Athira Pharma, Inc. (ATHA) 2024年年度報告「NASDAQ」.pdf

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

2、OF 1934 FOR THE TRANSITION PERIOD FROM TO Commission File Number 001-39503 Athira Pharma,Inc.(Exact name of registrant as specified in its charter)Delaware45-3368487(State or other jurisdiction ofincorporation or organization)(I.R.S.EmployerIdentification No.)18706 North Creek Parkway,Suite 104Bothe

3、ll,Washington 98011(Address of principal executive officer)(425)620-8501(Registrants telephone number,including area code)Securities registered pursuant to Section 12(b)of the Act:Title of each class TradingSymbol(s)Name of each exchange on which registeredCommon Stock,$0.0001 par value per share AT

4、HA The Nasdaq Stock Market LLC(The Nasdaq Global Select Market)Securities registered pursuant to Section 12(g)of the Act:None Indicate by check mark if the Registrant is a well-known seasoned issuer,as defined in Rule 405 of the Securities Act.YES NO Indicate by check mark if the Registrant is not r

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

6、ant 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(232.405 of this

7、 chapter)during 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 filer,an accelerated filer,a non-accelerated filer,smaller reporting company,or an emerging growth com

8、pany.See the definitions 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 c

9、ompany,indicate by 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 att

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

11、n 12(b)of the Act,indicate 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 anal

12、ysis of incentive-based compensation received by any of the registrants executive officers during the relevant recovery period pursuant to 240.10D-1(b).Indicate by check mark whether the Registrant is a shell company(as defined in Rule 12b-2 of the Exchange Act).YES NO The aggregate market value of

13、the common stock held by non-affiliates of the registrant,based on the closing price of the shares of common stock on June 28,2024(the last business day of the registrants most recently completed second fiscal quarter)as reported by The Nasdaq Stock Market LLC on such date was approximately$86.0 mil

14、lion.Shares of the registrants common stock held by each executive officer and director and by each other person who may be deemed to be an affiliate of the registrant have been excluded from this computation.This calculation does not reflect a determination that certain persons are affiliates of th

15、e registrant for any other purpose.The number of shares of Registrants Common Stock outstanding as of February 24,2025 was 39,042,445.DOCUMENTS INCORPORATED BY REFERENCEPortions of the definitive proxy statement to be delivered to stockholders in connection with the 2025 annual meeting of stockholde

16、rs are incorporated by reference into Part III of this Annual Report on Form 10-K.Such proxy statement will be filed with the Securities and Exchange Commission not later than 120 days following the end of the Registrants fiscal year ended December 31,2024.iTable of Contents PagePART I Item 1.Busine

17、ss5Item 1A.Risk Factors32Item 1B.Unresolved Staff Comments101Item 1C.Cybersecurity101Item 2.Properties102Item 3.Legal Proceedings102Item 4.Mine Safety Disclosures103 PART II Item 5.Market for Registrants Common Equity,Related Stockholder Matters and Issuer Purchases of Equity Securities104Item 6.Res

18、erved104Item 7.Managements Discussion and Analysis of Financial Condition and Results of Operations105Item 7A.Quantitative and Qualitative Disclosures About Market Risk118Item 8.Financial Statements and Supplementary Data118Item 9.Changes in and Disagreements with Accountants on Accounting and Finan

19、cial Disclosure142Item 9A.Controls and Procedures142Item 9B.Other Information143Item 9C.Disclosure Regarding Foreign Jurisdictions that Prevent Inspections.143 PART III Item 10.Directors,Executive Officers and Corporate Governance144Item 11.Executive Compensation144Item 12.Security Ownership of Cert

20、ain Beneficial Owners and Management and Related Stockholder Matters144Item 13.Certain Relationships and Related Transactions,and Director Independence144Item 14.Principal Accounting Fees and Services144 PART IV Item 15.Exhibits,Financial Statement Schedules145Item 16Form 10-K Summary148 1Summary Ri

21、sk FactorsOur business is subject to numerous risks and uncertainties,including those highlighted in the section of this report captioned“Risk Factors.”The following is a summary of the principal risks we face:We are a clinical-stage biopharmaceutical company with a limited operating history.Our dev

22、elopment of ATH-1105 may never lead to a marketable product.Our ability to generate revenue and achieve profitability depends significantly on our ability to achieve a number of objectives.Our approach to targeting neurotrophic factors through the use of small molecules is based on a novel therapeut

23、ic approach,which exposes us to unforeseen risks.We have limited data from preclinical studies and clinical trials to date,including for ATH-1105,and we cannot be certain that future trials will yield data in support of the safety,efficacy and tolerability of our drug candidates.We may not be succes

24、sful in identifying and implementing any strategic transaction and any strategic transactions that we may consummate in the future may not be successful.We have concentrated our research and development efforts on the treatment of central and peripheral nervous system degenerative disorders,a field

25、that has seen very limited success in product development.Clinical development involves a lengthy and expensive process with an uncertain outcome,and results of early,smaller-scale preclinical studies and clinical trials with a single or few clinical trial sites may not be predictive of eventual saf

26、ety or effectiveness in large-scale potentially pivotal clinical trials across multiple clinical trial sites.We may encounter substantial delays in clinical trials,or may not be able to conduct or complete clinical trials on the expected timelines,if at all.We may expend our limited resources to pur

27、sue a particular drug candidate or indication and fail to capitalize on drug candidates or indications that may be more profitable or for which there is a greater likelihood of success.We have been and may in the future be subject to claims,lawsuits,arbitration proceedings,government investigations,

28、securities class action litigation and other legal,regulatory and administrative proceedings and face potential liability and expenses related thereto,which could divert managements attention,and insurance coverage may not be sufficient to cover all costs and damages.This could have a material adver

29、se effect on our business,operating results and financial condition.Any“topline”,interim,initial,or preliminary data from our clinical trials that we announce or publish from time to time may change as more patient data become available and are subject to audit and verification procedures that could

30、 result in material changes in the final data.Our reporting of topline or final data for our clinical trials may be delayed and our regulatory submissions or receipt of necessary marketing approvals could be delayed or prevented.If we engage in future acquisitions or strategic partnerships,this may

31、increase our capital requirements,dilute our stockholders,cause us to incur debt or assume contingent liabilities,and subject us to other risks.We will require substantial additional funding to finance our operations,complete the development and commercialization of ATH-1105 and develop and commerci

32、alize other current and potential drug candidates.If we are unable to raise this funding and access capital when needed,we may be forced to delay,reduce,or eliminate our drug product development programs,commercialization efforts or other operations.Our success depends on our ability to protect our

33、intellectual property and our proprietary technologies.2If the scope of any patent protection we obtain is not sufficiently broad,or if we lose any of our patent protection,our ability to prevent our competitors from commercializing similar or identical product candidates would be adversely affected

34、.We face significant competition,and if our competitors develop and market technologies or products more rapidly than we do or that are more effective,safer,or less expensive than the drug candidates we develop,our commercial opportunities will be negatively impacted.The loss of any of our key perso

35、nnel could significantly harm our business,results of operations and competitive position.We have incurred significant losses since our inception and anticipate that we will continue to incur significant losses for the foreseeable future.The regulatory approval processes of the U.S.Food and Drug Adm

36、inistration,or FDA,and other comparable foreign regulatory authorities are lengthy,time consuming and inherently unpredictable.If we are not able to obtain,or if there are delays in obtaining,required regulatory approvals for our drug candidates,we will not be able to commercialize,or will be delaye

37、d in commercializing,our drug candidates,and our ability to generate revenue will be materially impaired.We rely on third parties to conduct our nonclinical studies and clinical trials.If these third parties do not properly and successfully carry out their contractual duties or meet expected deadlin

38、es,we may not be able to obtain regulatory approval of or commercialize our drug candidates.Even if approved,our drug candidates may not achieve adequate market acceptance among physicians,patients,healthcare payors and others in the medical community necessary for commercial success.We have never c

39、ommercialized a drug candidate before and may lack the necessary expertise,personnel and resources to successfully commercialize any drug products on our own or together with suitable collaborators.Intellectual property discovered or developed through government funded programs may be subject to fed

40、eral regulations such as“march-in”rights,certain reporting requirements and a manufacturing preference for U.S.-based companies.Compliance with such regulations may limit our exclusive rights and limit our ability to contract with non-U.S.manufacturers,which could adversely affect our ability to suc

41、cessfully develop and commercialize our drug products.If we do not regain compliance with or continue to satisfy the Nasdaq continued listing requirements,our common stock could be delisted from the Nasdaq,which may make it more difficult for investors to sell shares of our common stock and conseque

42、ntly may negatively impact the price of our common stock.The market price of our common stock has been and may continue to be volatile,which could result in substantial losses for investors.We and certain of our directors and executive officers have been,and may in the future be,named as defendants

43、in lawsuits that could result in substantial costs and divert managements attention.Actions by activist stockholders have in the past been,and may in the future be,disruptive and could cause uncertainty about the strategic direction of our business.Our Risk Factors are not guarantees that no such co

44、nditions exist as of the date of this report and should not be interpreted as an affirmative statement that such risks or conditions have not materialized,in whole or in part.3PART ISpecial Note Regarding Forward-Looking StatementsThis Annual Report on Form 10-K contains forward-looking statements t

45、hat are based on our managements beliefs and assumptions and on information currently available to our management.This section should be read in conjunction with our audited consolidated financial statements and related notes included in Part II,Item 8 of this report.The statements contained in this

46、 report that are not purely historical areforward-looking statements within the meaning of Section 27A of the Securities Act of 1933,as amended,or the Securities Act,and Section 21E of the Securities Exchange Act of 1934,as amended,or the Exchange Act.In some cases,you can identify forward-looking s

47、tatements by the following words:“anticipate,”“believe,”“continue,”“could,”“estimate,”“expect,”“intend,”“may,”“ongoing,”“plan,”possible,“potential,”“predict,”“project,”“should,”“target”,“will,”“would”or the negative of these terms or other comparable terminology,although not all forward-looking stat

