Aligos Therapeutics, Inc. (ALGS) 2024年年度報告「NASDAQ」.pdf

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1、 UNITED STATESSECURITIES AND EXCHANGE COMMISSION Washington,D.C.20549 FORM 10-K (Mark One)ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1934 For the fiscal year ended December 31,2024 OR 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:001-39617 Aligos Therapeutics,Inc.(Exact name of Registrant as specified in its Charter)Delaware82-4724808(State or other jurisdiction ofincorporation or organization)(I.R.S.EmployerIdentification No.)One Corporate Drive,2 FloorSouth S

3、an Francisco,California94080(Address of principal executive offices)(Zip Code)Registrants telephone number,including area code:(800)466-6059 Securities registered pursuant to Section 12(b)of the Act:Title of each class Trading Symbol(s)Name of each exchange on which registeredCommon Stock,par value,

4、$0.0001 per share ALGS The Nasdaq Stock Market LLC(Nasdaq Capital 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 Registran

5、t is not required 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 t

6、he Registrant was required to file such reports),and(2)has been subject to such filing requirements for the past 90 days.YES NO Indicate by check mark whether the Registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T(232.4

7、05 of this 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,a smaller reporting company,or an emergin

8、g growth company.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 emerg

9、ing growth company,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 repor

10、t on and attestation 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 pursua

11、nt to Section 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 checkmark whether any of those error corrections are restatements that required a re

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

13、value of voting and non-voting common stock held by non-affiliates of the Registrant was approximately$38.7 million as of June 28,2024,the last business day of the Registrants most recently completed second fiscal quarter,based on(i)3,191,425 shares of common stock,$0.0001 par value per share,outsta

14、nding,comprised of 3,067,732 shares of voting common stock,$0.0001 par value per share and 123,693 shares of non-voting common stock,$0.0001 par value per share,and(ii)the closing sales price for the Registrants common stock on the Nasdaq Capital Market on such date.As of March 6,2025,the Registrant

15、 had 6,114,311 shares of common stock,$0.0001 par value per share,outstanding,comprised of 5,314,311 shares of voting common stock,$0.0001 par value per share and 800,000 shares of non-voting common stock,$0.0001 par value per share.This number does not include 4,363,916 shares of common stock issua

16、ble upon the exercise of pre-funded warrants outstanding as of March 6,2025(which are immediately exercisable at an exercise price of$0.0025 and$0.0001 per share of common stock,respectively,subject to beneficial ownership limitations)sold in the Registrants private placement on October 23,2023 and

17、February 13,2025.See Note 8 Common Warrants and Pre-Funded Warrants to the Registrants audited financial statements.nd DOCUMENTS INCORPORATED BY REFERENCEPortions of the Registrants Definitive Proxy Statement relating to the 2025 Annual Meeting of Stockholders,which will be filed with the Securities

18、 and Exchange Commission within 120 days after the end of the Registrants fiscal year ended December 31,2024,are incorporated by reference into Part III of this Report.Table of Contents PagePART I Item 1.Business1Item 1A.Risk Factors28Item 1B.Unresolved Staff Comments87Item 1C.Cybersecurity87Item 2.

19、Properties88Item 3.Legal Proceedings88Item 4.Mine Safety Disclosures88 PART II Item 5.Market for Registrants Common Equity,Related Stockholder Matters and Issuer Purchases of Equity Securities89Item 6.Reserved89Item 7.Managements Discussion and Analysis of Financial Condition and Results of Operatio

20、ns90Item 7A.Quantitative and Qualitative Disclosures About Market Risk101Item 8.Financial Statements and Supplementary Data102Item 9.Changes in and Disagreements with Accountants on Accounting and Financial Disclosure134Item 9A.Controls and Procedures134Item 9B.Other Information134 Item 9C.Disclosur

21、e Regarding Foreign Jurisdictions that Prevent Inspections134 PART III Item 10.Directors,Executive Officers and Corporate Governance135Item 11.Executive Compensation135Item 12.Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters135Item 13.Certain Relationshi

22、ps and Related Transactions,and Director Independence135Item 14.Principal Accounting Fees and Services135 PART IV Item 15.Exhibits,Financial Statement Schedules136Item 16.Form 10-K Summary136 SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTSThis Annual Report on Form 10-K contains forward-looking st

23、atements concerning our business,operations and financial performance and condition,as well as our plans,objectives and expectations for our business,operations and financial performance and condition.Any statements contained herein that are not statements of historical facts may be deemed to be for

24、ward-looking statements.These statements involve known and unknown risks,uncertainties and other important factors that are in some cases beyond our control and may cause our actual results,performance or achievements to be materially different from any future results,performance or achievements exp

25、ressed or implied by the forward-looking statements.In some cases,you can identify forward-looking statements by terminology such as“aim,”“anticipate,”“assume,”“believe,”“contemplate,”“continue,”“could,”“due,”“estimate,”“expect,”“goal,”“intend,”“may,”“objective,”“plan,”“predict,”“potential,”“positio

26、ned,”“seek,”“should,”“target,”“will,”“would,”and other similar expressions that are predictions of or indicate future events and future trends,or the negative of these terms or other comparable terminology.These forward-looking statements include,but are not limited to,statements about:the scope,pro

27、gress,results and costs of developing our drug candidates or any other future drug candidates,and conducting nonclinical studies and clinical trials;the scope,progress,results and costs related to the research and development of our pipeline;the timing of,and costs involved in,obtaining and maintain

28、ing regulatory approval for any of our current or future drug candidates,and any related restrictions or limitations;our expectations regarding the potential market size and size of the potential patient populations for our drug candidates and any future drug candidates,if approved for commercial us

29、e;our ability to maintain existing,and establish new,collaborations,licensing or other arrangements and the financial terms of any such agreements;our commercialization,marketing and manufacturing capabilities and expectations;the rate and degree of market acceptance of our drug candidates,as well a

30、s the pricing and reimbursement of our drug candidates,if approved;the implementation of our business model and strategic plans for our business,drug candidates and technology,including additional indications for which we may pursue;the scope of protection we are able to establish and maintain for i

31、ntellectual property rights covering our drug candidates,including the projected term of patent protection;any lawsuits related to our drug candidates or commenced against us;estimates of our expenses,future revenue,capital requirements,our needs for additional financing and our ability to obtain ad

32、ditional capital;developments and projections relating to our competitors and our industry,including competing therapies and procedures;regulatory and legal developments in the United States and foreign countries;the performance of our third-party suppliers and manufacturers;our ability to attract a

33、nd retain key management,scientific and medical personnel;our expectations regarding our ability to obtain,maintain,enforce and defend our intellectual property protection for our drug candidates;andother risks and uncertainties,including those listed under the caption“Risk Factors.”We have based th

34、ese forward-looking statements largely on managements current expectations,estimates,forecasts and projections about our business and the industry in which we operate and managements beliefs and assumptions and are not guarantees of future performance or development and involve known and unknown ris

35、ks,uncertainties and other factors that are in some cases beyond our control.These forward-looking statements speak only as of the date of this Annual Report on Form 10-K and are subject to a number of risks,uncertainties and assumptions described in the section titled“Risk Factors”and elsewhere in

36、this Annual Report on Form 10-K.Because forward-looking statements are inherently subject to risks and uncertainties,some of which cannot be predicted or quantified,you should not rely on these forward-looking statements as predictions of future events.The events and circumstances reflected in our f

37、orward-looking statements may not be achieved or occur and actual results could differ materially from those projected in the forward-looking statements.Except as required by applicable law,we do not plan to publicly update or revise any forward-looking statements contained herein until after we dis

38、tribute this Annual Report on Form 10-K,whether as a result of any new information,future events or otherwise.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 d

39、ate of this report,and while we believe such 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 an exhaustive inquiry into,or review of,all potentially available relevant info

40、rmation.These statements are inherently uncertain,and you are cautioned not to unduly rely upon these statements.Investors and others should note that we may announce material business and financial information to our investors using our investor relations website,Securities and Exchange Commission,

41、or SEC,filings,webcasts,press releases and conference calls.We use these mediums,including our website,to communicate with our stockholders and the public about our company,our products and other issues.It is possible that the information that we make available may be deemed to be material informati

42、on.We therefore encourage investors and others interested in our company to review the information that we make available on our website.Summary of material risks associated with our businessThe principal risks and uncertainties affecting our business include the following:We are a clinical-stage bi

43、otechnology company with a limited operating history and no products approved for commercial sale.We have incurred significant losses since inception.We expect to incur losses for at least the next several years and may never achieve or maintain profitability for a full fiscal year,which,together wi

44、th our limited operating history,makes it difficult to assess our future viability.We have never generated revenue from product sales and may never be profitable for a full fiscal year.We will require substantial additional financing to achieve our goals,which may not be available on acceptable term

45、s,or at all.A failure to obtain this necessary capital when needed could force us to delay,limit,reduce or terminate our product development or commercialization efforts.We are early in our development efforts,and our business is dependent on the successful development of our current and future drug

46、 candidates.If we are unable to advance our current or future drug candidates through clinical trials,obtain marketing approval and ultimately commercialize any drug candidates we develop,or experience significant delays in doing so,our business will be materially harmed.Our current or future drug c

