Axsome Therapeutics Inc. (AXSM) 2024年年度報告「NASDAQ」.pdf

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

2、E ACT OF 1934 For the transition period from _ to _ Commission File Number 001-37635 AXSOME THERAPEUTICS,INC.(Exact name of registrant as specified in its charter)Delaware(State or other jurisdiction ofincorporation or organization)45-4241907(I.R.S.EmployerIdentification No.)One World Trade Center22

3、nd FloorNew York,New York(Address of principal executive offices)10007(Zip Code)Registrants telephone number,including area code:(212)332-3241 Securities registered pursuant to Section 12(b)of the Act:Title of each class:Common Stock,Par Value$0.0001 Per Share(Title of Class)Trading Symbol(s)AXSMNam

4、e of Each Exchange on Which Registered The Nasdaq Global Market Securities registered pursuant to Section 12(g)of the Act:NoneIndicate by check mark if the registrant is a well-known seasoned issuer,as defined in Rule 405 of the Securities Act.Yes No Indicate by check mark if the registrant is not r

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

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

7、the preceding 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 filed,an accelerated filer,a non-accelerated filer,a smaller reporting company or an emerging growth company.See defin

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

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

10、nagements assessment of the effectiveness of its internal control over financial reporting under Section 404(b)of the Sarbanes-Oxley(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,indi

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

12、d compensation received by any of the registrants executive officers during the relevant recovery period pursuant to 240.10D-1(b).Indicate by check mark whether the registrant is a shell company(as defined in Rule 12b-2 of the Exchange Act).Yes No The aggregate market value of voting common stock he

13、ld by non-affiliates of the registrant(assuming for purposes of this calculation,without conceding,that all executive officers and directors are“affiliates”)was approximately$3.2 billion as of June 30,2024,based on the closing sale price of such stock as reported on The Nasdaq Global Market.There we

14、re 48,765,403 shares of the registrants common stock outstanding as of February 11,2025.DOCUMENTS INCORPORATED BY REFERENCEPortions of the registrants definitive proxy statement for its 2025 Annual Meeting of Stockholders(the“Proxy Statement”),to be filed within 120 days of the registrants fiscal ye

15、ar ended December 31,2024,are incorporated by reference in Part III of this Annual Report on Form 10-K.Except with respect to information specifically incorporated by reference in this Annual Report on Form 10-K,the Proxy Statement is not deemed to be filed as part of this Annual Report on Form 10-K

16、.2Table of ContentsAXSOME THERAPEUTICS,INC.ANNUAL REPORT ON FORM 10-KFOR THE FISCAL YEAR ENDED DECEMBER 31,2024 TABLE OF CONTENTS Page SPECIAL CAUTIONARY NOTICE REGARDING FORWARD-LOOKING STATEMENTS3 PART IITEM 1Business4ITEM 1ARisk Factors46ITEM 1BUnresolved Staff Comments104ITEM 1CCybersecurity104I

17、TEM 2Properties105ITEM 3Legal Proceedings106ITEM 4Mine Safety Disclosures108 PART II ITEM 5Market for Registrants Common Equity,Related Stockholder Matters and Issuer Purchases of Equity Securities109ITEM 6Reserved110ITEM 7Managements Discussion and Analysis of Financial Condition and Results of Ope

18、rations111ITEM 7AQuantitative and Qualitative Disclosure About Market Risk126ITEM 8Financial Statements and Supplementary Data126ITEM 9Changes in and Disagreements with Accountants on Accounting and Financial Disclosure126ITEM 9AControls and Procedures127ITEM 9BOther Information128ITEM 9CDisclosure

19、Regarding Foreign Jurisdictions that Prevent Inspections128 PART III ITEM 10Directors,Executive Officers and Corporate Governance129ITEM 11Executive Compensation129ITEM 12Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters129ITEM 13Certain Relationships and

20、 Related Transactions and Director Independence129ITEM 14Principal Accountant Fees and Services129 PART IV ITEM 15Exhibits and Financial Statement Schedules130ITEM 16Form 10-K Summary135 Signatures136 3Table of ContentsCAUTIONARY NOTE REGARDING FORWARDLOOKING STATEMENTSCertain matters discussed in t

21、his report,including matters discussed under the caption“Managements Discussion and Analysis of Financial Condition and Results of Operations,”may constitute forward-looking statements for purposes of the Securities Act of 1933,as amended,or the Securities Act,and the Securities Exchange Act of 1934

22、,as amended,or the Exchange Act,and involve known and unknown risks,uncertainties and other factors that may cause our actual results,performance or achievements to be materially different from the future results,performance or achievements expressed or implied by such forward-looking statements.The

23、 words“anticipate,”“believe,”“estimate,”“may,”“expect”and similar expressions are generally intended to identify forward-looking statements.Our actual results may differ materially from the results anticipated in these forward-looking statements due to a variety of factors,including,without limitati

24、on,those discussed under the captions“Risk Factors,”“Managements Discussion and Analysis of Financial Condition and Results of Operations”and elsewhere in this report,as well as other factors which may be identified from time to time in our other filings with the U.S.Securities and Exchange Commissi

25、on,or the SEC,or in the documents where such forward-looking statements appear.All written or oral forward-looking statements attributable to us are expressly qualified in their entirety by these cautionary statements.Such forward-looking statements include,but are not limited to,statements about:ou

26、r expectations for increases or decreases in expenses;our expectations for the clinical and preclinical development,manufacturing and regulatory approval of our product candidates,and commercialization of our pharmaceutical products or any other products that we may acquire or in-license;our estimat

27、es of the sufficiency of our existing capital resources combined with future anticipated cash flows to finance our operating requirements;our expectations for incurring capital expenditures to expand our research and development and manufacturing capabilities;unforeseen circumstances or other disrup

28、tions to normal business operations arising from or related to geopolitical conflicts or pandemics;our future revenue projections,sales forecasts,and potential peak market data;our expectations for generating revenue or becoming profitable on a sustained basis;our expectations or ability to enter in

29、to marketing and other partnership agreements;our expectations or ability to enter into product acquisitions and in-licensing transactions;our expectations or ability to build our own commercial infrastructure to manufacture,market and sell our products;our expected losses;our ability to obtain and

30、maintain intellectual property protection for our products;the acceptance of our products by doctors,patients,or payors;our stock price and its volatility;our ability to attract and retain key personnel;the performance of third-party manufacturers;our expectations for future capital requirements;and

31、our ability to successfully implement our strategy.The forward-looking statements contained in this report reflect our views and assumptions only as of the date that this report is signed.Except as required by law,we assume no responsibility for updating any forward-looking statements.We qualify all

32、 of our forward-looking statements by these cautionary statements.In addition,with respect to all of our forward-looking statements,we claim the protection of the safe harbor for forward-looking statements contained in the Private Securities Litigation Reform Act of 1995.4Table of ContentsPART IUnle

33、ss the context requires otherwise,references in this report to“Axsome,”“Company,”“we,”“us”and“our”and similar designations refer to Axsome Therapeutics,Inc.and our subsidiaries.ITEM 1.BUSINESS.OVERVIEWWe are a biopharmaceutical company dedicated to the development and delivery of transformative medi

34、cines for people impacted by central nervous system,or CNS,conditions.We deliver scientific breakthroughs by identifying critical gaps in care and develop differentiated products with a focus on novel mechanisms of action that enable meaningful advancements in patient outcomes.Together,we are on a m

35、ission to solve some of the brains biggest problems so patients and their loved ones can flourish.Our PipelineOur pipeline consists of three commercial products for major depressive disorder,or MDD,and excessive daytime sleepiness,or EDS,associated with narcolepsy and obstructive sleep apnea,our rec

36、ently FDA-approved product for the acute treatment of migraine,as well as multiple innovative,late-stage,patent-protected product candidates addressing a broad range of serious neurological and psychiatric conditions that collectively impact over 150 million people in the United States.We are levera

37、ging our deep expertise and experience in neuroscience to maximize the potential of our approved products for additional CNS conditions,as well as advance our novel product candidates that we believe may offer distinct advantages over currently available therapies.5Table of ContentsCommercial Produc

38、ts 1.Auvelity.Auvelity(dextromethorphan-bupropion)is a novel,oral,N-methyl-D-aspartate(NMDA)receptor antagonist,sigma-1 receptor agonist,aminoketone,and CYP2D6 inhibitor indicated for the treatment of MDD in adults.Auvelity was developed by the Company and approved by the U.S.Food and Drug Administr

39、ation,or FDA,for the treatment of MDD in adults in August 2022.We initiated the commercial launch of Auvelity in the United States in October 2022.We refer to the proprietary dextromethorphan-bupropion formulation contained in Auvelity as AXS-05.As used in this report,“Auvelity”refers to AXS-05 appr

40、oved by the FDA for the treatment of MDD in adults,and“AXS-05”refers to AXS-05 in development programs for the treatment of indications beyond MDD in adults.2.Sunosi.Sunosi(solriamfetol)is a novel,oral,dopamine and norepinephrine reuptake inhibitor(DNRI),trace amine-associated receptor 1(TAAR1)agoni

41、st,and 5-HT agonist indicated for the treatment of EDS in patients with narcolepsy or obstructive sleep apnea,or OSA.Sunosi was approved for the treatment of EDS in the United States in 2019 and by the European Commission in 2022.We acquired the U.S.rights to Sunosi from Jazz Pharmaceuticals plc,or

42、Jazz,in May 2022 and the ex-U.S.rights(excluding certain Asian markets)from Jazz in November 2022.We have been commercializing Sunosi since we completed these acquisitions.SK Biopharmaceuticals Co.Ltd.,or SK,is the originator of Sunosi and retains rights in 12 Asian markets,including China,Korea,and

43、 Japan.We refer to the acquisition of Sunosi herein as the Acquisition.In February 2023,we entered into a licensing agreement,or the Pharmanovia License Agreement,with Atnahs Pharma UK Limited,or Pharmanovia,that granted to Pharmanovia the exclusive right to market Sunosi in Europe and certain count

44、ries in the Middle East and North Africa,referred to as the Licensed Territory.As used in this report,“Sunosi”refers to solriamfetol approved for the treatment of EDS in patients with narcolepsy or OSA,and“solriamfetol”refers to solriamfetol in development programs for the treatment of indications b

45、eyond EDS in patients with narcolepsy or OSA.3.Symbravo.Symbravo(MoSEIC meloxicam rizatriptan),or AXS-07,is a novel,oral,rapidly absorbed,multi-mechanistic,selective COX-2 inhibitor and 5-HT agonist indicated for the acute treatment of migraine with or without aura.Symbravo was developed by the Comp

46、any and approved by the FDA for the acute treatment of migraine with or without aura in adults in January 2025.Development ProgramsAXS-05(dextromethorphan-bupropion)is a novel,oral,investigational NMDA receptor antagonist,sigma-1 receptor agonist,aminoketone,and CYP2D6 inhibitor being developed for

