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1、Table of ContentsUNITED STATESSECURITIES AND EXCHANGE COMMISSIONWashington,D.C.20549FORM 10-K(Mark One)ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1934For the fiscal year ended December 31,2024ORTRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXC
2、HANGE ACT OF 1934 FOR THE TRANSITION PERIODFROM TOCommission File Number:001-40544Aerovate Therapeutics,Inc.(Exact name of Registrant as specified in its Charter)Delaware83-1377888(State or other jurisdiction of(I.R.S.Employerincorporation or organization)Identification No.)930 Winter Street,Suite M
3、-500Waltham,MA 0245102451(Address of principal executive offices)(Zip Code)Registrants telephone number,including area code:(617)443-2400Securities registered pursuant to Section 12(b)of the Act:Title of each class Trading Symbol(s)Name of each exchange on which registeredCommon stock,par value$0.00
4、01 per shareAVTEThe Nasdaq Global MarketSecurities registered pursuant to Section 12(g)of the Act:NoneIndicate by check mark if the Registrant is a well-known seasoned issuer,as defined in Rule 405 of the Securities Act.YES NO Indicate by check mark if the Registrant is not required to file reports
5、pursuant 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 preceding12 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 NOIndicate 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 preced
7、ing 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,smaller reporting company,or an emerging growthcompany.See the definitions of
8、“large accelerated filer,”“accelerated filer,”“smaller reporting company,”and“emerging growth company”in Rule 12b-2 of the Exchange Act.Large accelerated filerAccelerated filerNon-accelerated filerSmaller reporting companyEmerging growth companyIf an emerging growth company,indicate by check mark if
9、 the registrant has elected not to use the extended transition period for complying with any new or revised financialaccounting standards provided pursuant to Section 13(a)of the Exchange Act.Indicate by check mark whether the registrant has filed a report on and attestation to its managements asses
10、sment of the effectiveness of its internal control over financialreporting under Section 404(b)of the Sarbanes-Oxley Act(15 U.S.C.7262(b)by the registered public accounting firm that prepared or issued its audit report.If securities are registered pursuant to Section 12(b)of the Act,indicate by chec
11、k mark whether the financial statements of the registrant included in the filing reflect thecorrection of an error to previously issued financial statements.Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensatio
12、n received by any of theregistrants executive officers during the relevant recovery period pursuant to 240.10D-1(b).Indicate by check mark whether the Registrant is a shell company(as defined in Rule 12b-2 of the Exchange Act).YES NO As of June 30,2024(the last business day of the Registrants most r
13、ecently completed second quarter)the aggregate market value of the Registrants common stock held by non-affiliates of the Registrant was$23.0 million,based on the closing price of the Registrants common stock as reported on the Nasdaq Global Market of$1.66 per share.Indetermining the market value of
14、 non-affiliate common stock,shares of the Registrants common stock beneficially owned by officers,directors and affiliates have been excluded.This determination of affiliate status is not necessarily a conclusive determination for other purposes.The number of shares of Registrants Common Stock outst
15、anding as of March 24,2025 was 28,985,019.DOCUMENTS INCORPORATED BY REFERENCEThe registrant intends to file a definitive proxy statement pursuant to Regulation 14A relating to the 2025 Annual Meeting of Stockholders within 120 days of the end of theregistrants fiscal year ended December 31,2024.Port
16、ions of such definitive proxy statement are incorporated by reference into Part III of this Annual Report on Form 10-K tothe extent stated herein.Table of Contents2Table of ContentsPagePART I6Item 1.Business6Item 1A.Risk Factors33Item 1B.Unresolved Staff Comments65Item 1C.Cybersecurity66Item 2.Prope
17、rties66Item 3.Legal Proceedings66Item 4.Mine Safety Disclosures67PART II67Item 5.Market for Registrants Common Equity,Related Stockholder Matters and Issuer Purchases of EquitySecurities67Item 6.Reserved68Item 7.Managements Discussion and Analysis of Financial Condition and Results of Operations68It
18、em 7A.Quantitative and Qualitative Disclosures About Market Risk76Item 8.Financial Statements and Supplementary Data77Item 9.Changes in and Disagreements With Accountants on Accounting and Financial Disclosure77Item 9A.Controls and Procedures77Item 9B.Other Information78Item 9C.Disclosure Regarding
19、Foreign Jurisdictions that Prevent Inspections78PART III78Item 10.Directors,Executive Officers and Corporate Governance78Item 11.Executive Compensation79Item 12.Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters79Item 13.Certain Relationships and Related T
20、ransactions,and Director Independence79Item 14.Principal Accounting Fees and Services79PART IV79Item 15.Exhibits,Financial Statement Schedules79Item 16.Form 10-K Summary79Signatures82Table of Contents3SUMMARY OF THE MATERIAL AND OTHER RISKS ASSOCIATED WITH OUR BUSINESSOur business is subject to nume
21、rous material and other risks and uncertainties that you should be aware of in evaluating ourbusiness.These risks include,but are not limited to,the following:We may not be successful in consummating the Merger.If we are successful in completing the Merger,we may be exposed to other operational and
22、financial risks.If the Merger is not completed,our board of directors may pursue a dissolution and liquidation.In such event,theamount of cash available for distribution to our stockholders will depend heavily on the timing of such liquidationand the amount of cash that will need to be reserved for
23、commitments and contingent liabilities.Failure to complete the Merger may result in either Jade or us paying a termination fee to the other party andcould harm our common stock price and the future business and operations of each company.Some of Jades and our executive officers and directors have in
24、terests in the Merger that are different from yours.We are a biopharmaceutical company with a limited operating history.We have incurred significant operating losses since our inception and anticipate that we will continue to incurlosses for the foreseeable future.We may never achieve or maintain pr
25、ofitability.We have no products approved for commercial sale and have not generated any revenue from product sales.The results of earlier studies and trials may not be predictive of future trial results.We have six issued U.S.patents and many pending patent applications with respect to AV-101,howeve
26、r,we havebegun the process of abandoning our patent estate and we are no longer prosecuting our patent applications.Further,we can provide no assurance that any of our future patent applications will result in issued patents.If wecannot protect our patent rights or our other proprietary rights,other
27、s may develop products similar or identical toours,and we may not be able to compete effectively in our market or successfully commercialize any productcandidates we may develop.We may be unable to obtain regulatory approval under applicable regulatory requirements.The denial or delay ofany such app
28、roval would delay commercialization of any product candidates and adversely impact our potentialto generate revenue,our business and our results of operations.Unfavorable global economic or political conditions could adversely affect our business,financial condition orresults of operations.The mater
29、ial and other risks summarized above should be read together with the text of the full risk factors below and inthe other information set forth in this Annual Report on Form 10-K,including our consolidated financial statements and therelated notes,as well as in other documents that we file with the
30、U.S.Securities and Exchange Commission,or the SEC.Ifany such material and other risks and uncertainties actually occur,our business,prospects,financial condition and results ofoperations could be materially and adversely affected.The risks summarized above or described in full under Item 1A ofthis A
31、nnual Report on Form 10-K are not the only risks that we face.Additional risks and uncertainties not currentlyknown to us,or that we currently deem to be immaterial may also materially adversely affect our business,prospects,financial condition and results of operations.Table of Contents4SPECIAL NOT
32、E REGARDING FORWARD-LOOKING STATEMENTSThis Annual Report on Form 10-K contains express or implied forward-looking statements that are based on ourmanagements belief and assumptions and on information currently available to our management.Although we believe thatthe expectations reflected in these fo
33、rward-looking statements are reasonable,these statements relate to future events or ourfuture operational or financial performance,and involve known and unknown risks,uncertainties and other factors thatmay cause our actual results,performance or achievements to be materially different from any futu
34、re results,performanceor achievements expressed or implied by these forward-looking statements.Forward-looking statements contained in thisAnnual Report on Form 10-K include,but are not limited to,statements about:anticipated expenses and cost savings in connection with our discontinuation of develo
35、pment of AV-101;the proposed merger with Jade,and related transactions;estimates of our future expenses,revenues,capital requirements and our needs for additional financing;our expectations for clinical and regulatory development plans;our expectations regarding our ability to obtain and maintain in
36、tellectual property protection for any productcandidates we may develop;our ability to identify products,product candidates or technologies with significant commercial potential that areconsistent with our commercial objectives;the scope of protection we are able to establish and maintain for intell
37、ectual property rights covering our productcandidates,including the projected terms of patent protection;potential regulatory developments in the United States and foreign countries;developments relating to our competitors and our industry,including the impact of government laws andregulations;our a
38、bility to retain key management personnel in order to operate our business following announcement of ourworkforce reduction plan and the proposed merger with Jade and related transactions;our ability to obtain additional funding for our operations,if needed,should we decide to pursue development ofo
39、ther product candidates;and other risks and uncertainties,including those listed under the section titled“Risk Factors.”In some cases,you can identify forward-looking statements by terminology such as“may,”“should,”“expects,”“intends,”“plans,”“anticipates,”“believes,”“estimates,”“predicts,”“potentia
40、l,”“continue”or the negative of these terms or othercomparable terminology.These statements are only predictions.You should not place undue reliance on forward-lookingstatements because they involve known and unknown risks,uncertainties,and other factors,which are,in some cases,beyond our control an
41、d which could materially affect results.Factors that may cause actual results to differ materially fromcurrent expectations include,among other things,those listed above under“Summary of the Material Risks Associatedwith Our Business”and under the section titled“Risk Factors”and elsewhere in this An
42、nual Report on Form 10-K.If oneor more of these risks or uncertainties occur,or if our underlying assumptions prove to be incorrect,actual events or resultsmay vary significantly from those implied or projected by the forward-looking statements.No forward-looking statement isa guarantee of future pe
43、rformance.You should read this Annual Report on Form 10-K and the documents that we referencein this Annual Report on Form 10-K and have filed with the SEC as exhibits hereto completely and with the understandingthat our actual future results may be materially different from any future results expre
44、ssed or implied by these forward-looking statements.Table of Contents5The forward-looking statements in this Annual Report on Form 10-K represent our views as of the date of this AnnualReport on Form 10-K.We anticipate that subsequent events and developments will cause our views to change.However,wh