47、andidates may cause undesirable side effects or have other properties when used alone or in combination with other approved products or investigational new drugs that could delay or halt their clinical development,prevent their marketing approval,limit their commercial potential or result in signifi

48、cant negative consequences.We depend on collaborations with third parties for the development of certain of our potential drug candidates,and we may depend on additional collaborations in the future for the development and commercialization of these or other potential candidates.If our collaboration

49、s are not successful,we may not be able to capitalize on the market potential of these drug candidates.We intend to develop our current drug candidates,and expect to develop other future drug candidates,in combination with other therapies,which exposes us to additional risks.We face significant comp

50、etition,and if our competitors develop and market products that are more effective,safer or less expensive than the drug candidates we develop,our commercial opportunities will be negatively impacted.If we and our collaborators are unable to obtain,maintain,protect and enforce sufficient patent and

51、other intellectual property protection for our drug candidates and technology,our competitors could develop and commercialize products and technology similar or identical to ours,and we may not be able to compete effectively in our market or successfully commercialize any drug candidates we may deve

52、lop.Third parties may initiate legal proceedings alleging that we are infringing,misappropriating or otherwise violating their intellectual property rights,the outcome of which would be uncertain and could negatively impact the success of our business.We have entered into licensing and collaboration

53、 agreements with third parties.If we fail to comply with our obligations in the agreements under which we license intellectual property rights to or from third parties,or these agreements are terminated,or we otherwise experience disruptions to our business relationships with our licensors or licens

54、ees,our competitive position,business,financial condition,results of operations and prospects could be harmed.We are highly dependent on our key personnel,and if we are not successful in attracting,motivating and retaining highly qualified personnel,we may not be able to successfully implement our b

55、usiness strategy.The summary risk factors described above should be read together with the text of the full risk factors below in the section entitled“Risk Factors”and the other information set forth in this Annual Report on Form 10-K,including our consolidated financial statements and the related n

56、otes,as well as in other documents that we file with the SEC.The risks summarized above or described in full below are not the only risks that we face.Additional risks and uncertainties not precisely known to us or that we currently deem to be immaterial may also materially adversely affect our busi

57、ness,financial condition,results of operations,and future growth prospects.1PART IItem 1.Business.OverviewWe are a clinical-stage biotechnology company focused on developing novel therapeutics to address unmet medical needs in liver diseases and viral infections,including in the areas of chronic hep

58、atitis B virus(HBV)infection,metabolic dysfunction-associated steatohepatitis(MASH),and coronavirus infections(e.g.,SARSCoV2,SARSCoV,MERSCoV,and other related infections).The Aligos team has a demonstrated track record of success in drug development and medicinal chemistry in liver and viral disease

59、s,resulting in three potential bestinclass drug candidates.Our pipeline of drug candidates includes ALG000184 for chronic HBV infection,ALG055009 for MASH,ALG097558 for coronavirus infections,and a portfolio of preclinical programs.ALG000184 is our potential best/firstinclass Capsid Assembly Modulat

60、or(CAME)for chronic HBV infection with enhanced pharmacologic properties petitor CAME drugs and has demonstrated greater hepatitis B virus deoxyribonucleic acid(HBV DNA)suppression compared to the standard of care,nucleos(t)ide analogs(NAs),as well as multi-log10 reductions in viral antigens in an o

61、ngoing,multi-part Phase 1 clinical trial spanning up to 96 weeks of treatment.ALG055009 is our potential bestinclass thyroid hormone receptor beta(THR)agonist for MASH with enhanced pharmacologic properties petitor THR agonists.Phase 2a topline data demonstrated that ALG055009 dose groups met the pr

62、imary endpoint with statistically significant reductions in liver fat at Week 12 as measured by Magnetic Resonance Imaging Proton Density Fat Fraction(MRI-PDFF).ALG097558 is our potential best-in-class small molecule coronavirus 3CL protease inhibitor(PI)which is at least 3fold more potent in cellba

63、sed assays of coronavirus infection than other approved CoV PIs and can be dosed twice daily without the requirement for ritonavir co-dosing based on Phase 1 clinical studies conducted to date.Our PipelineWe are focused on liver and viral diseases,areas in which our employees have expertise and deca

64、des of experience.In the area of chronic HBV infection,our most advanced drug candidate,ALG000184,plays an important role in disrupting the HBV lifecycle with greater viral suppression as well as reductions in viral antigens,and has the potential to replace standard of care NAs and become the backbo

65、ne of next-generation treatments.We have advanced our THR agonist for MASH through a Phase 2a study and are evaluating a variety of options to fund continued development,including potential out-licensing.Our ritonavirfree pancoronavirus protease inhibitor(PI)for the treatment of COVID19 also appears

66、 to be favorably differentiated in a Phase 1 study and is currently in clinical studies in highrisk COVID-19 patients.Figure 1:Aligos Development Pipeline 2Chronic HBV InfectionChronic HBV infection is the most common viral infection in the world and an area of substantial unmet medical need.There a

67、re over 296 million chronic carriers worldwide and approximately 1.5 million individuals become newly infected every year despite the availability of an efficacious prophylactic vaccine.In 2019,there were more than 90 million cases of chronic HBV infection in China alone,while the European Union(EU)

68、,United States and Japan accounted for nearly 8 million cases.Complications from chronic HBV infection include cirrhosis,end-stage liver disease,and hepatocellular carcinoma(HCC),which collectively resulted in approximately 1.1 million deaths in 2022,according to the World Health Organization(WHO).C

69、hronic HBV infection is the primary cause of liver cancer worldwide,and the mortality associated with HBVrelated liver cancer continues to increase.The primary treatment goal is to reduce HBV DNA to undetectable levels,normalize liver enzymes,prevent liver damage,and reduce the risk of developing HC

70、C.The WHO 2024 guidelines currently recommend treatment in the presence of significant fibrosis,or HBV DNA 2,000 IU/mL and ALTULN,or the presence of special risk factors.Current therapy for chronic HBV infection may entail life-long treatment and does not eliminate the virus in a meaningful number o

71、f patients.In the case of NAs,long-term treatment can lower the amount of HBV DNA in systemic circulation,resulting in improvements in long-term disease outcomes,but virological relapse is common after treatment cessation.In addition,certain patients continue to progress to liver disease while on NA

72、 treatment.Our goal for ALG000184 is to achieve superior rates of viral suppression(as measured by HBV DNA and a combination of HBV markers)with the potential to replace standard of care NA treatment and become the backbone of next-generation treatments.This includes the potential to meaningfully in

73、crease rates of functional cure,which is defined as a sustained loss of HBsAg and HBV DNA with or without hepatitis B surface antibody seroconversion after a finite treatment course.In addition,ALG000184 has the potential to treat all chronic HBV infection patients,with the possibility of lowering H

74、BsAg,which may allow more patients to be eligible for curative therapies.We have developed a portfolio of differentiated drug candidates for chronic HBV infection,including a small molecule CAME that has entered clinical development,is designed to interfere with the HBV life cycle.We are also pursui

75、ng a strategy to restore immune function in patients with chronic HBV infection through targeting of the PD1/PDL1 pathway and have recently selected a development candidate,ALG093940.ALG000184:Potential best-in-class small molecule CAME for chronic hepatitis B virus infectionIn 2018,we inlicensed a

76、lead drug candidate(GLP26)and the associated IP for a CAME from the laboratory of Professor Raymond Schinazi at Emory University.Our scientists optimized this lead drug candidate to discover the highly potent CAME,ALG001075,which was further optimized to the prodrug ALG000184.ALG000184 has superior

77、DMPK properties with enhanced absorption and high liver uptake,with a 2-300-fold improvement in in vitro potency compared to other known CAMs.CAMEs are a class of small molecule antiviral agents that accelerate HBV capsid assembly and inhibit pgRNA encapsidation(1st MOA),resulting in empty viral cap

78、sids and lower circulating HBV DNA and RNA levels.CAMEs are also believed to regulate the establishment of cccDNA(2nd MOA),a major factor for the persistence of HBV infection which can be assessed by circulating HBV antigen levels(HBsAg,HBcrAg,and HBeAg).In clinical trials,competitor CAMEs have show

79、n reductions in HBV DNA and RNA(1st MOA),but have rarely or inconsistently shown reductions in HBV antigens(2nd MOA).There have also been observations of the emergence of viral CAM-E drug resistance.3Figure 2 ALG000184(CAM-E)vs.Nucleos(t)ide AnalogsSuppressing the Entire HBV Lifecycle A multipart Ph

80、ase 1 study is ongoing,with the completed evaluation of the safety,tolerability,and pharmacokinetic profile of ALG000184 in healthy volunteers(HVs).Additionally,a dose-ranging Phase 1 study assessing the safety,pharmacokinetics,and antiviral activity of 10-300 mg doses of ALG000184 administered over

81、 28 days in untreated HBeAg+/-subjects with chronic HBV infection has also been completed.ALG000184 was found to be well tolerated with a favorable PK profile and demonstrated substantial HBV DNA and RNA reductions at all doses tested as well as HBsAg reductions in a subset of HBeAg positive subject

82、s receiving 300 mg ALG000184(Hou et al.,AASLD 2022).Figure 3 Antiviral Effect in Subjects(HBeAg+)with Chronic HBV Infection Mean HBV DNA Change from Baseline Based on the favorable profile after dosing up to 300 mg ALG000184 x 28 days,additional ongoing cohorts are evaluating the safety and efficacy

