Products.We agreed to sup

206、ply Licensed Products to Sobi for development and for commercialization outside of the United States in accordance with a supply agreement to be negotiated by the parties.The Sobi collaboration agreement grants Sobi the right to perform or have performed drug product manufacturing of Licensed Produc

207、ts for development and for commercialization outside the United States and to manufacture or have manufactured drug substance under certain circumstances.We entitled to receive tiered,double-digit royalties(ranging from high teens to high twenties)on sales of Licensed Products outside of the United

208、States,subject to customary deductions and third-party payment obligations,until the latest to occur of:(i)expiration of the last-to-expire of specified licensed patent rights;(ii)expiration of regulatory exclusivity;and(iii)ten(10)years after the first commercial sale of the applicable Licensed Pro

209、duct,in each case on a Licensed Product-by-Licensed Product and country-by-country basis.Under the Sobi collaboration agreement,we remain responsible for its license fee obligations(including royalty obligations)to the Trustees of the University of Pennsylvania(“Penn”),as a licensor of Apellis.We re

210、ceived$18.4 million in royalties from Sobi during the year ended December 31,2024 and$10.0 million in royalties from Sobi in the year ended December 31,2023.Unless earlier terminated,the agreement will expire upon the expiration of the last royalty term for the last Licensed Product outside of the U

211、nited States.The agreement may be terminated in its entirety by Sobi upon 90 days prior written notice at any time.Either party may,subject to specified cure periods,terminate the agreement in its entirety in the event of the other partys uncured material breach.In addition,we may,subject to specifi

212、ed cure periods,terminate the agreement in any of China,Japan,Brazil,or Canada if Sobi materially breaches its obligation to use commercially reasonable efforts to develop,obtain regulatory approval for,and commercialize a Licensed Product for PNH in such country.Either party may also terminate the

213、agreement under specified circumstances relating to the other partys insolvency.We may terminate the agreement in the event Sobi or its specified affiliates or sublicensees challenges the validity,scope or enforceability of the licensed patent rights under specified circumstances.Research Collaborat

214、ion with BeamIn June 2021,we entered into an exclusive five-year research collaboration(the“Beam collaboration agreement”)with Beam focused on the use of Beams proprietary base editing technology to discover new treatments for complement-driven diseases.We and Beam agreed to collaborate on up to six

215、 research programs focused on C3 and other complement targets in the eye,liver and brain.Under the terms of the Beam collaboration agreement,we are responsible for selecting specific genes within the complement system in various organs including the eye,liver and brain(the“Target List”)and providing

216、 analytical support while Beam will apply its base editing technology and conduct preclinical research on up to six base editing programs for the Target List.During the first five years of the Beam collaboration agreement,Beam is prohibited from developing on its own or with a third party any base e

217、diting therapies associated with the items on the Target List but does not prevent Beam from licensing its intellectual property to a third-party for another purpose outside of the Target List.We will have exclusive rights to license each of the six programs and will assume responsibility for subseq

218、uent development and commercialization.Beam may elect to enter a 50-50 co-development and U.S.co-commercialization agreement with us with respect to any one program licensed under the Beam collaboration agreement and upon such election any license agreement in place at that time,would be terminated.

219、As part of the Beam collaboration agreement,we paid$50.0 million up-front,non-refundable payment to Beam in July 2021 and$25.0 million in June 2022.We and Beam are each responsible for their own costs during the research collaboration.If and after the opt-in license rights are exercised for each of

220、the up to six programs,Beam will be eligible to receive development,regulatory and sales milestones from us,as well as royalty payments on sales.The Beam collaboration agreement has an initial term of five years and may be extended up to two years on a per year program-by-program basis.Intellectual

221、Property Our success depends in part on our ability to obtain and maintain proprietary protection for our product candidates,technology and know-how,to operate without infringing the proprietary rights of others and to prevent others from infringing our proprietary rights.We seek to protect our prop