48、ements contain these words.You should read these statements carefully because they discuss future expectations,contain projections of future results of operations or financial condition,or state other“forward-looking”information.These statements relate to our future plans,objectives,expectations,int

49、entions and financial performance and the assumptions that underlie these statements.These forward-looking statements include,but are not limited to,statements about:our financial performance;the sufficiency of our existing cash,cash equivalents and investments to fund our future operating expenses

50、and capital expenditure requirements;our expectations regarding the costs and expected cost savings and related benefits from our workforce reduction initiated in September 2024,or the Restructuring;our ability to obtain funding for our operations,including funding necessary to develop and commercia

51、lize our drug candidates;the ability of our nonclinical studies and clinical trials to demonstrate safety and efficacy of our drug candidates;the success,cost and timing of our development activities,nonclinical studies and clinical trials;the rate and degree of market acceptance of our drug candida

52、tes;the timing or likelihood of regulatory filings and approvals;the potential learnings from our ACT-AD and SHAPE trials,LIFT-AD independent unblinded interim efficacy and futility analysis,and LIFT-AD trial and their ability to inform and improve future clinical development plans;the potential of

53、our Phase 1 ATH-1105 clinical trial and any subsequent clinical trials to show the clinical benefits of ATH-1105;the timing and focus of our future clinical trials,and the reporting of data from those trials;anticipated milestone timelines,such as the timing of data releases,and our ability to meet

54、such timelines;our plans relating to commercializing our drug candidates,if approved;our plans and ability to establish sales,marketing and distribution infrastructure to commercialize any drug candidates for which we obtain approval;our ability to attract and retain key managerial,scientific and cl

55、inical personnel;our ability to contract with third-party suppliers and manufacturers and their ability to perform adequately;4the accuracy of our estimates regarding expenses,future revenue,capital requirements and needs for additional financing;the pricing and reimbursement of our drug candidates,

56、if approved;our reliance on third parties to conduct clinical trials of our drug candidates,and for the manufacture of our drug candidates for nonclinical studies and clinical trials;the success of competing therapies that are or may become available;the beneficial characteristics,safety and efficac

57、y of our drug candidates;regulatory developments in the United States and other jurisdictions;our ability to obtain and maintain regulatory approval of our drug candidates in the United States and other jurisdictions,and any related restrictions,limitations or warnings in the label of any approved d

58、rug candidate;future agreements with third parties in connection with the commercialization of our drug candidates;our plans,capacity and capability relating to the further development and manufacturing of our drug candidates,including additional indications for which we may pursue regulatory approv

59、al;our plans and ability to obtain or protect intellectual property rights,including extensions of existing patent terms where available;the scope of protection we are able to establish and maintain for intellectual property rights covering our drug candidates and technology;the outcome of legal pro

60、ceedings which have been or may in the future be instituted against us and certain of our directors and officers,including the legal proceedings discussed in Part I,Item 3 Legal Proceedings,”and elsewhere in this report;the actions by activist stockholders,which have in the past been,and may in the

61、future be,disruptive and could cause uncertainty about the strategic direction of our business;our plans and ability to regain compliance with the Nasdaq listing rules;the size and growth potential of the markets for our drug candidates,if approved for commercial use,and our ability to serve those m

62、arkets;the potential benefits of any strategic collaborations,partnerships,or other transactions we may enter into;our expectations regarding the time during which we will be an emerging growth company under the JOBS Act;andour plans and expectations regarding our exploration of strategic alternativ

63、es focused on maximizing stockholder value,including whether or not such process will result in a strategic transaction on terms satisfactory to us,or other alternatives which increase stockholder value.These forward-looking statements are subject to certain risks and uncertainties that could cause

64、actual results to differ materially from those anticipated in the forward-looking statements.Factors that might cause such a difference include,but are not limited to,those discussed in this report in Part I,Item 1A “Risk Factors,”and elsewhere in this report.These statements,like all statements in

65、this report,speak only as of their date,and we undertake no obligation to update or revise these statements in light of future developments.Our Risk Factors are not guarantees that no such conditions exist as of the date of this report and should not be interpreted as an affirmativestatement that su

66、ch risks or conditions have not materialized,in whole or in part.In addition,statements that“we believe”and similar statements reflect our beliefs and opinions on the relevant subject.These statements are based upon information available to us as of the date of this report,5and although we believe s

67、uch information forms a reasonable basis for such statements,such information may be limited or incomplete,and our statements should not be read to indicate that we have conducted a thorough inquiry into,or review of,all potentially available relevant information.These statements are inherently unce

68、rtain and you are cautioned not to unduly rely upon these statements.This report includes our trademarks and registered trademarks,including Athira,Athira Pharma,the Athira logo,and other trademarks,trade names,or service marks of Athira.Each other trademark,trade name or service mark appearing in t

69、his report belongs to its holder.Solely for convenience,trademarks,trade names,and service marks referred to in this report are listed without or TM symbols,but we will assert,to the fullest extent under applicable law,our or the rights of the applicable licensors to these trademarks,trade names,and

70、 service marks.In this report,“we,”“our,”“us,”“Athira,”and“the Company”refer to Athira Pharma,Inc.and its wholly-owned subsidiary.Item 1.Business.OverviewAthira is a clinical-stage biopharmaceutical company focused on developing small molecules engineered to restore neuronal health and slow neurodeg

71、eneration.Athiras approach is designed to modulate the neurotrophic hepatocyte growth factor,or HGF,system,that is critical to normal brain function and may play a key role in maintaining the health and functioning of neuronal networks.Athira believes that by acting on the neurotrophic HGF system an

72、d its multiple downstream signaling pathways,it may be able to enhance the bodys natural ability to protect and repair neuronal networks by reducing inflammation,promoting regeneration,and reducing disease-specific protein pathologies,thereby positively impacting the course of disease.Athira aims to

73、 achieve these goals by advancing its pipeline of novel small molecule compounds which are designed to and have exhibited properties in enhancing the neurotrophic HGF system in either the centralnervous system,or CNS,by crossing the blood brain barrier,or BBB,or the peripheral nervous system,or PNS.

74、Athira is actively reviewing options for partnerships or arrangements that will allow it to realize the potential of its drug candidates.The companys lead drug candidate is ATH-1105.ATH-1105 is a novel,orally available,brain-penetrant,next-generation small molecule drug candidate designed to positiv

75、ely modulate the neurotrophic HGF system for potential treatment of neurodegenerative diseases,including amyotrophic lateral sclerosis,or ALS,Alzheimers disease,or AD,and Parkinsons disease,or PD.ATH-1105 is currently in development for the potential treatment of ALS.Athira conducted a first-in-huma

76、n Phase 1 double-blind,placebo-controlled trial that enrolled 80 healthy volunteers to evaluate single and multiple oral ascending doses of ATH-1105.The study was completed in November 2024 and evaluated the safety and tolerability of ATH-1105 and included measurements of pharmacokinetic outcomes.Th

77、e results of the Phase 1 trial showed that ATH-1105 demonstrated a favorable safety profile and was well-tolerated in healthy volunteers,supporting continued clinical development.Athiras previous lead drug candidate,fosgonimeton,is a small molecule drug candidate designed to positively modulate the

78、neurotrophic HGF system for potential treatment of neurodegenerative diseases.In September 2024,Athira announced the topline results for LIFT-AD,a randomized,double-blind,placebo-controlled,parallel-group 26-week Phase 2/3 clinical trial with fosgonimeton in mild-to-moderate AD.The primary and key s

79、econdary endpoints of the LIFT-AD trial did not reach statistical significance compared with placebo at 26 weeks.Based on these results,Athira decided to pause further development of fosgonimeton and to shift its focus to the clinical development of ATH-1105.6Athiras StrategyTo further its goal of d

80、eveloping small molecules engineered to restore neuronal health and slow neurodegeneration,Athiras strategy is to advance its pipeline of small molecule drug candidates,focusing on drug candidates that show both strong pharmacokinetics and pharmacodynamics,or PK/PD,translation and early predictive c

81、linical data.Athiras PipelineFigure 1 below illustrates the current development stage of Athiras proprietary drug candidates and early discovery and development programs,of which only ATH-1105 is currently in clinical development,for the potential treatment of ALS.Athira has also explored the use of

82、 its drug candidates in other indications in the CNS and PNS with the goal of improving neuronal health in multiple neurodegenerative diseases.In addition,Athiras drug discovery efforts have focused on designing and testing new early compounds to enhance the neurotrophic HGF system for a variety of

83、clinical applications.Figure 1.Summary of Our Preclinical and Clinical ATH Programs.ATH-1105ATH-1105 is a novel,orally available,brain-penetrant,next generation,small molecule drug candidate designed to positively modulate the neurotrophic HGF system.Athira conducted a first-in-human Phase 1 double-

84、blind,placebo-controlled trial that enrolled 80 healthy volunteers to evaluate single and multiple oral ascending doses of ATH-1105.The study was completed in November 2024 and evaluated the safety and tolerability of ATH-1105 and included measurements of pharmacokinetic outcomes.The results of the

85、Phase 1 trial showed that ATH-1105 demonstrated a favorable safety profile and was well-tolerated in healthy volunteers,supporting continued clinical development.7In preclinical models of ALS,treatment with ATH-1105 resulted in improvements in motor neuron survival and function.In vitro,ATH-1105 tre

86、atment protected primary spinal motor neurons from glutamate toxicity and prevented accumulation of toxic protein aggregates.Additionally,ATH-1105 induced target activation in cultures of ALS patient-derived motor neurons.In a preclinical mouse model of ALS,treatment with ATH-1105 significantly prev

87、ented loss of body weight,and improved motor function including balance,coordination and muscle strength.Athira additionally reported that treatment with ATH-1105 significantly improved electrophysiological measures of functional nerve signaling and protected against motor neuron axon degeneration a