83、 of daily doses up to 300 mg doses of ALG000184,with or without entecavir(ETV)for 96 weeks in HBeAg+/-subjects.Preliminary data from several of these cohorts(Agarwal et al.,EASL 2024;Yuen et al.,AASLD 2024)have been presented,showing that ALG000184(ETV),administered for up to 92 weeks,was well toler

84、ated,exhibited a favorable PK profile,and demonstrated potentially bestinclass antiviral activity.Specifically,antiviral activity data demonstrated that 300 mg ALG000184 monotherapy resulted in 4profound reductions in HBV DNA which were greater than achieved with ETV alone(Figure 3).Furthermore,the

85、extent of HBV DNA suppression was similar whether ALG000184 was dosed alone or in combination with ETV,potentially indicating ETV did not meaningfully contribute to observed HBV DNA lowering effects.Also of note,ALG000184 monotherapy was not associated with viral breakthrough as assessed by HBV DNA

86、levels(Figure 3).These data indicate robust antiviral effects occur through the CAME 1st MOA.Antiviral activity data has also indicated that ALG000184 may be inhibiting cccDNA establishment(2nd MOA),which is an important component of maintaining the HBV life cycle and the disruption of which may enh

87、ance the rates of functional cure.Evidence for the inhibition of cccDNA establishment/replenishment can be found in Figure 4,where the rates of multiple important cccDNAderived viral antigens(HBsAg,HBcrAg,and HBeAg)are reduced over time and in a dose responsive manner(Yuen et al.,AASLD 2024).Figure

88、4 Antiviral Effect of 300mg ALG000184 Monotherapy in Subjects(HBeAg+)with Chronic HBV Infection Mean HBV Antigen Change from Baseline Dosing in HBeAg+/-subjects will continue through 2025,with 96-week safety,PK,and antiviral activity data to be presented at upcoming scientific conferences.An explora

89、tory combination study with mipeginterferon alfa2b is expected to begin in 2025.In addition,enabling activities for a randomized,doubleblind,active controlled Phase 2 study of monotherapy with ALG000184 vs.tenofovir disoproxil fumarate in HBeAg+and HBeAg-subjects are underway,with the Phase 2 study

90、expected to begin in mid-2025.MASHOne of the effects of improper diet and insufficient exercise is the accumulation of fatty deposits in the liver,referred to as metabolic dysfunction-associated steatotic liver disease(MASLD),which was estimated to occur in approximately 30%of the worldwide populati

91、on as of 2019.An estimated 1.5%to 6.5%of the global population was estimated to have an ongoing inflammatory response to these excess fat deposits,which was previously referred to as NASH(non-alcoholic steatohepatitis),and is now called MASH.Over the past several years,the prevalence of MASH has con

92、tinued to rise.In the United States alone,the prevalence of MASH is projected to increase from approximately 16.5 million in 2015 to 27.0 million in 2030.In the absence of changes in diet and exercise,the inflammation inherent in MASH persists and may result in progressive fibrosis of the liver,whic

93、h may result in cirrhosis.These fibrotic changes are associated with numerous morbidities including recurrent hospitalization for complications of cirrhosis,HCC,need for liver transplant,and death.There is currently one approved drug to treat MASH,a THR agonist,resmetirom.5 ALG055009:Potential besti

94、nclass small molecule THRb agonist for MASHThe thyroid hormone triiodothyronine(T3)has many physiological effects throughout the body,ranging from increasing metabolism,including fat metabolism,to stimulating growth and development.T3 exerts its effects by binding to the thyroid hormone receptor(THR

95、),which has two subtypes:alpha(THR-)and beta(THR-b).The distribution of the two THR subtypes varies by organ,with THRb predominantly expressed in the liver and THR predominantly expressed in other tissues(e.g.,heart,skeletal muscles and bone).Drugs like resmetirom,which preferentially binds the THRb

96、 subtype,have been shown in clinical trials to lower lipid levels in serum and the liver,while avoiding the unwanted effects associated with THR-stimulation.In addition to the intended effect of lowering liver lipid levels in MASH patients,lowering serum lipid levels via THRb agonism may also have f

97、avorable cardiovascular consequences in this population,which has a high rate of underlying cardiovascular disease.The most advanced THRb agonist is resmetirom,which received FDA approval in March 2024 based on favorable Phase 3 data(Harrison et al.,EASL 2023).This drug has demonstrated significant

98、reductions in lipid levels in the liver and serum and,to date,has an acceptable risk-benefit profile.In addition,resmetirom has demonstrated histologic evidence of MASH resolution and fibrosis improvement in Phase 3,which are both FDA approvable MASH endpoints.Our THRb drug candidate ALG055009 may h

99、ave important advantages over this compound.Side-by-side cell-based experiments in HEK293T cells indicate that ALG055009 is 50-fold more potent and 2-fold more selective for the b receptor compared to resmetirom.A Phase 1 first in human study of ALG055009 in HVs(oral single doses)and subjects with h

100、yperlipidemia(14 oral daily doses)has been completed.Data after single doses up to 4 mg and multiple daily doses up to 1 mg have previously been reported at EASL 2022 and AASLD 2023,respectively.At these conferences,data were presented that showed ALG055009 was well tolerated,had dose proportional P

101、K and low variability,and demonstrated expected thyromimetic effects(i.e.,generally dose proportional increases in sex hormone binding globulin and decreases in various atherogenic lipids and thyroid hormones without any clinical evidence of thyroid dysfunction).A second Phase 1 study evaluating whe

102、ther there is the potential for a drug-drug interaction(DDI)between ALG-055009 and atorvastatin has also been completed,with data demonstrating no clinically meaningful safety concerns or evidence of a DDI with atorvastatin.We completed a Phase 2a proof of concept study(HERALD)under an amendment to

103、an open investigational new drug application(IND)in 2024.The study was designed as a 12week randomized,doubleblind,placebocontrolled trial evaluating 4 doses of ALG055009 vs.placebo in 102 subjects with presumed liver fibrosis stage 1-3(F1-F3)MASH.The primary endpoint of this study was percent relat

104、ive change in liver fat content by MRI-PDFF at Week 12.This study also evaluated the safety and PK of ALG055009 treatment and its effect on multiple other efficacy biomarkers.Twelve weeks of once daily oral dose of ALG055009 treatment in MASH patients met the primary endpoint,with robust reductions

105、in liver fat content at Week 12.Doses of 0.5 mg to 0.9 mg ALG055009 demonstrated statistically significant reductions in liver fat at Week 12,with placebo-adjusted median relative reductions up to 46.2%as measured by MRI-PDFF(Figure 5).Up to 70%of subjects achieved 30%relative reduction in liver fat

106、 compared to baseline,a positive prognostic indicator of histological improvements in MASH resolution and fibrosis reduction.Eighteen subjects who were on stable GLP-1 agonist therapy qualified for enrollment in the study,with liver fat content meeting the inclusion criteria of 10%at baseline as mea

107、sured by MRI-PDFF.Notably,11 out of 14 subjects on stable GLP-1 agonists treated with ALG055009 had liver fat decreases,whereas 4 out of 4 subjects on stable GLP-1 agonists treated with placebo had increases in liver fat over the 12-week dosing period(Figure 6).6Figure 5 Placebo-Adjusted Median Rela

108、tive Change in Liver Fat at Week 12 Note:Only subjects weighing 85kg were enrolled in the 0.9 mg dose group,no body weight restrictions were implemented in other dose groups.Data from MRI-PDFF analysis dataset,defined as all randomized subjects who have MRI-PDFF measurements available at both baseli

109、ne and Week 12;median%change in placebo was+7.2%;*p0.05*p3 x EC90 for HBsAg inhibition)there was no meaningful HBsAg reduction.Furthermore,higher doses levels(maximum feasible dose is 600 mg)that were planned to be evaluated in a subsequent cohort were very unlikely to reach the 1 log10 IU/mL HBsAg

110、reduction level that we had previously defined as necessary to advance the program.As another example,in March 2022,we discontinued further development of our ASO drug candidate for CHB,ALG020572,due to an unanticipated serious adverse event involving significant increase in ALT in one CHB subject a

111、nd several other subjects experiencing ALT flares in the same study.Finally,for our siRNA drug candidate targeting HBsAg production,ALG125755,we conducted a Phase 1 study evaluating single doses ranging from 20-200 mg and 50-320 mg in HVs and virologically suppressed HBeAg negative subjects with chr

112、onic HBV infection,respectively.In this study,we found that these single doses were well tolerated with a favorable PK profile.With respect to antiviral activity,while available data indicate evidence of HBsAg lowering at all 3 dose levels evaluated,the comparative efficacy of ALG-125755 petitor siR

113、NAs is inconclusive.Because further clinical evaluation of ALG-125755 is not prioritized with current funding,any further advancement of ALG-125755 will require additional external funding which we may not be able to obtain.We may experience delays in completing our clinical trials and initiating or

114、 completing additional clinical trials.We may also experience numerous unforeseen events prior to,during,or as a result of our nonclinical studies 37or clinical trials that could delay or prevent our ability to receive marketing approval or commercialize the drug candidates we develop,including:regu