47、the treatment of Alzheimers disease agitation,or AD agitation,and smoking cessation.AXS-05 utilizes a proprietary formulation and dose of dextromethorphan and bupropion,and Axsomes metabolic inhibition technology,to modulate the delivery of the components.AXS-05 has been granted FDA Breakthrough The

48、rapy designation for AD agitation.In December 2024,we announced the successful completion of our Phase 3 clinical program of AXS-05 in AD agitation,which consists of the ADVANCE-1 Phase 2/3 trial,ADVANCE-2 Phase 3 trial,ACCORD-1 Phase 3 trial,and ACCORD-2 Phase 3 trial evaluating the efficacy and sa

49、fety of AXS-05 in patients with AD agitation,as well as an open-label extension trial evaluating the long-term safety of AXS-05.A positive Phase 2 trial of AXS-05 in smoking cessation has been completed under a research collaboration with Duke University.AXS-12(reboxetine)is a novel,oral,investigati

50、onal,highly selective and potent norepinephrine reuptake inhibitor and cortical dopamine modulator being developed for the treatment of narcolepsy.AXS-12 has been granted FDA Orphan Drug Designation for narcolepsy.Our clinical program for AXS-12 in narcolepsy includes our completed positive CONCERT

51、Phase 2 trial and SYMPHONY Phase 3 trial evaluating the efficacy and safety of AXS-12 compared to placebo,as well as our completed positive ENCORE Phase 3 trial evaluating the long-term efficacy and safety of AXS-12 in patients with narcolepsy with cataplexy.AXS-14(esreboxetine)is a novel,oral,inves

52、tigational,highly selective and potent norepinephrine reuptake inhibitor being developed for the management of fibromyalgia.Esreboxetine,the SS-enantiomer of reboxetine,is more potent and selective than racemic reboxetine.We have in-licensed data from Pfizer Inc.,or Pfizer,which includes a completed

53、 positive Phase 2 and Phase 3 trial in fibromyalgia.1ATM1B/1D 6Table of ContentsSolriamfetol is an oral,DNRI,TAAR1 agonist,and 5-HT1A agonist being developed for the treatment of attention deficit hyperactivity disorder,or ADHD,major depressive disorder,or MDD,binge eating disorder,or BED,and excess

54、ive sleepiness associated with shift work disorder,or SWD.We are currently conducting four Phase 3,randomized,double-blind,placebo-controlled,multicenter trials evaluating the efficacy and safety of solriamfetol in each of these indications,including the FOCUS study in ADHD,the PARADIGM study in MDD

55、,the ENGAGE study in BED,and the SUSTAIN study in SWD.Additionally,we are currently evaluating other product candidates that we intend to develop for CNS disorders.We aim to become a fully integrated biopharmaceutical company that develops and commercializes differentiated therapies that increase av

56、ailable treatment options and improve the lives of patients living with CNS disorders.Our product candidates are protected by a combination of patents,trade secrets,and proprietary know-how.If approved,they may also be eligible for periods of regulatory exclusivity.Our intellectual property portfoli

57、o includes issued U.S.and foreign patents with claims extending to 2034,2040,2041,and 2043 for AXS-05 and to 2039 for AXS-12,as well as U.S.and foreign patent applications for AXS-05,AXS-12,and AXS-14.Our issued U.S.and foreign patents for Symbravo include claims extending out to 2040.Our Orange Boo

58、k listed patents in the United States for Sunosi extend out to 2042.We also have patents in various other countries pertaining to Sunosi.In June 2024,we entered into a settlement agreement with Unichem Laboratories Ltd.,or Unichem,resolving patent litigation related to Sunosi that permits Unichem to

59、 begin selling its generic version of Sunosi on June 30,2042,or earlier under certain circumstances.In August 2024,we reached an agreement with Sandoz Inc.,or Sandoz,to dismiss the patent litigation related to Sunosi following Sandozs withdrawal of its Abbreviated New Drug Application,or ANDA,for a

60、generic equivalent of Sunosi.As a result,the litigation has been dismissed without prejudice.In February 2025,we entered into a settlement agreement resolving all outstanding patent litigation related to Auvelity.The litigation resulted from submission by Teva of an ANDA to the FDA seeking approval

61、to market a generic version of Auvelity in the U.S.prior to the expiration of applicable Axsome patents.Under the terms of the settlement agreement,Axsome will grant Teva a license to sell its generic version of Auvelity beginning on or after March 31,2039,if pediatric exclusivity is granted,or on o

62、r after September 30,2038,if no pediatric exclusivity is granted,subject to FDA approval and conditions and exceptions customary for agreements of this type.Our StrategyOur goal is to efficiently develop and commercialize novel,differentiated therapies for the treatment of CNS disorders.The primary

63、elements of our strategy to achieve this goal are the following:Pursue novel CNS indications with high unmet medical need.We believe that CNS disorders are significantly underserved therapeutic segments with currently limited treatment options.We are developing our product candidates for CNS indicat

64、ions where there exist significant unmet medical needs,or that have no or few FDAapproved pharmacological treatments.CNS disorders are often disabling,difficult to treat,and associated with significant comorbidities.By focusing on areas of unmet medical need,we aim to develop products that have the

65、potential to change current medical practice,and that are highly relevant to patients,physicians,and regulatory bodies.Many of these indications have significant patient populations,which,when combined with the limitations of current treatments,should provide us with attractive commercial opportunit

66、ies.Develop products with our proprietary medicinal chemistry and formulation technologies.Our proprietary medicinal chemistry and formulation technologies allow us to continue to design new and innovative medicines to treat CNS conditions.These technologies and capabilities include:(1)chiral chemis

67、try and formulation to identify,isolate and stabilize chirally pure enantiomers,(2)metabolic inhibition as a novel drug delivery method to increase the bioavailability and prolong the half-life of target drug molecules,(3)the MoSEIC,or Molecular Solubility Enhanced Inclusion Complex,technology which

68、 is designed to substantially increase the solubility and speed the absorption of target drug molecules,and(4)proprietary chemical synthesis and analysis to produce target drug molecules.7Table of ContentsDevelop products with differentiated profiles.We aim to develop products with novel mechanisms

69、of action for the intended indications that may yield differentiated product profiles.For example,AXS-05 combines several mechanisms of action resulting in a unique pharmacological profile that may be relevant to the treatment of numerous CNS disorders.The MoSEIC technology is designed to improve th

70、e absorption of drug molecules after oral administration and is utilized in Symbravo(AXS-07).We believe that products with clearly differentiated features will be attractive to patients and their physicians and will provide us with a competitive commercial advantage.Reduce clinical and regulatory ri

71、sk,limit development costs,and accelerate time to market.Some of our product candidates incorporate chemical entities with long histories of clinical use and well characterized safety profiles.Use of well characterized molecules has allowed us to rapidly complete early clinical development of our pr

72、oduct candidates and may reduce the risk of late-stage clinical failures due to unexpected toxicities.This strategy may allow us to seek FDA approval for some of our product candidates using the 505(b)(2)regulatory pathway.Section 505(b)(2)of the Federal Food,Drug,and Cosmetic Act,or FDCA,permits an

73、 applicant to file a new drug application,or NDA,that relies,in part,on the FDAs prior findings of safety and efficacy in the approval of a similar drug,or on published literature.It therefore allows us to leverage previous preclinical and clinical experience with the active molecules in some of our

74、 product candidates and potentially forego conducting certain lengthy and costly preclinical studies,reduce clinical and regulatory risk,limit development costs,and accelerate our time to commercialization.Retain commercial rights in the United States,where appropriate,and selectively partner outsid

75、e of the United States to maximize the value of our product candidates.We intend to commercialize our product candidates,if approved,in the United States through the establishment of our own focused,costeffective sales and marketing organization.We intend to selectively partner commercial rights out

76、side of the United States with third parties to maximize the value of our product candidates without the substantial investment required to develop independent sales forces in those geographies.We continue to evaluate strategic options for the commercialization of our other product candidates.CNS Pr

77、oduct CandidatesAXS05OverviewAXS-05(dextromethorphan-bupropion)is a novel,oral,investigational NMDA receptor antagonist,sigma-1 receptor agonist,aminoketone,and CYP2D6 inhibitor being developed for the treatment of CNS disorders.AXS-05 consists of a proprietary formulation and dose of dextromethorph

78、an and bupropion and utilizes Axsomes metabolic inhibition technology.The dextromethorphan component of AXS-05 is an uncompetitive antagonist of the NMDA receptor,an ionotropic glutamate receptor,and a sigma-1 receptor agonist.Dextromethorphan is quickly eliminated from the body following administra

79、tion due to extensive first pass metabolism,which results in low blood levels even at high doses.The bupropion component of AXS-05 serves to increase the bioavailability of dextromethorphan by inhibiting its metabolism and is also a dopamine and norepinephrine reuptake inhibitor(DNRI).Based on its u

80、nique mechanism of action with multimodal activity,we believe that AXS-05 has potential therapeutic benefit for a variety of CNS disorders.We are currently developing AXS-05 for the treatment of AD agitation and smoking cessation.Alzheimers Disease(AD)AgitationAD is an irreversible,progressive neuro

81、degenerative disorder that manifests initially as forgetfulness and advances to severe cognitive impairment and memory loss.It is the most common form of dementia,affecting approximately 7 million people in the United States,a number that is anticipated to double by 2060.Approximately 70%of AD patie

82、nts experience agitation,which is characterized by emotional distress,verbal and physical aggressiveness,disruptive irritability,and disinhibition.AD agitation is associated with increased caregiver burden,decreased functioning,earlier institutionalization,and death.8Table of ContentsThere is only o

83、ne FDA-approved pharmacological treatment for the treatment of AD agitation.Currently,AD patients with agitation are often treated with antipsychotic medications despite black box warnings for the use of these medications in this patient population.Typical antipsychotics prescribed for agitation,agg

84、ression,or insomnia are associated with functional decline,extrapyramidal symptoms,cardiovascular effects,and sedation in patients with AD,while studies indicate that atypical antipsychotics may be associated with increased rates of cerebrovascular events and death in patients with dementia.In June

85、2020,we announced that AXS-05 had received FDA Breakthrough Therapy designation for AD agitation.In August 2020,we announced confirmation of the pivotal development status and plan for AXS-05 for the treatment of AD agitation following a Breakthrough Therapy meeting with the FDA.In December 2024,we

86、announced the successful completion of our Phase 3 clinical program of AXS-05 in AD agitation,which consists of the ADVANCE-1 Phase 2/3 trial,ADVANCE-2 Phase 3 trial,ACCORD-1 Phase 3 trial,and ACCORD-2 Phase 3 trial evaluating the efficacy and safety of AXS-05 in patients with AD agitation,as well a