45、ile we may elect to update these forward-looking statements at some point in the future,we have no current intention ofdoing so except to the extent required by applicable law.You should therefore not rely on these forward-looking statementsas representing our views as of any date subsequent to the
46、date of this Annual Report on Form 10-K.This Annual Report on Form 10-K also contains estimates,projections and other information concerning our industry,ourbusiness and the markets for our product candidates.Information that is based on estimates,forecasts,projections,marketresearch or similar meth
47、odologies is inherently subject to uncertainties and actual events or circumstances may differmaterially from events and circumstances that are assumed in this information.Unless otherwise expressly stated,weobtained this industry,business,market,and other data from our own internal estimates and re
48、search as well as fromreports,research surveys,studies,and similar data prepared by market research firms and other third parties,industry,medical and general publications,government data and similar sources.While we are not aware of any misstatementsregarding any third-party information presented i
49、n this Annual Report on Form 10-K,their estimates,in particular as theyrelate to projections,involve numerous assumptions,are subject to risks and uncertainties and are subject to change basedon various factors,including those discussed under the section titled“Risk Factors”and elsewhere in this Ann
50、ual Reporton Form 10-K.Table of Contents6PART IItem 1.Business.Unless the context requires otherwise,references in this Annual Report on Form 10-K to“Aerovate”,“we”,“us”and“our”refer to Aerovate Therapeutics,Inc.OverviewWe are a biopharmaceutical company.Our initial focus was on advancing AV 101,our
51、 dry powder inhaled formulation ofimatinib for the treatment of pulmonary arterial hypertension,or PAH,a devastating disease impacting approximately70,000 people in the United States and Europe.On June 17,2024,we announced topline results from the Phase 2b portionof our Phase 2b/Phase 3 Inhaled Imat
52、inib Pulmonary Arterial Hypertension Clinical Trial of AV-101,or IMPAHCT.Topline data showed that,while AV-101 was generally well tolerated across all dose groups,the study did not meet itsprimary endpoint for improvement in pulmonary vascular resistance compared to placebo for any of the studied do
53、ses orshow meaningful improvements in the secondary endpoint of change in six minute walk distance.We also reviewed datafrom several additional secondary endpoints of the Phase 2b portion of IMPAHCT,which also failed to show meaningfulimprovements.Based upon these results and in agreement with the i
54、ndependent study advisory committee,we haltedenrollment and shut down the Phase 3 portion of IMPAHCT as well as the long-term extension study.AV-101 for thetreatment of PAH was our only product candidate in development.At this time,we do not intend to resume development ofAV-101 or any other product
55、 candidates.In July 2024,we announced the decision to conduct a comprehensive review ofstrategic alternatives focused on maximizing shareholder value.We also engaged Wedbush Securities Inc.,or WedbushPacGrow,as our exclusive strategic financial advisor to assist in the process of exploring strategic
56、 alternatives.In June 2024,following our decision to halt further development of AV-101,we announced our plan to terminate nearly allof our workforce in the coming months,or the Workforce Reduction Plan.As of December 31,2024,47 individuals,orapproximately 92%of our workforce,have been terminated.Th
57、e affected individuals have been and will be providedseverance benefits,including cash severance payments.Each affected individuals eligibility for severance benefits iscontingent upon entering into a separation agreement,which includes a general release of claims against our company.Inconnection wi
58、th the Workforce Reduction Plan,we incurred costs(in consideration of releases)of approximately$6.7million,which are primarily one-time severance benefits.On October 30,2024,we entered into an Agreement and Plan of Merger,or the Merger Agreement,by and among us,Caribbean Merger Sub I,Inc.,a Delaware
59、 corporation and our wholly owned subsidiary,or Merger Sub I,CaribbeanMerger Sub II,LLC,a Delaware limited liability company and our wholly owned subsidiary,or Merger Sub II and togetherwith Merger Sub I,Merger Subs,and Jade Biosciences,Inc.,a Delaware corporation,or Jade,pursuant to which,andsubjec
60、t to the satisfaction or waiver of the conditions set forth in the Merger Agreement,among other things,Merger Sub Iwill merge with and into Jade,with Jade surviving the merger as the surviving corporation,or the First Merger,and as partof the same overall transaction,Jade will merge with and into Me
61、rger Sub II,with Merger Sub II continuing as our whollyowned subsidiary and the surviving corporation of the merger,or the Second Merger and together with the First Merger,theMerger.The Merger is intended to qualify for federal income tax purposes as a tax-free reorganization under the provisionsof
62、Section 368(a)of the Internal Revenue Code of 1986,as amended,or the Code.In addition,in connection with the closing of the Merger,or the Closing,we expect to declare a cash dividend to our pre-Merger stockholders of approximately$65.0 million in the aggregate,or the Cash Dividend,provided such amou
63、nt issubject to adjustment as set forth in the Merger Agreement.Subject to the terms and conditions of the Merger Agreement,at the effective time of the Merger,or the Effective Time,(a)each then-outstanding share of Jades common stock,par value$0.0001 per share,or Jade Common Stock,will beconverted
64、into the right to receive a number of shares of our common stock,par value$0.0001 per share,or AerovateCommon Stock,based on a ratio calculated in accordance with the Merger Agreement,or the Exchange Ratio,providedthat any unvested restricted shares of Jade Common Stock will be subject to the same t
65、erms and conditions(including,without limitation,vesting and repurchase provisions)that are otherwise applicable to such unvested shares as ofimmediately prior to the Effective Time,(b)each then-outstanding share of Jades preferred stock,par value$0.0001 pershare,or Jade Preferred Stock,will be conv
66、erted into the right to receive a number of shares of our newly authorizedTable of Contents7convertible preferred stock,par value$0.0001 per share,equal to(x)the Exchange Ratio divided by(y)1,000,(c)eachthen-outstanding option to purchase Jade Common Stock will be assumed by us,subject to adjustment
67、 as set forth in theMerger Agreement and(d)each then-outstanding warrant to purchase shares of Jade Common Stock or Jade PreferredStock will be assumed by us,subject to adjust as set forth in the Merger Agreement.We and Jade have each agreed to customary representations,warranties and covenants in t
68、he Merger Agreement,including,among others,covenants relating to(1)obtaining the requisite approval of our respective stockholders,(2)non-solicitationof alternative acquisition proposals and(3)the conduct of our respective businesses during the period between the date ofsigning the Merger Agreement
69、and the Closing.On October 30,2024,Jade entered into a Securities Purchase Agreement,or the Purchase Agreement,with certain existingJade stockholders and new investors,or the Investors.Pursuant to the Purchase Agreement,and subject to the terms andconditions thereof,Jade agreed to sell,and the Inves
70、tors agreed to purchase,immediately prior to the consummation of theMerger,shares of Jade Common Stock and pre-funded warrants for an aggregate purchase price of approximately$300.0million,or the Concurrent Investment,which reflects the conversion of the previously issued$95 million of convertibleno
71、tes.The consummation of the Concurrent Investment is conditioned on the satisfaction or waiver of the conditions setforth in the Merger Agreement and in the Purchase Agreement.Shares of Jade Common Stock and pre-funded warrantsissued pursuant to this financing transaction will be converted into shar
72、es of Aerovate Common Stock and pre-fundedwarrants to acquire shares of Aerovate Common Stock,in accordance with the Exchange Ratio and the Merger Agreement.Consummation of the Merger is subject to certain closing conditions,including,among other things,(1)requisite approvalby our stockholders,(2)ap
73、proval by the requisite Jade stockholders of the adoption and approval of the Merger Agreementand the transactions contemplated thereby,(3)Nasdaqs approval of the listing of the shares of Aerovate Common Stock tobe issued in connection with the Merger,and(4)an executed Purchase Agreement for the Con
74、current Investment in fullforce and effect evidencing cash proceeds of not less than$80.0 million to be received by the combined companyimmediately prior to or following the Closing.The Merger Agreement contains certain termination rights of each of us and Jade.Upon termination of the MergerAgreemen
75、t under specified circumstances,we may be required to pay Jade a termination fee of$2,340,000,and in certainother circumstances,Jade may be required to pay us a termination fee of$5,250,000.At the Effective Time,our board of directors is expected to consist of six members,all of whom will be designa
76、ted by Jade.Concurrently and in connection with the execution of the Merger Agreement,(i)certain stockholders of Jade(solely intheir respective capacities as Jade stockholders)holding approximately 99%of the outstanding shares of Jade capital stockhave entered into support agreements with us and Jad
77、e to vote all of their shares of Jade capital stock in favor of theadoption and approval of the Merger Agreement and the transactions contemplated thereby and(ii)certain of ourstockholders holding approximately 38.1%of the outstanding shares of Aerovate Common Stock have entered into supportagreemen
78、ts with us and Jade to vote all of their shares of Aerovate Common Stock in favor of,among other things,theadoption and approval of the Merger Agreement and the transactions contemplated thereby.Our Strategy to DatePAH is an orphan disease with unmet medical need and is characterized by high pressur
79、e in the vessels transporting bloodfrom the right side of the heart to the lungs.This high pressure is caused by abnormal cellular hyperproliferation andresistance to apoptosis,driven by improper signaling in cells of the distal pulmonary arteries,which over time results innarrowing of the pulmonary
80、 vessels and forces the heart to work harder to pump blood through the lungs.The severe bloodflow restriction and strain on the heart becomes increasingly severe over time and ultimately leads to heart failure that isoften fatal.We estimate there are between 30,000 to 40,000 patients treated with ap
81、proved PAH therapies in the U.S.alone,many of whom are on two or more approved PAH therapies.It is estimated that the combined global sales for PAHproducts in 2023 was$6.2 billion.Despite the availability of multiple approved therapies,PAH has a five-year survival ratefor newly diagnosed and prevale
82、nt patients between 61%and 65%.None of the approved therapies directly addressTable of Contents8the abnormal cellular hyperproliferation of the pulmonary vasculature that causes the increased resistance to blood flow.We believe that novel treatments that primarily address abnormal cellular hyperprol
83、iferation may provide therapeuticbenefit to PAH patients and lead to improved quality of life.Our focus on developing AV-101 had been driven by historical results from the Phase 3 IMPRES clinical trial of oralimatinib for the treatment of PAH patients.Oral imatinib is a well-characterized targeted k
84、inase inhibitor and approvedoncology treatment,but clinical trials had also supported its potential for the treatment of PAH.On June 17,2024,we announced topline results from the Phase 2b portion of the Phase 2b/Phase 3 IMPAHCT.Resultsshowed that,while AV-101 was well tolerated across all dose group
85、s,the study did not meet its primary endpoint forimprovement in pulmonary vascular resistance,or PVR,compared to placebo for any of the studied doses or showmeaningful improvements in the secondary endpoint of change in 6MWD.Primary Endpoint ITT analysis of PVR(dynes*sec/cm5)DoseLeast-squares mean d
86、ifference ascompared with placebo(95%CI)dP value10mg BID(N=50)42.8(-80.57 to 166.09)0.496835mg BID(N=49)-5.5(-129.16 to 118.18)0.930670mg BID(N=51)-57.0(-181.14 to 67.20)0.3685Secondary Endpoint ITT analysis of 6MWD(meters)DoseLeast-squares mean difference as compared withplacebo(95%CI)d10mg BID(N=5