88、nd demyelination.ATH-1105 treatment also significantly reduced biomarkers of inflammation and neurodegeneration and prolonged survival.Study results were presented at the Motor Neurone Disease Association International Symposium in December 2022 and 2023 and published in Frontiers in Neuroscience,20

89、24.Weight loss,motor deficits,inflammation,loss of functional nerve signaling,and motor neurondegeneration and demyelination are all hallmarks of ALS disease;treatment with ATH-1105 significantly improved all of these aspects in the preclinical models tested.ATH-1020ATH-1020 is a novel,orally availa

90、ble,next generation,small molecule drug candidate designed to positively modulate the neurotrophic HGF system.Athira filed an IND application with the FDA for ATH-1020 at the end of 2021 and received notice of acceptance in January 2022.This compound was originally assessed for neuropsychiatric indi

91、cations in preclinical models as presented at the American Society for Experimental Therapeutics Annual Conference in February 2022.In preclinical models of diabetic neuropathic pain,Athira demonstrated significant improvements in two aspects of disease that are prominent symptoms in people sufferin

92、g from neuropathic pain:increased sensitivity to mechanical and thermal stimulation.The significant improvements in neuropathic pain were partially sustained after seven days of not receiving ATH-1020,suggesting persistent and potentially disease-modifying effects.Data from these studies were presen

93、ted at the Society for Neuroscience Annual Conference in November 2022 and the American Society for Experimental Neurotherapeutics in March 2023.Athira has completed the SAD escalation portion of the Phase 1 trial,in which ATH-1020 demonstrated a favorable safety profile and was well-tolerated in he

94、althy volunteers.Early CompoundsIn addition to the compounds described above,Athira has evaluated several other compounds in preclinical discovery and development for neurodegenerative diseases and other indications where it believes positive modulation of the neurotrophic HGF system may have therap

95、eutic potential.Mechanism of DiseaseCauses of neurodegenerative diseases are not fully understood as these diseases are complex with several contributing factors including inflammation,oxidative stress,neurotoxicity,excitotoxicity,synaptic dysfunction,and protein pathologies that ultimately lead to

96、neuronal damage,neuronal network degeneration and a decline in function.Intrinsic to these diseases is the disruption of a healthy neuronal network that can be overcome and repaired or maintained when the bodys natural repair mechanisms are intact.However,a loss of or reduction in ability of the bod

97、y to repair itself can lead to dysregulation that then manifests as symptoms and overall functional decline.One such naturally occurring repair mechanism is the neurotrophic HGF system.8Scientific evidence supporting the neurotrophic HGF system as a naturally occurring repair mechanism is backed by

98、over 30 years of research.MET is one of the most stably expressed genes in the adult human brain and is essential to a healthy,functional nervous system.HGF/MET signaling plays a critical role in both the development and maintenance of nervous system tissue.In ALS,studies have highlighted the import

99、ance of HGF in key processes affected by the disease.HGF functions as a potent survival factor for motor neurons,and impaired HGF/MET signaling has detrimental effects on neuromuscular junction integrity.Preclinical studies in ALS animal models show that HGF delivery reduces motor neuron degeneratio

100、n,improves motor function,and prolongs lifespan.Additionally,HGF signaling has been linked to muscle function,the loss of which is a key feature of ALS.And although evidence supports the neurotrophic HGF system as an attractive target for combating neurodegenerative diseases,such as ALS,with its mul

101、timodal mechanism of action,it has proven a difficult drug target.There are approved and in-development gene therapy approaches to increase HGF expression beyond normal physiological levels,but these are limited as potentially viable treatment options for neurological disorders due to limited distri

102、bution and more invasive delivery requirements,such as intrathecal or intravenous,or locally restricted to the periphery,such as via intramuscular routes of administration.To date,drug developers have been deploying approaches that typically address only a single factor of the cascade of pathologies

103、 that lead to neurodegeneration,yet translating early successful results to meaningful clinical benefit has been mixed if not elusive.Athira believes that to address such complex and multifactorial diseases requires a novel multimodal approach,such as targeting the neurotrophic HGF system through no

104、n-invasive small molecules that enhance levels of HGF system activation to protect and repair neuronal networks.Mechanism of ActionAthira has developed a pipeline of proprietary small molecule compounds,or ATH positive modulators,designed to enhance the neurotrophic HGF system and promote its neurop

105、rotective,neurotrophic and anti-inflammatory effects,including protection of neurons from a variety of insults.These novel small molecules are designed to cross the blood-brain barrier for CNS disorders or remain in the periphery for PNS and other indications,and mechanistically produce a series of

106、multimodal effects that support their therapeutic promise to:reduce inflammation,promote regeneration,provide neuroprotection,and,ultimately,slow disease progression.Figure 2 below illustrates the hypothesized mechanism of action of ATH positive modulators and the cellular disease state where diseas

107、ed neurons generate a biomarker of neurodegeneration,NfL,as well as other signature markers of neuronal damage.Contributing to a diseased neuron are also proinflammatory cytokines produced by activated microglia.In the treated neuron state where ATH positive modulators are designed to enhance HGF/ME

108、T signaling to promote neuroprotective and neurotrophic pathways,reduced neuron degeneration and NfL production occur while the treated glia show reduced activation and production of proinflammatory cytokines,illustrating the potential reduction in neurodegeneration and inhibition of neuroinflammati

109、on through the enhancement of the neurotrophic HGF system.9Figure 2.Hypothesized Mechanism of Action of ATH Positive Modulators.As ATH positive modulators interact with the HGF system,neurotrophic and neuroprotective pathways are activated downstream,including the activation of the extracellular-sig

110、nal regulated kinase,or ERK and protein kinase B,or AKT pathways,which play critical roles in protecting neurons from damage and death,including from oxidative stress,excitotoxicity,and apoptosis.Figure 3 below shows cell culture data demonstrating that one of the key mechanisms of action of ATH pos

111、itive modulators is through activation of AKT and ERK via MET activation.10Figure 3.ATH-1105 enhances HGF signaling and promotes neurotrophic and neuroprotective pathways.Positively modulating the neurotrophic HGF system promotes its multimodal effects,which Athira believes can potentially address t

112、he complex pathology in neurodegenerative diseases.These positive multimodal effects taken together may lead to improvement in function.ATH-1105ATH-1105 Preclinical Evidence for ALSATH-1105 is a novel oral small molecule drug candidate being assessed as a potential treatment for ALS.In a spinal moto

113、r neuron model,ATH-1105 significantly protected against neuron death by glutamate-induced excitotoxicity,while reducing pathological aggregation of TAR DNA-binding protein 43,or TDP-43.Figure 4 summarizes the data with images of microtubule-associated protein-2,or MAP-2-labeled spinal motor neurons

114、in green,and extranuclear TDP-43 in red.In the control image on the left with no excitotoxic insult(glutamate),there is minimal overlap of MAP-2 neurons with extranuclear TDP-43.When glutamate is applied to the motor neuron cultures,theres an overall reduction in the number of neurons and increased

115、extranuclear TDP-43 as shown by overlapping red-green staining in the middle image.When cell cultures were treated with ATH-1105,the effect of glutamate-induced excitotoxicity on the overall number of motor neurons and extranuclear TDP-43 protein aggregation was significantly reduced,as seen in the

116、rightmost image and as quantified in the bar graphs.11Figure 4.ATH-1105 is Neuroprotective Against Excitotoxic Insult and Reduces Extranuclear TDP-43 Levels in Spinal Motor Neurons.Data presented as mean+SEM.Statistics applied:1-way ANOVA with Fisher least significant difference test.*p0.05;*p0.01;*

117、p0.001 versus Glutamate Control.Scale bar:100 m.n=5-6 per group.MAP-2,microtubule-associated protein-2;TDP-43,TAR DNA-binding protein 43.ATH-1105 has also demonstrated target engagement in ALS patient-derived induced pluripotent stem cells(iPSCs)that were differentiated into motor neurons.In this mo

118、del,as summarized in Figure 5,ALS patient-derived motor neurons treated with ATH-1105 100 nM exhibited a significant increase in MET activation(pMET)demonstrating engagement of HGF signaling,when compared to motor neurons treated with vehicle.These results were presented at the Motor Neurone Disease

119、 Association International Symposium in December 2024.Figure 5.ATH-1105 increases MET activation in ALS patient-derived motor neurons.Human iPSC-derived motor neurons sourced from Cedar Sinai via AnswerALS consortium.Motor neurons were cultured in growth factor deprived media and treated with vehicl

120、e or ATH-1105 every 48h for 6 days.MET activation was measured 24h post ATH-1105 treatment.Data presented as mean SEM.Statistical significance was determined via paired t-test comparing MET activation(pMET/Total MET)in motor neurons treated with vehicle or ATH-1105 100 nM;n=2 technical replicates fr

121、om each donor.Plasma biomarkers of inflammation and neurodegeneration were significantly reduced following treatment with ATH-1105 in a transgenic TDP-43-driven mouse model of ALS(Figure 6).These results support the anti-inflammatory and neuroprotective effects of ATH-1105 through enhancement of neu

122、rotrophic HGF system signaling.In the TDP-43-driven ALS model,significant increases in the proinflammatory cytokines tumor necrosis factor alpha,or TNF-alpha,and interleukin 6,or IL-6,were 12observed compared to healthy wild-type,or WT,control animals.When ALS-model mice,or ALS mice,were treated wit

123、h ATH-1105 significant reductions in both TNF-alpha and IL-6 were observed,demonstrating anti-inflammatory activity.Consistent with the neuroprotective effects demonstrated in cell-based models,a significant reduction in plasma levels of the neurodegeneration biomarker,NfL,was observed in ALS mice t

124、reated with ATH-1105,which is indicative of neuroprotection.Figure 6.ATH-1105 Improves Biomarkers of Inflammation and Neurodegeneration in a Mouse Model of ALS.Graphical representation of plasma IL-6,TNF-in fold-difference over the WT+vehicle group,and NfL levels in ng/ml at two months of treatment.