115、lators,Institutional Review Boards(IRBs)or ethics committees may not authorize us or our investigators to commence a clinical trial or conduct a clinical trial at a prospective trial site;we may experience delays in reaching,or fail to reach,agreement on acceptable terms with prospective trial sites

116、 and prospective contract research organizations(CROs);the number of patients required for clinical trials may be larger than we anticipate;it may be difficult to enroll a sufficient number of suitable patients,or enrollment in these clinical trials may be slower than we anticipate or participants m

117、ay drop out of these clinical trials or fail to return for post-treatment follow-up at a higher rate than we anticipate;our third-party contractors may fail to comply with regulatory requirements or meet their contractual obligations to us in a timely manner,or at all,or may deviate from the clinica

118、l trial protocol or drop out of the trial,which may require us to add new clinical trial sites or investigators;the supply or quality of materials for drug candidates we develop or other materials necessary to conduct clinical trials may be insufficient or inadequate;and we may experience disruption

119、s by man-made or natural disasters or public health pandemics or epidemics or other business interruptions.We could encounter delays if a clinical trial is suspended or terminated by us,by the IRBs or ethics committees of the institutions in which such trials are being conducted,by a Data Safety Mon

120、itoring Board for such trial or by the FDA or other regulatory authorities.Such authorities may impose such a suspension or termination due to a number of factors,including failure to conduct the clinical trial in accordance with regulatory requirements or our clinical protocols,inspection of the cl

121、inical trial operations or trial site by the FDA or other regulatory authorities resulting in the imposition of a clinical hold,unforeseen safety issues or adverse side effects,failure to demonstrate a benefit from using a product,changes in governmental regulations or administrative actions or lack

122、 of adequate funding to continue the clinical trial.Many of the factors that cause,or lead to,a delay in the commencement or completion of clinical trials may also ultimately lead to the denial of marketing approval of our drug candidates.Further,we are currently conducting clinical trials in many c

123、ountries(e.g.,New Zealand,Hong Kong,the United Kingdom).We may also in the future conduct clinical trials for these and other drug candidates in other countries and territories which presents additional risks that may delay completion of our clinical trials.These risks include the possibility that w

124、e could be required to conduct additional nonclinical studies before initiating any clinical trials,may be unable to enroll and retain patients as a result of differences in healthcare services,research guidelines or cultural customs,or may face additional administrative burdens associated with comp

125、arable foreign regulatory schemes,as well as political and economic risks relevant to such foreign countries.If we experience termination or delays in the completion of any clinical trial of our drug candidates,the commercial prospects of our drug candidates will be harmed,and our ability to generat

126、e product revenues from any of these drug candidates will be delayed.In addition,any delays in completing our clinical trials will increase our costs,slow down our drug candidate development and approval process and jeopardize our ability to commence product sales and generate revenues.Significant c

127、linical trial delays could also allow our competitors to bring products to market before we do,shorten any periods during which we may have the exclusive right to commercialize our drug candidates,impair our ability to commercialize our drug candidates and harm our business and results of operations

128、.Specifically,should we experience another pandemic or epidemic outbreak on a similar if not greater scale as the COVID-19 outbreak,the clinical trial sites for our current drug trials,and future planned trials may be affected due to prioritization of hospital resources toward the outbreak efforts,t

129、ravel or quarantine restrictions imposed by national,federal,state or local governments,and the inability to access sites for initiation and patient monitoring and enrollment.As a result,patient screening,new patient enrollment,monitoring and data collection may be affected or delayed.Some of our th

130、ird-party manufacturers we use for the supply of materials for drug candidates or other materials necessary to manufacture product to conduct clinical trials may be located in countries affected by the 38outbreak,and,should they experience disruptions such as temporary closures or suspension of serv

131、ices,we would likely experience delays in advancing these trials.In addition,the U.S.House of Representatives has passed the BIOSECURE Act and the Senate has advanced a substantially similar bill,which legislation,if passed and enacted into law,would have the potential to restrict the ability of U.S

132、.biopharmaceutical companies like us to purchase services or products from,or otherwise collaborate with,certain Chinese biotechnology companies“of concern”without losing the ability to contract with,or otherwise receive funding from,the U.S.government.We do business with companies in China and it i

133、s possible some of our contractual counterparties could be impacted by this legislation.Separately,principal investigators for our clinical trials serve as scientific advisors or consultants to us from time to time and may receive cash or equity compensation in connection with such services.If these

134、 relationships and any related compensation result in perceived or actual conflicts of interest,or a regulatory authority concludes that the financial relationship may have affected the interpretation of the clinical trial,the integrity of the data generated at the applicable clinical trial site may

135、 be questioned and the utility of the clinical trial itself may be jeopardized,which could result in the delay or rejection of any applications we submit.Any such delay or rejection could prevent or delay us from commercializing our current or future drug candidates.There is also uncertainty as to h

136、ow measures being implemented by the new administration will impact the operations of various agencies.Any of these occurrences may harm our business,financial condition and prospects significantly.In addition,many of the factors that cause,or could lead to,a delay in the commencement or completion

137、of clinical trials may also ultimately lead to the denial of regulatory approval of our drug candidates or result in the development of our drug candidates being terminated.Our pursuit of potential treatments for CHB is at an early stage and we may be unable to produce a therapy that successfully tr

138、eats CHB.Even if successful,we may be unable to obtain regulatory approval for and successfully commercialize our drug candidates.We have invested a significant portion of our time and financial resources in the pursuit of a treatment for CHB,including ALG000184,a CAM-E that is currently in a multip

139、art Phase 1 trial.If we cannot successfully develop,obtain regulatory approval for and commercialize our drug candidates for the treatment of CHB,our business may be harmed.The mechanism of action of our CHB drug candidates is complex,and we do not know the degree to which it will translate into a t

140、herapeutic benefit,if any,in CHB or any other indication,and we do not know the degree to which the complex mechanism of action may contribute to long-term safety issues or adverse events when our drug candidates are taken for prolonged periods,as is inherent in the treatment of CHB.In addition,the

141、standards implemented by clinical or regulatory agencies may change at any time and we cannot be certain what efficacy endpoints the FDA or foreign clinical or regulatory agencies may require at the time we plan to conduct clinical trials with respect to CHB or any other applicable indication.Also,i

142、f we are able to obtain accelerated approval of our drug candidates,we may be required to conduct one or more post-approval clinical outcome trials to confirm the clinical benefit of the drug candidate;if any such post-approval trial is not successful,we would not be able to continue marketing the p

143、roduct.If we are successful and any of our drug candidates are approved for the treatment of CHB,our drug candidates will likely compete with products that have already been approved or may in the future be approved for the treatment of CHB prior to our drug candidates and/or that have greater effic

144、acy than our drug candidates,either alone or in combination.Our pursuit of potential treatments for MASH is at an early stage and we may be unable to produce a therapy that successfully treats MASH.Even if successful,we may be unable to obtain regulatory approval for and successfully commercialize o

145、ur drug candidates.We have invested a significant portion of our time and financial resources in the pursuit of a treatment for MASH,including ALG-055009,our THR agonist which is currently in a Phase 2a trial.If we cannot successfully develop,obtain regulatory approval for and commercialize our drug

146、 candidates for the treatment of MASH,our business may be harmed.The mechanism of action of our MASH drug candidates is complex,and we do not know the degree to which it will translate into a therapeutic benefit,if any,in MASH or any other indication,and we do not know the degree to which the comple

147、x mechanism of action may contribute to long-term safety issues or adverse events when our drug candidates are taken for prolonged periods,as is inherent in the treatment of MASH.39In addition,the standards implemented by clinical or regulatory agencies may change at any time and we cannot be certai

148、n what efficacy endpoints the FDA or foreign clinical or regulatory agencies may require at the time we plan to conduct clinical trials with respect to MASH or any other applicable indication.Also,if we are able to obtain accelerated approval of our drug candidates,we may be required to conduct one

149、or more post-approval clinical outcome trials to confirm the clinical benefit of the drug candidate;if any such post-approval trial is not successful,we would not be able to continue marketing the product.If we are successful and any of our drug candidates are approved for the treatment of MASH,our

150、drug candidates will likely compete with products that have already been approved or may in the future be approved for the treatment of MASH prior to our drug candidates and/or that have greater efficacy than our drug candidates,either alone or in combination.Behavioral modifications,such as diet an

151、d exercise,can also decrease or eliminate the demand for our potential MASH treatments.Our pursuit of potential therapies for COVID-19 is at an early stage.In response to the outbreak of COVID-19,the disease caused by the virus SARS-CoV-2,we are pursuing various potential therapies to address the di

152、sease,including our drug candidate ALG-097558,an oral protease inhibitor which is currently in a Phase 1 trial.Our development of this potential therapy is at an early stage,and we may be unable to produce in a timely manner a therapy that successfully treats the virus or that has broad clinical app

153、licability,if at all.For example,in June 2020,we entered into a Research,Licensing and Commercialization Agreement with KU Leuven under which we were collaborating with KU Leuvens Rega Institute for Medical Research,as well as its CD3,to research,develop,manufacture and commercialize potential prote

154、ase inhibitors for the treatment of coronaviruses,including SARS-CoV-2.In July 2023,we amended our license agreement with KU Leuven(as amended,KU Leuven Agreement)to further our collaboration.While ALG-097558 has been selected as our drug candidate to move forward into development,the KU Leuven Agre