87、0)-11.7(-34.75 to 11.26)35mg BID(N=49)-4.2(-27.74 to 19.37)70mg BID(N=51)+1.3(-22.09 to 24.60)We also reviewed data from several additional secondary endpoints of the Phase 2b portion of IMPAHCT,which also failedto show meaningful improvements.Based upon these results,we,in agreement with the indepe
88、ndent study advisorycommittee,halted enrollment and shut down the Phase 3 portion of IMPAHCT as well as the long-term extension study.We plan to release full data from the Phase 2b portion of IMPAHCT at a later date,the timing of which is to be determined.Manufacturing and SupplyWe use third-party c
89、ontract manufacturers for the production of our combination product,AV-101.Our activepharmaceutical ingredient,or API,is generic and can be purchased from multiple commercial vendors in compliance withthe U.S.Food and Drug Administrations,or the FDAs,current Good Manufacturing Practice,or current GM
90、P,regulationsand European Pharmacopoeia,or EP,standards.To be used in our inhaled product,the API requires an additionalmanufacturing step,which is completed at our contract manufacturing organization that complies with the FDAs currentGMP regulations.The API is converted into drug product for aeros
91、ol use by one of our two contract fill/finish providers inthe United States.As AV-101 is a drug-device combination product,we have contracted with a third-party to manufacturethe single-dose inhaler device that we use for delivering inhaled AV-101 to patients in our Phase 2b/Phase 3 clinical trial.R
92、elease and stability testing to date supports stability of at least 36 months for API under ambient conditions and supportsstability of at least 36 months for drug product also under ambient conditions.Our API,finished product,and single-dose inhaler producers are accepted by the health authorities
93、in all countries thatwere included in our global Phase 2b/Phase 3 clinical trial.We have paused manufacturing of AV-101 as we engage in our process to evaluate strategic alternatives,including theMerger.Table of Contents9Sales and MarketingOur commercialization strategy was previously to develop AV-
94、101 into a leading therapy worldwide for the treatment ofPAH.Should we resume product development activities and obtain approval for any products,we would need to establish asales and marketing organization.We cannot guarantee that AV-101 or any future product candidate will receive coverage and rei
95、mbursement by public andcommercial payors.Intellectual PropertyOur commercial success depends in part on our ability to obtain and maintain proprietary protection for our products,noveldiscoveries,drug development technologies and know-how;to operate without infringing on or otherwise violating thep
96、roprietary rights of others;and to prevent others from infringing or otherwise violating our proprietary rights.Our policyis to seek to protect our proprietary position by,among other methods,filing or in-licensing U.S.and foreign patents andpatent applications related to our products and other prop
97、rietary technology,inventions and improvements that areimportant to the development and implementation of our business.We also rely on trademarks,trade secrets,know-how,continuing technological innovation and potential in-licensing opportunities to develop and maintain our proprietaryposition.In Jun
98、e 2024,we announced our decision to halt enrollment and shut down the Phase 3 portion of IMPAHCT aswell as the long-term extension study of AV-101 in PAH,and we do not intend to continue to seek or maintain intellectualproperty protection on the technology underlying AV-101.Our intellectual property
99、 portfolio includes issued patents in the United States,pending patent applications in the UnitedStates,under the Patent Cooperation Treaty,or the PCT international applications,and in commercially relevant foreignjurisdictions for our products.The PCT international applications preserve all of our
100、rights to file patent applications incommercially relevant foreign jurisdictions for our products.As of December 31,2024,we own six U.S.patents,sevenU.S.patent applications,no pending PCT international applications,and 19 foreign patent applications.Our U.S.patentportfolio is expected to expire betw
101、een May 14,2040 and February 15,2042,excluding any extension of patent term thatmay be available and assuming that the filed patent applications will issue as patents.Our foreign patent portfolio isexpected to expire between May 14,2040 and February 15,2042,excluding any extension of patent terms th
102、at may beavailable and assuming that filed applications will issue as patents and that the foreign patent terms are calculated similarlyto the calculation of U.S.patent terms for the corresponding U.S.portion of the patent portfolio.Our patent portfolio issummarized in the following table.APPLICATIO
103、N/PATENT NO.RELATED PRODUCTPROTECTION SOUGHTPROJECTED EXPIRATION*JURISDICTION62/849,054A V-101Composition of Matter;UseN/AUS11,229,650A V-101Composition of Matter;Use5/14/2040US11,806,349A V-101Composition of Matter;Use5/14/2040US18/377,561A V-101Composition of Matter;Use5/14/2040US20806383.4A V-101
104、Composition of Matter;Use;Process5/14/2040Europe202080051359.5A V-101Composition of Matter;Use;Process5/14/2040China2021-568694A V-101Composition of Matter;Use;Process5/14/2040Japan2020274521A V-101Composition of Matter;Use;Process5/14/2040Australia3140641A V-101Composition of Matter;Use;Process5/14
105、/2040Canada288111A V-101Composition of Matter;Use;Process5/14/2040Israel202117055928A V-101Composition of Matter;Use;Process5/14/2040India11202112719XA V-101Composition of Matter;Use;Process5/14/2040Singapore10-2021-7041312A V-101Composition of Matter;Use;Process5/14/2040Republic ofKoreaMX/A/2021/10
106、4029A V-101Composition of Matter;Use;Process5/14/2040MexicoBR1120210230149A V-101Composition of Matter;Use;Process5/14/2040Brazil2021/09070A V-101Composition of Matter;Use;Process5/14/2040South Africa20210285A V-101Composition of Matter;Use;Process5/14/2040Bahrain305/2021A V-101Composition of Matter
107、;Use;Process5/14/2040JordanKW/P/2021/466A V-101Composition of Matter;Use;Process5/14/2040KuwaitOM/P/2021/00467A V-101Composition of Matter;Use;Process5/14/2040OmanQA/202111/000655A V-101Composition of Matter;Use;Process5/14/2040QatarNOPRODUCTEXPIRATION*Table of Contents10521430873A V-101Composition
108、of Matter;Use;Process5/14/2040Saudi ArabiaP6002085/2021A V-101Composition of Matter;Use;Process5/14/2040UAEPCT/US20/32872A V-101Composition of Matter;Use;ProcessN/AInternationalPCT62/849,056A V-101Composition of Matter;UseN/AUS11,298,355A V-101Composition of Matter;Use5/14/2040US62/849,058A V-101Pro
109、cessN/AUS11,413,289A V-101Process5/14/2040US11,813,263A V-101Process5/14/2040US18/378,949A V-101Process5/14/2040US62/849,059A V-101Composition of Matter;UseN/AUS16/874,128A V-101Composition of Matter;Use5/14/2040US62/877,575A V-101Composition of Matter;ProcessN/AUS16/874,143A V-101Composition of Mat
110、ter;Process5/14/2040US62/942,408A V-101Composition of Matter;UseN/AUS11,464,776A V-101Composition of Matter;Use5/14/2040US17/963,607A V-101Composition of Matter;Use5/14/2040US62/984,037A V-101Use;KitN/AUS16/874,168A V-101Use;Kit5/14/2040US17/685,704A V-101Use;Kit5/14/2040US62/958,481A V-101UseN/AUS1
111、6/874,190A V-101Use5/14/2040USPCT/US20/32874A V-101UseN/AInternationalPCT20806763.7A V-101UseEurope63/117,258A V-101Composition of Matter;Combination Products;UseN/AUS63/150,731A V-101Composition of Matter;Combination Products;UseN/AUS18/034,558A V-101Composition of Matter;Combination Products;Use11
112、/23/2041US2021382051A V-101Composition of Matter;Combination Products;Use11/23/2041Australia3199091A V-101Composition of Matter;Combination Products;Use11/23/2041Canada202180076594.2A V-101Composition of Matter;Combination Products;Use11/23/2041China21895804.9A V-101Composition of Matter;Combination
113、 Products;Use11/23/2041Europe202317028210A V-101Composition of Matter;Combination Products;Use11/23/2041India2023-530592A V-101Composition of Matter;Combination Products;Use11/23/2041JapanPCT/US21/60526A V-101Composition of Matter;Combination Products;UseN/AInternationalPCT63/149,446A V-101Process;C
114、omposition of MatterN/AUS18/276,396A V-101Process;Composition of Matter2/15/2042US2022220017A V-101Process;Composition of Matter2/15/2042Australia3211077A V-101Process;Composition of Matter2/15/2042Canada202280024931.8A V-101Process;Composition of Matter2/15/2042China22753517.6A V-101Process;Composi
115、tion of Matter2/15/2042Europe2023-548863A V-101Process;Composition of Matter2/15/2042JapanPCT/US22/16422A V-101Process;Composition of MatterN/AInternationalPCT63/619,079A V-101UseN/AUS*Projected patent expiration dates were calculated for pending U.S.Nonprovisional Applications and ForeignApplicatio
116、ns based on filing date.These calculations do not take into account any terminal disclaimers or patent termadjustments that may occur during prosecution or for pharmaceutical patents in Australia.U.S.Provisional andInternational PCT filings will not issue as patents and therefore do not have a proje
117、cted expiration date.Europeanfilings will issue only in validated European countries and the projected expiration date will apply to those individualcountry patents.Our intellectual property estate strategy is designed to provide multiple layers of protection,including:(1)proprietarypatent rights wi
118、th claims directed to our drug product;(2)proprietary patent rights covering methods of treatment using ourdrug product;and(3)proprietary patent rights covering innovative manufacturing processes.While we seek broad coverage under our pending patent applications,there is always a risk that a modific
119、ation of theproduct or manufacturing process may allow a competitor to avoid infringement claims.In addition,patents,if granted,expire,and we cannot provide any assurance that any patents will be issued from our pending or any future applications orthat any issued patents will adequately protect our
120、 products.Table of Contents11We have conducted freedom to operate analyses of the current patent landscape with respect to our lead product candidates.In doing so,we have strived to ensure our ability to operate freely within the complex patent landscape of inhalable kinaseinhibitors and the use of
121、such products in the field of PAH.New formulations of drug products and new uses for such products would require seeking patent protection on our own toexpand the layers of protection provided by our intellectual property estate.Patent Protection and TermsIndividual patents extend for varying period
122、s depending on the date of filing of the patent application or the date of patentissuance and the legal term of patents in the countries in which they are obtained.Generally,patents issued from regularlyfiled applications in the United States are granted a term of 20 years from the earliest effectiv
123、e filing date.In addition,incertain instances,a patent term can be adjusted to recapture a portion of the United States Patent and Trademark Office,orthe USPTO,delay in issuing the patent,and extended to recapture a portion of the patent term effectively lost as a result ofthe FDA regulatory review
124、period of the drug covered by the patent.However,as to the FDA component,the restorationperiod cannot be longer than five years,the total patent term including the restoration period must not exceed 14 yearsfollowing FDA approval of the drug,and the extension may only apply to one patent that covers
125、 the approved drug(and toonly those patent claims covering the approved drug,a method for using it,or a method for manufacturing it).There can beno assurance that any such patent term adjustment or extension will be obtained.The duration of foreign patents varies inaccordance with provisions of appl
126、icable local law,but typically is also 20 years from the earliest effective filing date.However,the actual protection afforded by a patent varies on a product-by-product basis,from country to country,anddepends upon many factors,including the type of patent,the scope of its coverage,the availability
127、 of regulatory-relatedextensions,the availability of legal remedies in a particular country and the validity and enforceability of the patent.Furthermore,the patent positions of biotechnology and pharmaceutical products and processes are generally uncertain andinvolve complex legal and factual quest