125、N=10 per group.Data presented as mean SEM.Statistical significance was determined by 1-way ANOVA with the Dunnetts test versus ALS+vehicle.*p0.0001.ALS,amyotrophic lateral sclerosis;IL-6,interleukin 6;NfL,neurofilament light chain;TNF-,tumor necrosis factor alpha;WT,wild-type.Treatment with ATH-1105

126、 in a mouse model of ALS protected against axon degeneration and demyelination as observed from histological examination of cross-sections of the sciatic nerve.Figure 7 below includes an image of the sciatic nerve from a WT healthy control animal,on the left,featuring a large number of large diamete

127、r axons surrounded by a consistent and highly regular coating of myelin sheath.In the middle,a sciatic nerve image from an ALS disease control animal is shown,where a marked reduction in the number of axons,a decrease in average axon diameter,and irregular myelination is observed.On the right,when A

128、LS animals are treated with ATH-1105,sciatic nerve integrity is preserved with a greater population of large diameter axons and preservation of regular myelination.Graphs below the images are quantified data showing these effects of ATH-1105 in a mouse model of ALS.13Figure 7.Treatment with ATH-1105

129、 Protected Against Axon Degeneration and Demyelination in a Mouse Model of ALS.Histology images of sciatic nerve cross-sections stained with toluidine blue to label myelin.Scale is 10 m(all panels).Graphical representation of the number of axons(per 100 m2),axonal diameter(in micrometers),and mean o

130、f myelin g-ratio,defined as the ratio of the inner axonal diameter to the total axonal diameter,following two months of treatment.Data presented as mean+SEM.Statistical significance was determined by 1-way ANOVA with the Dunnetts test versus ALS+vehicle.*p0.0001.ALS,amyotrophic lateral sclerosis;WT,

131、wild-type.Further analyses of electrophysiological and behavioral assessments indicated the protection of the motor neurons with ATH-1105 translated to improved nerve and motor function(Figure 8).Compound muscle action potential,or CMAP,and nerve conduction velocity,or NCV,are two electrophysiologic

132、al measures of functional nerve signaling.Treatment with ATH-1105 in a mouse model of ALS demonstrated consistent and significant improvements of nerve function compared to ALS disease control animals.Two examples of motor function improvements are shown by the rotarod,an assessment of balance and c

133、oordination,and the grip test,an assessment of strength.ALS disease control animals showed significant motor impairments compared to WT healthy control animals.ATH-1105 treatment in this mouse model of ALS led to significant improvements in both the rotarod and grip tests compared to the vehicle tre

134、ated ALS disease control animals,demonstrating preservation of motor function.Other motor behavior tests assessing balance,coordination and muscle strength were the balance beam and Kondziela screen tests.Across all motor function measures,significant improvements were seen in ALS animals treated wi

135、th ATH-1105 compared to ALS animals treated with vehicle.14Figure 8.Treatment with ATH-1105 Improves Nerve and Motor Function in a Mouse Model of ALS.Graphical representation of CMAP amplitude,NCV,rotarod latency,and grip strength at baseline and after one and two months of treatment.Data presented

136、as mean SEM.Statistical significance was determined by 2-way ANOVA with the Dunnetts test versus ALS+vehicle.*p0.01;*p0.001;*p0.0001.N=10 per group.ALS,amyotrophic lateral sclerosis;CMAP,compound muscle action potential;NCV,nerve conduction velocity;WT,wild-type.The above study results,depicted in F

137、igure 8,were presented at the American Academy of Neurology,or AAN,in April 2023,and the ALS Drug Development Summit in May 2023.Treatment with ATH-1105 in a mouse model of ALS extends survival and improves other disease-related measures.Figure 9 below compares ALS mice treated with oral ATH-1105 20

138、 mg/kg once daily in blue with oral vehicle once daily treated ALS mice in red.Mice were treated from one month of age to a humane endpoint maximum of five months of age,for a total of up to four months of treatment.ATH-1105 increased time to first mortality and significantly prolonged survival comp

139、ared to ALS disease control animals(p=0.0035).ATH-1105 also significantly protected against body weight reduction(p0.01).These findings were reported at the AAN 2023 Annual Meeting in April 2023.15Figure 9.ATH-1105 Significantly Improved Survival in a Mouse Model of ALS.Data presented as Kaplan-Meie

140、r curveStatistics applied:Log-rank(Mantel-Cox)test for survival curve comparison,*p0.01.n=20 mice per group at start Treatment with ATH-1105 in a mouse model of ALS outperforms treatment with riluzole under the conditions tested in assessments of motor function,nerve function,and in reducing disease

141、-related plasma biomarkers.Figure 10 below compares performance in the grip test of WT mice(grey)and transgenic ALS mice treated daily with vehicle(red),intraperitoneal riluzole 5 mg/kg(green),oral ATH-1105 20 mg/kg(blue),or both ATH-1105 and riluzole(purple).Mice treated with ATH-1105 alone and co-

142、administration of riluzole and ATH-1105 consistently outperformed the vehicle-treated ALS disease control group.In both the ATH-1105 and the co-administration of ATH-1105 and riluzole groups,performance on the test approached that of the WT healthy control group.ATH-1105 treatment outperformed riluz

143、ole treatment in tests of motor function including the grip,rotarod,Kondziela screen,and balance beam tests.ATH-1105 also outperformed riluzole in tests of nerve function preservation including CMAP amplitude and NCV.ATH-1105 treatment further reduced plasma levels of IL-6 and TNF-alpha compared to

144、riluzole,which are biomarkers of inflammation.ATH-1105 treatment also more greatly reduced plasma levels of NfL compared to riluzole,which is a biomarker of neurodegeneration.These findings were reported at the Northeast ALS Consortium meeting in October 2023,and the Motor Neurone Disease Associatio

145、n conference in December 2023.16Figure 10.ATH-1105 Preserves Motor and Nerve Function and Reduces Plasma NfL Compared with Riluzole in a Mouse Model of ALS.Graphical representation of change from baseline following two months of treatment in grip test,CMAP amplitude,and Plasma Nfl.Data presented as

146、mean SEM,or box-and-whisker plotsStatistics applied:One-way ANOVA with Dunnetts test.*p0.05;*p0.01;*p0.001;*p0.0001.n=10 mice per group;Abbreviations:CFB,change from baseline,CMAP,compound muscle action potential,NfL,neurofilament light chain Clinical Development Plan for ATH-1105 in ALSWeight loss,

147、motor deficits,inflammatory effects,loss of muscle integrity,nerve degeneration and demyelination are all classical hallmarks of disease in people with ALS;treatment with ATH-1105 significantly improved all of these deficits preclinically.Athira conducted a first-in-human Phase 1 double-blind,placeb

148、o-controlled trial that enrolled 80 healthy volunteers to evaluate single and multiple oral ascending doses of ATH-1105.The study was completed in November 2024 and evaluated the safety and tolerability of ATH-1105 and included measurements of pharmacokinetic outcomes.The results of the Phase 1 tria

149、l showed that ATH-1105 demonstrated a favorable safety profile and was well-tolerated in healthy volunteers,supporting continued clinical development.17ATH-1020ATH-1020 Preclinical Evidence for Neuropathic PainATH-1020 is a novel,orally available,next generation,small molecule drug candidate designe

150、d to positively modulate the neurotrophic HGF system.Enhancing HGF/MET signaling promotes neuroprotective,neurotrophic,and anti-inflammatory effects,and as neuropathic pain disorders,including diabetic neuropathy,or DNP,have components of oxidative stress,nerve damage,and inflammation,positive modul

151、ation of the HGF/MET pathway may provide therapeutic benefit in these disease areas.Data below were presented at the Society for Neuroscience Annual Conference in November 2022.This compound was originally assessed for neuropsychiatric indications in preclinical models as presented at the American S

152、ociety for Experimental Therapeutics Annual Conference in February 2022.In animal models of DNP hypersensitivity to mechanical and thermal pain are commonly experienced,which are also representative of symptoms in people with neuropathic pain.Shown in Figure 11 below,treatment with ATH-1020 signific

153、antly reduced pain behaviors over the testing period compared to DNP controls alone.Figure 11.Reduced Mechanical and Thermal Pain-Related Behaviors Following ATH-1020 Treatment in a Rat Model of Diabetic Neuropathic Pain.Data presented as means+SEM.*p0.0001 using one-way ANOVA with Dunnett test vs D

154、NP control.ANOVA,analysis of variance;AUC,area under the curve;DNP,diabetic neuropathic pain;PWL,paw withdrawal latency;PWT,paw withdrawal threshold.Persistence of reduced pain behaviors following ATH-1020 treatment were assessed after a short-term(23-hour)or a long-term(7-day)washout period.Study r

155、esults demonstrated that even after short-and long-term washout periods,where no drug is present,the effects of ATH-1020 reduction of pain behaviors remained persistent,suggesting a potential disease modifying effect(Figure 12).18Figure 12.Persistent Pain Reduction after 7-day Washout Following ATH-

156、1020 Treatment.Data presented as means+SEM.*p0.05;*p0.01;*p0.0001 using one-way ANOVA with Dunnett test vs DNP control.ANOVA,analysis of variance;AUC,area under the curve;DNP,diabetic neuropathic pain;PWL,paw withdrawal latency;PWT,paw withdrawal threshold.ATH-1020 Clinical Phase 1 Trial in Healthy

157、VolunteersAthira filed an IND application with the FDA for ATH-1020 at the end of 2021 and received notice of acceptance in January 2022.In September 2022,it completed the single-ascending dose escalation portion of the Phase 1 trial.ATH-1020 demonstrated a favorable safety profile and was well-tole