87、s an open-label extension trial evaluating the long-term safety of AXS-05 in AD agitation.ADVANCE-1 StudyIn July 2017,we initiated the ADVANCE-1 study,a Phase 2/3,randomized,double-blind,controlled,multicenter U.S.trial to evaluate the efficacy and safety of AXS-05 in patients with AD agitation.A to

88、tal of 366 patients with a diagnosis of probable AD and clinically meaningful agitation associated with their AD were 1:1 randomized to receive AXS-05(dextromethorphan-bupropion tablet,dose escalated to 45 mg-105 mg twice daily),bupropion(dose escalated to 105 mg twice daily),or matching placebo for

89、 5 weeks.An independent data monitoring committee performed an interim futility analysis and recommended no further randomization to the bupropion arm.Subsequently,patients were 1:1 randomized to receive AXS-05 or placebo.The primary endpoint was the change from baseline in the Cohen-Mansfield Agita

90、tion Inventory,or CMAI,total score compared to placebo at Week 5.In April 2020,we announced that AXS-05 achieved the primary endpoint and rapidly and substantially improved agitation in patients with AD.AXS-05 met the primary endpoint by demonstrating a statistically significant mean reduction in th

91、e CMAI total score compared to placebo at Week 5,with mean reductions from baseline of 15.4 points for AXS-05 and 11.5 points for placebo(p=0.010).These results represent a mean percentage reduction from baseline of 48%for AXS-05 compared to 38%for placebo.AXS-05 was also superior to bupropion on th

92、e CMAI total score(p0.001),establishing component contribution.Improvement on the CMAI total score numerically favored AXS-05 over placebo starting as early as Week 2 and achieved statistical significance by Week 3(p=0.007),only one week after full dosing with AXS-05.Additionally,a statistically sig

93、nificantly greater proportion of patients in the AXS-05 group achieved a clinical response on the CMAI,defined asa 30%or greater improvement from baseline,compared to placebo at Week 5(73%for AXS-05 vs.57%for placebo,p=0.005).Consistent with these results,AXS-05 demonstrated a statistically signific

94、antly greater improvement in agitation as measured by clinicians global assessments of change measured using the modified Alzheimers Disease Cooperative Study-Clinical Global Impression of Change for Agitation,or mADCS-CGIC,compared to placebo(p=0.036).AXS-05 was well tolerated in the ADVANCE-1 tria

95、l.The most common adverse events were somnolence(8.2%for AXS-05 vs.4.1%for bupropion vs.3.2%for placebo),dizziness(6.3%for AXS-05 vs.10.2%for bupropion vs.3.2%for placebo),and diarrhea(4.4%for AXS-05 vs.6.1%for bupropion vs.4.4%for placebo).Discontinuation rates due to adverse events were low and ba

96、lanced among treatment groups(1.3%for AXS-05 vs.2.0%for bupropion vs.1.3%for placebo).Serious adverse events were reported in 3.1%of patients in the AXS-05 group,8.2%of patients in the bupropion group,and 5.7%of patients in the placebo group,none of which were deemed related to the study drug.There

97、were no deaths in the AXS-05 group,one death in the bupropion group,and one death in the placebo group.AXS-05 was not associated with sedation or cognitive decline as measured by the Mini-Mental State Examination,or MMSE.9Table of ContentsACCORD-1 StudyIn December 2020,we initiated the ACCORD-1 stud

98、y,a Phase 3,randomized,double-blind,placebo-controlled,multicenter trial to evaluate the efficacy and safety of AXS-05 in patients with AD agitation.The trial consisted of a 9-week,open-label period during which patients were treated with AXS-05 and monitored for a sustained clinical response,follow

99、ed by a 26-week,double-blind,placebo-controlled,randomized withdrawal period.Sustained clinical response was defined as a 30%improvement from baseline in the CMAI total score and improvement on the Patient Global Impression of Change,or PGI-C,scale(score of 3)that were maintained for at least 4 cons

100、ecutive weeks.A total of 178 patients were enrolled into the open-label period and treated with AXS-05,and 108 patients were 1:1 randomized to continue AXS-05(n=53)or to switch to placebo(n=55)for up to 26 weeks or until a relapse of agitation occurred.Relapse was defined as a 10-point worsening in

101、the CMAI total score from randomization,or a CMAI total score greater than that at study entry,or hospitalization or other institutionalization due to AD agitation.The primary endpoint was the time from randomization to relapse of AD agitation calculated by Kaplan-Meier estimates and the hazard rati

102、o.Secondary assessments included the CMAI,clinician-and caregiver-rated scales,and safety parameters.The key secondary endpoint was the percentage of patients who relapsed compared to placebo.In November 2022,we announced that AXS-05 achieved the primary endpoint in the ACCORD-1 Phase 3 trial by sub

103、stantially and statistically significantly delaying the time to relapse of AD agitation compared to placebo,with a hazard ratio for time to relapse of 0.275(p=0.014),representing a 3.6-fold lower risk of relapse compared to placebo.AXS-05 also met the key secondary endpoint by statistically signific

104、antly preventing relapse of AD agitation compared to placebo,with 7.5%of patients in the AXS-05 group relapsing compared to 25.9%of patients in the placebo group(p=0.018).In the open-label treatment period,AXS-05 demonstrated a rapid,substantial,and statistically significant improvement in AD agitat

105、ion compared to baseline as measured by the CMAI total score,starting at Week 1 and continuing throughout at all timepoints(p0.001).Additionally,rapid and substantial improvement in AD agitation was reported by both clinicians and caregivers on global measures.Clinicians reported improvement in AD a

106、gitation with open-label AXS-05 treatment in 66%of patients at 2 weeks and 86%at 5 weeks as measured by the mADCS-CGIC scale.Caregivers reported improvement in AD agitation in 68%of patients at 2 weeks and 89%at 5 weeks as measured by the PGI-C scale.AXS-05 was well tolerated in the ACCORD-1 trial.T

107、he rates of adverse events in the double-blind period were 28.3%in the AXS-05 group and 22.2%in the placebo group.Discontinuation rates due to adverse events were low(0%for AXS-05 vs.1.9%for placebo).One serious adverse event was reported in the AXS-05 group(faecaloma),which was determined by the in

108、vestigator to be not related to the study drug,and two serious adverse events were reported in the placebo group(cardiac arrest,femur fracture).Falls were reported in four patients in the AXS-05 group,none of which were associated with serious adverse events and all of which were determined by the i

109、nvestigators to be not related to the study drug,and in two patients in the placebo group,one of which was associated with a femur fracture.There were no deaths in the AXS-05 group and one death in the placebo group.AXS-05 was not associated with sedation or cognitive decline as measured by the MMSE

110、.ADVANCE-2 StudyIn September 2022,we initiated the ADVANCE-2 study,a Phase 3,randomized,double-blind,placebo-controlled,multicenter trial to evaluate the efficacy and safety of AXS-05 in patients with AD agitation.A total of 408 patients were 1:1 randomized to receive AXS-05(dextromethorphan-bupropi

111、on tablet,dose escalated to 45 mg-105 mg twice daily)or matching placebo for 5 weeks.In December 2024,we announced topline results from the ADVANCE-2 trial.AXS-05 did not achieve statistical significance for the primary endpoint,the change in the CMAI total score compared to placebo at Week 5,with m

112、ean reductions from baseline of 13.8 points for AXS-05 and 12.6 points for placebo.However,results for the primary and nearly all secondary endpoints numerically favored AXS-05 placebo at all time points in the trial.10Table of ContentsAXS-05 was safe and well tolerated in the ADVANCE-2 trial.The ra

113、tes of adverse events in the trial were 26.0%in the AXS-05 group and 21.6%in the placebo group.The most common adverse events were dizziness(5.9%for AXS-05 vs.1.5%for placebo)and headache(4.4%for AXS-05 vs.3.4%for placebo).Falls were reported in one patient(0.5%)in the AXS-05 group,which was determi

114、ned by the investigator to be not related to study drug,and one patient(0.5%)in the placebo group.Two patients in the AXS-05 group reported three serious adverse events,none of which were determinedby the investigators to be related to study drug(asthenia,urinary tract infection,and cerebrovascular

115、accident).Discontinuation rates due to adverse events were low(1.5%for AXS-05 vs.0%for placebo).There were no deaths in the trial,and AXS-05 was not associated with sedation or cognitive decline as measured by the MMSE.ACCORD-2 StudyIn May 2024,we announced that we had initiated the ACCORD-2 study,a

116、 Phase 3,randomized,double-blind,placebo-controlled,multicenter trial to evaluate the efficacy and safety of AXS-05 in patients with AD agitation.The trial consisted of an open-label treatment period followed by a 24-week,double-blind,placebo-controlled,randomized withdrawal period.A total of 167 pa

117、tients,who rolled over from the open-label extension trial of AXS-05,experienced a sustained clinical response with AXS-05 and were 1:1 randomized to continue AXS-05(n=83)or to switch to placebo(n=84).Treatment was continued for up to 24 weeks or until a relapse of agitation occurred.The primary end

118、point was the time from randomization to relapse of AD agitation calculated by Kaplan-Meier estimates and the hazard ratio.The key secondary endpoint was the percentage of patients who relapsed compared to placebo.In December 2024,we announced that AXS-05 achieved the primary endpoint in the ACCORD-

119、2 Phase 3 trial and demonstrated a highly statistically significant delay in the time to relapse of AD agitation compared to placebo,with a hazard ratio for time to relapse of 0.276(p=0.001),representing a 3.6-fold lower risk of relapse compared to placebo.AXS-05 also met the key secondary endpoint

120、by statistically significantly preventing relapse of AD agitation compared to placebo,with 8.4%of patients in the AXS-05 group relapsing compared to 28.6%of patients in the placebo group(p=0.001).Additionally,AXS-05 substantially and statistically significantly prevented worsening of overall Alzheim

121、ers disease severity compared to placebo as measured by the Clinical Global Impression of Severity,or CGI-S,scale for Alzheimers disease,with 13.3%of patients in the AXS-05 group worsening on the CGI-S for Alzheimers disease overall clinical status compared to 39.3%of patients who switched to placeb

122、o(p0.001).In the open-label period,treatment with AXS-05 was associated with a 20.4-point reduction in the CMAI total score at 6 weeks,representing a 46%reduction from the mean baseline score.Additionally,substantial improvement in AD agitation was reported by both clinicians and caregivers on globa

123、l measures.Clinicians reported improvement in AD agitation with open-label AXS-05 treatment in 78%of patients at 8 weeks as measured by the mADCS-CGIC scale.Caregivers reported improvement in AD agitation in 71%of patients at 4 weeks and 78%of patients at 8 weeks as measured by the PGI-C scale.Of th

124、e patients treated for at least 8 weeks during the open-label period,70%experienced a sustained clinical response and were randomized in the double-blind period.AXS-05 was safe and well tolerated in the ACCORD-2 trial.The rates of adverse events in the double-blind period were 29.3%in the AXS-05 gro