222、rietary position in a variety of ways,including by pursuing patent protection in certain jurisdictions 2025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm27/274142025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/ap

223、ls-20241231.htm28/274 Table of Contentswhere it is available.For example,we file U.S.and certain foreign patent applications related to our proprietary technology,inventions and improvements that are important to the development of our business.We also rely on trade secrets,know-how,continuing techn

224、ological innovation and in-licensing opportunities to develop and maintain our proprietary position.As of December 31,2024,we own a total of 27 U.S.patents and 35 pending U.S.patent applications,including original filings,continuations,and divisional applications,as well as numerous foreign counterp

225、arts of many of these patents and patent applications.Pegcetacoplan is an analog of the cyclic peptide compstatin,based on technologies that we have developed internally or have exclusively licensed from Penn.Our patents and patent applications include families of United States and foreign patent an

226、d patent applications relating,for example,to the composition of matter of certain compstatin analogs with a prolonged in vivo half-life,including pegcetacoplan,and/or to methods of treatment and dosing regimens for treating particular complement-dependent diseases.Patents in these families would ex

227、pire in 2032 or 2033.We have submitted applications for patent term extension for certain of these patents.Our patent applications also include families relating in part to particular doses and dosing regimens for intravitreally or subcutaneously administered pegcetacoplan that are granted or pendin

228、g in the United States and a number of other jurisdictions.Patents in these families would expire between 2036 and 2038.Seven of our U.S.patents are listed for EMPAVELI in the FDAs Orange Book.Our filings also include certain U.S.and foreign patents and patent applications relating to methods of tre

229、ating eye disorders associated with complement activation.These patent rights include issued U.S.patents with claims to methods of treating AMD by administration of compstatin analogs and a granted European patent with claims to a class of compstatin analogs for use in treatment of macular degenerat

230、ion.These patents have terms that extend into 2026.Eight of our U.S.patents are listed for SYFOVRE in the FDAs Orange Book.We also own a patent family relating in part to use of C3 inhibitors,including pegcetacoplan,to facilitate gene therapy with AAV vectors.Patents in this family would have terms

231、extending into 2040.In addition,we own patent families relating to use of pegcetacoplan for the treatment of PNH or for the treatment of GA that have terms extending into 2041 through 2043.In addition to the technology that we developed internally relating to compstatin analogs,we hold exclusive lic

232、enses from Penn.The intellectual property in-licensed under our two license agreements with Penn includes four U.S.patents and numerous foreign counterparts,with claims granted in Europe,Japan and elsewhere.These licensed patent rights include issued patents with claims that recite a class of compou

233、nds generically covering pegcetacoplan,and that specifically recite the active component.These patents have terms that extend to 2026.We also own or have exclusive rights to a number of patent applications relating to additional modalities and molecules for inhibiting complement,including nucleic ac

234、id,small molecule,and protein-based approaches.The filings cover,for example,the composition of matter of certain of our product candidates and methods of use for treating particular complement-mediated disorders.Patents issuing based on these applications would have terms extending into 2041 throug

235、h 2044.We have a non-exclusive license to intellectual property covering aspects of base editing technology,including CRISPR proteins and base editors,for use in the context of our collaboration with Beam,and have an exclusive license from Beam to this intellectual property to the extent it specific

236、ally covers therapeutic candidates developed under the collaboration.The term of individual patents depends upon the legal term for patents in the countries in which they are granted.In most countries,including the United States,the patent term is generally 20 years from the earliest claimed filing

237、date of a non-provisional patent application in the applicable country.In the United States,a patents term may,in certain cases,be lengthened by patent term adjustment,which compensates a patentee for administrative delays by the U.S.Patent and Trademark Office in examining and granting a patent or

238、may be shortened if a patent is terminally disclaimed over a commonly owned patent or a patent naming a common inventor and having an earlier expiration date.The Drug Price Competition and Patent Term Restoration Act of 1984,or the Hatch-Waxman Act,permits a patent term extension of up to five years