158、rated in healthy volunteers.FosgonimetonAthiras previous lead drug candidate,fosgonimeton,is a small molecule drug candidate designed to positively modulate the neurotrophic HGF system for potential treatment of neurodegenerative diseases.In September 2024,Athira announced the topline results for LI

159、FT-AD,a randomized,double-blind,placebo-controlled,parallel-group 26-week Phase 2/3 clinical trial with fosgonimeton in mild-to-moderate AD.The primary and key secondary endpoints did not reach statistical significance compared with placebo at 26 weeks.However,both components of the Global Statistic

160、al Test(GST),cognition(ADAS-Cog11)and function(ADCS-ADL23),directionally favored fosgonimeton treatment,and in pre-specified subgroups characterized by more rapid disease progression(moderate AD and APOE4 carriers),cognition and function improved or stabilized in the fosgonimeton treated group.In ad

161、dition,data across biomarkers of protein pathology(A42/40,p-Tau181,and p-Tau217),inflammation(GFAP)and neurodegeneration(NfL)showed directional improvements with fosgonimeton treatment that are consistent with the broad neuroprotective mechanism of HGF modulation.Based on these results,Athira decide

162、d to pause further development of fosgonimeton and to shift its focus to the clinical development of ATH-1105.Market OpportunityThe potential target indications for Athiras small molecule positive modulators include ALS and other neurodegenerative diseases.A recent study estimated that approximately

163、 33,000 persons in the United States are affected with ALS.This number was projected to increaseto approximately 36,000 by 2030.Prevalence at the global level varies geographically.Cases worldwide have been projected to increase from approximately 223,000 in 2015 to approximately 377,000 in 2040.Cur

164、rently,there are only four approved drugs that are specifically indicated for the treatment of ALS,of which none targets neurotrophic factor systems with a multimodal mechanism of action with the potential to offer neuroprotective,anti-inflammatory and potentially disease modifying effects.19Potenti

165、al Commercialization PlanATH-1105 is currently in development for the potential treatment of ALS.The potential commercialization strategy is expected to consider the following key elements:potential first-line therapy;an add-on therapy for patients on existing therapies;anda therapy for patients who

166、 have stopped existing therapies.Athira aims to demonstrate the therapeutic potential of ATH-1105 in ALS as an initial indication.Given the unique potential of ATH-1105 to provide broad protection against neurodegeneration,there may be therapeutic application in additional neurodegenerative indicati

167、ons including but not limited to frontal temporal dementia,Parkinsons,polyneuropathies,and others.Athira expects its commercialization strategies,including distribution plans,will evolve as clinical development progressesAthira is actively reviewing options for partnerships or other arrangements tha

168、t will allow it to realize the commercial potential of its drug candidates.ManufacturingAthiras focus on small molecule therapeutics enables it to use well-established and widely available manufacturing processes and infrastructure,formulation compositions,and drug administration technologies or dev

169、ices.Athira does not operate its own facilities for manufacturing,storing,or distributing drug candidates.It utilizes third-party contract development and manufacturing organizations,or CDMOs,to manufacture and supply preclinical and clinical materials during the development of drug candidates.Athir

170、a and various regulatory bodies have audited the CDMOs it contracts with,and such CDMOs have a proven track record of GMP-compliant manufacturing.ATH-1105 is purified as a stable solid and then released to other CDMOs for formulation and packaging into the final drug product for use in clinical test

171、ing.Athira believes the synthesis of ATH-1105 is reliable and reproducible and the synthetic routes can be further optimized to enable large-scale production that continues to avoid use of toxic materials or specialized equipment or handling during the manufacturing process.For the potential commerc

172、ialization of any drug candidates that receive regulatory approval,Athira expects to rely on partners manufacturing capabilities or use similar third-party CDMO contract resources.CompetitionThe biotechnology and biopharmaceuticals industries are characterized by rapid technological advancement,sign

173、ificant competition,and an emphasis on intellectual property.As a clinical-stage biopharmaceutical company developing small molecules to restore neuronal health and slow neurodegeneration,with its principal drug candidate focused on the treatment of ALS,Athira faces,and in the future may face,increa

174、sed competitive pressures from both large and small pharmaceutical companies and from established and emerging biotechnology companies,as well as academic,government,and public and private research institutions.Any drug candidates that Athira successfully develops and commercializes will compete wit

175、h current treatments and new treatments that may become available in the future.With the advancement of ATH-1105 as a novel small molecule therapeutic that positively modulates the neurotrophic HGF system,Athira must consider companies as competitors who are developing other novel approaches,includi

176、ng those that target other neurotrophic systems to address ALS and other neurological diseases.Additionally,because ATH-1105 is orally administered,Athira must also consider as competitors companies developing ALS therapies as oral therapeutics or with other routes of administration.20Because of the

177、 range of potential competitors,many of Athiras competitors,alone or with strategic partners,have greater access to financial resources,market presence,and resources and expertise in development,preclinical and clinical testing,manufacturing,commercialization,the regulatory approval process,or marke

178、ting and sales than Athira does.In addition,these same competitors,who may be in a clinical development stage,could also be competing with Athira for patient recruitment,clinical research organization,and operational resources.These entities also compete with Athira in the recruitment and retaining

179、of qualified scientific and management personnel,as well as the acquisition of enabling or complementary technologies for advancing Athiras product candidates across all competitors.Merger and acquisition activity in the biotechnology and biopharmaceutical industries may result in even more resource

180、s being concentrated among a smaller number of Athiras competitors.Smaller or early-stage companies may also prove to be significant competitors,particularly through collaborative arrangements with large and established companies.Athiras commercial opportunity could be substantially limited if its c

181、ompetitors develop and commercialize products that are more effective,safer,more convenient or less expensive than Athiras comparabledrug products.In geographies that are critical to Athiras commercial success,competitors may also obtain regulatory approvals first,resulting in these competitors buil

182、ding a strong market position in advance of the entry of Athiras drug candidates.In addition,Athiras ability to compete may be affected in many cases by insurers or other third-party payors seeking to encourage the use of other treatments.Specific to targeting HGF/MET,however,Athira is not aware of

183、any direct competitors currently developing small molecules targeting the neurotrophic HGF system for ALS.Athira is aware of two companies developing HGF/MET-directed therapies for ALS,including VM202,a plasmid DNA encoding human HGF developed by Helixmith,and KP-100,a recombinant HGF protein develo

184、ped by Kringle Pharma.Both assets have been investigated in Phase 2 clinical trials for ALS,where they were shown to be safe and well-tolerated but failed to reach statistical significance on efficacy endpoints.ATH-1105 has the potential to offer neuroprotective and anti-inflammatory effects by targ

185、eting the HGF/MET system.Athiras preclinical data have demonstrated this multimodal approach may have positive benefits across several biological and clinical measures.While several potential direct competitors may exist,Athira has not yet identified any competitive asset that has demonstrated consi

186、stent and congruent positive effects offering neuroprotection,anti-inflammation,reduction in disease-specific protein pathologies,and neurotrophic and functional benefits.Intellectual PropertyAthira owns or has in-licensed numerous patents and patent applications and possesses substantial know-how a

187、nd trade secrets relating to the development and commercialization of its drug candidates,including related manufacturing processes and technologies.As of December 31,2024,the companys patent portfolio includes its exclusively owned intellectual property,including issued patents and pending patent a

188、pplications in the United States,issued patents and pending patent applications in jurisdictions outside of the United States,and a pending international patent application filed under the Patent Cooperation Treaty.The patents and patent applications issued and pending outside of the United States a

189、re counterparts to the foregoing United States patents and patent applications and are generally held in Argentina,Australia,Brazil,Canada,Chile,China,Eurasia,Europe,Hong Kong,India,Indonesia,Israel,Japan,Mexico,Malaysia,New Zealand,Philippines,Singapore,South Africa,South Korea,Taiwan,and Thailand.

190、Athiras owned patents and patent applications have claims directed to ATH-1105 and its other small molecule drug candidates,including ATH-1020 and fosgonimeton,as compositions of matter and methods of use thereof.Individual patents are in force for varying periods of time,depending upon the date of

191、filing of the patent application,the date of patent issuance,and the legal term of patents in the countries in which they are obtained.Generally,patents issued for applications filed in the United States are in force for 20 years from the earliest nonprovisional filing date.In addition,in certain in

192、stances,a patent term can be adjusted or extended to recapture a portion of the term effectively lost as a result of the United States Patent and Trademark Office,or USPTO,delay or the FDA regulatory review period(a patent term adjustment or patent 21term extension,respectively).The restoration peri

193、od for FDA delay cannot be longer than five years and the total patent term,including the restoration period,must not exceed 14 years following FDA approval.The duration of patents outside of the United States varies in accordance with provisions of applicable local law,but typically is also 20 year

194、s from the earliest nonprovisional filing date.However,the actual protection afforded by a patent varies on a product-by-product basis,from country-to-country,and depends upon many factors,including the type of patent,the scope of its coverage,the availability of regulatory-related extensions,the av

195、ailability of legal remedies in a particular country,and the validity and enforceability of the patent.Athiras owned issued patents will expire on dates ranging from 2037 to 2042,exclusive of any patent term adjustment or patent term extension.If patents are issued on Athiras owned pending non-provi

196、sional patent applications,the resulting patents are projected to expire on dates ranging from 2037 to 2043,exclusive of any patent term adjustment or patent term extension.When appropriate,Athira seeks to protect aspects of its technology and business not amenable to,or that it does not consider ap

197、propriate for,patent protection as trade secrets.Athira seeks to protect this intellectual property,in part,as trade secrets,by entering into confidentiality agreements with those who have access to its confidential information,including employees,contractors,consultants,collaborators,and advisors.T

198、he company also seeks to preserve the integrity and confidentiality of its proprietary technology and processes by maintaining physical security of its premises and physical and electronic security of its information technology systems.Athira seeks trademark protection in the United States and in ce