125、up and 32.1%in the placebo group,with no individual adverse event occurring in more than 3.7%of patients.Discontinuation rates due to adverse events were low(0%for AXS-05 vs.1.2%for placebo).There were two serious adverse events reported in the trial,both of which occurred in the placebo group(cellu

126、litis and urinary retention).Falls were reported in two patients(2.4%)in the AXS-05 group,only one of which was determined by the investigator to be related to study drug.There were no deaths in the trial,and AXS-05 was not associated with sedation or cognitive decline as measured by the MMSE.11Tabl

127、e of ContentsLong-Term Safety StudyIn December 2024,we announced topline results from the open-label extension trial evaluating the long-term safety and tolerability of AXS-05 in patients with AD agitation.A total of 456 patients were treated with AXS-05 for up to 12 months.AXS-05 was well tolerated

128、 with long-term dosing,with a safety profile consistent with the controlled efficacy and safety trials.The rate of adverse events in the trial was 39.9%,with headache(5.5%)being the only adverse event reported in 5%of patients.Discontinuations due to adverse events with long-term dosing were low(0.7

129、%).Falls were reported in 3.1%of patients,with only 0.2%deemed to be related to the study drug.There were no deaths in the trial,and AXS-05 was not associated with sedation or cognitive decline as measured by the MMSE.Smoking CessationWe are also evaluating AXS-05 as an aid to smoking cessation trea

130、tment.Over 34 million adults in the U.S.smoke cigarettes,50%of whom live with a smoking-related disease.Approximately 70%of smokers report that they want to quit,but only an estimated 3-5%who attempt to quit without assistance are successful for 6-12 months,and even with the currently available trea

131、tment options,relapse rates remain above 80%.Tobacco use results in approximately 500,000 premature deaths each year in the U.S.,according to the Centers for Disease Control and Prevention.Smoking is the single largest cause of preventable disease and death in the U.S.,accounting for nearly 1 in 5 d

132、eaths.Direct health care and lost productivity costs as a result of smoking total approximately$300 billion annually in the U.S.alone.In December 2017,we entered into a research collaboration agreement with Duke University to evaluate AXS-05 in a Phase 2 clinical trial in smoking cessation under an

133、Investigator Sponsored Investigational New Drug Application,or IND.In April 2018,we announced the enrollment of the first patient into a Phase 2 clinical trial of AXS-05 for smoking cessation treatment,which was being conducted under our research collaboration agreement with Duke University.In April

134、 2019,we announced that AXS-05 met the prespecified primary endpoint in the Phase 2 trial in smoking cessation.In November 2021,we announced that we had received from the FDA positive Pre-Investigational New Drug Application,or Pre-IND,meeting written guidance on a proposed clinical developmental pl

135、an for AXS-05 as an aid to smoking cessation.Based on this feedback,Axsome plans to proceed to a pivotal Phase 2/3 trial in this indication.AXS-12 OverviewAXS-12(reboxetine)is a novel,oral,potent,highly selective investigational norepinephrine reuptake inhibitor and cortical dopamine modulator being

136、 developed for the treatment of narcolepsy.In October 2018,we received Orphan Drug Designation from the FDA for AXS-12 for the treatment of narcolepsy.In January 2020,we entered into an exclusive license agreement with Pfizer for Pfizers clinical and nonclinical data,and intellectual property for re

137、boxetine,the active pharmaceutical ingredient in AXS-12.In September 2020,we announced that the Phase 2 CONCERT study and a single Phase 3 study would be sufficient to support the filing of an NDA.In July 2021,we announced that we were notified by the FDA that the FDA had rescinded our Breakthrough

138、Therapy Designation for AXS-12 for the treatment of cataplexy in narcolepsy,due to the FDAs approval of an additional drug product for the treatment of cataplexy in narcolepsy subsequent to their granting AXS-12 Breakthrough Therapy designation.12Table of ContentsNarcolepsyNarcolepsy is a serious an

139、d debilitating orphan neurological condition that causes dysregulation of the sleep-wake cycle and is characterized clinically by EDS,cataplexy,hypnagogic hallucinations,sleep paralysis,and disrupted nocturnal sleep.Narcolepsy afflicts an estimated 185,000 individuals in the U.S.Cataplexy is seen in

140、 an estimated 70%of narcolepsy patients and is characterized by a sudden reduction or loss of muscle tone while a patient is awake,typically triggered by strong emotions such as laughter,fear,anger,stress,or excitement.Narcolepsy is a life-long condition that interferes with cognitive,psychological,

141、and social functioning,increases the risk of work-and driving-related accidents,and is associated with a 1.5-fold higher mortality rate.Our clinical program for AXS-12 in narcolepsy includes our completed positive CONCERT Phase 2 trial and SYMPHONY Phase 3 trial evaluating the efficacy and safety of

142、 AXS-12 compared to placebo,as well as our completed positive ENCORE Phase 3 trial evaluating the long-term efficacy and safety of AXS-12 in patients with narcolepsy with cataplexy.CONCERT StudyIn January 2019,we initiated the CONCERT study to evaluate the efficacy and safety of AXS-12 in narcolepsy

143、.In December 2019,we announced that AXS-12 met the prespecified primary endpoint and significantly reduced the total number of cataplexy attacks compared to placebo.CONCERT was a Phase 2,randomized,double-blind,placebo-controlled,crossover,multicenter,U.S.trial in which 21 patients with a diagnosis

144、of narcolepsy with cataplexy were all treated with orally administered AXS-12 for 2 weeks,and with placebo for 2 weeks,with the treatment periods separated by 1 week of down-titration and washout.AXS-12 met the prespecified primary endpoint by demonstrating a highly statistically significant reducti

145、on from baseline in the mean weekly number of cataplexy attacks,averaged for the 2-week treatment period,the overall treatment effect,compared to placebo(p0.001).At Week 2,AXS-12 demonstrated a mean reduction of 14.6 cataplexy attacks per week compared to a reduction of 2.6 attacks per week for plac

146、ebo(p=0.002),representing mean reductions of 48.8%and 8.6%from baseline,respectively.The proportion of patients achieving a 50%or greater reduction in the weekly number of cataplexy attacks was 76.2%for AXS-12,compared to 30.0%for placebo at Week 2(p=0.003).The improvement in cataplexy was rapid,wit

147、h AXS-12 demonstrating significant benefit over placebo as early as Week 1(p0.001).AXS-12 significantly improved EDS symptoms compared to placebo,as measured by the Epworth Sleepiness Scale,or ESS,and by the frequency of inadvertent naps.The improvement on the ESS with AXS-12 treatment was twice tha

148、t observed with placebo,with reductions from baseline in the ESS score of 6.0 and 3.1,respectively for AXS-12 and placebo(p=0.003).AXS-12 treatment resulted in a 31.8%mean reduction from baseline in the average weekly number of inadvertent naps compared to a 5.3%mean reduction for placebo at Week 2(

149、p0.001).Improvement in the frequency of inadvertent naps was rapid,with AXS-12 demonstrating significant benefit over placebo as early as Week 1(p=0.038).AXS-12 significantly improved cognitive function compared to placebo over the 2-week treatment period as measured by the Ability to Concentrate it

150、em of the Narcolepsy Symptom Assessment Questionnaire,or NSAQ,which was assessed daily(p0.001).For this assessment,patients rated their ability to concentrate on a 5-point scale(1=very good to 5=very poor).At the end of treatment,42.9%of patients had an ability to concentrate that was“good”to“very g

151、ood”with AXS-12 treatment,compared to 25.0%of patients with placebo,and 0%of patients at baseline.The improvement in the ability to concentrate was rapid,with AXS-12 demonstrating significant improvement over placebo as early as Week 1(p=0.007).13Table of ContentsAXS-12 significantly improved sleep

152、quality,as measured by overall improvement and by number of awakenings at night,and reduced sleep-related symptoms,compared to placebo.AXS-12 treatment resulted in 45.0%of patients reporting improved sleep quality compared to 5.3%of patients with placebo(p=0.007).AXS-12 treatment resulted in 30.0%of

153、 patients reporting a reduction in the number of awakenings at night compared to 5.3%of patients with placebo(p=0.044).AXS-12 treatment also resulted in greater proportions of patients with reductions in sleep paralysis episodes,and in hypnagogic hallucinations,compared to placebo(p=ns).AXS-12 was w

154、ell tolerated in the trial.The most common adverse events in the AXS-12 group were anxiety,constipation,and insomnia.SYMPHONY StudyIn September 2021,we enrolled the first patient in SYMPHONY study,a Phase 3,randomized,double-blind,placebo-controlled,multicenter trial evaluating the efficacy and safe

155、ty of AXS-12 in patients with narcolepsy.A total of 90 patients were 1:1 randomized to receive AXS-12 or placebo for 5 weeks.Patients took either AXS-12(5 mg)or placebo once daily during Week 1 followed by twice daily dosing during Weeks 2-5.The primary endpoint was the change in frequency of weekly

156、 cataplexy attacks.Other symptoms of narcolepsy as well as safety and tolerability were also assessed in the trial.In March 2024,we announced that AXS-12 achieved the primary endpoint in the SYMPHONY Phase 3 trial and statistically significantly reduced the frequency of cataplexy attacks in patients

157、 with narcolepsy compared to placebo.AXS-12 also reduced EDS severity,improved cognitive function,and reduced overall narcolepsy severity compared to placebo.AXS-12 met the primary endpoint by demonstrating a substantial and statistically significant reduction from baseline in weekly cataplexy attac

158、ks compared to placebo at Week 5,with reductions of 83%for AXS-12 and 66%for placebo(p=0.018).AXS-12 rapidly reduced weekly cataplexy attacks,demonstrating a reduction of 56%compared to 31%for placebo at Week 1(p=0.007).Additionally,AXS-12 resulted in remission of cataplexy and increased cataplexy-f

159、ree days compared to placebo.Remission of cataplexy,defined as a 100%reduction from baseline,was achieved by 33%of AXS-12 patients compared to 9.5%of placebo patients at Week 5(p=0.008).Achievement of remission was rapid,with 24%of AXS-12 patients achieving remission at Week 2 compared to 4.5%of pla

160、cebo patients(p=0.008).AXS-12 increased the percentage of cataplexy-free days per week,defined as days with zero cataplexy attacks,to 84.5%at Week 5 compared to 22.6%for placebo(p=0.014).AXS-12 significantly reduced EDS severity as measured by the CGI-S scale for EDS compared to placebo at Week 5,wi

161、th mean reductions of 1.8 points for AXS-12 compared to 0.9 points for placebo(p=0.027).Statistical significance was observed as early as Week 1(p=0.006).Concurrent EDS and cataplexy response was achieved by 57%of patients in the AXS-12 group compared to 33%of patients in the placebo group at Week 5