239、 beyond the expiration date of a U.S.patent as partial compensation for the length of time the drug is under regulatory review while the patent is in force.A patent term extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval,only one paten

240、t applicable to each regulatory review period may be extended and only those claims covering the approved drug,a method for using it or a method for manufacturing it may be extended.Similar provisions are available in the European Union and certain other foreign jurisdictions to extend the term of a

241、 patent that covers an approved drug,and we have applied for and will continue to apply for such extensions in jurisdictions in which pegcetacoplan is approved.In the future,if and when our product candidates receive approval by the FDA or foreign regulatory authorities,we expect to apply for patent

242、 term extensions on issued patents covering those products,depending upon the length of the clinical trials for each drug and other factors.Expiration dates referred to above are without regard to potential patent term adjustment or extension or other market exclusivity that may be available to us.W

243、e granted worldwide rights to use and license the intellectual property that we hold with respect to pegcetacoplan to our wholly owned subsidiaries,APL DEL Holdings,LLC and Apellis International GmbH(f/k/a Apellis Switzerland GmbH).Certain of 2025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data

244、/1492422/000095017025029507/apls-20241231.htm29/274152025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm30/274 Table of Contentsour wholly owned subsidiaries hold rights to use our intellectual property to manage our clinical trials in certain juris

245、dictions or territories and exclusive rights to distribute our product with respect to specific indications within certain jurisdictions or territories.We granted Sobi an exclusive(subject to certain retained rights),sublicensable license of certain patent rights and know-how to develop and commerci

246、alize pegcetacoplan for non-ophthalmological indications in all countries outside of the United States.We may rely,in some circumstances,on trade secrets to protect our technology.However,trade secrets can be difficult to protect.We seek to protect our proprietary technology and processes,in part,by

247、 confidentiality agreements with our employees,consultants,scientific advisors and contractors.We also seek to preserve the integrity and confidentiality of our data and trade secrets by maintaining physical security of our premises and physical and electronic security of our information technology

248、systems.Patent License Agreement with The Trustees of the University of Pennsylvania(Non-ophthalmic Fields of Use)We are party to an agreement with Penn for an exclusive worldwide license,under specified patent rights controlled by Penn,to develop and commercialize products covered by the licensed p

249、atent rights for all fields except the treatment of ophthalmic indications.We have the right to grant sublicenses under this license.The patent rights licensed to us by Penn include patents with claims that recite a class of compounds generically covering pegcetacoplan,and specifically recite the ac

250、tive component.Three of these patents are listed for EMPAVELI in the FDAs Orange Book.Under the license agreement,we were obligated to make a$0.1 million annual license maintenance payment to Penn until the first commercial sale of a licensed product,some of which may become creditable against miles

251、tone payments under specified circumstances.We may also become obligated to make payments to Penn aggregating up to$1.7 million,based on achieving specified development and regulatory approval milestones and up to$2.5 million based on achieving specified annual sales milestones with respect to each

252、of the first two licensed products,and to pay low single-digit royalties to Penn based on net sales of each licensed product by us and our affiliates and sublicensees and specified minimum quarterly royalty thresholds.In addition,we are obligated to pay Penn a specified portion of income we receive

253、from sublicensees.Our royalty obligation with respect to each licensed product in a country extends until the later of the expiration of the last-to-expire patent licensed from Penn covering the licensed product in the country or the expiration of a specified number of years after the first commerci

254、al sale of the licensed product in the country.As of December 31,2024 and 2023,respectively,we have incurred royalty expense of$6.4 million and$4.8 million on sales of EMPAVELI and Aspaveli.We also are obligated to use commercially reasonable efforts to develop licensed products in accordance with a

255、 development plan,which we will update annually,and a development milestone timetable specified in the agreement and to use commercially reasonable efforts to commercialize licensed products.Penn has the right to terminate the agreement if we breach the agreement and fail to cure our breach within s