199、rtain other jurisdictions where available and when it deems appropriate.Athiras trademark portfolio includes issued trademark registrations for Athira Pharma and other pending trademark applications in the United States and internationally.Government RegulationGovernment authorities in the United St

200、ates,at the federal,state,and local level,and other countries extensively regulate,among other things,the research,development,nonclinical and clinical testing,manufacture,quality control,approval,labeling,packaging,storage,record-keeping,promotion,advertising,distribution,post-approval monitoring a

201、nd reporting,marketing,and export and import of products such as those we are developing.Generally,before a new drug can be marketed,considerable data must be generated,which demonstrate the drugs quality,safety,and efficacy.Such data must then be organized into a format specific for each regulatory

202、 authority,submitted for review and approved by the regulatory authority.U.S.Drug Development ProcessIn the United States,the FDA regulates drugs under the federal Food,Drug,and Cosmetic Act,or FDCA,and its implementing regulations.The process of obtaining regulatory approvals and the subsequent com

203、pliance with appropriate federal,state,local and foreign statutes and regulations require the expenditure of substantial time and financial resources.Failure to comply with the applicable U.S.requirements at any time during the product development process,the approval process or after approval may s

204、ubject an applicant to administrative or judicial sanctions.These sanctions could include the FDAs refusal to approve pending applications,withdrawal of an approval,a clinical hold,warning letters,product recalls,product seizures,total or partial suspension of production or distribution,injunctions,

205、fines,refusals of government contracts,restitution,disgorgement,or civil or criminal penalties.Any agency or judicial enforcement action could have a material adverse effect on us.22The process required by the FDA before a drug may be marketed in the United States generally involves the following:co

206、mpletion of nonclinical laboratory tests,animal studies,and formulation studies in accordance with FDAs good laboratory practice,or GLP,requirements and other applicable regulations;submission to the FDA of an IND,which must become effective before human clinical trials may begin;approval by an inde

207、pendent institutional review board,or IRB,ethics committee,either centralized or with respect to each clinical site,before each clinical trial may be initiated;performance of adequate and well-controlled human clinical trials in accordance with good clinical practice,or GCP,requirements to establish

208、 the safety and efficacy of the proposed drug for its intended use;submission to the FDA of a New Drug Application,or NDA,after completion of all pivotal trials;determination by the FDA within 60 days of its receipt of an NDA to accept the filing for substantive review;satisfactory completion of an

209、FDA advisory committee review,if applicable;satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the drug is produced to assess compliance with current good manufacturing practice,or cGMP,requirements to ensure that the facilities,methods and controls are

210、 adequate to preserve the drugs identity,strength,quality,and purity,and of selected clinical investigation sites to assess compliance with GCPs;and FDA review and approval of the NDA to permit commercial marketing of the product for particular indications for use in the United States.Prior to begin

211、ning the first clinical trial with a product candidate in the United States,we must submit an IND to the FDA.An IND is a request for authorization from the FDA to administer an investigational new drug product to humans.The central focus of an IND submission is on the general investigational plan an

212、d the protocol(s)for clinical studies.The IND also includes results of animal and in vitro studies assessing the toxicology,pharmacology,and PK/PD characteristics of the product;chemistry,manufacturing,and controls information;and any available human data or literature to support the use of the inve

213、stigational product.An IND must become effective before human clinical trials may begin.The IND automatically becomes effective 30 days after receipt by the FDA,unless the FDA,within the 30-day time period,raises safety concerns or questions about the proposed clinical trial.In such a case,the IND m

214、ay be placed on clinical hold and the IND sponsor and the FDA must resolve any outstanding concerns or questions before the clinical trial can begin.Submission of an IND therefore may or may not result in FDA authorization to begin a clinical trial.Clinical trials involve the administration of the i

215、nvestigational product to human subjects under the supervision of qualified investigators in accordance with GCPs,which include the requirement that all research subjects provide their informed consent for their participation in any clinical study.Clinical trials are conducted under protocols detail

216、ing,among other things,the objectives of the study,the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated.A separate submission to the existing IND must be made for each successive clinical trial conducted during product development and for any subsequent proto

217、col amendments.Furthermore,an independent IRB for each site proposing to conduct the clinical trial must review and approve the plan for any clinical trial and its informed consent form before the clinical trial begins at that site and must monitor the study until completed.Regulatory authorities,th

218、e IRB or the sponsor may suspend a clinical trial at any time on various grounds,including a finding that the subjects are being exposed to an unacceptable health risk or that the clinical trial is unlikely to meet its stated objectives.Some studies also include oversight by an independent group of

219、qualified experts organized by the clinical study sponsor,known as a data safety monitoring board,which may review data and endpoints at designated check points,make recommendations or halt the clinical trial if it determines that there is an unacceptable safety risk for subjects or other grounds,su

220、ch as no demonstration of efficacy.There are also requirements governing the reporting of ongoing clinical studies and clinical study results to public registries.23Human clinical trials are typically conducted in three sequential phases that may overlap or be combined:Phase 1:The product candidate

221、is initially introduced into healthy human subjects or patients with the target disease or condition.These studies are designed to test the safety,dosage tolerance,absorption,metabolism,and distribution of the investigational product in humans,the side effects associated with increasing doses,and,if

222、 possible,to gain early evidence on effectiveness.In the case of some products for severe or life-threatening diseases,especially when the product may be too inherently toxic to ethically administer to healthy volunteers,the initial human testing is often conducted in patients.Phase 2:The product ca

223、ndidate is administered to a limited patient population with a specified disease or condition to evaluate the preliminary efficacy,optimal dosages,and dosing schedule and to identify possible adverse side effects and safety risks.Multiple Phase 2 clinical trials may be conducted to obtain informatio

224、n prior to beginning larger and more expensive Phase 3 clinical trials.Phase 3:The product candidate is administered to an expanded patient population to further evaluate dosage,to provide statistically significant evidence of clinical efficacy and to further test for safety,generally at multiple ge

225、ographically dispersed clinical trial sites.These clinical trials are intended to establish the overall risk/benefit ratio of the investigational product and to provide an adequate basis for product approval.Post-approval clinical trials,sometimes referred to as Phase 4 studies,may be conducted afte

226、r initial marketing approval.These clinical trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication.In certain instances,the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of an NDA.The FDA or the spon

227、sor may suspend a clinical trial at any time on various grounds,including a finding that the research subjects or patients are being exposed to an unacceptable health risk.Similarly,an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being con

228、ducted in accordance with the IRBs requirements or if the drug has been associated with unexpected serious harm to patients.In addition,some clinical trials are overseen by an independent group of qualified experts organized by the sponsor,known as a data safety monitoring board or committee.Dependi

229、ng on its charter,this group may determine whether a clinical trial may move forward at designated check points based on access to certain data from the clinical trial.During the development of a new drug,sponsors are given opportunities to meet with the FDA at certain points.These points may be pri

230、or to submission of an IND,at the end of Phase 2,and before an NDA is submitted.Meetings at other times may be requested.These meetings can provide an opportunity for the sponsor to share information about the data gathered to date,for the FDA to provide advice,and for the sponsor and the FDA to rea

231、ch agreement on the next phase of development.Sponsors typically use the meetings at the end of the Phase 2 clinical trial to discuss Phase 2 clinical results and present plans for the pivotal Phase 3 clinical trials that they believe will support approval of the new drug.Concurrent with clinical tr

232、ials,companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the drug and finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.The manufacturing pro

233、cess must be capable of consistently producing quality batches of the product candidate and,among other things,the manufacturer must develop methods for testing the identity,strength,quality,and purity of the final drug.In addition,appropriate packaging must be selected and tested,and stability stud

234、ies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.While the IND is active and before approval,progress reports summarizing the results of the clinical trials and nonclinical studies performed since the last progress report

235、 must be submitted at least annually to the FDA,and written IND safety reports must be submitted to the FDA and investigators for serious and 24unexpected suspected adverse events,findings from other studies suggesting a significant risk to humans exposed to the same or similardrugs,findings from an

236、imal or in vitro testing suggesting a significant risk to humans,and any clinically important increased incidence of a serious suspected adverse reaction compared to that listed in the protocol or investigator brochure.NDA Review and Approval Process Assuming successful completion of all required te

237、sting in accordance with all applicable regulatory requirements,the results of product development nonclinical and clinical trials,along with descriptions of the manufacturing process,analytical tests conducted on the chemistry of the drug,proposed labeling and other relevant information are submitt

238、ed to the FDA as part of an NDA requesting approval to market the product.The submission of an NDA is subject to the payment of substantial user fees;a waiver of such fees may be obtained under certain limited circumstances.Additionally,no user fees are assessed on NDAs for products designated as or

239、phan drugs,unless the product also includes a non-orphan indication.The FDA reviews an NDA to determine,among other things,whether a product is safe and effective for its intended use and whether its manufacturing is cGMP-compliant to assure and preserve the products identity,strength,quality,and pu

240、rity.Under the Prescription Drug User Fee Act,or PDUFA,guidelines that are currently in effect,the FDA has a goal of ten months from the date of“filing”of a standard NDA for a new molecular entity to review and act on the submission.This review typically takes 12 months from the date the NDA is subm

241、itted to FDA because the FDA has approximately two months to make a“filing”decision after the application is submitted.The FDA conducts a preliminary review of all NDAs within the first 60 days after submission,before accepting them for filing,to determine whether they are sufficiently complete to p

242、ermit substantive review The FDA may request additional information rather than accept an NDA for filing.In this event,the NDA must be resubmitted with the additional information.The resubmitted application is also subject to review before the FDA accepts it for filing.The FDA may refer an applicati

243、on for a novel drug to an advisory committee.An advisory committee is a panel of independent experts,including clinicians and other scientific experts,that reviews,evaluates and provides a recommendation as to whether the application should be approved and under what conditions.The FDA is not bound