128、ions.No consistent policy regarding the breadth of claims allowed in such patentshas emerged to date in the United States.The patent situation outside the United States is even more uncertain.Changes ineither the patent laws or in interpretations of patent laws in the United States and other countri
129、es can diminish the ability toprotect inventions and enforce intellectual property rights,can make it easier to challenge the validity,enforceability orscope of any patents that may issue,and,more generally,could affect the value of intellectual property.Accordingly,thebreadth of claims that may be
130、allowed or enforced in our patents or in third-party patents cannot be predicted.Third-Party Patent FilingsNumerous U.S.and foreign issued patents and patent applications owned by third parties exist in the fields in which wemay resume developing products.In addition,because patent applications can
131、take many years to issue,there may beapplications unknown to us,which may later result in issued patents that our products or proprietary technologies mayinfringe.Moreover,we may be aware of patent applications,but incorrectly predict the likelihood of those applicationsissuing with claims of releva
132、nce to us.Under U.S.law,a person may be able to patent a discovery of a new way to use a previously known compound,even ifsuch compound itself is patented,provided the newly discovered use is novel and non-obvious.Such a method-of-usepatent,however,if valid,only protects the use of a claimed compoun
133、d for the specified methods claimed in the patent.Thistype of patent does not prevent persons from using the compound for any previously known use of the compound.Further,this type of patent does not prevent persons from making and marketing the compound for an indication that is outside thescope of
134、 the patented method.Trade Secrets and Other ProtectionsIn addition to the protections afforded by patents and other regulatory protections,we may rely,in some circumstances,ontrade secrets to protect our technology.Trade secrets may be useful to protect proprietary know-how that is not patentableor
135、 which we elect not to patent.Trade secrets may also be useful for processes or improvements for which patents aredifficult to enforce.Table of Contents12We also protect our products and proprietary technology through confidentiality agreements with employees,consultants,advisors,contractors and col
136、laborators.These agreements are designed to protect our proprietary information and,in thecase of the invention assignment agreements,to grant us ownership of technologies that are developed through arelationship with a third party.These agreements may be breached,and we may not have adequate remedi
137、es for any suchbreach.In addition,our trade secrets may otherwise become known or be independently discovered by competitors.To theextent that our commercial partners,collaborators,employees and consultants use intellectual property owned by others intheir work for us,disputes may arise as to the ri
138、ghts in related or resulting know-how and inventions.We also seek to preserve the integrity and confidentiality of our data and trade secrets by maintaining physical security ofour premises and physical and electronic security of our information technology systems.Infringement of Third-Party Proprie
139、tary RightsOur commercial success will depend in part on not infringing upon or otherwise violating the intellectual property andproprietary rights of third parties.If we are found to infringe a third partys intellectual property rights,we could berequired to obtain a license from such third party t
140、o continue developing and marketing our products and technology.However,we may not be able to obtain any required license on commercially reasonable terms or at all.Even if we wereable to obtain a license,it could be non-exclusive,thereby giving our competitors access to the same technologies licens
141、edto us.We could also be forced,including by court order,to cease commercializing the infringing product or technology.Inaddition,we could be found liable for monetary damages,including treble damages and attorneys fees,if we are found tohave willfully infringed a patent.A finding of infringement co
142、uld prevent us from commercializing our products or forceus to cease some of our business operations.For more information regarding these risks,please see“Risk FactorsRisksRelated to Our Intellectual Property.”CompetitionThe biotechnology and pharmaceutical industries are characterized by rapidly ad
143、vancing technologies,intense competitionand a strong emphasis on proprietary products.We have faced potential competition from many different sources,includingmajor pharmaceutical,specialty pharmaceutical and biotechnology companies,academic institutions and governmentalagencies and public and priva
144、te research institutions.In June 2024,we announced our decision to halt enrollment and shutdown the Phase 3 portion of IMPAHCT as well as the long-term extension study of AV-101 in PAH and will not advancedevelopment of AV-101 in PAH.Some of our historical competitors have had significantly greater
145、financial resources and expertise in research anddevelopment,manufacturing,preclinical testing,conducting clinical trials,obtaining regulatory approvals and marketingapproved products than we did.Smaller or early-stage companies may also prove to be significant competitors,particularlythrough collab
146、orative arrangements with large and established companies.The key competitive factors that differentiate products,if approved,are likely to be efficacy,safety,convenience,price,andthe availability of reimbursement from commercial,government and other third-party payors.Government RegulationUnited St
147、atesFDA ProcessIn the United States,pharmaceutical products are subject to extensive regulation by the FDA.The FDCA and other federaland state statutes and regulations,govern,among other things,the research,development,testing,manufacture,storage,recordkeeping,approval,labeling,promotion and marketi
148、ng,distribution,post-approval monitoring and reporting,sampling,and import and export of pharmaceutical products.We,along with third-party contractors,will be required tonavigate the various preclinical,clinical and commercial approval requirements of the governing regulatory authorities ofthe count
149、ries in which we wish to conduct studies or seek approval of our product candidates.Failure to comply withapplicable United States requirements may subject a company to a variety of administrative or judicial sanctions,such asFDA refusal to approve pending New Drug Applications,or NDAs,withdrawal of
150、 an approval,warning or untitled letters,clinical holds,product recalls or withdrawals from the market,product seizures,total or partial suspension of productionTable of Contents13or distribution,injunctions,fines,refusals of government contracts,restitution,disgorgement of profits,civil penalties,a
151、ndcriminal prosecution.FDA approval is required before any new unapproved product or a product with certain changes to a previously approvedproduct,including a new use of a previously approved drug,can be marketed in the United States.The steps required to becompleted by the FDA before a drug may be
152、 marketed in the United States generally includes the following:completion of preclinical laboratory tests,animal studies,and formulation studies performed in accordance withthe FDAs Good Laboratory Practice,or GLP,regulations;submission to the FDA of an investigational new drug,or IND,application f
153、or human clinical testing,which mustbecome effective before human clinical trials may begin and must be updated annually or when significantchanges are made;approval by an independent institutional review board,or IRB,or ethics committee at each clinical site before theclinical trial is commenced;pe
154、rformance of adequate and well-controlled human clinical trials in accordance with applicable IND regulations,GCP,requirements and other clinical-trial related regulations to establish the safety and efficacy of the proposeddrug for each indication;preparation and submission to the FDA of a NDA afte
155、r completion of all pivotal clinical trials,which includes notonly the results of the clinical trials,but also,detailed information on the chemistry,manufacture and qualitycontrols for the product candidate and proposed labeling;satisfactory completion of an FDA Advisory Committee review,if applicab
156、le;a determination by the FDA within 60 days of its receipt of an NDA to file the application for review;satisfactory completion of an FDA pre-approval inspection of the manufacturing facility or facilities at which theproposed drug is produced to assess compliance with current GMP regulations and o
157、f selected clinical trial sitesto assess compliance with GCPs;andFDA review and approval of the NDA to permit commercial marketing of the product for particular indicationsfor use in the United States.Satisfaction of FDA pre-market approval requirements typically takes many years and the actual time
158、 required may varysubstantially based upon the type,complexity,and novelty of the product or disease.Preclinical and Clinical DevelopmentPreclinical tests include laboratory evaluation of product chemistry,formulation,and toxicity,as well as animal trials toassess the characteristics and potential s
159、afety and efficacy of the product candidate.The conduct of the preclinical testsmust comply with federal regulations and requirements,including GLPs.The results of preclinical testing are submitted tothe FDA as part of an IND application along with other information,including information about the p
160、roduct candidate,chemistry,manufacturing and controls,any available human data or literature to support the use of the product candidateand a proposed clinical trial protocol.Long term preclinical tests,such as animal tests of reproductive toxicity andcarcinogenicity,may continue after the IND is su
161、bmitted.An IND application must become effective before human clinical trials may begin.The IND application automaticallybecomes effective 30 days after receipt by the FDA,unless the FDA,within the 30-day period,raises safety concerns orquestions relating to one or more proposed clinical trials and
162、places the clinical trial on clinical hold.In such a case,theIND sponsor and the FDA must resolve any outstanding concerns or questions before the clinical trial can begin.The FDATable of Contents14may also impose clinical holds on a product candidate at any time before or during clinical trials due
163、 to safety concerns,non-compliance or other issues affecting the integrity of the trial.Accordingly,submission of an IND application may ormay not result in the FDA allowing clinical trials to commence and,once begun,issues may arise that could cause the trialto be suspended or terminated.Clinical t
164、rials involve the administration of the investigational drug product to human subjects under the supervision of aqualified investigator.Clinical trials must be conducted:(i)in compliance with federal regulations;(ii)in compliance withGCP,an international standard meant to protect the rights and heal
165、th of clinical research participants and to define the rolesof clinical trial sponsors,administrators,and monitors;as well as(iii)under protocols detailing the objectives of the trial,the parameters to be used in monitoring safety,and the effectiveness criteria to be evaluated.Each protocol involvin
166、gtesting on United States patients and subsequent protocol amendments must be submitted to the FDA as part of the IND.Furthermore,an independent IRB or ethics committee for each site proposing to conduct the clinical trial must review andapprove the plan for any clinical trial and its informed conse
167、nt form before the clinical trial begins at that site,and mustmonitor the study until completed.An IRB is charged with protecting the welfare and rights of trial participants andconsiders such items as whether the risks to individuals participating in the clinical trials are minimized and are reason
168、ablein relation to anticipated benefits.Regulatory authorities,the IRB or the sponsor may suspend a clinical trial at any time on various grounds,including afinding that the subjects are being exposed to an unacceptable health risk or that the trial is unlikely to meet its statedobjects.The FDA may
169、order the temporary,or permanent,discontinuation of a clinical trial at any time,or impose othersanctions,if it believes that the clinical trial either is not being conducted in accordance with FDA requirements.Further,an IRB may also require the clinical trial at the site to be halted,either tempor