256、pecified cure periods or in the event of specified bankruptcy,insolvency and liquidation events.We have the right to terminate the agreement for our convenience at any time on 60 days notice to Penn.In January 2021,we paid$25.0 million for a sublicense fee owed to Penn related to the Sobi collaborat

257、ion agreement and another licensing transaction.In August 2021,we paid$1.0 million to Penn upon the achievement of a development milestone,net of a credit for the annual license maintenance payment.In June 2022,we paid an additional$5.0 million to Penn upon the achievement of a development milestone

258、.In January 2023,we paid$1.0 million to Penn upon the achievement of a sales milestone for EMPAVELI in 2022.In January 2024,we paid$0.5 million for a sublicense fee owed to Penn related to Sobi obtaining regulatory approval in Japan.Additionally,in January 2024,we paid$1.5 million as a result of the

259、 achievement of a sales milestone for EMPAVELI and Aspaveli.Amended and Restated Patent License Agreement with The Trustees of the University of Pennsylvania(Ophthalmic Field of Use)We are party to an agreement with Penn for an exclusive worldwide license,under specified patent rights controlled by

260、Penn,to develop and commercialize products covered by the licensed patent rights for the treatment of ophthalmic indications.Three of the licensed patents are listed for SYFOVRE in the FDAs orange book.We have the right to grant sublicenses under the license.Under the license agreement,we were oblig

261、ated to make a$0.1 million annual license maintenance payment to Penn until the first commercial sale of a licensed product.We also became obligated to make payments to Penn aggregating up to$3.2 million based on achieving specified development and regulatory approval milestones,including$2.3 millio

262、n upon approval of an NDA,and up to$5.0 million based on achieving specified annual sales milestones with respect to each licensed product,and to pay low single-digit 2025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm31/274162025/5/19 10:0010-Khttp

263、s:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm32/274 Table of Contentsroyalties to Penn based on net sales of each licensed product by us and our affiliates and sublicensees and specified minimum quarterly royalty thresholds.In addition,we are obligated to pay Penn a

264、 specified portion of income we receive from sublicensees.In April 2023,the Company paid$2.3 million for the achievement of a regulatory milestone as a result of the FDA approval of SYFOVRE in February 2023.In 2023,the Company incurred$5.0 million as a result of the achievement of sales milestones f

265、or SYFOVRE of which the Company paid$2.0 million in October 2023 and the remaining$3.0 million in January 2024.As of December 31,2024 and 2023,respectively,we have incurred royalty expense of$19.8 million and$8.9 million as a result of sales of SYFOVREOur royalty obligation with respect to each lice

266、nsed product in a country will extend until the later of the expiration of the last-to-expire patent licensed from Penn covering the licensed product in the country or the tenth anniversary of the first commercial sale of the licensed product in the country.We also are obligated to use commercially

267、reasonable efforts to develop licensed products in accordance with a development plan,which we will update annually,and a development milestone timetable specified in the agreement and to use commercially reasonable efforts to commercialize licensed products.Penn has the right to terminate the agree

268、ment if we breach the agreement and fail to cure our breach within specified cure periods or in the event of specified bankruptcy,insolvency and liquidation events.We have the right to terminate the agreement for our convenience at any time on 60 days notice to Penn.CompetitionThe biotechnology and

269、pharmaceutical industries are characterized by rapidly advancing technologies,intense competition and a strong emphasis on proprietary products.While we believe that our technologies,knowledge,experience and scientific resources provide us with competitive advantages,we face potential competition fr

270、om many different sources,including major pharmaceutical,specialty pharmaceutical and biotechnology companies,academic institutions and governmental agencies and public and private research institutions.Any product candidates that we successfully develop and commercialize will compete with existing

271、therapies and new therapies that may become available in the future.There are a number of currently marketed products and product candidates in preclinical research and clinical development by third parties to treat the various diseases that we are targeting.In general,these products and product can