244、by the recommendations of an advisory committee,but it considers such recommendations carefully when making decisions.Before approving an NDA,the FDA will typically inspect the facility or facilities where the product is manufactured.The FDA will not approve an application unless it determines that

245、the manufacturing processes and facilities are in compliance with cGMP and adequate to assure consistent production of the product within required specifications.Additionally,before approving an NDA,the FDA will typically inspect one or more clinical sites to assure compliance with GCPs.If the FDA d

246、etermines that the application,manufacturing process,or manufacturing facilities are not acceptable,it will outline the deficiencies in the submission and often will request additional testing or information.Notwithstanding the submission of any requested additional information,the FDA ultimately ma

247、y decide that the application does not satisfy the regulatory criteria for approval.After the FDA evaluates an NDA,it will issue an approval letter or a Complete Response Letter.An approval letter authorizes commercial marketing of the drug with prescribing information for specific indications.A Com

248、plete Response Letter indicates that the review cycle of the application is complete,and the application will not be approved in its present form.A Complete Response Letter usually describes the specific deficiencies in the NDA identified by the FDA and may require additional clinical data,such as a

249、n additional pivotal Phase 3 clinical trial or other significant and time-consuming requirements related to clinical trials,nonclinical studies,or manufacturing.If a Complete Response Letter is issued,the sponsor must resubmit the NDA,addressing all of the deficiencies identified in the letter,or wi

250、thdraw the application.Even if such data and information are submitted,the FDA may decide that the NDA does not satisfy the criteria for approval.25If regulatory approval of a product is granted,such approval will be granted for particular indications and may entail limitations on the indicated uses

251、 for which such product may be marketed.For example,the FDA may approve the NDA with a risk evaluation and mitigation strategy,or REMS,to ensure the benefits of the product outweigh its risks.A REMS is a safety strategy to manage a known or potential serious risk associated with a medicine and to en

252、able patients to have continued access to such medicines by managing their safe use.It could include medication guides,physician communication plans,or elements to assure safe use,such as restricted distribution methods,patient registries,and other risk minimization tools.The FDA also may offer cond

253、itional approval subject to,among other things,changes to proposed labeling or the development of adequate controls and specifications.Once approved,the FDA may withdraw the product approval if compliance with pre-and post-marketing requirements is not maintained or if problems occur after the produ

254、ct reaches the marketplace.The FDA may also require one or more Phase 4 post-market studies and surveillance to further assess and monitor the products safety and effectiveness after commercialization,and may limit further marketing of the product based on the results of these post-marketing studies

255、.In addition,new government requirements,including those resulting from new legislation,may be established,or the FDAs policies may change,which could impact the timeline for regulatory approval or otherwise impact ongoing development programs.In addition,the FDA and other regulatory authorities may

256、 change their policies,issue additional regulations or revise existing regulations,any of which could delay Athiras ability to obtain approvals,increase the costs of compliance or restrict the companys ability to maintain any regulatory approvals it may have obtained.In June 2024,the U.S.Supreme Cou

257、rt overruled the Chevron doctrine,which gives deference to federal agencies statutory interpretations in litigation against the agencies where the law is ambiguous.This Supreme Court decision may invite various stakeholders to bring lawsuits against the FDA or other federal agencies to challenge lon

258、gstanding decisions and policies,including FDAs statutory interpretations of market exclusivities and the substantial evidence requirements for drug approvals,which could undermine the FDAs authority,lead to uncertainties in the industry,and disrupt the agencys normal operations.Athira cannot predic

259、t the full impact of this decision on the company or the pharmaceutical industry in general.Further,changes in the leadership of the FDA and other federal agencies under the new Trump administration can result in further changes in the funding,operations,and policies of the federal agencies,which ma

260、y impact Athiras clinical development plans and timelines.Expedited Development and Review Programs The FDA has a fast track designation program that is intended to expedite or facilitate the process for reviewing new drug products that meet certain criteria.Specifically,new drugs are eligible for f

261、ast track designation if they are intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition.With regard to a fast track product,the FDA may consider for review sections of the NDA on a rolling basis

262、before the complete application is submitted,if the sponsor provides a schedule for the submission of the sections of the NDA,the FDA agrees to accept sections of the NDA and determines that the schedule is acceptable,and the sponsor pays any required user fees upon submission of the first section o

263、f the NDA.Any product submitted to the FDA for approval,including a product with a fast track designation,may also be eligible for other types of FDA programs intended to expedite development and review,such as priority review and accelerated approval.A product is eligible for priority review if it

264、has the potential to provide safe and effective therapy where no satisfactory alternative therapy exists or a significant improvement in the treatment,diagnosis,or prevention of a disease compared to marketed products.The FDA will attempt to direct additional resources to the evaluation of an applic

265、ation for a new drug designated for priority review in an effort to facilitate the review.The FDA endeavors to review applications with priority review designations within six months of the filing date as compared to ten months for review of new molecular entity NDAs under its current PDUFA review g

266、oals.In addition,a product may be eligible for accelerated approval.Drug products intended to treat serious or life-threatening diseases or conditions may be eligible for accelerated approval upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to pre

267、dict clinical benefit,or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality,that is reasonably 26likely to predict an effect on irreversible morbidity or mortality or other clinical benefit,taking into account the severity,rarity,or prevalence of the conditi

268、on and the availability or lack of alternative treatments.As a condition of approval,the FDA may require that a sponsor of a drug receiving accelerated approval perform adequate and well-controlled post-marketing clinical trials.In addition,the FDA currently requires pre-approval of promotional mate

269、rials as a condition for accelerated approval,which could adversely impact the timing of the commercial launch of the product.The Food and Drug Administration Safety and Innovation Act established a category of drugs referred to as“breakthrough therapies”that may be eligible to receive breakthrough

270、therapy designation.A sponsor may seek FDA designation of a product candidate as a“breakthrough therapy”if the product is intended,alone or in combination with one or more other products,to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the

271、product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints,such as substantial treatment effects observed early in clinical development.The designation includes all of the fast track program features,as well as more intensive FDA interacti

272、on and guidance.The breakthrough therapy designation is a distinct status from both accelerated approval and priority review,which can also be granted to the same drug if relevant criteria are met.If a product is designated as breakthrough therapy,the FDA will work to expedite the development and re

273、view ofsuch drug.Fast track designation,priority review,accelerated approval,and breakthrough therapy designation do not change the standards for approval,but may expedite the development or approval process.Even if a product qualifies for one or more of these programs,the FDA may later decide that

274、the product no longer meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.We may explore some of these opportunities for our drug product candidates as appropriate.On December 29,2022,the Consolidated Appropriations Act,2023,includin

275、g the Food and Drug Omnibus Reform Act,or FDORA,was signed into law.FDORA made several changes to the FDAs authorities and its regulatory framework,including,among other changes,reforms to the accelerated approval pathway,such as requiring the FDA to specify conditions for post-approval study requir

276、ements and setting forth procedures for the FDA to withdraw a product on an expedited basis for non-compliance with post-approval requirements.Post-Approval Requirements Any products manufactured or distributed by us pursuant to FDA approvals are subject to pervasive and continuing regulation by the

277、 FDA,including,among other things,requirements relating to record-keeping,reporting of adverse experiences,periodic reporting,product sampling and distribution,and advertising and promotion of the product.After approval,most changes to the approved product,such as adding new indications or other lab

278、eling claims,are subject to prior FDA review and approval.There are continuing,annual program fees for any marketed products.Drug manufacturers and their subcontractors are required to register their establishments with the FDA and certain state agencies,and are subject to periodic unannounced inspe

279、ctions by the FDA and certain state agencies for compliance with cGMP,which impose certain procedural and documentation requirements upon us and our third-party manufacturers.Changes to the manufacturing process are strictly regulated,and,depending on the significance of the change,may require prior

280、 FDA approval before being implemented.FDA regulations also require investigation and correction of any deviations from cGMP and impose reporting requirements upon us and any third-party manufacturers that we may decide to use.Accordingly,manufacturers must continue to expend time,money,and effort i

281、n the area of production and quality control to maintain compliance with cGMP and other aspects of regulatory compliance.The FDA may withdraw approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market.Later discovery

282、of previously unknown problems with a product,including adverse events of unanticipated severity or frequency,or with manufacturing processes,or failure to comply with regulatory requirements,may result in revisions to the approved labeling to add new safety information;imposition of post-market stu

283、dies or clinical studies to 27assess new safety risks;or imposition of distribution restrictions or other restrictions under a REMS program.Other potential consequences include,among other things:restrictions on the marketing or manufacturing of the product,complete withdrawal of the product from th

284、e market or product recalls;fines,warning letters,or untitled letters;clinical holds on post-approval or Phase IV clinical studies,if applicable;refusal of the FDA to approve pending applications or supplements to approved applications,or suspension or revocation of product license approvals;drug pr

285、oduct seizure or detention,or refusal to permit the import or export of products;consent decrees,corporate integrity agreements,debarment,or exclusion from federal healthcare programs;mandated modification of promotional materials and labeling and the issuance of corrective information;the issuance

286、of safety alerts,Dear Healthcare Provider letters,press releases,and other communications containing warnings or other safety information about the product;orinjunctions or the imposition of civil or criminal penalties.The FDA closely regulates the marketing,labeling,advertising,and promotion of dru

287、g products.A company can make only those claims relating to safety and efficacy that are approved by the FDA and in accordance with the provisions of the approved label.The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses.Failure to comply

288、with these requirements can result in,among other things,adverse publicity,warning letters,corrective advertising,and potential civil and criminal penalties.Physicians may prescribe,in their independent professional medical judgment,legally available products for uses that are not described in the p

289、roducts labeling and that differ from those tested by us and approved by the FDA.Physicians may believe that such off-label uses are the best treatment for many patients in varied circumstances.The FDA does not regulate the behavior of physicians in their choice of treatments.The FDA does,however,re