170、arily or permanently,for failure to complywith the IRBs requirements,or may impose other conditions.Some trials also include oversight by an independent groupof qualified experts organized by the clinical trial sponsor,known as a data safety monitoring board,which providesauthorization for whether o
171、r not a study may move forward at designated check points based on access to certain data fromthe study and may recommend a clinical trial to be halted if it determines that there is an unacceptable safety risk forsubjects or other grounds,such as futility.Clinical trials to support an NDA for marke
172、ting approval are typically conducted in three sequential phases,but the phasesmay overlap or be combined.In Phase 1 clinical trials,the investigational product is typically introduced into a limitedpopulation of healthy human subjects or patients with the target disease or condition.These trials ar
173、e designed to test thesafety,dosage tolerance,pharmacokinetics and pharmacological actions of the investigational product,to identify sideeffects associated with increasing doses,and,if possible,to gain early evidence on effectiveness.Phase 2 clinical trialsusually involve administering the investig
174、ational product to a limited patient population with the specified disease orcondition to evaluate the preliminarily efficacy,dosage tolerance,and optimum dosage,and to identify possible adverseeffects and safety risks.Phase 3 clinical trials are typically undertaken in a larger number of patients,t
175、ypically atgeographically dispersed clinical trial sites,to provide substantial evidence of clinical efficacy and to further test for safetyin an expanded and diverse patient population.These clinical trials are intended to permit the FDA to evaluate the overallbenefit-risk relationship of the inves
176、tigational product and to provide adequate information for the labeling of the productcandidate.In reviewing an NDA,the FDA will consider all information submitted in the NDA,including the results of all clinicaltrials conducted.In some cases,the FDA may require,or companies may voluntarily pursue,a
177、dditional clinical trials aftera product is approved to gain more information about the product.These so-called Phase 4 studies may be made acondition to approval of the NDA.These trials are used to gain additional experience from the treatment of patients in theintended therapeutic indication and f
178、urther document clinical benefit in the case of drugs approved under acceleratedapproval regulations.Failure to exhibit due diligence with regard to conducting Phase 4 clinical trials could result in thewithdrawal of approval for products.Concurrent with clinical trials,companies may complete additi
179、onal animal studies and develop additional informationabout the biological characteristics of the product candidate,and must finalize a process for manufacturing the product incommercial quantities in accordance with current GMP requirements.The manufacturing process must be capable ofconsistently p
180、roducing quality batches of the product candidate and,among other things,must develop methods for testingthe identity,strength,quality and purity of the final product.Additionally,appropriate packaging must be selected andTable of Contents15tested and stability studies must be conducted to demonstra
181、te that the product candidate does not undergo unacceptabledeterioration over its shelf life.During all phases of clinical development,regulatory agencies require extensive monitoring and auditing of all clinicalactivities,clinical data,and clinical study investigators.Progress reports detailing the
182、 results of the clinical trials,amongother information,must be submitted at least annually to the FDA,and written IND safety reports must be submitted to theFDA and the investigators for serious and unexpected suspected adverse events,findings from other studies suggesting asignificant risk to human
183、s exposed to the product candidate,findings from animal or in vitro testing that suggest asignificant risk for human subjects,and any clinically important increase in the rate of a serious suspected adverse reactionover that listed in the protocol or investigator brochure.NDA Submission and ReviewAs
184、suming successful completion of the required clinical testing in accordance with all applicable regulatory requirements,an NDA application which includes,among other information,the results of product development,preclinical studies andclinical trials are submitted to the FDA.FDA approval of the NDA
185、 is required before marketing of the product may beginin the United States.The NDA must include,among other things,the results of all trials and preclinical testing,and othertesting and a compilation of data relating to the products pharmacology,chemistry,manufacture,controls and proposedlabeling.Th
186、e cost of preparing and submitting an NDA is substantial.The FDA has 60 days from its receipt of an NDA to either issue a Refuse to File Letter or accept the NDA for filing,indicating that it is sufficiently complete to permit substantive review.Once the submission is accepted for filing,the FDAbegi
187、ns an in-depth review.The FDA has agreed to certain performance goals in the review of NDAs.Under thePrescription Drug User Fee Act,the FDA has a goal of responding to standard review NDAs within ten months after itaccepts the application for filing,or,if the application qualifies for priority revie
188、w,six months after the FDA accepts theapplication for filing,but this timeframe can be extended such as by the submission of major amendments by applicantsduring the review period.The FDA reviews an NDA to determine,among other things,whether the product is safe andeffective and the facility in whic
189、h it is manufactured,processed,packed or held meets standards designed to assure theproducts continued safety,purity and potency.The FDA may refer applications for novel drug products,or drug products that present difficult questions of safety orefficacy,to an advisory committeetypically a panel tha
190、t includes clinicians and other expertsfor review,evaluation,and a recommendation as to whether the application should be approved.The FDA is not bound by the recommendation ofan advisory committee,but it generally follows such recommendations.Before approving an NDA,the FDA will typicallyinspect on
191、e or more clinical sites to assure compliance with GCPs.Additionally,the FDA will inspect the facility or thefacilities at which the proposed product is manufactured.If the FDA determines that the application,manufacturing processor manufacturing facilities are not acceptable,it will outline the def
192、iciencies in the submission and often will requestadditional testing or information.Notwithstanding the submission of any requested additional information,the FDAultimately may decide that the application does not satisfy the regulatory criteria for approval.After the FDA evaluates the NDA and condu
193、cts inspections of the manufacturing facilities where the investigationalproduct and/or its drug substance will be produced,it issues either an approval letter or a Complete Response letter.Anapproval letter authorizes commercial marketing of the drug with approved prescribing information for specif
194、ic indications.A Complete Response letter indicates that the review cycle of the application is complete and the application is not readyfor approval.A Complete Response letter generally outlines the deficiencies in the submission,except that where the FDAdetermines that the data supporting the appl
195、ication are inadequate to support approval,the FDA may issue the CompleteResponse letter without first conducting required inspections or reviewing proposed labeling.In issuing the CompleteResponse letter,the FDA may require substantial additional clinical data and/or other significant,expensive,and
196、 time-consuming requirements related to clinical trials,preclinical studies and/or manufacturing.If a Complete Response letter isissued,the applicant may either resubmit the NDA,addressing all of the deficiencies identified in the letter,withdraw theapplication or request a hearing.The FDA has commi
197、tted to reviewing resubmissions of the NDA addressing suchdeficiencies in two or six months depending on the type of information included.Even if such data are submitted,however,the FDA may ultimately decide that the NDA does not satisfy the criteria for approval.Table of Contents16If regulatory app
198、roval of a product is granted,such approval will be granted for a particular indication(s)and may includelimitations on the indicated use(s)for which such product may be marketed.Further,the FDA may require that certaincontraindications,warnings or precautions be included in the product labeling or
199、may condition the approval of the NDAon other changes to the proposed labeling,development of adequate controls and specifications,or a commitment toconduct post-market testing or clinical trials and surveillance to monitor the effects of approved products.As a condition ofNDA approval,the FDA may r
200、equire a risk evaluation and mitigation strategy,or REMS,to help ensure that the benefits ofthe drug outweigh the potential risks.REMS can include medication guides,communication plans for healthcareprofessionals,and elements to assure safe use,or ETASU.ETASU can include,but are not limited to,speci
201、al training orcertification for prescribing or dispensing,dispensing only under certain circumstances,special monitoring,and the use ofpatient registries.The requirement for REMS can materially affect the potential market and profitability of the product.Moreover,product approval may also be conditi
202、oned on substantial post-approval testing,such as Phase 4 post-marketstudies,and surveillance to monitor the products safety or efficacy,and FDA may limit further marketing of the productbased on the results of these post-approval studies.Once granted,product approvals may be withdrawn if compliance
203、 withregulatory standards is not maintained or problems are identified following initial marketing.Changes to some of the conditions established in an approved application,including changes in indications,labeling,ormanufacturing processes or facilities,require submission and FDA approval of a new N
204、DA or NDA supplement before thechange can be implemented.An NDA supplement for a new indication typically requires clinical data similar to that in theoriginal application,and the FDA uses the same procedures and actions in reviewing NDA supplements as it does inreviewing NDAs.As with new NDAs,the r
205、eview process is often significantly extended by the FDA requests foradditional information or clarification.505(b)(2)NDA Approval ProcessSection 505(b)(2)of the FDCA provides an alternate regulatory pathway for the FDA to approve a new product andpermits reliance for such approval on published lite
206、rature or an FDA finding of safety and effectiveness for a previouslyapproved drug product.Specifically,section 505(b)(2)permits the filing of an NDA where one or more of theinvestigations relied upon by the applicant for approval were not conducted by or for the applicant and for which theapplicant
207、 has not obtained a right of reference.Typically,505(b)(2)applicants must perform additional trials to support thechange from the previously approved drug and to further demonstrate the new products safety and effectiveness.The FDAmay then approve the new product candidate for all or some of the lab
208、eled indications for which the referenced product hasbeen approved,as well as for any new indication sought by the section 505(b)(2)applicant.Regulation of Combination Products in the United StatesCertain products may be comprised of components,such as drug components and device components,that woul
209、d normallybe regulated under different types of regulatory authorities,and frequently by different centers at the FDA.These productsare known as combination products.Specifically,under regulations issued by the FDA,a combination product may be:a product comprised of two or more regulated components
210、that are physically,chemically,or otherwise combinedor mixed and produced as a single entity;two or more separate products packaged together in a single package or as a unit and comprised of drug anddevice products,device and biological products,or biological and drug products;a drug,or device,or bi