272、didates can be categorized based on their proposed mechanisms of action.The mechanisms of action for these product candidates include inflammation suppression by agents such as complement inhibitors and corticosteroids,as well as immune modulators,visual cycle modulators,anti-amyloid agents,antioxid

273、ants,neuroprotectants,cell and gene therapies and vascular and interstitial tissue remodeling agents.Our approved product competes,and if our product candidates are approved for the indications for which we are currently undertaking or planning clinical trials,they will compete,with the products and

274、 product candidates discussed below.GA.In August 2023,Astellas Pharma Inc.received FDA approval for avacincaptad pegol,a C5 inhibitor,for the treatment of GA.We are aware of other companies that are actively developing product candidates for the treatment of GA,including the following product candid

275、ates that are in clinical development:ANX007,a C1q inhibitor being developed by Annexon Biosciences,Inc.in Phase 3 clinical trials;pozelimab,an anti-C5 antibody developed by Regeneron Pharmaceuticals Inc.in combination with cemdisiran,an RNAi therapeutic targeting C5 developed by Alnylam Pharmaceuti

276、cals,Inc.,in Phase 3 clinical trials;JNJ1887,an intravitreal gene therapy targeting CD59 being developed by The Janssen Pharmaceutical Companies of Johnson&Johnson in Phase 2 clinical trials;AVD104,a glycan-coated nanoparticle targeting macrophage and complement factor H,being developed by Aviceda T

277、herapeutics,Inc.in Phase 2 clinical trials;BI 771716,a C3 antibody fragment being developed by Boehringer Ingelheim Pharmaceuticals,Inc.in Phase 2 clinical trials;and other product candidates that do not target the complement system that are either in a single Phase 3 or in Phase 2 clinical trials,i

278、ncluding but not limited to therapies being developed by Stealth BioTherapeutics,Inc.,Belite Bio,Inc.,Lineage Cell Therapeutics,Inc.(in collaboration with Roche/Genentech),Boehringer Ingelheim Pharmaceuticals,Inc.,ONL Therapeutics,Inc.,and Ocugen Inc.Novartis has initiated a Phase 2 trial of orally

279、administered iptacopan,a factor B inhibitor,in patients with early or intermediate AMD.PNH.The principal competitors for EMPAVELI,and possibly other indications in our hematology and nephrology programs are eculizumab(marketed as Soliris)and ravulizumab(marketed as Ultomiris),which are C5 inhibitors

280、 marketed by AstraZeneca.The FDA approved danicopan as an add-on treatment to eculizumab and ravulizumab in April 2024.In December 2023,the FDA approved iptacopan,which is marketed by Novartis AG,or Novartis,for the treatment of adults with PNH.Iptacopan is an oral,Factor B inhibitor of the alternat

281、ive complement pathway.The FDA approved crovalimab,an anti-C5 antibody developed by Roche and Chugai Pharmaceutical Co,in the United States in June 2024.2025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm33/274172025/5/19 10:0010-Khttps:/www.sec.gov

282、/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm34/274 Table of ContentsWe are aware of several other companies that are actively developing product candidates using complement inhibition for the treatment of PNH in late-stage clinical development,including pozelimab+cemdisiran,curr

283、ently in Phase 3 clinical trials,and as other products in early stages of development.Amgen Inc.developed ABP959,a biosimilar for eculizumab,which has been approved in the European Union,as has Epysgli from Samsung Bioepis.Other non-U.S.entities are developing biosimilars for eculizumab in local mar

284、kets.The approval of a biosimilar or a generic to one of our products or a product with which we compete could have a material impact on our business because it may be significantly less costly to bring to market and may be priced significantly lower than our products or the other products with whic

285、h we compete.C3G.There are currently no approved drugs for C3 glomerulopathy.There are treatments in clinical development,including iptacopan being developed by Novartis,which is currently under review with the FDA;OMS906,a MASP-3 inhibitor monoclonal antibody being developed by Omeros Corp.,in a Ph