155、ement may ultimately not result in a therapy that successfully treats SARS-CoV-2.Further,if the KU Leuven Agreement does result in such a therapy,the therapy may not be developed and commercialized in a timely manner,or at all.We are also committing significant personnel to the development of ALG-09

156、7558 for COVID-19,which may cause delays in or otherwise negatively impact our other development programs,despite uncertainties surrounding the longevity and extent of COVID-19 as a global health concern.COVID-19 may be substantially eradicated prior to our development of a successful therapy or a v

157、accine may be developed that is highly efficacious and widely adopted,reducing or eliminating the need for therapies to treat the disease.For instance,the Pfizer/BioNTech BNT162b2,the adenovirus type 26(Ad26)vaccine by Janssen Pharmaceutical Companies of Johnson&Johnson,Moderna mRNA-1273 and Novavax

158、 NVX-CoV2373 COVID-19 vaccines have been approved and/or authorized for emergency use and are in the process of being widely being administered in various countries throughout the world which could adversely impact the need for our potential COVID-19 therapies.Further,while we hope to develop potent

159、ial therapies that are effective against other or future coronaviruses,in addition to SARS-CoV-2,we cannot be certain this will be the case.If our potential therapies are not effective against other or future coronaviruses,the value and/or sales potential of our therapies will be reduced or eliminat

160、ed.Our business could be negatively impacted by our allocation of significant resources to a global health threat that is unpredictable and could rapidly dissipate or against which our potential therapies,if developed,may not be partially or fully effective,and may ultimately prove unsuccessful or u

161、nprofitable.Furthermore,there are no assurances that our therapy will be approved for inclusion in government stockpile programs,which may be material to the commercial success of any approved coronavirus-related drug candidate,either in the United States or abroad.We will also need to enter into ma

162、nufacturing arrangements in the future in order to create a supply chain for our COVID-19 drug candidates that can adequately support demand.Even if we are successful in developing and manufacturing an effective treatment for COVID-19,the SARS-CoV-2 virus could develop resistance to our treatment,wh

163、ich could affect any long-term demand or sales potential for our potential therapies.In addition,another party may be successful in producing a more efficacious therapy for COVID-19 or a therapy with a more convenient or preferred route of administration or in producing a therapy in a more timely ma

164、nner,which may lead to the diversion of funding away from us and toward other companies or lead to decreased demand for our potential therapies.For instance,on May 25,2023,Pfizer,Inc.received an approval from the FDA for Paxlovid,an orally administered SARS-CoV-2 protease inhibitor co-administered w

165、ith ritonavir.Similarly,Merck(together with Ridgeback Bio),is developing the drug molnupiravir,an oral antiviral drug which has been 40issued an emergency use authorization by the FDA on December 23,2021.Several drugs are likely being used off-label for treatment,such as dexamethasone.Several approv

166、ed drugs are being studied for their utility in reducing the severity of SARS-CoV-2 infections,including Soliris by Alexion Pharmaceuticals Inc.,Atea Pharmaceuticals,Inc.,Jakafi by Incyte Corporation,and Kevzara by Sanofi S.A./Regeneron Pharmaceuticals,Inc.There are significant efforts by other comp

167、anies globally to develop both therapeutic and prophylactic drug candidates.These other entities may be more successful at developing,manufacturing or commercializing a therapy for COVID-19,especially given that several of these other organizations are much larger than we are and have access to larg

168、er pools of capital,including U.S.government funding,and broader manufacturing infrastructure.The success or failure of other entities,or perceived success or failure,may adversely impact our ability to obtain any future funding for our development and manufacturing efforts or to ultimately commerci

169、alize a therapy for COVID-19,if approved.The results of nonclinical studies and early-stage clinical trials may not be predictive of future results.The results of nonclinical studies may not be predictive of the results of clinical trials,and the results of any early-stage clinical trials we commenc

170、e may not be predictive of the results of the later-stage clinical trials.Drug candidates in later stages of clinical trials may fail to show the desired safety and efficacy despite having progressed through nonclinical studies and initial clinical trials.There is a high failure rate for drugs proce

171、eding through clinical trials,and a number of companies in the pharmaceutical and biotechnology industries have suffered significant setbacks in clinical development even after achieving promising results in earlier studies.There can be no assurance that any of our current or future clinical trials

172、will ultimately be successful or support further clinical development of any of our drug candidates.Even if our clinical trials are completed,the results may not be sufficient to obtain regulatory approval of any products.Any such setbacks in our clinical development could have a material adverse ef

173、fect on our business and operating results.Interim,“topline”and preliminary data from our clinical trials may differ materially from the final data.From time to time,we may disclose interim data from our clinical trials.Interim data from clinical trials are subject to the risk that one or more of th

174、e clinical outcomes may materially change as patient enrollment continues and more data on existing patients become available.Adverse differences between interim data and final data could significantly harm our business,financial condition,results of operations and prospects.From time to time,we may

175、 also publicly disclose preliminary or“topline”data from our clinical trials,which are based on a preliminary analysis of then-available data,and the results and related findings and conclusions are subject to change following a more comprehensive review of the data related to the particular study o

176、r trial.We also make assumptions,estimations,calculations and conclusions as part of our analyses of data,and we may not have received or had the opportunity to fully and carefully evaluate all data.As a result,the topline results that we report may differ from future results of the same clinical tr

177、ials,or different conclusions or considerations may qualify such topline results,once additional data have been received and fully evaluated.Topline data also remain subject to audit and verification procedures that may result in the final data being materially different from the preliminary data we

178、 previously published.As a result,topline data should be viewed with caution until the final data are available.Further,others,including regulatory agencies,may not accept or agree with our assumptions,estimates,calculations,conclusions or analyses or may interpret or weigh the importance of data di

179、fferently,which could impact the value of the particular program,the approvability or commercialization of the particular drug candidate or product and the value of our company in general.In addition,the information we choose to publicly disclose regarding a particular study or clinical trial is typ

180、ically a summary of extensive information,and you or others may not agree with what we determine is the material or otherwise appropriate information to include in our disclosure,and any information we determine not to disclose may ultimately be deemed significant with respect to future decisions,co

181、nclusions,views,activities or otherwise regarding a particular product,drug candidate or our business.If the topline data that we report differ from actual results,or if others,including regulatory authorities,disagree with the conclusions reached,our ability to obtain approval for,and commercialize

182、,our drug candidates may be harmed,which could harm our business,financial condition,operating results and prospects.41If we encounter difficulties enrolling patients in our clinical trials,our clinical development activities could be delayed or otherwise adversely affected.The timely completion of

183、clinical trials in accordance with their protocols depends,among other things,on our ability to enroll a sufficient number of patients who remain in the trial until its conclusion.We may experience difficulties in patient enrollment in our clinical trials for a variety of reasons.The enrollment of p

184、atients depends on many factors,including:the patient eligibility criteria defined in the protocol;the size of the patient population required for analysis of the trials primary endpoints;the proximity of patients to study sites;the design of the trial;our ability to recruit clinical trial investiga

185、tors with the appropriate competencies and experience;clinicians and patients perceptions as to the potential advantages of the drug candidate being studied in relation to other available therapies,including any new products that may be approved for the indications we are investigating;our ability t

186、o obtain and maintain patient consents for participation in our clinical trials and,where appropriate,biopsies for future patient enrichment efforts;the risk that patients enrolled in clinical trials will not remain in the trial through the completion of evaluation;and disruption by man-made or natu

187、ral disasters,or public health pandemics or epidemics or other business interruptions.In addition,our clinical trials will compete with other clinical trials for drug candidates that are in the same therapeutic areas as our current and potential future drug candidates.This competition will reduce th

188、e number and types of patients available to us,because some patients who might have enrolled in our trials may instead opt to enroll in a trial conducted by one of our competitors.Since the number of qualified clinical investigators is limited,we may conduct some of our clinical trials at the same c

189、linical trial sites that some of our competitors use,which would reduce the number of patients who are available for our clinical trials at such sites.Moreover,because our current and potential future drug candidates may represent a departure from more commonly used methods for treatment,potential p

190、atients and their doctors may be inclined to use conventional therapies rather than enroll patients in our clinical trials.Delays in patient enrollment may result in increased costs or may affect the timing or outcome of clinical trials,which could prevent completion of these trials and adversely af

191、fect our ability to advance the development of our drug candidates.Changes in methods of drug candidate manufacturing or formulation may result in additional costs or delay.As drug candidates proceed from nonclinical studies to late-stage clinical trials towards potential approval and commercializat

192、ion,it is common that various aspects of the development program,such as manufacturing methods and formulation,are altered to optimize results.However,any change could entail additional cost and risks potential delay if the reformulated or otherwise altered drug candidate performs differently than e

193、xpected or intended,which could require modification to the nonclinical or clinical program.Such changes may also require additional testing,including bridging or comparability testing to demonstrate the validity of clinical data obtained in clinical trials following manufacturing changes,FDA notifi

194、cation or FDA approval.Moreover,we have not yet manufactured or processed on a commercial scale any of our drug candidates.We may make changes as we work to optimize our manufacturing processes,but we cannot be sure that even minor changes in our processes will result in therapies that are safe and