211、ological product packaged separately that according to its investigational plan or proposedlabeling is intended for use only with an approved individually specified drug,or device,or biological productwhere both are required to achieve the intended use,indication,or effect and where upon approval of
212、 theproposed product the labeling of the approved product would need to be changed,e.g.,to reflect a change inintended use,dosage form,strength,route of administration,or significant change in dose;orany investigational drug,or device,or biological product packaged separately that according to its p
213、roposedlabeling is for use only with another individually specified investigational drug,device,or biological productwhere both are required to achieve the intended use,indication,or effect.Table of Contents17Under the FDCA and its implementing regulations,the FDA is charged with assigning a center
214、with primary jurisdiction,or a lead center,for review of a combination product.The designation of a lead center generally eliminates the need toreceive approvals from more than one FDA component for combination products,although it does not precludeconsultations by the lead center with other compone
215、nts of FDA.The determination of which center will be the lead centeris based on the“primary mode of action”of the combination product.Thus,if the primary mode of action of a drug-devicecombination product is attributable to the drug product,the FDA center responsible for premarket review of the drug
216、product would have primary jurisdiction for the combination product.The FDA has also established an Office ofCombination Products to address issues surrounding combination products and provide more certainty to the regulatoryreview process.That office serves as a focal point for combination product
217、issues for agency reviewers and industry.It isalso responsible for developing guidance and regulations to clarify the regulation of combination products,and forassignment of the FDA center that has primary jurisdiction for review of combination products where the jurisdiction isunclear or in dispute
218、.A combination product with a drug primary mode of action generally would be reviewed and approved pursuant to thedrug approval processes under the FDCA.In reviewing the NDA application for such a product,however,FDA reviewersin the drug center could consult with their counterparts in the device cen
219、ter to ensure that the device component of thecombination product met applicable requirements regarding safety,effectiveness,durability and performance.In addition,under FDA regulations,combination products are subject to current GMP requirements applicable to both drugs anddevices,including the Qua
220、lity System,or QS,regulations applicable to medical devices.Post-Approval RequirementsOnce an NDA is approved,a product will be subject to pervasive and continuing regulation by the FDA including,amongother things,requirements relating to current GMPs,quality controls,record-keeping,reporting of adv
221、erse experiences,periodic reporting,product sampling and distribution,and advertising and promotion of the product.For instance,the FDAclosely regulates the post-approval marketing and promotion of drugs,including standards and regulations for direct-to-consumer advertising,off-label promotion,indus
222、try-sponsored scientific and educational activities and promotionalactivities involving the internet.Drugs may be marketed only for the approved indications and in accordance with theprovisions of the approved labeling.Failure to comply with these requirements can result in adverse publicity,warning
223、letters,corrective advertising,and potential civil and criminal penalties.Physicians may prescribe legally availableproducts for uses that are not described in the products labeling and that differ from those tested by us and approved by theFDA.Such off-label uses are common across medical specialti
224、es.Physicians may believe that such off-label uses are thebest treatment for many patients in varied circumstances.The FDA does not regulate the practice of medicine byphysicians or their choice of treatments.The FDA does,however,regulate manufacturers communications on the subjectof off-label use o
225、f their products.In addition,quality control,drug manufacture,packaging,and labeling procedures must continue to conform to currentGMPs after approval.Drug manufacturers and certain of their subcontractors are required to register their establishmentswith the FDA and certain state agencies,and are s
226、ubject to periodic unannounced inspections by the FDA,and certain stateagencies for compliance with current GMPs,which impose certain organizational,procedural and documentationrequirements with respect to manufacturing and quality assurance activities.Changes to the manufacturing process arestrictl
227、y regulated,and,depending on the significance of the change,may require prior FDA approval before beingimplemented.FDA regulations also require investigation and correction of any deviations from current GMPs and imposereporting requirements upon us and any third-party manufacturers that we may deci
228、de to use.NDA holders using contractmanufacturers,laboratories or packagers are responsible for the selection and monitoring of qualified firms,and,in certaincircumstances,qualified suppliers to these firms.Drug manufacturers and other parties involved in the drug supply chainfor prescription drug p
229、roducts must also comply with product tracking and tracing requirements and for notifying the FDAof counterfeit,diverted,stolen and intentionally adulterated products or products that are otherwise unfit for distribution inthe United States.The discovery of violative conditions,including failure to
230、conform to current GMP,could result inenforcement actions that interrupt the operation of any such facilities or the ability to distribute products manufactured,processed or tested by them.Accordingly,manufacturers must continue to expend time,money,and effort in the areas ofproduction and quality-c
231、ontrol to maintain compliance with current GMPs.Table of Contents18The FDA may withdraw product approvals or request product recalls if a company fails to comply with regulatorystandards or is not maintained,if problems occur following initial marketing,or if previously unrecognized problems aresubs
232、equently discovered.Later discovery of previously unknown problems with a product,including adverse events ofunanticipated severity or frequency,or with manufacturing processes,or failure to comply with regulatory requirements,may result in revisions to the approved labeling to add new safety inform
233、ation;imposition of post-market studies or clinicaltrials to assess new safety risks;or imposition of distribution restrictions or other restrictions under a REMS program.Other potential consequences include,among other things:restrictions on the marketing or manufacturing of a product,complete with
234、drawal of the product from the marketor product recalls;fines,warning letters or holds on post-approval clinical trials;refusal of the FDA to approve pending applications or supplements to approved applications,or suspension orrevocation of existing product approvals;product seizure or detention,or
235、refusal of the FDA to permit the import or export of products;consent decrees,corporate integrity agreements,debarment or exclusion from federal healthcare programs;mandated modification of promotional materials and labeling and the issuance of corrective information;the issuance of safety alerts,De
236、ar Healthcare Provider letters,press releases and other communicationscontaining warnings or other safety information about the product;orinjunctions or the imposition of civil or criminal penalties.U.S.Patent Term RestorationDepending upon the timing,duration and specifics of the potential FDA appr
237、oval of AV-101 and any future productcandidates,some of our U.S.patents may be eligible for limited patent term extension.The Hatch-Waxman Amendmentspermit a patent restoration term,often referred to as patent term extension,of up to five years as compensation for patentterm lost during product deve
238、lopment and the FDA regulatory review process.However,patent term restoration cannotextend the remaining term of a patent beyond a total of 14 years from the products approval date.The patent termrestoration period is generally one-half the time between the effective date of an IND and the submissio
239、n date of an NDAplus the time between the submission date of an NDA and the approval of that application.Only one patent applicable to anapproved drug is eligible for the extension and the application for the extension must be submitted prior to the expiration ofthe patent.The USPTO,in consultation
240、with the FDA,reviews and approves or denies the application for any patent termextension or restoration.U.S.Marketing ExclusivityMarket exclusivity provisions under the FDCA can also delay the submission or the approval of certain marketingapplications,including 505(b)(2)applications.The FDA provide
241、s three years of marketing exclusivity for an NDA(including a 505(b)(2)application),or supplement to an existing NDA,if new clinical investigations,other thanbioavailability studies,that were conducted or sponsored by the applicant are deemed by the FDA to be essential to theapproval of the applicat
242、ion.Three-year exclusivity is typically awarded to innovative changes to a previously-approveddrug product,such as new indications,dosage forms or strengths.This three-year exclusivity covers only the modificationfor which the drug received approval on the basis of the new clinical investigations an
243、d does not prohibit the FDA fromapproving applications for drugs that do not have the innovative change,such as generic copies of the original,unmodifieddrug product.Three-year exclusivity blocks approval of 505(b)(2)applications and Abbreviated NDAs,but will not delaythe submission or approval of a
244、 full NDA.However,an applicant submitting a full NDA would be required to conduct orobtain a right of reference to all of the nonclinical studies and adequate and well-controlled clinical trials necessary toTable of Contents19demonstrate safety and effectiveness.Orphan drug exclusivity,as described
245、above,may offer a seven-year period ofmarketing exclusivity,except in certain circumstances.Pediatric exclusivity is another type of regulatory marketexclusivity in the United States.Pediatric exclusivity,if granted,adds six months to existing exclusivity periods,includingexclusivity attaching to ce
246、rtain patent certifications.This six-month exclusivity,which runs from the end of otherexclusivity protection and patent terms,may be granted based on the voluntary completion of a pediatric trial in accordancewith an FDA-issued“Written Request”for such a trial,provided that at the time pediatric ex
247、clusivity is granted there is notless than nine months of term remaining.Orphan Drug DesignationUnder the Orphan Drug Act,the FDA may grant orphan drug designation to a drug intended to treat a rare disease orconditiongenerally a disease or condition with either a patient population that affects few
248、er than 200,000 individuals inthe United States or a patient population greater than 200,000 individuals in the United States and there is no reasonableexpectation that the cost of developing and making available the drug will be recovered from sales of the drug in theUnited States.Orphan drug desig
249、nation must be requested before submitting an NDA.After the FDA grants orphan drugdesignation,the generic identity of the product and its potential orphan use are disclosed publicly by the FDA.Orphan drugdesignation does not convey any advantage in,or shorten the duration of,the regulatory review an
250、d approval process.The first NDA applicant to receive FDA approval for a particular active ingredient to treat a particular disease with FDAorphan drug designation is entitled to a seven-year exclusive marketing period in the United States for that product,for thatindication.During the seven-year ex
251、clusivity period,the FDA may not approve any other applications to market the sameproduct for the same disease,except in limited circumstances,such as a showing of clinical superiority to the product withorphan drug exclusivity or if the FDA finds that the holder of the orphan drug exclusivity has n
252、ot shown that it can assurethe availability of sufficient quantities of the orphan drug to meet the needs of the patients with the disease or condition forwhich the product was designated.Orphan drug exclusivity does not prevent the FDA from approving a different productfor the same disease or condi