162、(p=0.029).Response was defined as a 30%reduction in inadvertent naps and a 50%reduction in cataplexy attacks,respectively.The improvement in frequency of inadvertent naps was rapid,with 54%of patients in the AXS-12 group experiencing a decrease in the number of inadvertent naps compared to 28%of pat

163、ients in the placebo group,as measured by the NSAQ,at Week 5(p=0.016).AXS-12 significantly improved concentration and memory compared to placebo at Week 5 as measured by the Cognitive Function Items of the Functional Outcomes of Sleep Questionnaire,or FOSQ-10,(p=0.004).Concurrent cognitive and catap

164、lexy response was achieved by 41%of patients in the AXS-12 group compared to 17%of patients in the placebo group at Week 5(p=0.016).Response was defined by an increase in days patients rated their Ability to Concentrate as very good or good and a 50%reduction in cataplexy attacks,respectively.AXS-12

165、 also demonstrated improvements in overall narcolepsy,patient function,and quality of life.Clinicians reported a rapid and significant reduction in overall narcolepsy severity in patients in the AXS-12 group compared to patients in the placebo group,as measured by the CGI-S for narcolepsy,at Week 5(

166、p=0.007),with improvements observed as early as Week 1(p0.001).Statistically significant improvements in overall patient function and quality of life as measured by the FOSQ-10 total score was observed with AXS-12 compared to placebo at Week 5(p=0.005).14Table of ContentsENCORE StudyIn October 2021,

167、we initiated the ENCORE study,a Phase 3,randomized,double-blind,placebo-controlled trial to evaluate the long-term efficacy and safety of AXS-12 in patients with narcolepsy.The trial consisted of a 24-week open-label treatment period followed by a 3-week,double-blind,randomized withdrawal period.A t

168、otal of 68 patients,who rolled over from the SYMPHONY Phase 3 trial,were enrolled into the open-label period and treated with AXS-12(5 mg)once-daily for the first week,followed by twice-daily dosing for the subsequent 23 weeks.Patients who completed the open-label treatment period(n=42)were then 1:1

169、 randomized to continue AXS-12(n=22)or to switch to placebo(n=20).The primary endpoint was the change in frequency of weekly cataplexy attacks from randomization to week 3 of the double-blind period.Other symptoms of narcolepsy as well as safety and tolerability were also assessed throughout the tri

170、al.In March 2024,we announced that AXS-12 achieved the primary endpoint in the SYMPHONY Phase 3 trial and statistically significantly reduced the frequency of cataplexy attacks in patients with narcolepsy compared to placebo.AXS-12 also reduced EDS severity,improved cognitive function,and reduced ov

171、erall narcolepsy severity compared to placebo.AXS-12 met the primary endpoint of the change from randomization in the frequency of cataplexy attacks compared to placebo at week 3 of the double-blind period.Patients randomized to switch to placebo experienced a statistically significant worsening in

172、the average weekly number of cataplexy attacks compared to patients randomized to continue AXS-12 treatment,with an increase of 10.29 attacks per week for placebo compared to 1.32 attacks per week for AXS-12,at 3 weeks(p=0.017).Additionally,AXS-12 demonstrated a statistically significant improvement

173、 in cognitive function compared to placebo at Week 5 as measured by the NSAQ and the PGI-C.A significantly greater percentage of patients who switched to placebo experienced worsening in the NSAQ Ability to Concentrate item compared to those who continued AXS-12 treatment at 3 weeks(52.6%for placebo

174、 vs.14.3%for AXS-12,p=0.011).A significantly greater percentage of patients who switched to placebo also reported worsening in their ability to concentrate compared to patients who continued AXS-12 treatment at 3 weeks(57.9%for placebo vs.22.2%for AXS-12,p=0.029).Additionally,AXS-12 demonstrated imp

175、rovements in overall narcolepsy as measured by the PGI-C scale.A significantly greater percentage of patients who switched to placebo reported worsening of their narcolepsy compared to those who continued AXS-12 treatment at 3 weeks(52.6%for placebo vs.16.7%for AXS-12,p=0.024).In the open-label peri

176、od,treatment with AXS-12 led to substantial and sustained improvement of cataplexy,with patients experiencing a 71%reduction from baseline in mean weekly cataplexy attacks at 1 month,which was sustained with long-term treatment,resulting in a 77%reduction at 6 months.Cataplexy response,defined as 50

177、%reduction from baseline in weekly cataplexy attacks,was achieved by 72%of patients at 1 month,and by 82%of patients at 6 months with AXS-12 treatment.Treatment with AXS-12 also substantially increased the percentage of cataplexy-free days(days with zero cataplexy attacks)per week from 14%at baselin

178、e to 61%at 1 month and 70%at 6 months.Long-term open-label treatment with AXS-12 resulted in substantial improvements in EDS,assessed using the ESS and the Clinician Global Impression of Change,or CGI-C,scale.Mean ESS scores were reduced by 5.6 points at 1 month,with the improvement maintained with

179、long-term treatment resulting in a mean reduction of 7.3 points at 6 months.Clinicians reported improvement in EDS in a substantial proportion of patients on the CGI-C scale,with 84%of patients achieving EDS improvement at 1 month and 78%of patients at 6 months.A substantial proportion of patients r

180、eported improvement in cognition which was sustained with long-term open-label treatment.Improvement in cognition,assessed by the NSAQ Ability to Concentrate item,was reported by 55%of patients at 1 month and 59%at 6 months with AXS-12 treatment.Change in the ability to concentrate was also assessed

181、 using the PGI-C scale.The percentage of patients reporting improvement in the ability to concentrate on the PGI-C was 67%at 1 month and 70%at 6 months with AXS-12 treatment.Long-term open-label treatment with AXS-12 was also associated with improvement in overall narcolepsy status and patient funct

182、ioning,assessed using the CGI-C,the PGI-C,and the Work Productivity and Activity Impairment Questionnaire,or WPAI.On the CGI-C,clinicians reported overall improvement in narcolepsy in 90%of patients at 1 month and 90%of patients at 6 months with AXS-12 treatment.Results were similar with the patient

183、-reported PGI-C.Impairment due to narcolepsy while working was assessed after treatment with AXS-12 using the WPAI.The percentage of time impaired while working decreased substantially with AXS-12 treatment from 53%at baseline to 34%at 1 month and 24%at 6 months.15Table of ContentsAXS-12 was well to

184、lerated with long-term dosing,with a safety profile consistent with prior trials of AXS-12 in narcolepsy.During the 6-month open-label treatment period,the most common adverse events(5%)were nausea(5.9%)and tachycardia(5.9%).Over the 6-month treatment period,17.6%of patients discontinued due to adve

185、rse events,with no individual adverse event leading to discontinuation by more than one patient.Treatment-related adverse events during the double-blind period were reported in 4.5%of patients in the AXS-12 group and 15%of patients in the placebo group.Rates of discontinuation due to adverse events

186、in the double-blind period were 0%and 5%in the AXS-12 and placebo groups,respectively.AXS-14OverviewAXS-14(esreboxetine)is a novel,oral,potent,highly selective investigational norepinephrine reuptake inhibitor being developed for the management of fibromyalgia.Esreboxetine,the SS-enantiomer of rebox

187、etine,is more potent and selective than racemic reboxetine.In January 2020,we received from Pfizer an exclusive license to develop and commercialize esreboxetine in the U.S.for fibromyalgia and other indications.The license encompasses nonclinical and clinical data for esreboxetine including results

188、 from a positive Phase 3 and a positive Phase 2 trial of esreboxetine in the treatment of fibromyalgia conducted by Pfizer.FibromyalgiaFibromyalgia is a chronic disorder often characterized by widespread musculoskeletal pain,fatigue,disturbed sleep,depression,and cognitive impairment.Other symptoms

189、of this disorder can include tingling in the hands and feet and headaches.Fibromyalgia is considered to be mediated mainly in the central nervous system.Approximately 17 million people in the U.S.suffer from fibromyalgia.Treatment options for fibromyalgia are limited with only three pharmacologic tr

190、eatments currently approved by the FDA.In a Phase 3 trial conducted by Pfizer in 1,122 patients with fibromyalgia treated with esreboxetine or placebo for 14 weeks,esreboxetine met the two primary endpoints by demonstrating statistically significant improvements in the weekly mean pain score compare

191、d to placebo(p0.001,p0.001,and p=0.025 for 4 mg,8 mg and 10 mg daily doses,respectively),and the Fibromyalgia Impact Questionnaire,or FIQ,total score(p0.001,p0.001,and p=0.023 for 4 mg,8 mg and 10 mg daily doses,respectively).Esreboxetine also resulted in statistically significant improvements in pa

192、tient-reported global functioning compared to placebo as measured by the PGI-C scale(p=0.002,p=0.001,and p=0.007 for 4 mg,8 mg and 10 mg daily doses,respectively),and in fatigue as measured by the Global Fatigue Index(p=0.001 and p=0.001 for 4 mg and 8 mg daily doses,respectively).In a Phase 2 trial

193、 conducted by Pfizer in 267 patients with fibromyalgia treated with esreboxetine(dose escalated to 8 mg/day)or placebo for 8 weeks,esreboxetine met the primary endpoint by demonstrating statistically significant improvements in the weekly mean pain score compared to placebo(p=0.006).The study also d

194、emonstrated statistically significant improvements in additional efficacy outcomes including the FIQ total score(p0.001),the PGI-C scale(p0.001),and fatigue as measured by the Multidimensional Assessment of Fatigue scale(p0.001).SolriamfetolOverviewSolriamfetol is an oral,DNRI,TAAR1 agonist,and 5-HT

195、1A agonist being developed for the treatment of CNS disorders.We are currently developing solriamfetol in ADHD,MDD,BED,and SWD.16Table of ContentsAttention Deficit Hyperactivity DisorderADHD is a chronic neurobiological and developmental disorder characterized by a persistent pattern of inattention,

196、hyperactivity,or impulsivity that interferes with functioning or development.Impairments in cognition are apparent in attention,planning and problem solving,working memory,and behavioral inhibition.An estimated 22 million people in the U.S.are affected by ADHD,including approximately 7 million child

197、ren aged 3-17 years old.Approximately two-thirds or more children with ADHD continue to have symptoms and challenges into adulthood.ADHD is associated with significant impairment in social,academic,and occupational functioning and development.The total annual societal excess costs associated with ad

198、ult ADHD in the U.S.have been estimated at$122.8 billion.FOCUS Study In July 2023,we initiated the FOCUS study,a Phase 3,randomized,double-blind,placebo-controlled,multicenter trial to evaluate the efficacy and safety of solriamfetol for the treatment of ADHD in adults.Approximately 450 patients wil