195、effective or that will be approved for commercial sale.42Our current or future drug candidates may cause undesirable side effects or have other properties when used alone or in combination with other approved products or investigational new drugs that could delay or halt their clinical development,p

196、revent their marketing approval,limit their commercial potential or result in significant negative consequences.Undesirable or clinically unmanageable side effects from one or more of our drug candidates or potential future products could occur and cause us or regulatory authorities to interrupt,del

197、ay or terminate clinical trials,could result in a more restrictive label or could cause the delay or denial of marketing approval by the FDA or comparable foreign regulatory authorities.Further,results of our planned clinical trials could reveal unacceptably severe and prevalent side effects or unex

198、pected characteristics.If unacceptable toxicities or other undesirable side effects arise in the development of any of our current or future drug candidates,we could suspend or terminate our trials,or the FDA or comparable foreign regulatory authorities could order us to cease clinical trials or den

199、y approval of the drug candidate for any or all targeted indications.Treatment-related side effects could also affect patient recruitment or the ability of enrolled subjects to complete the trial,or result in potential product liability claims.In addition,these side effects may not be appropriately

200、recognized or managed by the treating medical staff.Inadequately recognizing or managing the potential side effects of our drug candidates could result in patient injury or death.Any of these occurrences may prevent us from achieving or maintaining market acceptance of the affected drug candidate an

201、d may harm our business,financial condition and prospects significantly.Although our current and future drug candidates will undergo safety testing to the extent possible and,where applicable,under such conditions discussed with regulatory authorities,not all adverse effects of drugs can be predicte

202、d or anticipated.Unforeseen side effects could arise either during clinical development or,if such side effects are more rare,after our products have been approved by regulatory authorities and the approved product has been marketed,resulting in the exposure of additional patients.To date,we have no

203、t demonstrated that any of our drug candidates are safe in humans,and we cannot predict if ongoing or future clinical trials will do so.Furthermore,we plan to evaluate our drug candidates in combination with approved and/or experimental therapies.These combinations may have additional or more severe

204、 side effects than caused by our drug candidates as monotherapies or may cause side effects at lower doses.The uncertainty resulting from the use of our drug candidates in combination with other therapies may make it difficult to accurately predict side effects in potential future clinical trials.If

205、 any of our drug candidates receives marketing approval and we or others later identify undesirable side effects caused by such products,a number of potentially significant negative consequences could occur,including:regulatory authorities may withdraw their approval of the product;we may be require

206、d to recall a product or change the way such product is administered to patients;additional restrictions may be imposed on the marketing of the particular product or the manufacturing processes for the product or any component thereof;regulatory authorities may require the addition of labeling state

207、ments,such as a“black box”warning or a contraindication;we may be required to implement a Risk Evaluation and Mitigation Strategy(REMS)or create a Medication Guide outlining the risks of such side effects for distribution to patients;we could be sued and held liable for harm caused to patients;the p

208、roduct may become less competitive;and our reputation may suffer.Any of the foregoing events could prevent us from achieving or maintaining market acceptance of the particular drug candidate,if approved,and result in the loss of significant revenue to us,which would adversely affect our business,fin

209、ancial condition,results of operations and prospects.In addition,if one or more of our drug candidates prove to be unsafe,our entire technology platform and pipeline could be affected,which would have a material adverse effect on our business,financial condition,results of operations and prospects.4

210、3Even if we complete the necessary nonclinical studies and clinical trials,the marketing approval process is expensive,time-consuming and uncertain and may prevent us or any of our future collaboration partners from obtaining approvals for the commercialization of our current drug candidates and any

211、 other drug candidate we develop.Any current or future drug candidates we may develop and the activities associated with their development and commercialization,including their design,testing,manufacture,safety,efficacy,recordkeeping,labeling,storage,approval,advertising,promotion,sale,and distribut

212、ion,are subject to comprehensive regulation by the FDA and other regulatory authorities in the United States and by comparable authorities in other countries.Failure to obtain marketing approval for a drug candidate will prevent us from commercializing the drug candidate in a given jurisdiction.We h

213、ave not received approval to market any drug candidates from regulatory authorities in any jurisdiction and it is possible that none of our current or future drug candidates will ever obtain regulatory approval.As an organization,we have no experience in filing and supporting the applications necess

214、ary to gain marketing approvals and expect to rely on third-party CROs or regulatory consultants to assist us in this process.Securing regulatory approval requires the submission of extensive nonclinical and clinical data and supporting information to the various regulatory authorities for each ther

215、apeutic indication to establish the drug candidates safety and efficacy.Securing regulatory approval also requires the submission of information about the product manufacturing process to,and inspection of manufacturing facilities by,the relevant regulatory authority.Any drug candidates we develop m

216、ay not be effective,may be only moderately effective,or may prove to have undesirable or unintended side effects,toxicities or other characteristics that may preclude our obtaining marketing approval or prevent or limit commercial use.The process of obtaining marketing approvals,both in the United S

217、tates and abroad,is expensive,may take many years if additional clinical trials are required,if approval is obtained at all,and can vary substantially based upon a variety of factors,including the type,complexity,and novelty of the drug candidates involved.Changes in marketing approval policies duri

218、ng the development period,changes in or the enactment of additional statutes or regulations,or changes in regulatory review for each submitted product application,may cause delays in the approval or rejection of an application.There is also uncertainty as to how measures being implemented by the new

219、 administration will impact the operations of various agencies.For example,the potential loss of personnel at various agencies could lead to disruptions and delays in review of our product candidates.The FDA and comparable authorities in other countries have substantial discretion in the approval pr

220、ocess and may refuse to accept any application or may decide that our data are insufficient for approval and require additional nonclinical,clinical or other studies.In addition,varying interpretations of the data obtained from nonclinical and clinical testing could delay,limit,or prevent marketing

221、approval of a drug candidate.Any marketing approval we ultimately obtain may be limited or subject to restrictions or post-approval commitments that render the approved product not commercially viable.If we experience delays in obtaining marketing approval or if we fail to obtain marketing approval

222、of any current or future drug candidates we may develop,the commercial prospects for those drug candidates may be harmed,and our ability to generate revenues will be materially impaired.Even if a current or future drug candidate receives marketing approval,it may fail to achieve the degree of market

223、 acceptance by physicians,patients,third-party payors and others in the medical community necessary for commercial success.If any current or future drug candidate we develop receives marketing approval,whether as a single agent or in combination with other therapies,it may nonetheless fail to gain s

224、ufficient market acceptance by physicians,patients,third-party payors,and others in the medical community,or such participants may prefer existing treatment options such as nucleos(t)ide analogs including tenofovir and entecavir.If the drug candidates we develop do not achieve an adequate level of a

225、cceptance,we may not generate significant product revenues and we may not become profitable for a full fiscal year.The degree of market acceptance of any drug candidate,if approved for commercial sale,will depend on a number of factors,including:efficacy and potential advantages compared to alternat

226、ive treatments;the ability to offer our products,if approved,for sale at competitive prices;convenience and ease of administration compared to alternative treatments;44the willingness of the target patient population to try new therapies and of physicians to prescribe these therapies;the strength of

227、 marketing and distribution support;the ability to obtain sufficient third-party coverage and adequate reimbursement,including with respect to the use of the approved product as a combination therapy;adoption of a companion diagnostic and/or complementary diagnostic(if any);and the prevalence and se

228、verity of any side effects.Adverse events in our therapeutic areas of focus,including hepatological indications and viral diseases,could damage public perception of our current or future drug candidates and negatively affect our business.The commercial success of our products will depend in part on

229、public acceptance of our therapeutic areas of focus.Adverse events in clinical trials of our drug candidates,or post-marketing activities,or in clinical trials of others developing similar products or targeting similar indications and the resulting publicity,as well as any other adverse events in ou

230、r therapeutic areas of focus,including hepatological indications and viral diseases,could result in decreased demand for any product that we may develop.If public perception is influenced by claims that the use of therapies in our therapeutic areas of focus are unsafe,whether related to our therapie

231、s or those of our competitors,our products may not be accepted by the general public or the medical community.Future adverse events in our therapeutic areas of focus or the biopharmaceutical industry could also result in greater governmental regulation,stricter labeling requirements and potential re

232、gulatory delays in the testing or approvals of our products.Any increased scrutiny could delay or increase the costs of obtaining marketing approval for the drug candidates we have developed,are developing and may in the future develop.Negative developments and negative public opinion of technologie

233、s on which we rely may damage public perception of our drug candidates or adversely affect our ability to conduct our business or obtain regulatory approvals for our drug candidates.The clinical and commercial success of our drug candidates will depend in part on public acceptance of the use of tech

234、nologies for the prevention or treatment of human diseases.Adverse public attitudes may adversely impact our ability to enroll clinical trials.Moreover,our success will depend upon physicians specializing in our targeted diseases prescribing,and their patients being willing to receive,our drug candi

235、dates as treatments in lieu of,or in addition to,existing,more familiar,treatments for which greater clinical data may be available.Any increase in negative perceptions of the technologies that we rely on may result in fewer physicians prescribing our products(if approved)or may reduce the willingne

236、ss of patients to utilize our products or participate in clinical trials for our drug candidates.Increased negative public opinion or more restrictive government regulations in response thereto,would have a negative effect on our business,financial condition,results of operations or prospects and ma