286、ase 2 trial;KP104,an anti C5-Factor H bifunctional protein being developed by Kira Pharmaceuticals,currently in a Phase 2 renal basket trial;and ARO-C3,an RNAi to reduce C3 production developed by Arrowhead Pharmaceuticals,currently in a Phase 1/2 renal basket trial.IC-MPGN.There are currently no ap

287、proved drugs for IC-MPGN.There are potential treatments in clinical development,including iptacopan being developed by Novartis,currently in Phase 3 clinical trials,and OMS906,a MASP-3 inhibitor monoclonal antibody being developed by Omeros Corp.,in a Phase 2 clinical trial.HSCT-TMA.Currently there

288、are three treatments in late-stage clinical development:ravulizumab,developed by AstraZeneca,nomacopan being developed by Akari,and narsoplimab,being developed by Omeros,are all in Phase 3 trials.Sales and MarketingWe retain U.S.commercialization rights for systemic pegcetacoplan and worldwide comme

289、rcialization rights for intravitreal pegcetacoplan.We are conducting commercialization efforts for EMPAVELI and SYFOVRE in the United States and plan to conduct commercial development for EMPAVELI in the United States if it is approved in other indications.Sobi has global co-development and exclusiv

290、e ex-U.S.commercialization rights for Aspaveli.We plan to conduct commercial development for intravitreal pegcetacoplan in select countries outside of the U.S.We have developed focused capabilities to commercialize development programs for certain indications where we believe that the medical specia

291、lists for the indications are sufficiently concentrated to allow us to effectively promote the product with a targeted sales team.For EMPAVELI and SYFOVRE we have defined our marketing,disease education,patient support and distribution strategies,identified primary and secondary payers representing

292、a significant percentage of patients with PNH and GA,have built our field market access team and our sales team.For programs involving compounds other than pegcetacoplan,we plan to develop our own capabilities to commercialize our products worldwide.We may seek to enter into collaborations that we b

293、elieve may contribute to our ability to advance development and ultimately commercialize our product candidates.We may also seek to enter into collaborations where we believe that realizing the full commercial value of our development programs will require access to broader geographic markets or the

294、 pursuit of broader patient populations or indications.ManufacturingWe do not currently own or operate manufacturing facilities for the production of clinical or commercial quantities of our product candidates.Although we rely on third-party contract manufacturers to produce our products,we have rec

295、ruited personnel with experience to manage the third-party contract manufacturers producing our products,product candidates and other product candidates that we may develop in the future.The process for manufacturing our products and product candidates consists of chemical synthesis,purification usi

296、ng liquid chromatography,and freeze drying into solid form.The drug substance is then dissolved in solution and aliquoted into small vials for individual dosing.Each of these steps involves a relatively routine chemical engineering process.We believe the costs associated with manufacturing drug prod

297、uct for our products and product candidates is comparable to the current manufacturing costs for other similarly sized peptide-based components.We have engaged a limited number of third-party manufacturers to provide all of our raw materials,drug substances and finished products for use in clinical

298、trials and commercial sale.We have entered into a commercial supply agreement with Bachem Americas,Inc.,or Bachem,agreeing to purchase a significant portion of our requirements for the pegcetacoplan drug substance,and a commercial supply agreement with NOF Corporation,or NOF,to purchase activated po

299、lyethylene glycol derivative,or PEG,which is 2025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm35/274182025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm36/274 19Table of Contentsa component of pe

300、gcetacoplan.We also have a separate supply agreement for the manufacture of the drug product for each of EMPAVELI and SYFOVRE.Our raw materials,drug substances and finished products have been produced under master service contracts and specific work orders from these manufacturers pursuant to agreem

301、ents that include specific supply timelines and volume and quality expectations.We choose the third-party manufacturers of the raw materials and drug substances based on the volume required and the regulatory requirements at the relevant stage of development.All lots of drug substances and finished