199、l be randomized in a 1:1:1 ratio to receive solriamfetol(150 mg or 300 mg)or placebo for 6 weeks.The primary endpoint is the change in the Adult ADHD Investigator Symptom Report Scale,or AISRS.Major Depressive Disorder MDD is a debilitating,chronic,biologically based disorder characterized by low mo

200、od,inability to feel pleasure,feelings of guilt and worthlessness,low energy,and other emotional and physical symptoms,which impair social,occupational,educational,or other important functioning.In severe cases,MDD can result in suicide.MDD is one of the most common mental disorders in the U.S.where

201、 approximately 1 in 5 individuals will experience MDD at some point in their life.According to the U.S.Department of Health and Human Services,or HHS,an estimated 21 million adults in the U.S.experience MDD each year.In addition,according to the World Health Organization,or WHO,depression is the lea

202、ding cause of disability worldwide and is a major contributor to the overall global burden of disease.Over 70%of patients experience only a partial improvement in symptoms with first-line standard of care.PARADIGM Study In March 2024,we initiated the PARADIGM study,a Phase 3,randomized,double-blind,

203、placebo-controlled,multicenter trial to evaluate the efficacy and safety of solriamfetol for the treatment of MDD in adults.Approximately 300 patients will be randomized in a 1:1 ratio to receive solriamfetol(300 mg)or placebo for 6 weeks.The primary endpoint is the change in the Montgomery sberg De

204、pression Rating Scale,or MADRS.Binge Eating DisorderBED is the most common eating disorder,affecting an estimated 7 million people in the U.S.While BED is 1.75 times more common in women than men,it is still more common in men than other eating disorders.BED is thought to involve issues with food re

205、ward processing,impulse control,and appetite regulation,and is associated with a 2-to 3-fold increased risk of psychiatric or medical comorbidities.Most people with BED remain untreated with approximately one quarter of patients having received treatment in the past year and less than half receiving

206、 treatment in their lifetime.Treatment options are limited,with only one product currently approved for the treatment of BED.In November 2023,we announced that we had received from the FDA positive Pre-IND meeting written guidance on a proposed clinical developmental plan for solriamfetol in BED.In

207、November 2023,we announced that we had received from the FDA positive Pre-IND meeting written guidance on a proposed clinical developmental plan for solriamfetol in BED.17Table of ContentsENGAGE StudyIn April 2024,we initiated the ENGAGE study,a Phase 3,randomized,double-blind,placebo-controlled,mul

208、ticenter trial to evaluate the efficacy and safety of solriamfetol for the treatment of BED in adults.Approximately 450 patients will be randomized in a 1:1:1 ratio to receive solriamfetol(150 or 300 mg)or placebo for 12 weeks.The primary endpoint is the change in days with binge eating episodes.Shi

209、ft Work DisorderSWD is a combination of excessive sleepiness,or ES,during wakefulness and persistent insomnia during daytime sleep when working outside a 7 a.m.to 6 p.m.workday.An estimated 15 million working Americans may suffer from SWD,of whom 10-43%are diagnosed with SWD.Shift work has long been

210、 associated with multiple serious health complaints and a 23%greater risk of sustaining a work-related injury.Treatment options are limited,with only two products currently approved for the treatment of ES associated with SWD.In November 2023,we announced that we had received from the FDA positive P

211、re-IND meeting written guidance on a proposed clinical developmental plan for solriamfetol for ES associated with SWD.SUSTAIN StudyIn August 2024,we announced we had initiated the SUSTAIN study,a Phase 3,randomized,double-blind,placebo-controlled,multicenter trial to evaluate the efficacy and safety

212、 of solriamfetol for the treatment of SWD in adults.Approximately 450 patients will be randomized in a 1:1:1 ratio to receive solriamfetol(150 or 300 mg)or placebo for 12 weeks.The primary endpoint is the change in the CGI-C score.Pain and Primary CareWe continue to own and maintain the intellectual

213、 property covering our pain and primary care assets that we are not currently developing.Commercial AgreementsWe have customary clinical and commercial supply agreements and customary agreements with third-parties to help manage our clinical trials.Our commercial agreements are generally nonexclusiv

214、e,and we have no material contractual obligations under such agreements,except to the extent we order supply or request services to be performed.18Table of ContentsMaterial License AgreementsExclusive License Agreement with PfizerIn January 2020,we entered into an agreement with Pfizer for an exclus

215、ive U.S.license to Pfizers clinical and nonclinical data,and intellectual property for reboxetine,the active pharmaceutical ingredient in AXS-12 which Axsome is developing for the treatment of narcolepsy.The agreement also provides Axsome exclusive rights to develop and commercialize esreboxetine,a

216、new late-stage product candidate now referred to as AXS-14,in the U.S.for the treatment of fibromyalgia.Under the terms of the agreement,we received from Pfizer an exclusive U.S.license to Pfizer data for reboxetine and esreboxetine encompassing a full range of nonclinical studies,and short-term and

217、 long-term clinical trials involving more than five thousand patients.The licensed data includes results of a positive Phase 3 and a positive Phase 2 trial of esreboxetine in the treatment of fibromyalgia.we will have the exclusive right and sole responsibility of developing AXS-14(esreboxetine)in t

218、he U.S.for the treatment of fibromyalgia and for other indications.Pfizer received 82,019 shares of our common stock having a value of$8 million,based on the average closing price of our common stock for the 10 prior trading days of$97.538,in consideration for the license and rights.Pfizer also rece

219、ived an upfront cash payment of$3 million and will receive up to$323 million in regulatory and sales milestones and tiered mid-single to low double-digit royalties on future sales.Pfizer will also have a right of first negotiation on any potential future strategic transactions involving AXS-12 and A

220、XS-14.Under the agreement,we are obligated to use commercially reasonable efforts to develop,manufacture and commercialize the compounds and products in the United States and to seek and maintain regulatory approvals for the compounds and products.The agreement will expire on a product-by-product ba

221、sis upon expiration of the last-to-expire royalty term for such product.On expiration(but not earlier termination),we will have a perpetual,non-exclusive,fully paid-up,royalty-free and irrevocable license under the licensed patent rights and related data to develop,manufacture,use,commercialize and

222、otherwise exploit the compounds.Either party may terminate the agreement for the other partys material breach following a cure period.Pfizer may immediately terminate the agreement upon certain insolvency events relating to us.We may terminate the agreement for any reason upon ninety days written no

223、tice to Pfizer at any time after the first anniversary of the agreement.Exclusive License Agreements with Antecip In 2012,we entered into three exclusive license agreements with Antecip Bioventures II LLC,or Antecip,an entity owned by our Chief Executive Officer and Chairman of the Board of Director

224、s,or the Board,Herriot Tabuteau,M.D.,in which we were granted exclusive licenses to develop,manufacture,and commercialize Antecips patents and applications related to the development of AXS-05 anywhere in the world for veterinary and human therapeutic and diagnostic use,and additional patents and ap

225、plications that are not relevant to our current programs in development.The agreements were amended in August 2015 to update the schedule of patents and applications subject to the license agreements.Pursuant to the agreements,we are required to use commercially reasonable efforts to develop,obtain

226、regulatory approval for,and commercialize AXS-05.Under the terms of the agreements,we are required to pay to Antecip a royalty equal to 3.0%for AXS-05,of net sales of products containing the licensed technology by us,our affiliates,or permitted sublicensees.These royalty payments are subject to redu

227、ction by an amount up to 50.0%of any required payments to third parties.Unless earlier terminated by a party for cause or by us for convenience,the agreements remain in effect on a product by product and country by country basis until the later to occur of(1)the applicable product is no longer cover

228、ed by a valid claim in that country or(2)10 years from the first commercial sale of the applicable product in that country.Upon expiration of the agreements with respect to a product in a country,our license grant for that product in that country will become a fully paid-up,royalty-free,perpetual,no

229、n-exclusive license.If Antecip terminates any of the agreements for cause,or if we exercise our right to terminate any of the agreements for convenience,the rights granted to us under such terminated agreement will revert to Antecip.Due to product sales of Auvelity since the fourth quarter of 2022,w

230、e recorded royalty expense for royalty payments due to Antecip equal to 3.0%of net sales.This is considered to be a related party transaction.19Table of ContentsRoyalty Agreement with Jazz Pharmaceuticals,SK Biopharmaceuticals Co.,Ltd.and Aerial Biopharma,LLCIn connection with the Acquisition,in add

231、ition to the upfront purchase price,we assumed certain liabilities in connection with the Acquisition and agreed to make non-refundable,non-creditable royalty payments to Jazz on U.S.net sales.There are no royalty payments due to Jazz for net sales outside of the U.S.In addition,we assumed all of th

232、e commitments of Jazz to SK and Aerial Biopharma,LLC,or Aerial.The assumed commitments to SK and Aerial include single-digit tiered royalties based on the Companys sales of Sunosi,and additionally,the Company is committed to pay up to$165 million based on revenue milestones and$1 million based on de

233、velopment milestones.We are dependent on these agreements,and if we breach these agreements,our business,financial condition,results of operations,and prospects will be materially harmed.PharmanoviaIn February 2023,we announced a licensing transaction with Pharmanovia to market Sunosi in Europe and

234、certain countries in the Middle East/North Africa.Refer to Note 16.License Agreements to our consolidated financial statements included in Part IV,Exhibits and Financial Statement Schedules,of this Annual Report on Form 10-K for further detail.Intellectual PropertyWe seek to protect our product cand

235、idates and our technology through a combination of patents,trade secrets,proprietary know-how,FDA and EMA exclusivity,and contractual restrictions on disclosure.Our policy is to pursue,maintain,and defend patent rights whether developed internally or licensed from third parties and to protect the pr

236、oprietary position of our product candidates by,among other methods,filing U.S.and foreign patent applications related to our proprietary technology,inventions,and improvements that are important to the development of our business.U.S.patents generally have a term of 20 years from the earliest effec

237、tive date of the application.As of February 11,2025,our intellectual property portfolio contains more than 600 issued patents and more than 400 pending applications in the United States and worldwide.More than 140 issued United States patents and more than 91 issued foreign patents cover our AXS-05

238、product candidate,which has claims covering method of treatment,pharmaceutical composition,drug delivery,and pharmacokinetics,with protection extending through 2043.More than 98 issued United States patents and more than 131 issued foreign patents covering our AXS-07 product candidate,and related co

239、mpounds,have claims covering various aspects,including pharmacokinetics,pharmaceutical composition,method of delivery,and methods of use with protection extending through 2040.Eight issued United States patents and two issued foreign patents covering our AXS-12 product candidate with protection exte

240、nding through 2039.We have pending PCT applications,as well as pending applications in Australia,Brazil,Canada,Chile,China,Europe,Hong Kong,Israel,Japan,Mexico,Panama,Singapore,South Korea,and New Zealand.We have other patent applications with claims covering the other programs in our pipeline,inclu