237、y delay or impair the development and commercialization of our drug candidates or demand for such drug candidates.Adverse events in our nonclinical studies or clinical trials or those of our competitors or of academic researchers utilizing similar technologies,even if not ultimately attributable to

238、drug candidates we may discover and develop,and the resulting publicity could result in increased governmental regulation,unfavorable public perception,potential regulatory delays in the testing or approval of potential drug candidates we may identify and develop,stricter labeling requirements for t

239、hose drug candidates that are approved,a decrease in demand for any such drug candidates and a suspension or withdrawal of approval by regulatory authorities of our drug candidates.Even if we receive marketing approval of a drug candidate,we will be subject to ongoing regulatory obligations and cont

240、inued regulatory review,which may result in significant additional expense,and we may be subject to penalties if we fail to comply with regulatory requirements or experience unanticipated problems with our products,if approved.Any marketing approvals that we receive for any current or future drug ca

241、ndidate may be subject to limitations on the approved indicated uses for which the product may be marketed or contain requirements for potentially costly post-market testing and surveillance to monitor the safety and efficacy of the drug candidate.The FDA may also require a REMS as a condition of ap

242、proval of any drug candidate,which could include requirements for a 45Medication Guide,physician communication plans or additional elements to ensure safe use,such as restricted distribution methods,patient registries and other risk-minimization tools.In addition,if the FDA or a comparable foreign r

243、egulatory authority approves a drug candidate,the manufacturing processes,labeling,packaging,distribution,adverse event reporting,storage,advertising,promotion,import and export and record keeping for the product will be subject to extensive and ongoing regulatory requirements.These requirements inc

244、lude submissions of safety and other post-marketing information and reports,establishment registration,as well as continued compliance with cGMP,and GCP,for any clinical trials that we conduct post-approval.Later discovery of previously unknown problems with any approved candidate,including adverse

245、events of unanticipated severity or frequency,or with our third-party manufacturers or manufacturing processes,or failure to comply with regulatory requirements,may result in,among other things:restrictions on the marketing or manufacturing of the product,withdrawal of the product from the market,or

246、 product recalls;fines,untitled and warning letters,or holds on clinical trials;refusal by the FDA or other regulatory authorities to approve pending applications or supplements to approved applications we filed or suspension or revocation of license approvals;product seizure or detention,or refusal

247、 to permit the import or export of the product;and injunctions or the imposition of civil or criminal penalties.The FDAs and other regulatory authorities policies may change and additional government regulations may be enacted that could prevent,limit or delay marketing approval of a product.We cann

248、ot predict the likelihood,nature or extent of government regulation that may arise from future legislation or administrative action,either in the United States or abroad.If we are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies,or if we are

249、 not able to maintain regulatory compliance,we may lose any marketing approval that we may have obtained,and we may not achieve profitability for a full fiscal year.Even if we obtain and maintain approval for our drug candidates from the FDA,we may never obtain approval outside the United States,whi

250、ch would limit our market opportunities.Approval of a drug candidate in the United States by the FDA does not ensure approval of such drug candidate by regulatory authorities in other countries or jurisdictions,and approval by one foreign regulatory authority does not ensure approval by regulatory a

251、uthorities in other foreign countries.Sales of our drug candidates outside the United States will be subject to foreign regulatory requirements governing clinical trials and marketing approval.Even if the FDA grants marketing approval for a drug candidate,comparable foreign regulatory authorities al

252、so must approve the manufacturing and marketing of the drug candidate in those countries.Approval procedures vary among jurisdictions and can involve requirements and administrative review periods different from,and more onerous than,those in the United States,including additional nonclinical studie

253、s or clinical trials.In many countries outside the United States,a drug candidate must be approved for reimbursement before it can be approved for sale in that country.In some cases,the price that we intend to charge for any drug candidates,if approved,is also subject to approval.Obtaining approval

254、for our drug candidates in the European Union from the European Commission following the opinion of the EMA,if we choose to submit a marketing authorization application there,would be a lengthy and expensive process.Even if a drug candidate is approved,the EMA may limit the indications for which the

255、 product may be marketed,require extensive warnings on the product labeling or require expensive and time-consuming additional clinical trials or reporting as conditions of approval.Approval of certain drug candidates outside of the United States,particularly those that target diseases that are more

256、 prevalent outside of the United States,will be particularly important to the commercial success of such drug candidates.Obtaining foreign regulatory approvals and compliance with foreign regulatory requirements could result in significant delays,difficulties and costs for us and could delay or prev

257、ent the introduction of our drug candidates in certain countries.Further,clinical trials conducted in one country may not be accepted by regulatory authorities in other countries.For example,we have or are currently conducting initial clinical trials for ALG-000184,ALG-055009 and ALG-097558 in many

258、countries(e.g.,New Zealand,Hong Kong,the United Kingdom),and plan to conduct additional clinical trials in several other countries and territories within the Asia Pacific and/or Europe and our conduct of the trials must satisfy specific requirements in order for the FDA to accept the data in support

259、 of an IND or NDA in the United States.Further,any regulatory approval for our drug candidates may be withdrawn.If we fail 46to comply with the applicable regulatory requirements,our target market will be reduced and our ability to realize the full market potential of our drug candidates will be har

260、med and our business,financial condition,results of operations and prospects could be harmed.Risks associated with our international operations,including seeking and obtaining approval to commercialize our drug candidates in foreign jurisdictions,could harm our business.We engage in international op

261、erations with offices in the United States,Belgium and China and intend to seek approval to market our drug candidates outside of the United States.We may also do so for future drug candidates.We expect that we are or will be subject to additional risks related to these international business market

262、s and relationships,including:different regulatory requirements for approval of drug candidates in foreign countries,including challenging processes for marketing biopharmaceutical products;reduced protection for and enforcement of intellectual property rights;heightened or different data privacy an

263、d information security laws,regulations and policies;unexpected changes in tariffs,trade barriers and regulatory requirements;economic weakness,including inflation or political instability in particular foreign economies and markets;compliance with tax,employment,immigration and labor laws for emplo

264、yees living or traveling abroad;foreign currency fluctuations,which could result in increased operating expenses and reduced revenue,and other obligations incident to doing business in another country;foreign reimbursement,pricing and insurance regimes;workforce uncertainty in countries where labor

265、unrest is more common than in the United States;production shortages resulting from any events affecting raw material supply or manufacturing capabilities;business interruptions resulting from geopolitical actions,including war and terrorism,or natural disasters including earthquakes,typhoons,floods

266、 and fires;and disruptions resulting from the impact of public health pandemics or epidemics(including,for example,the COVID-19 pandemic).In addition,there are complex regulatory,tax,labor and other legal requirements imposed by many of the individual countries in which we may operate,with which we

267、will need to comply.Disruptions at the FDA and other government agencies caused by funding shortages or global health concerns could hinder their ability to hire,retain or deploy key leadership and other personnel,or could otherwise prevent new or modified products from being developed,approved or c

268、ommercialized in a timely manner or at all,which could negatively impact our business.The ability of the FDA to review and approve new products can be affected by a variety of factors,including government budget and funding levels,statutory,regulatory,and policy changes,the FDAs hiring and retention

269、 of key personnel and receipt of user fees,changes in senior leadership at FDA and HHS,and other events that may otherwise affect the FDAs performance of routine functions.Average review times at the agency have fluctuated in recent years as a result.Disruptions at the FDA and other agencies may als

270、o slow the time necessary for new products to be reviewed and/or approved by necessary government agencies,which would adversely affect our business.For example,over the last several years,including for 35 days beginning on December 22,2018,the U.S.government has shut down several times and certain

271、regulatory agencies,such as the FDA,have had to furlough critical FDA employees and stop critical activities.Relatedly,in response to the COVID-19 pandemic,the FDA postponed most inspections of domestic and foreign manufacturing facilities at various points.Even though the FDA has since resumed stan

272、dard inspection 47operations,any resurgence of the virus or emergence of new variants may lead to further inspectional or administrative delays.If a prolonged government shutdown occurs,or if global health concerns continue to prevent the FDA or other regulatory authorities from conducting their reg

273、ular inspections,reviews,or other regulatory activities,it could significantly impair the ability of the FDA or other regulatory authorities to timely review and process our regulatory submissions,which could have a material adverse effect on our business.If the market opportunities for our drug can

274、didates are smaller than we believe or any approval we obtain is based on a narrower definition of the patient population,our business may suffer.We currently focus our product development on novel therapeutics to address unmet needs in hepatological indications and viral diseases.Our eligible patie

275、nt population,pricing estimates and available coverage and reimbursement may differ significantly from the actual market addressable by our drug candidates.Our estimates of both the number of people who have these diseases,as well as the subset of people with these diseases who have the potential to

276、 benefit from treatment with our drug candidates,are based on our beliefs and analyses based on a variety of sources,including scientific literature,patient foundations or market research,and may prove to be incorrect.Further,new studies may change the estimated incidence or prevalence of the diseas

277、es we are targeting.The number of patients may turn out to be lower than expected,and the potentially addressable patient population for each of our drug candidates may be limited or may not be receptive to treatment with our drug candidates,and new patients may become increasingly difficult to iden

278、tify or access.Certain potential patients may have or develop a resistance to our potential therapies or otherwise be unable to be treated with our potential therapies for HBV,COVID-19 or other viral diseases as a result of their genetic makeup.In addition,the route of administration for our potenti