302、products used in clinical trials and for commercial use are manufactured under current good manufacturing practices.Separate third-party manufacturers are for fill and finish services and for labeling and shipment of the final drug products to the clinical trial sites and for commercial use.We belie

303、ve that our manufacturing arrangements are sufficient to supply pegcetacoplan at the scale and with the quality required for our ongoing and planned clinical trials,our commercialization efforts and our collaboration with Sobi.We continuously review our supply chain risk,including with respect to ou

304、r manufacturing footprint,and update and implement risk mitigation plans.Commercial Supply Agreement with BachemIn December 2020,we entered into a commercial supply agreement,or the Bachem Agreement,with Bachem to supply the drug substance for the finished dosage form of systemic pegcetacoplan and i

305、ntravitreal pegcetacoplan.Under the Bachem Agreement,we agreed to purchase from Bachem a significant portion of our requirements for the drug substance during the term of the agreement,and to purchase all of our requirements for drug substance for commercial sale,subject to certain exceptions,for a

306、period after the effective date of the agreement.The initial term of the Bachem Agreement continues until December 31,2025.Thereafter,unless terminated earlier,the Bachem Agreement will automatically renew for an additional two-year term.We may terminate the Bachem Agreement in the event any require

307、d license,permit or certificate of Bachem related to the manufacturing facility or the drug substance is not approved or issued(or is withdrawn)by the relevant governmental authority.Additionally,each party may terminate the Bachem Agreement upon an uncured material breach of the Bachem Agreement by

308、 the other party or upon the other partys insolvency or bankruptcy.The Bachem Agreement also includes customary provisions relating to,among others,delivery,inspection procedures,warranties,quality,storage,handling and transport,intellectual property,confidentiality and indemnification.Amended and R

309、estated Commercial Supply Agreement with NOFIn March 2021,we entered into an amended and restated commercial supply agreement,or the NOF Agreement,with NOF to purchase PEG,which is a component of each of systemic pegcetacoplan and intravitreal pegcetacoplan.Under the NOF Agreement,NOFs affiliate,NOF

310、 America Corporation,supplies PEG to us on a non-exclusive basis.NOF agreed to manufacture and deliver PEG to us in accordance with purchase orders issued by us pursuant to the NOF Agreement.We may purchase PEG or any polyethylene glycol derivative from other third-party suppliers.Notwithstanding th

311、e foregoing,we agreed to purchase at least a minimum purchase obligation,which will be based on our 24-month rolling forecasts as set forth in the NOF Agreement.In the event we fail to meet the minimum purchase obligation,we will pay NOF the amount equal to a specified percentage of the remaining qu

312、antity of the minimum purchase obligation for the relevant time period,in addition to any payments due for all outstanding firm orders.We may eliminate the minimum purchase obligation on or before October 1 of the preceding calendar year by paying a specified percentage of the then-applicable supply

313、 price of the remaining minimum purchase obligation for the remainder of the term.In September 2024,we terminated the minimum purchase obligation with NOF for 2025.As a result of this termination,we incurred an expense of$6.4 million,which is included in Cost of Sales on the consolidated statements

314、of operations and comprehensive loss income.As the amount is not due until January 2026,it is included in Other Liabilities on the consolidated balance sheet as of December 31,2024.Unless earlier terminated,the term of the NOF Agreement continues through December 31,2025.Either party may terminate t

315、he NOF Agreement upon an uncured material breach by the other party,upon the other partys insolvency or bankruptcy or for convenience upon twenty-four(24)months prior written notice.We may terminate the NOF Agreement for safety,efficacy or regulatory issues.If the NOF Agreement is terminated by NOF

316、for convenience or by us for NOFs breach,we have no minimum purchase obligations and any agreement to buy out such minimum purchase obligations shall be of no force or effect.The NOF Agreement also includes customary provisions relating to,among others,delivery,inspection procedures,warranties,quali