241、ding those that are not relevant to our current programs in development.As with respect to Sunosi,Orange Book listed patents in the United States extend out to 2042.We also have patents in various other countries pertaining to Sunosi.20Table of ContentsMany pharmaceutical companies,biotechnology com

242、panies,and academic institutions are competing with us in the field of CNS disorders and filing patent applications potentially relevant to our business.In order to contend with the inevitable possibility of third-party intellectual property conflicts,from time to time we review and assess the third

243、-party intellectual property landscape for competitive and other developments that may inform or impact our intellectual property development and commercialization strategies.With respect to third-party intellectual property,it is impossible to establish with certainty that our product candidates or

244、 discovery platform will be free of claims by third-party intellectual property holders or whether we will require licenses from such third parties.Even with modern databases and online search engines,literature searches are imperfect and may fail to identify relevant patents and published applicati

245、ons.Even when a third-party patent is identified,we may conclude,upon a thorough analysis,that we do not infringe the patent or that the patent is invalid.If the third-party patent owner disagrees with our conclusion and we continue with the business activity in question,we might have patent litigat

246、ion forced upon us.Alternatively,we might decide to initiate litigation in an attempt to have a court declare the third-party patent invalid or not infringed by our activity.In either scenario,patent litigation typically is costly and time consuming,and the outcome is uncertain.The outcome of patent

247、 litigation is subject to uncertainties that cannot be quantified in advance,for example,the credibility of expert witnesses who may disagree on technical interpretation of scientific data.Ultimately,in the case of an adverse outcome in litigation,we could be prevented from commercializing a product

248、 or using certain aspects of our discovery platform as a result of patent infringement claims asserted against us.This could have a material adverse effect on our business.In addition to patents,we rely upon unpatented trade secrets,know how,and continuing technological innovation to develop and mai

249、ntain a competitive position.We seek to protect our proprietary information,including our trade secrets and proprietary know how,by requiring our employees to execute Proprietary Information,Inventions,Non-Solicitation,and Non-Competition Agreements upon the commencement of their employment.Consulta

250、nts and other advisors are required to sign consulting agreements.These agreements generally provide that all confidential information developed or made known during the course of the relationship with us be kept confidential and not be disclosed to third parties except in specific circumstances.In

251、the case of our employees,the agreements also typically provide that all inventions resulting from work performed for us,utilizing our property,or relating to our business and conceived or completed during employment shall be our exclusive property to the extent permitted by law.Further,we require c

252、onfidentiality agreements from entities that receive our confidential data or materials.Sales and MarketingWe have built a commercial infrastructure in the United States to commercialize our products and will further expand that team as we plan for anticipated drug approvals of our product candidate

253、s.We believe that we have cost-effectively implemented a targeted sales force required to commercialize our products.Support for this team includes sales management,internal sales support,market access,distribution support,and an internal marketing group.We may seek co-promotion partners for our sal

254、es efforts to achieve broader reach or call frequency with other United States target physicians.We believe that there are significant market opportunities for our products outside of the United States.As a result,we plan to seek strategic partnerships with third parties,which may have greater reach

255、 and resources by virtue of their size and experience in the field,for the development and commercialization of our products outside the United States.We may elect in the future to utilize strategic partners,distributors,or contract sales forces to assist in the commercialization of our products.In

256、order to implement this infrastructure,we will have to allocate management resources and make significant financial investments including some prior to product approval.21Table of ContentsCompetitionOverviewOur industry is highly competitive and subject to rapid and significant technological change.

257、The large size and expanding scope of the CNS markets make them attractive therapeutic areas for biopharmaceutical businesses.Our competitors include pharmaceutical,biotechnology,and specialty pharmaceutical companies.While we believe that our employees and consultants,scientific knowledge,technolog

258、y,and development experience provide us with competitive advantages,we face competition from many different sources,including major pharmaceutical,specialty pharmaceutical,and biotechnology companies,academic institutions and governmental agencies,and public and private research institutions.Several

259、 of these entities have robust drug pipelines,readily available capital,and established research and development organizations.Any product candidates that we successfully develop and commercialize will compete with existing therapies and new therapies that may become available in the future.Many of

260、our competitors may have significantly greater financial resources and expertise in research and development,manufacturing,preclinical testing,conducting clinical trials,obtaining regulatory approvals,and marketing approved products than we do.Mergers and acquisitions in the pharmaceutical,biotechno

261、logy,and diagnostic industries may result in even more resources being concentrated among a smaller number of our competitors.These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient registratio

262、n for clinical trials,as well as in acquiring technologies complementary to,or necessary for,our programs.Small or early-stage companies may also prove to be significant competitors,particularly through collaborative arrangements with large and established companies.The key competitive factors affec

263、ting the success of all of our product candidates are likely to be their efficacy,safety,convenience,price,the level of branded and generic competition,and the availability of reimbursement from government and other third party payors.Patients with MDD are typically treated with a variety of anti-de

264、pressant medications.Some of these treatments include:generic and/or branded forms of Prozac,the branded form of which is marketed by Eli Lilly and Company;Zoloft,which is marketed by Pfizer;Trintellix,which is marketed by Takeda Pharmaceuticals America,Inc.and H.Lundbeck A/S;Rexulti,which is market

265、ed by Otsuka Pharmaceutical Co.,Ltd.,and Lundbeck A/S;Vraylar and Viibryd,which are marketed by AbbVie;Effexor,which is marketed by Pfizer;and Wellbutrin,which is marketed by GlaxoSmithKline.We are aware of several companies developing compounds for the treatment of depression,including Xenon Pharma

266、ceuticals,Inc.,Neumora Therapeutics,Inc.,Johnson&Johnson,Otsuka Pharmaceutical Co.Ltd.,Neurocrine Biosciences,Inc.,Intra-Cellular Therapies,Inc.,and Biohaven Ltd.Patients with EDS have available to them a variety of medications,such as generic and/or branded forms of Xyrem and Xywav,which are market

267、ed by Jazz;Wakix,which is marketed by Harmony Biosciences LLC;Lumryz,which is marketed by Avadel Pharmaceuticals plc;Provigil and Nuvigil,which are manufactured by Teva Pharmaceutical Industries Limited,or Teva.CNS Product CandidatesAXS05 CompetitionWe are aware of other companies working to develop

268、 therapeutics for the treatment of agitation associated with AD,including Otsuka Pharmaceutical Co.Ltd.,which is working to develop a combination of deuterated dextromethorphan and quinidine,and Otsuka and Lundbeck A/S,which recently received approval for Rexulti for this indication.Products approve

269、d for smoking cessation include Chantix,which is marketed by Pfizer;Zyban,which is marketed by GlaxoSmithKline;and various nicotine replacement therapies,including skin patches,chewing gums,and lozenges.We are aware of several companies developing compounds for AD agitation,including Bristol-Myers S

270、quibb Co.,BioXcel Therapeutics,Inc.,Neumora Therapeutics,Inc.,and Intra-Cellular Therapies,Inc.AXS07 CompetitionThere are a number of products approved for the acute treatment of migraine,including generic and/or branded forms of Maxalt,the branded form of which is marketed by Merck&Co.,Inc.,generic

271、 and/or branded forms of Treximet,the branded form of which is marketed by Pernix Therapeutics Holdings,Inc.,Reyvow,which is marketed by Eli Lilly and Company;Nurtec,which is marketed by Pfizer,and Ubrelvy,which is marketed by AbbVie,and Trudhesa which is marketed by Impel.We are aware of several co

272、mpanies developing compounds for migraine,including Biohaven Ltd.,Kallyope,Inc.,and Lundbeck A/S.22Table of ContentsAXS12 CompetitionProducts approved to treat the symptoms of narcolepsy include generic and/or branded forms of Ritalin,the branded form of which is marketed by Novartis Pharmaceuticals

273、;Provigil and Nuvigil,which are both marketed by Teva;Xyrem and Xywav,which are both marketed by Jazz;and Wakix which is marketed by Harmony Biosciences LLC.We are aware of several companies developing compounds for the treatment of the symptoms of narcolepsy,including Takeda Pharmaceuticals Company

274、,Centessa Pharmaceuticals plc,Harmony Biosciences LLC,Eisai Co.,Ltd.,and Alkermes plc.AXS-14 CompetitionProducts approved to treat fibromyalgia include generic and/or branded forms of Cymbalta,the branded form of which is marketed by Eli Lilly and Company;Lyrica,which is marketed by Pfizer;and Savel

275、la,which is marketed by AbbVie.We are aware of other companies working to develop therapeutics for the treatment of fibromyalgia,including Dogwood Therapeutics,Inc.and Tonix Pharmaceutical Holding Corp.ManufacturingManufacturing of the drug substance and drug product for our products and product can

276、didates are done by third parties and must comply with FDA current Good Manufacturing Practice,or cGMP,regulations.Our products and product candidates are comprised of synthetic small molecules made through a series of organic chemistry steps starting with commercially available organic chemical raw

277、 materials.We do not currently own or operate any manufacturing facilities for the clinical or commercial production of our drug candidates.We believe that our existing suppliers of our product and product candidate active pharmaceutical ingredients and finished products will be capable of providing

278、 sufficient quantities of each to meet our commercial and clinical trial supply needs.We conduct periodic quality audits of their facilities.Other contract manufacturing organization,or CMOs,may be used in the future for clinical supplies and/or commercial manufacturing.Government Regulation and Pro

279、duct ApprovalGovernment authorities in the United States,at the federal,state,and local level,and in other countries and supranational regions,extensively regulate,among other things,the research,development,testing,manufacture,packaging,storage,recordkeeping,labeling,advertising,promotion,distribut

280、ion,adverse event reporting and pharmacovigilance,marketing,import,and export of pharmaceutical products,such as those we are developing and for which we are seeking FDA approval.In addition,healthcare regulatory bodies in the United States and around the world impose a range of requirements related

281、 to the payment for pharmaceutical products,including laws intended to prevent fraud,waste,and abuse of healthcare dollars.This includes,for example,requirements that manufacturers of pharmaceutical products participating in Medicaid and Medicare comply with mandatory price reporting,discount,rebate

282、 requirements,and other cost control measures,as well as anti-kickback laws and laws prohibiting false claims.Some states also have enacted fraud,waste,and abuse laws that parallel(and in some cases apply more broadly than)federal laws,and in some cases price transparency requirements.The processes

283、for obtaining regulatory approvals in the United States and in foreign countries,along with subsequent compliance with applicable statutes and regulations,require the expenditure of substantial time and financial resources.Further,healthcare is an active area of governmental scrutiny,and it is reaso

284、nable to expect that the requirements may become more stringent within the foreseeable future.FDA RegulationIn the United States,the FDA regulates drugs under the FDCA and its implementing regulations.The process required by the FDA before product candidates may be marketed in the United States gene

285、rally involves the following:completion of preclinical laboratory tests,animal studies,and formulation studies in compliance with the FDAs Good Laboratory Practice,or GLP,regulations;23Table of Contentssubmission to the FDA of an IND which must become effective before human clinical trials may begin