253、tion,or the same product for a different disease or condition.Among the other benefits oforphan drug designation are tax credits for certain research and a waiver of the NDA or BLA application user fee.A designated orphan drug may not receive orphan drug exclusivity if it is approved for a use that
254、is broader than theindication for which it received orphan drug designation.In addition,orphan drug exclusive marketing rights in the UnitedStates may be lost if the FDA later determines that the request for designation was materially defective or if themanufacturer is unable to assure sufficient qu
255、antities of the product to meet the needs of patients with the rare disease orcondition.Fast Track Designation,Breakthrough Therapy Designation and Accelerated ApprovalThe FDA is required to facilitate the development,and expedite the review,of drugs that are intended for the treatment of aserious o
256、r life-threatening disease or condition which demonstrate the potential to address unmet medical needs for thecondition.These programs include fast track designation,priority review and accelerated approval.A product candidate is eligible for fast track designation if it is intended to treat a serio
257、us or life-threatening disease orcondition and demonstrates the potential to address unmet medical needs for such disease or condition.Fast trackdesignation applies to the combination of the product and the specific indication for which it is being studied.Under thefast track program,the sponsor of
258、a drug candidate may request that the FDA designate the candidate for a specificindication as a fast track product concurrent with,or after,the filing of the IND for the candidate.The FDA must determineif the product candidate qualifies for fast track designation within 60 days of receipt of the spo
259、nsors request.Fast trackdesignation provides increased opportunities for sponsor interactions with the FDA during preclinical and clinicaldevelopment,in addition to the potential for rolling review of sections of a the applicants NDA before the application iscomplete.This rolling review is available
260、 if the applicant provides,and the FDA approves,a schedule for the submission ofthe remaining information and the applicant pays applicable user fees.However,the FDAs time period goal for reviewingan application does not begin until the last section of the NDA is submitted.Additionally,the fast trac
261、k designation may bewithdrawn by the FDA if the FDA believes that the designation is no longer supported by data emerging in the clinical trialprocess.Table of Contents20Under the FDAs breakthrough therapy program,a sponsor may seek FDA designation of its product candidate as abreakthrough therapy i
262、f the product candidate is intended,alone or in combination with one or more other drugs orbiologics,to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that it maydemonstrate substantial improvement over existing therapies on one or more clinicall
263、y significant endpoints,such assubstantial treatment effects observed early in clinical development.Breakthrough therapy designation comes with all ofthe benefits of fast track designation.The FDA may take other actions appropriate to expedite the development and reviewof the product candidate,inclu
264、ding intensive guidance on an efficient product development program beginning as early asPhase 1,and FDA organizational commitment to expedited development,including involvement of senior managers andexperienced review staff in a cross-disciplinary review,where appropriate.Any product submitted to t
265、he FDA for marketing,including under the fast track or breakthrough designation program,mayalso be eligible for other types of FDA programs intended to expedite development and review,such as acceleratedapproval.Products are eligible for accelerated approval if they can be shown to have an effect on
266、 a surrogate endpoint thatis reasonably likely to predict clinical benefit,or on a clinical endpoint that can be measured earlier than an effect onirreversible morbidity or mortality,that is reasonably likely to predict an effect on irreversible morbidity or mortality orother clinical benefit,taking
267、 into account the severity,rarity,or prevalence of the condition and the availability or lack ofalternative treatments.In clinical trials,a surrogate endpoint is a measurement of laboratory or clinical signs of a disease or condition thatsubstitutes for a direct measurement of how a patient feels,fu
268、nctions,or survives.Surrogate endpoints can often bemeasured more easily or more rapidly than clinical endpoints.A product candidate approved on this basis is subject torigorous post-marketing compliance requirements,including the conduct of Phase 4,or post-approval,clinical trials toconfirm the eff
269、ect on the clinical endpoint which must be conducted with due diligence and,under the Food and DrugOmnibus Reform Act of 2022,or FDORA,the FDA may require,as appropriate,that such trials be underway prior toapproval or within a specific time period after the date accelerated approval is granted.Addi
270、tionally,under FDORA,theFDA has increased authority for expedited procedures to withdraw a product or indication approved under acceleratedapproval if,for example,the confirmatory trial fails to verify the predicted clinical benefit of the product.All promotionalmaterials for product candidates appr
271、oved under accelerated regulations are subject to prior review by the FDA unlessotherwise informed by the FDA.Priority ReviewA product is eligible for priority review if it has the potential to provide a significant improvement in safety oreffectiveness in the treatment,diagnosis or prevention of a
272、serious disease or condition.A priority review means that thegoal for the FDA to review an application is six months,rather than the standard review of ten months under currentPrescription Drug User Fee Act,or PDUFA,guidelines.Under the current PDUFA agreement,these six and ten monthreview periods a
273、re measured from the“filing”date rather than the receipt date for NDAs for new molecular entities,whichtypically adds approximately two months to the timeline for review and decision from the date of submission.Mostproducts that are eligible for fast track designation are also likely to be considere
274、d appropriate to receive a priority review.Pediatric InformationUnder the Pediatric Research Equity Act,or PREA,NDAs or supplements to NDAs must contain data to assess the safetyand effectiveness of the drug for the claimed indications in all relevant pediatric subpopulations and to support dosing a
275、ndadministration for each pediatric subpopulation for which the drug is safe and effective.The FDA may grant full or partialwaivers,or deferrals,for submission of data.Unless otherwise required by regulation,PREA does not apply to any drug foran indication for which orphan designation has been grant
276、ed.Disclosure of Clinical Trial InformationSponsors of clinical trials of FDA-regulated products,including drugs and combination products,are required to registerand disclose certain clinical trial information.Information related to the product,patient population,phase of investigation,trial sites a
277、nd investigators,and other aspects of the clinical trial is then made public as part of the registration.Sponsorsare also obligated to disclose the results of their clinical trials after completion.Competitors may use this publicly availableTable of Contents21information to gain knowledge regarding
278、the progress of development programs.Disclosure of the results of these trialscan be delayed until the new product or new indication being studied has been approved.Failure to timely register acovered clinical study or to submit study results as provided for in the law can give rise to civil monetar
279、y penalties and alsoprevent the non-compliant party from receiving future grant funds from the federal government.The Final Rule onClinicalTrials.gov registration and reporting requirements became effective in 2017,and both the National Institutes ofHealth and the FDA have signaled the governments w
280、illingness to begin enforcing those requirements against non-compliant clinical trial sponsors.European UnionProcessIn the European Union,or EU,our product candidate(s)may also be subject to extensive regulatory requirementsgoverning,among other things,clinical trials and any commercial sales and di
281、stribution of our product candidate(s).Whether or not we obtain FDA approval for a product candidate,we must obtain the requisite approvals from regulatoryauthorities located in the EU Member States prior to the commencement of clinical trials as well as EU or nationalregulatory approvals prior to m
282、arketing the product candidate(s).Non-Clinical Studies and Clinical TrialsSimilar to the United States,the various phases of non-clinical studies and clinical trials in the EU are subject to significantregulatory controls.Non-clinical studies are performed to demonstrate the health or environmental
283、safety of new chemical substances.Non-clinical studies must be conducted in compliance with the principles of GLP as set forth in EU Directive 2004/10/EC.Inparticular,non-clinical studies,both in vitro and in vivo,must be planned,performed,monitored,recorded,reported andarchived in accordance with t
284、he GLP principles,which define a set of rules and criteria for a quality system for theorganizational process and the conditions for non-clinical studies.These GLP standards reflect the Organization forEconomic Co-operation and Development requirements.Clinical trials of medicinal products in the EU
285、 must be conducted in accordance with the EU Clinical Trials Regulation(EU)No 536/2014,or CTR,(which was adopted in April 2014,and repealed the EU Clinical Trials Directive 2001/20/ECon January 31,2022),and the International Conference on Harmonization,or ICH,guidelines on GCP,as well as theapplicab
286、le regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.If thesponsor of the clinical trial is not established within the EU,it must appoint an EU entity to act as its legal representative(unless all EU Member States in which the trial is being con
287、ducted have chosen not to apply such rule,in which case itmay be that only a contact person in the EU is required),who shall be responsible for ensuring compliance with thesponsors obligations under the CTR and be the addressee for all communications provided for under the CTR.Thesponsor must take o
288、ut a clinical trial insurance policy,and in most EU Member States,the sponsor is liable to provide nofault compensation to any study subject injured in the clinical trial.The CTR is directly applicable in all Member States(meaning that no national implementing legislation in each EUMember State is r
289、equired).Under the CTR,there is a centralized application procedure where one national authority takesthe lead in reviewing the application and the other national authorities have only limited involvement(instead ofsubmitting applications separately to each national competent authority and ethics co
290、mmittee in the Member States inwhich the trial will be conducted,as was the case under the previous EU Clinical Trials Directive).The CTR also makes itmore efficient for EU Member States to evaluate and authorize applications together,via the Clinical Trials InformationSystem.Medicines used in clini
291、cal trials must be manufactured in accordance with Good Manufacturing Practices,orGMP.Other national and EU-wide regulatory requirements may also apply.Disclosure of Clinical Trial InformationThe CTR significantly enlarges the publication and transparency obligations for clinical trial sponsors from
292、 the previousposition under the Clinical Trials Directive.Additionally,the CTR requires that EU Member States adopt specificmeasures,including penalties,to adequately sanction infringements of the relevant transparency obligations.Table of Contents22Marketing AuthorisationsIn the EU,medicinal produc
293、ts can only be placed on the market after obtaining a marketing authorisation,or MA.Toobtain regulatory approval of a product in the EU,we must submit a marketing authorization application,or MAA.Theprocess for doing this depends,among other things,on the nature of the medicinal product.Centralized
294、ProcedureUnder the centralized procedure,the European Commission issues a single MA,based on the opinion of the EuropeanMedicines Agencys,or EMA,Committee for Medicinal Products for Human Use,or CHMP,which is valid across theentire territory of the EU,as well as Iceland,Liechtenstein and Norway(i.e.