317、ty,storage,handling and transport,intellectual property,confidentiality and indemnification.2025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm37/2742025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.h

318、tm38/274 20Table of ContentsGovernment Regulation and Product Approvals Government authorities in the United States,at the federal,state and local level,and in other countries and jurisdictions,including the European Union,extensively regulate,among other things,the research,development,testing,manu

319、facture,quality control,approval,packaging,storage,recordkeeping,labeling,advertising,promotion,distribution,marketing,pricing,reimbursement,post-approval monitoring and reporting,and import and export of pharmaceutical products.The processes for obtaining regulatory approvals in the United States a

320、nd in foreign countries and jurisdictions,along with subsequent compliance with applicable statutes and regulations and other regulatory authorities,require the expenditure of substantial time and financial resources.The regulatory requirements applicable to drug product development,approval and mar

321、keting are subject to change,and regulations and administrative guidance often are revised or reinterpreted by the agencies in ways that may have a significant impact on our business.Review,Approval and Regulation of Drug Products in the United StatesIn the United States,the FDA regulates drugs unde

322、r the Federal Food,Drug,and Cosmetic Act,or FDCA,and implementing regulations.The failure to comply with applicable requirements under the FDCA and other applicable laws at any time during the product development process,approval process or after approval may subject a sponsor to a variety of admini

323、strative or judicial sanctions,including refusal by the FDA to approve pending applications,withdrawal of an approval,imposition of a clinical hold,issuance of warning letters and other types of letters,product recalls,product seizures,total or partial suspension of production or distribution,injunc

324、tions,fines,refusals of government contracts,restitution,disgorgement of profits,or civil or criminal investigations and penalties brought by the FDA and the Department of Justice or other governmental entities,including state agencies.The FDA must approve our product candidates for therapeutic indi

325、cations before they may be marketed in the United States.A company,institution or organization which takes responsibility for the initiation and management of a clinical development program for such products is referred to as a sponsor.A sponsor seeking approval to market and distribute a new drug o

326、r biologic product in the United States must typically secure the following:completion of preclinical laboratory tests,animal studies and formulation studies in compliance with the FDAs good laboratory practice,or GLP,regulations;design of a clinical protocol and submission to the FDA of an investig

327、ational new drug application,or IND,which must take effect before human clinical trials may begin;approval by an independent institutional review board,or IRB,representing each clinical site before each clinical trial may be initiated;performance of adequate and well-controlled human clinical trials

328、 in accordance with good clinical practices,or GCP,to establish the safety and efficacy of the proposed drug product for each indication;preparation and submission to the FDA of an NDA for a new drug product,or a sNDA for a change to a previously approved drug product,which includes not only the res

329、ults of the clinical trials,but also,detailed information on the chemistry,manufacture and quality controls for the product candidate and proposed labeling for one or more proposed indication(s);review of the product by an FDA advisory committee,where appropriate or if applicable;satisfactory comple

330、tion of one or more FDA inspections of the manufacturing facility or facilities at which the product,or components thereof,are produced to assess compliance with current Good Manufacturing Practices,or cGMP,requirements and to assure that the facilities,methods and controls are adequate to preserve

331、the products identity,strength,quality and purity;satisfactory 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;securing FDA approval

332、of the NDA or sNDA authorizing marketing of the drug product for particular indications in the United States;and compliance with any post-approval requirements,including Risk Evaluation and Mitigation Strategies,or REMS,and post-approval studies required by the FDA.2025/5/19 10:0010-Khttps:/www.sec.

333、gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm39/2742025/5/19 10:0010-Khttps:/www.sec.gov/Archives/edgar/data/1492422/000095017025029507/apls-20241231.htm40/274 Table of ContentsPreclinical Studies Before a sponsor begins testing a product candidate with potential therapeutic value in humans,the product candidate enters the preclinical testing stage.Preclinical studies includ