286、;approval by an independent Institutional Review Board,or IRB,for each clinical site or centrally,before each trial may be initiated;adequate and wellcontrolled human clinical trials to establish the safety and efficacy of the proposed drug candidates for its intended use,performed in accordance wit

287、h current Good Clinical Practices,or GCP;development of manufacturing processes in compliance with cGMPs to ensure the drugs identity,strength,quality,and purity;compilation of required information and submission to the FDA of an NDA;satisfactory completion of an FDA advisory committee review,if app

288、licable;satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the product is produced to assess compliance with cGMPs,and to assure that the facilities,methods,and controls are adequate to preserve the drugs identity,strength,quality,and purity,as well as

289、satisfactory completion of an FDA inspection of selected clinical sites and selected clinical investigators to determine GCP compliance;andFDA review and approval of the NDA to permit commercial marketing for particular indications for use.Preclinical Studies and IND SubmissionThe testing and approv

290、al process of product candidates requires substantial time,effort,and financial resources.Preclinical studies include laboratory evaluation of drug substance chemistry,pharmacology,toxicity,and drug product formulation,as well as animal studies to assess potential safety and efficacy.Such studies mu

291、st generally be conducted in accordance with the FDAs GLP regulations.Prior to commencing the first clinical trial with a product candidate,an IND sponsor must submit the results of the preclinical tests and preclinical literature,together with manufacturing information,analytical data,any available

292、 clinical data or literature,and proposed clinical study protocols,among other things,to the FDA as part of an IND.In the case of 505(b)(2)applications,though,some of the IND components may not be required(for example,if previously established for an approved drug which is referenced).Some preclinic

293、al testing may continue even after the IND is submitted.An IND automatically becomes effective 30 days after receipt by the FDA,unless the FDA,within the 30day time period,notifies the applicant of safety concerns or questions related to one or more proposed clinical trials and places the trial on a

294、 clinical hold.In such a case,the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin.Clinical holds also may be imposed by the FDA at any time before or during trials due to safety concerns or noncompliance.As a result,submission of an IND may not resul

295、t in FDA authorization to commence a clinical trial.24Table of ContentsClinical TrialsClinical trials involve the administration of the investigational new drug to human subjects under the supervision of qualified investigators in accordance with GCP requirements,which include the requirements that

296、all research subjects provide their informed consent in writing for their participation in any clinical trial,as well as review and approval of the study by an IRB.Investigators must also provide certain information to the clinical trial sponsors to allow the sponsors to make certain financial discl

297、osures to the FDA.Clinical trials are conducted under protocols detailing,among other things,the objectives of the trial,the trial procedures,the parameters to be used in monitoring safety,the effectiveness criteria to be evaluated,and a statistical analysis plan.A protocol for each clinical trial,a

298、nd any subsequent protocol amendments,must be submitted to the FDA as part of the IND.In addition,an IRB at each study site participating in the clinical trial or a central IRB must review and approve the plan for any clinical trial,informed consent forms,and communications to study subjects before

299、a study commences at that site.An IRB considers,among other things,whether the risks to individuals participating in the trials are minimized and are reasonable in relation to anticipated benefits and whether the planned human subject protections are adequate.The IRB must continue to oversee the cli

300、nical trial while it is being conducted.Once an IND is in effect,each new clinical protocol and any amendments to the protocol must be submitted to the IND for FDA review,and to the IRB for approval.Progress reports detailing the results of the clinical trials must also be submitted at least annuall

301、y to the FDA and the IRB and more frequently if serious adverse events or other significant safety information is found.Information about certain clinical trials,including a description of the study and study results,must be submitted within specific timeframes to the National Institutes of Health,o

302、r NIH,for public dissemination on their clinicaltrials.gov website.Additionally,some clinical trials are overseen by an independent group of qualified experts organized by the clinical trial sponsor,known as a data safety monitoring board or committee.This group regularly reviews accumulated data an

303、d advises the study sponsor regarding the continuing safety of trial subjects,enrollment of potential trial subjects,and the continuing validity and scientific merit of the clinical trial.The data safety monitoring board receives special access to unblinded data during the clinical trial and may adv

304、ise the sponsor to halt the clinical trial if it determines there is an unacceptable safety risk for subjects or on other grounds,such as no demonstration of efficacy.The manufacture of investigational drugs for the conduct of human clinical trials(and their active pharmaceutical ingredients)is subj

305、ect to cGMP requirements.Investigational drugs and active pharmaceutical ingredients imported into the United States are also subject to regulation by the FDA relating to their labeling and distribution.Further,the export of investigational drug products outside of the United States is subject to re

306、gulatory requirements of the receiving country as well as U.S.export requirements under the FDCA.In general,for purposes of NDA approval,human clinical trials are typically conducted in three sequential phases,which may overlap or be combined.Phase 1Studies are initially conducted in healthy human v

307、olunteers or subjects with the target disease or condition and test the product candidate for safety,dosage tolerance,structureactivity relationships,mechanism of action,absorption,metabolism,distribution,and excretion.If possible,Phase 1 trials may also be used to gain an initial indication of prod

308、uct effectiveness.Phase 2Controlled studies are conducted in limited subject populations with a specified disease or condition to evaluate preliminary efficacy,identify optimal dosages,dosage tolerance and schedule,possible adverse effects and safety risks,and expanded evidence of safety.Phase 3Thes

309、e adequate and wellcontrolled clinical trials are undertaken in expanded subject populations,generally at geographically dispersed clinical trial sites,to generate enough data to provide statistically significant evidence of clinical efficacy and safety of the product for approval,to establish the o

310、verall riskbenefit profile of the product,and to provide adequate information for the labeling of the product.Typically,two Phase 3 trials are required by the FDA for product approval.25Table of ContentsThe FDA may also require,or companies may conduct,additional clinical trials for the same indicat

311、ion after a product is approved.These so-called Phase 4 studies may be required by the FDA as a condition of approval of the NDA,to be satisfied after approval.The results of Phase 4 studies can confirm the effectiveness of a product candidate and can provide important safety information.In addition

312、 to the above traditional kinds of clinical trial data required for the approval of an NDA,the 21st Century Cures Act provides for potential FDA use of different types and sources of data in regulatory decision-making,such as patient experience data,real world evidence for already approved products,

313、and,for appropriate indications sought through supplemental marketing applications,data summaries.Implementation of this law and related initiatives is still in progress and we do not know the extent to which we may in the future be able to utilize these types and sources of data.In the case of a 50

314、5(b)(2)NDA,which is a marketing application in which sponsors may rely on investigations that were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted,some of the above describ

315、ed studies and preclinical studies may not be required or may be abbreviated.Bridging studies may be needed,however,to demonstrate the applicability of the studies that were previously conducted by other sponsors to the drug that is the subject of the marketing application.Clinical trials at any pha

316、se may not be completed successfully within any specified period,or at all.Regulatory authorities,an IRB,or the sponsor may suspend or discontinue a clinical trial at any time on various grounds,including a finding that the subjects are being exposed to an unacceptable health risk,the clinical trial

317、 is not being conducted in accordance with the FDAs or the IRBs requirements,if the drug has been associated with unexpected serious harm to the subjects,or based on evolving business objectives or competitive climate.Concurrent with clinical trials,companies usually complete additional animal studi

318、es and must also develop additional information about the chemistry and physical characteristics of the product candidate as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.The manufacturing process must be capable of consistentl

319、y producing quality batches of the product candidate and,among other things,the manufacturer must develop methods for testing the identity,strength,quality,potency,and purity of the final product.Additionally,appropriate packaging must be selected and tested,and stability studies must be conducted t

320、o demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.During the development of a new drug,a sponsor may be able to request a SPA,the purpose of which is to reach agreement with the FDA on the Phase 3 clinical trial protocol design and analysis that

321、 will form the primary basis of an efficacy claim as well as preclinical carcinogenicity trials and stability studies.An SPA may only be modified with the agreement of the FDA and the trial sponsor or if the director of the FDA reviewing division determines that a substantial scientific issue essent

322、ial to determining the safety or efficacy of the drug was identified after the testing began.An SPA is intended to provide assurance that,in the case of clinical trials,if the agreed upon clinical trial protocol is followed,the clinical trial endpoints are achieved,and there is a favorable risk bene

323、fit profile,the data may serve as the primary basis for an efficacy claim in support of an NDA.However,SPA agreements are not a guarantee of an approval of a product candidate or any permissible claims about the product candidate.In particular,SPAs are not binding on the FDA if,among other reasons,p

324、reviously unrecognized public health concerns arise during the performance of the clinical trial,other new scientific concerns regarding the product candidates safety or efficacy arise,or if the sponsoring company fails to comply with the agreed upon clinical trial protocol.NDA Submission,Review by

325、the FDA,and Marketing ApprovalAssuming successful completion of the required clinical and preclinical testing,the results of product development,including CMC information,non-clinical studies,and clinical trial results,including negative or ambiguous results as well as positive findings,are all subm

326、itted to the FDA,along with the proposed labeling,as part of an NDA requesting approval to market the product for one or more indications.In most cases,the submission of an NDA is subject to a substantial application user fee,authorized every five years by Congress under PDUFA.User fees must be paid

327、 at the time of the first submission of the application,even if the application is being submitted on a rolling basis,and,if approved,program fees must be paid on an annual basis.Product candidates that are designated as orphan drugs,which are further described below,are also not subject to applicat

328、ion user fees unless the application includes an indication other than the orphan indication.26Table of ContentsIn addition,under the Pediatric Research Equity Act,or PREA,an NDA or supplement to an NDA for a new active ingredient,indication,dosage form,dosage regimen,or route of administration must

329、 contain data that are adequate to assess the safety and effectiveness of the drug for the claimed indications in all relevant pediatric subpopulations,and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.A sponsor who is planning to s

330、ubmit a marketing application for a drug product that includes a new active ingredient,new indication,new dosage form,new dosing regimen or new route of administration must submit an initial Pediatric Study Plan,or PSP,within 60 days of an End-of-Phase 2 meeting or as may be agreed between the spons

331、or and the FDA.The initial PSP must include an outline of the pediatric study or studies that the sponsor plans to conduct,including study objectives and design,age groups,relevant endpoints and statistical approach,or a justification for not including such detailed information,and any request for a

332、 deferral of pediatric assessments or a full or partial waiver of the requirement to provide data from pediatric studies along with supporting information.The FDA and the sponsor must reach agreement on the PSP.A sponsor can submit amendments to an agreed-upon initial PSP at any time if changes to t

333、he pediatric plan need to be considered based on data collected from preclinical studies,early phase clinical studies or other clinical development programs.The FDA may,on its own initiative or at the request of the applicant,grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults,or full or partial waivers from the pediatric data requirem