295、the European Economic Area,or EEA).Thecentralized procedure is compulsory for human medicines that are:(i)derived from biotechnology processes;(ii)advanced-therapy medicinal products(i.e.gene therapy,somatic cell-therapy or tissue-engineered medicines);(iii)contain a new active substance indicated f
296、or the treatment of certain diseases,such as HIV,AIDS,cancer,diabetes,neurodegenerative diseases,viral diseases or autoimmune diseases and other immune dysfunctions;and(iv)officiallydesignated orphan medicines.For medicines that do not fall within these categories,an applicant has the option ofsubmi
297、tting an application for a centralized MA to the EMA if the product contains a new active substance not yetauthorized in the EU,or the medicine concerned is a significant therapeutic,scientific or technical innovation,or that thegranting of a centralized authorization would be in the interest of pub
298、lic health at the EU-level.Under the centralized procedure the maximum timeframe for the evaluation of an MAA by the EMA is 210 days,excluding clock stops,when additional written or oral information is to be provided by the applicant in response toquestions asked by the CHMP.Clock stops may extend t
299、he timeframe of evaluation of an MAA considerably beyond 210days.Where the CHMP gives a positive opinion,the EMA provides the opinion together with supporting documentation tothe European Commission,who makes the final decision to grant an MA,which is issued within 67 days of receipt of theEMAs reco
300、mmendations.Accelerated assessment may be granted by the CHMP in exceptional cases,when a medicinalproduct is of major interest from the point of view of public health and,in particular,from the point of view of therapeuticinnovation.Accelerated assessment of an MAA will be performed by the CHMP in
301、no more than 150 days(excludingclock stops)but it is possible that the CHMP may revert to the standard time limit for the centralized procedure if itdetermines that the application is no longer appropriate to conduct an accelerated assessment.Innovative products thattarget an unmet medical need(ther
302、e is no satisfactory method of diagnosis,prevention or treatment in the EU or,if there is,the new medicine will bring a major therapeutic advantage)may be eligible for a number of expedited development andreview programs,such as the PRIME scheme,which provides incentives similar to the breakthrough
303、therapy designation inthe United States.PRIME is a voluntary scheme aimed at enhancing the EMAs support for the development of medicinesthat target unmet medical needs.It is based on increased interaction and early dialogue with companies developingpromising medicines,to optimize their product devel
304、opment plans and speed up their evaluation to help them reachpatients earlier.Product developers that benefit from PRIME designation can expect to be eligible for acceleratedassessment but this is not guaranteed.The benefits of a PRIME designation include the appointment of a CHMP rapporteurbefore s
305、ubmission of an MAA,early dialogue and scientific advice at key development milestones,and the potential toqualify products for accelerated review earlier in the application process.National Authorisation ProceduresThere are also two other possible routes to authorize medicinal products in several M
306、ember States.National MAs areissued by the national competent authorities of the EU Member States and only cover their respective territory.They areavailable for products that fall outside the scope of the centralized procedure:Decentralized procedure.If the product has not received a national MA in
307、 any Member State at the time ofapplication,an applicant may apply for simultaneous MAs in more than one EU Member State.Under thedecentralized procedure an identical dossier is submitted to the national competent authority of each of theMember States in which an MA is sought,one of which is selecte
308、d by the applicant as the Reference MemberState.Table of Contents23Mutual recognition procedure.Under the mutual recognition procedure,a medicine that has already beenauthorized in one EU Member State in accordance with the national procedures of that Member State,can berecognized in another Member
309、State.MAs have an initial duration of five years.After these five years,the authorization may be renewed for an unlimited periodon the basis of a reevaluation of the risk-benefit balance.Similar to the United States,there is a process for authorization of generic/biosimilar versions of innovator med
310、icinalproducts authorized in the EU.Abridged applications for the authorization of generic/biosimilar versions of medicinalproducts authorized via the EU centralized procedure can be submitted to the EMA through the centralized procedurereferencing the innovators data.Data and Market ExclusivityIn t
311、he EU,innovative medicinal products approved on the basis of a complete and independent data package qualify foreight years of data exclusivity upon the grant of an MA and an additional two years of market exclusivity.Data exclusivityprevents generic and biosimilar applicants from referencing the in
312、novators preclinical and clinical trial data contained inthe dossier of the reference product when applying for an MA for a period of eight years from the date on which thereference product was first authorized in the EU.During the additional two-year period of market exclusivity,a generic orbiosimi
313、lar MAA can be submitted and authorized,and the innovators data may be referenced,but no generic or biosimilarmedicinal product can be marketed until the expiration of the market exclusivity period.The overall 10 year period will beextended to a maximum of 11 years if,during the first eight years of
314、 those 10 years,the MA holder obtains anauthorization for one or more new therapeutic indications which,during the scientific evaluation prior to authorization,isheld to bring a significant clinical benefit in comparison with existing therapies.There is no guarantee that a product willbe considered
315、by the EMA to be an innovative medicinal product,and products may not qualify for data exclusivity.Evenif a product is considered to be an innovative medicinal product so that the innovator gains the prescribed period of dataexclusivity,another company may market another version of the product if su
316、ch company obtained an MA based on anMAA with a complete and independent data package of pharmaceutical tests,preclinical tests and clinical trials.Orphan Medicinal ProductsThe criteria for designating an“orphan medicinal product”in the EU are similar in principle to those in the United States.A med
317、icinal product may be designated as orphan if(1)it is intended for the diagnosis,prevention or treatment of a life-threatening or chronically debilitating condition;(2)either(a)such condition affects no more than five in 10,000 persons inthe EU when the application is made,or(b)it is unlikely that t
318、he marketing of the product,without the benefits derivedfrom orphan status,would generate sufficient return in the EU to justify the necessary investment in its development;and(3)there exists no satisfactory method of diagnosis,prevention or treatment of such condition authorized for marketing inthe
319、 EU or,if such a method exists,the product in question would be of significant benefit compared to products availablefor that condition.In the EU,orphan designation entitles a party to financial incentives such as reduction of fees or fee waivers,regulatoryassistance and the possibility to apply for
320、 a centralized MA.The application for orphan designation must be submittedbefore the application for an MA.Orphan designation does not convey any advantage in,or shorten the duration of,theregulatory review and approval process.The grant of an MA for an orphan medicinal product leads to ten years of
321、 marketexclusivity.During the ten-year market exclusivity period,the EMA cannot accept an MAA,or grant an MA,or accept anapplication to extend an MA,for the same therapeutic indication,in respect of a“similar medicinal product.”A“similarmedicinal product”is defined as a medicinal product containing
322、a similar active substance or substances as contained in anauthorized orphan medicinal product,and which is intended for the same therapeutic indication.An orphan medicinalproduct can also obtain an additional two years of market exclusivity in the EU for pediatric studies conducted incompliance wit
323、h an agreed pediatric investigation plan,or PIP.No extension to any supplementary protection certificatecan be granted on the basis of pediatric studies for orphan indications.The 10-year market exclusivity may be reduced to six years if,at the end of the fifth year,it is established that the orphan
324、designation criteria are no longer met,including where it is shown that the product is sufficiently profitable not to justifyTable of Contents24maintenance of market exclusivity.At any time,an MA may be granted to a similar medicinal product for the sametherapeutic indication if:(i)a second applican
325、t can establish that its product,although similar to the authorized product,issafer,more effective or otherwise clinically superior;(ii)the MA holder for the authorized orphan product consents to asecond orphan medicinal product application;or(iii)the MA holder for the authorized orphan product cann
326、ot supplyenough orphan medicinal product.Pediatric DevelopmentIn the EU,MAAs for new medicinal products have to include the results of trials conducted in the pediatric population,incompliance with a PIP agreed with the EMAs Pediatric Committee,or PDCO.The PIP sets out the timing and measurespropose
327、d to generate data to support a pediatric indication of the product for which an MA is being sought.The PDCO cangrant a deferral of the obligation to implement some or all of the measures of the PIP until there are sufficient data todemonstrate the efficacy and safety of the product in adults.Furthe
328、r,the obligation to provide pediatric clinical trial datacan be waived by the PDCO when these data are not needed or appropriate because the product is likely to be ineffective orunsafe in children,the disease or condition for which the product is intended occurs only in adult populations,or when th
329、eproduct does not represent a significant therapeutic benefit over existing treatments for pediatric patients.Once the MA isobtained in all Member States and study results are included in the product information,even when negative,the product iseligible for a six-months supplementary protection cert
330、ificate,or SPC extension(provided an application for suchextension is made at the same time as filing the SPC application for the product,or at any point up to two years before theSPC expires)or,in the case of orphan medicinal products,a two-year extension of the orphan market exclusivity is granted
331、.This pediatric reward is subject to specific conditions and is not automatically available when data in compliance with thePIP are developed and submitted.Failure to comply with EU and Member State laws that apply to the conduct of clinical trials,manufacturing approval,marketing of such products,b
332、oth before and after grant of the MA,manufacturing of pharmaceutical products,statutoryhealth insurance,bribery and anti-corruption or with other applicable regulatory requirements may result in administrative,civil or criminal penalties.These penalties could include delays or refusal to authorize t
333、he conduct of clinical trials,or togrant an MA,product withdrawals and recalls,product seizures,suspension,withdrawal or variation of the MA,total orpartial suspension of production,distribution,manufacturing or clinical trials,operating restrictions,injunctions,suspension of licenses,fines and criminal penalties.Reform of the Regulatory Framework in the European UnionThe European Commission intro
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