290、strict manufacturers communications on the subject of off-label use of their products.The federal government has levied large civil and criminal fines against companies for alleged improper promotion of off-label use and has enjoined companies from engaging in off-label promotion.The FDA and other r

291、egulatory agencies have also required that companies enter into consent decrees or permanent injunctions under which specified promotional conduct is changed or curtailed.However,companies may share truthful and not misleading information that is otherwise consistent with a products FDA-approved lab

292、elling.Orange Book ListingIn seeking approval of an NDA or a supplement thereto,NDA applicants are required to list with the FDA each patent with claims that cover the applicants product or an approved method of using the product.Upon FDA approval,each of the patents listed by the NDA applicant is p

293、ublished in the FDAs Approved Drug Products with Therapeutic Equivalence Evaluations,commonly known as the Orange Book.Upon submission of an ANDA or 505(b)(2)NDA,an applicant is required to certify to the FDA concerning any patents listed for the RLD in the Orange Book that:no patent information on

294、the drug product that is the subject of the application has been submitted to the FDA;such patent has expired;the date on which such patent expires;orsuch patent is invalid,unenforceable or will not be infringed upon by the manufacture,use,or sale of the drug product for which the application is sub

295、mitted.28Generally,the ANDA or 505(b)(2)NDA cannot be approved until all listed patents have expired,except where the ANDA or 505(b)(2)NDA applicant challenges a listed patent through the last type of certification,also known as a paragraph IV certification.If the applicant does not challenge the li

296、sted patents or indicates that it is not seeking approval of a patented method of use,the ANDA or 505(b)(2)NDA application will not be approved until all of the listed patents claiming the referenced product have expired.If the ANDA or 505(b)(2)NDA applicant has provided a paragraph IV certification

297、,the applicant must send notice of the paragraph IV certification to the NDA and patent holders once the application has been accepted for filing by the FDA.The NDA and patent holders may then initiate a patent infringement lawsuit in response to the notice of the paragraph IV certification.If the p

298、aragraph IV certification is challenged by an NDA holder,or the patent owner(s)asserts a patent challenge to the paragraph IV certification,the FDA may not approve that application until the earlier of 30 months from the receipt of the notice of the paragraph IV certification,the expiration of the p

299、atent,when the infringement case concerning each such patent was favorably decided in the applicants favor or settled,or such shorter or longer period as may be ordered by a court.This prohibition is generally referred to as the 30-month stay.In instances where an ANDA or 505(b)(2)NDA applicant file

300、s a paragraph IV certification,the NDA holder or patent owner(s)regularly take action to trigger the 30-month stay,recognizing that the related patent litigationmay take many months or years to resolve.Thus,approval of an ANDA or 505(b)(2)NDA could be delayed for a significant period of time,dependi

301、ng on the patent certification the applicant makes and the reference drug sponsors decision to initiate patent litigation.Marketing Exclusivity Market exclusivity provisions authorized under the FDCA can delay the submission and approval of certain marketing applications for products containing the

302、same active ingredient.The FDCA permits patent term restoration of up to five years as compensation for a patent term lost during product development and FDA regulatory review process to the first applicant to obtain approval of an NDA for a new chemical entity in the United States.Patent-term resto

303、ration,however,cannot extend the remaining term of a patent beyond a total of 14 years from the products approval date.A drug is a new chemical entity if the FDA has not previously approved any other new drug containing the same active moiety,which is the molecule or ion responsible for the action o

304、f the drug substance.During the exclusivity period,the FDA may not approve or even accept for review an abbreviated new drug application,or ANDA,or an NDA submitted under Section 505(b)(2)(505(b)(2)NDA),submitted by another company for another drug based on the same active moiety,regardless of wheth

305、er the drug is intended for the same indication as the original innovative drug or for another indication,where the applicant does not own or have a legal right of reference to all the data required for approval.However,an application may be submitted after four years if it contains a certification

306、of patent invalidity or non-infringement to one of the patents listed with the FDA by the innovator NDA holder.The FDCA alternatively provides three years of marketing exclusivity for an NDA,or supplement to an existing NDA if new clinical investigations,other than bioavailability studies,that were

307、conducted or sponsored by the applicant are deemed by the FDA to be essential to the approval of the application,for example new indications,dosages,or strengths of an existing drug.This three-year exclusivity covers only the modification for which the drug received approval on the basis of the new

308、clinical investigations and does not prohibit the FDA from approving ANDAs or 505(b)(2)NDAs for drugs containing the active agent for the original indication or condition of use.Five-year and three-year exclusivity will not delay the submission or approval of a full NDA.However,an applicant submitti

309、ng a full NDA would be required to conduct or obtain a right of reference to any nonclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.29Pediatric exclusivity is another type of marketing exclusivity available in the United States.Pedi

310、atric exclusivity provides for an additional six months of marketing exclusivity attached to another period of exclusivity if a sponsor conducts clinical trials in children in response to a written request from the FDA.The issuance of a written request does not require the sponsor to undertake the d

311、escribed clinical trials.In addition,orphan drug exclusivity,as described above,may offer a seven-year period of marketing exclusivity,except in certain circumstances.Other Healthcare Laws Pharmaceutical manufacturers are subject to additional healthcare laws,regulation,and enforcement by the federa

312、l government and by authorities in the states and foreign jurisdictions in which they conduct their business.Such laws include,without limitation,U.S.federal anti-kickback,anti-self-referral,false claims,transparency,including the federal Physician Payments Sunshine Act,consumer fraud,pricing report

313、ing,data privacy,data protection,and security laws and regulations as well as similar foreign laws in the jurisdictions outside the U.S.Similar state and local laws and regulations may also restrict business practices in the pharmaceutical industry,such as state anti-kickback and false claims laws,w

314、hich may apply to business practices,including but not limited to,research,distribution,sales,and marketing arrangements and claims involving healthcare items or services reimbursed by non-governmental third-party payors,including private insurers,or by patients themselves;state laws that require ph

315、armaceutical companies to comply with the pharmaceutical industrys voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government,or otherwise restrict payments that may be made to healthcare providers and other potential referral sources;state laws and re

316、gulations that require drug manufacturers to file reports relating to pricing and marketing information;state and local laws which require the tracking of gifts and other remuneration and any transfer of value provided to physicians,other healthcare providers and entities;and state and local laws th

317、at require the registration of pharmaceutical sales representatives;and state and local laws governing the privacy and security of health information in some circumstances,many of which differ from each other in significant ways and often are not preempted by the Health Insurance Portability and Acc

318、ountability Act of 1996,or HIPAA,thus complicating compliance efforts.The risk of our being found in violation of these or other laws and regulations is increased by the fact that many have not been fully interpreted by the regulatory authorities or the courts and their provisions are open to variou

319、s interpretations.These laws and regulations are subject to change,which can increase the resources needed for compliance and delay drug approval or commercialization.Any action brought against us for violations of these laws or regulations,even successfully defended,could cause us to incur signific

320、ant legal expenses and divert our managements attention from the operation of our business.Also,we may be subject to private“qui tam”actions brought by individual whistleblowers on behalf of the federal or state governments.Actual or alleged violation of any such laws or regulations may lead to inve

321、stigations and other claims and proceedings by regulatory authorities and in certain cases,private actors,and violation of any of such laws or any other governmental regulations that apply may result in penalties,including,without limitation,significant administrative,civil and criminal penalties,da

322、mages,fines,additional reporting obligations,and oversight if we become subject to a corporate integrity agreement or other agreement to resolve allegations of non-compliance with these laws,the curtailment or restructuring of operations,exclusion from participation in government healthcare programs

323、 and imprisonment.Coverage and Reimbursement Sales of any pharmaceutical product depend,in part,on the extent to which such product will be covered by third-party payors,such as federal,state,and foreign government healthcare programs,commercial insurance,and managed healthcare organizations,and the

324、 level of reimbursement for such product by third-party payors.Significant uncertainty exists as to the coverage and reimbursement status of any newly approved product.Decisions regarding the extent of coverage and amount of reimbursement to be provided are made on a plan-by-plan basis.One third-par

325、ty payors decision to cover a particular product does not ensure that other payors will also provide coverage for the product.As a result,the coverage determination process can require manufacturers to provide scientific details,information on cost-effectiveness,and clinical support for the use of a

326、 product to each payor separately.This can be a 30time-consuming process,with no assurance that coverage and adequate reimbursement will be applied consistently or obtained in the first instance.In addition,third-party payors are increasingly reducing reimbursements for pharmaceutical products and r

327、elated services.The U.S.government and state legislatures have continued implementing cost-containment programs,including price controls,restrictions on coverage and reimbursement and requirements for substitution of generic products.Third-party payors are increasingly challenging the prices charged

328、,examining the medical necessity and reviewing the cost effectiveness of pharmaceutical products,in addition to questioning their safety and efficacy.Adoption of price controls and cost-containment measures,and adoption of more restrictive policies in jurisdictions with existing controls and measure

329、s,could further limit sales of any product.Decreases in third-party reimbursement for any product or a decision by a third-party payor not to cover a product could reduce physician usage and patient demand for the product.In international markets,reimbursement and healthcare payment systems vary sig

330、nificantly by country,and many countries have instituted price ceilings on specific products and therapies.For example,the European Union provides options for its member states to restrict the range of medicinal products for which their national health insurance systems provide reimbursement and to

331、control the prices of medicinal products for human use.A member state may approve a specific price for the medicinal product or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product on the market.Pharmaceutical products may fac

332、e competition from lower-priced products in foreign countries that have placed price controls on pharmaceutical products and may also compete with imported foreign products.Furthermore,there is no assurance that a product will be considered medically reasonable and necessary for a specific indicatio

333、n,that it will be considered cost-effective by third-party payors,that an adequate level of reimbursement will be established even if coverage is available,or that the third-party payors reimbursement policies will not adversely affect the ability for manufacturers to sell products profitably.U.S.Healthcare Reform In the United States and certain foreign jurisdictions,there have been,and we expect