279、al therapies could be inconvenient and/or not commercially viable,which could also limit the potential market for our therapies.If the market opportunities for our drug candidates are smaller than we estimate,it could have an adverse effect on our business,financial condition,results of operations a

280、nd prospects.For example,we believe MASH to be one of the most prevalent chronic liver diseases worldwide,however,our projections of the number of people who have MASH,as well as the subset of people with the disease who have the potential to benefit from treatment with our drug candidates,are based

281、 on our beliefs and estimates.The effort to identify patients with MASH is in early stages,and we cannot accurately predict the number of patients for whom treatment might be possible.MASH is often undiagnosed and may be left undiagnosed for a long time,partly because a definitive diagnosis of MASH

282、is currently based on a histological assessment of a liver biopsy,which impairs the ability to easily identify patients.If improved diagnostic techniques for identifying MASH patients who will benefit from treatment are not developed,our market opportunity may be smaller than we currently anticipate

283、.Further,if government authorities and third-party payors choose to limit coverage and reimbursement of our MASH drug candidate,such as limiting the number of patients treatment that would be covered and reimbursable,this could result in a smaller market opportunity for our MASH drug candidate than

284、we anticipate.In addition,the number of people who have HBV,as well as the subset of people with the disease who have the potential to benefit from treatment with our drug candidates,may be reduced due to factors including the genotype or variant of HBV,more widespread use of vaccines or alternative

285、 therapies,political roadblocks to approval and/or treatment in certain countries and the viruss development of resistance to our potential treatments after long-term and persistent exposure to antiviral therapy.We intend to develop our current drug candidates,and expect to develop other future drug

286、 candidates,in combination with other therapies,which exposes us to additional risks.We intend to develop our current drug candidates,and expect to develop other future drug candidates,in combination with one or more therapies,including therapies that we develop and those developed externally.Even i

287、f a drug candidate we develop were to receive marketing approval or be commercialized for use in combination with other therapies,we would face the risk that the FDA or similar regulatory authority outside of the United States could revoke approval of the therapy used in combination with our drug ca

288、ndidate or that safety,efficacy,manufacturing or supply issues could arise with these other therapies.Combination therapies are commonly used for the treatment of viral diseases and it is generally believed they will be required for MASH,and we would be subject to similar risks if we develop any of

289、our drug candidates for use in combination with other drugs.This could result in our own products,if approved,being removed from the market or suffering commercially.In addition,we may 48evaluate our current drug candidates and other future drug candidates in combination with one or more other thera

290、pies that may have not yet been approved for marketing by the FDA or similar regulatory authorities outside of the United States.We will not be able to market and sell any drug candidate we develop in combination with any such unapproved therapies that do not ultimately obtain marketing approval.If

291、the FDA or similar regulatory authorities outside of the United States do not approve these other drugs or revoke their approval of,or if safety,efficacy,manufacturing,or supply issues arise with,the drugs we choose to evaluate in combination with or any of our drug candidate,we may be unable to obt

292、ain approval of or market any of our combination treatments.We face significant competition,and if our competitors develop and market products that are more effective,safer or less expensive than the drug candidates we develop,our commercial opportunities will be negatively impacted.The life science

293、s industry is highly competitive.We are currently developing therapies that will compete,if approved,with other products and therapies that currently exist or are being developed.Products we may develop in the future are also likely to face competition from other products and therapies,some of which

294、 we may not currently be aware of.We have competitors both in the United States and internationally,including major multinational pharmaceutical companies,established biotechnology companies,specialty pharmaceutical companies,universities and other research institutions.Many of our competitors have

295、significantly greater financial,manufacturing,marketing,product development,technical and human resources than we do.Large pharmaceutical companies,in particular,have extensive experience in clinical testing,obtaining marketing approvals,recruiting patients and manufacturing pharmaceutical products.

296、These companies also have significantly greater research and marketing capabilities than we do and may also have products that have been approved or are in late stages of development,and collaborative arrangements in our target markets with leading companies and research institutions.Established pha

297、rmaceutical companies may also invest heavily to accelerate discovery and development of novel compounds or toin-license novel compounds that could make the drug candidates that we develop obsolete.Further,mergers and acquisitions in the pharmaceutical and biotechnology industries may result in even

298、 more resources being concentrated among a smaller number of our competitors.As a result of all of these factors,our competitors may succeed in obtaining patent protection and/or marketing approval or discovering,developing and commercializing products in our field before we do.Current FDA-approved

299、treatments for chronic HBV infection include peg-IFN,marketed by Roche Holding AG(Roche),and oral antiviral agents such as nucleoside analogs,marketed by Gilead Sciences,Inc.(Gilead)and Bristol-Myers Squibb Company.These treatments do not lead to either a functional or a complete cure in the vast ma

300、jority of patients,and in the case of nucleoside analogs,may require life-long treatment.Several large and small pharmaceutical companies are developing programs with various mechanisms of action,to be used alone or in combination,with the goal of achieving higher rates of viral suppression or funct

301、ional cure in patients with CHB.Companies with oligonucleotide agents in clinical development include Arbutus Biopharma Corporation,Ionis Pharmaceuticals,Inc.(together with GlaxoSmithKline plc(GSK),Arrowhead Pharmaceuticals,Inc.(together with Janssen Pharmaceuticals,Inc.(Janssen),and Vir Biotechnolo

302、gy,Inc.(together with Alnylam Pharmaceuticals,Inc.).Several companies are developing CAM-Es,including Assembly Biosciences Inc.and Enanta Pharmaceuticals.Several companies,including GSK and Janssen,are developing therapeutic vaccines for HBV,and several others have approved HBV vaccines,including Dy

303、navax Technologies,Inc.,GSK,Johnson&Johnson,and Merck.Replicor,Inc.is developing nucleic acid polymers(NAPs)for use in CHB patients.There is one currently FDA-approved THR-b agonist treatment for MASH by Madrigal Pharmaceuticals,Inc.A number of pharmaceutical companies,including AbbVie,Inc.,AstraZen

304、eca PLC/MedImmune LLC,BristolMyers Squibb Company,Eli Lilly and Company,Merck,Pfizer,Inc.,Novo Nordisk,as well as large and small biotechnology companies such as 89bio,Inc.,Akero Therapeutics,Inc.,Gilead,Inventiva Pharma SA,MediciNova,Inc.,and Viking Therapeutics,Inc.are pursuing the development or

305、marketing of pharmaceuticals that target MASH.In addition to remdesivir,which is FDA-approved,on December 22,2021,Pfizer,Inc.received approval from the FDA for Paxlovid,an orally administered SARS-CoV-2 protease inhibitor coadministered with ritonavir.Similarly,Merck(together with Ridgeback Bio),is

306、developing the drug molnupiravir,an oral antiviral drug which has been issued an emergency use authorization by the FDA on December 23,2021.Several drugs are likely being used off-label for treatment,such as dexamethasone.Several approved drugs are being studied for their utility in 49reducing the s

307、everity of SARS-CoV-2 infections,including Soliris by Alexion Pharmaceuticals Inc.and Jakafi by Incyte Corporation.There are significant efforts globally to develop both therapeutic and prophylactic drug candidates including by Enanta Pharmaceuticals and Shionogi.Several companies are focused on ant

308、ibody treatments,including Regeneron Pharmaceuticals,Inc.and Vir Biotechnology,Inc.(together with GSK,Biogen Inc.and WuXi Biologics Ltd.).The availability of such COVID-19 vaccines and each of Pfizers and Mercks oral COVID-19 drug may reduce or eliminate the need for our potential COVID-19 therapies

309、 to treat the disease and therefore negatively impact the commercial opportunity.Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products that are safer,more effective,have fewer or less severe effects,are more convenient,have a broader label,ar

310、e marketed more effectively,including gaining exclusivity for their competing products on formularies thereby excluding our products from such formularies,are reimbursed or are less expensive than any products that we may develop.Our competitors also may obtain FDA,EMA or other marketing approval fo

311、r their products more rapidly than we may obtain approval for ours(if at all),which could result in our competitors establishing a strong market position before we are able to enter the market(if ever).Even if the drug candidates we develop achieve marketing approval,they may be priced at a signific

312、ant premium over competitive products,resulting in reduced competitiveness of our products.Smaller and other early stage companies may also prove to be significant competitors.In addition,academic research departments and public and private research institutions may be conducting research on compoun

313、ds that could prove to be competitive.These third parties compete with us not only in drug candidate development,but also in recruiting and retaining qualified scientific and management personnel,establishing clinical trial sites and patient registration for clinical trials,as well as in acquiring a

314、nd/or licensing technologies complementary to,or necessary for,our programs.In addition,the biopharmaceutical industry is characterized by rapid technological change.If we fail to keep pace with technological change,we may be unable to compete effectively.Technological advances or products developed

315、 by our competitors may render our drug candidates obsolete,less competitive or not economical,thereby adversely affecting our business,financial condition and results of operations.If any of our current or future drug candidates obtain regulatory approval,additional competitors could enter the mark

316、et with generic versions of such products,which may result in a material decline in sales of our competing products.Under the Drug Price Competition and Patent Term Restoration Act of 1984,or the Hatch-Waxman Amendments to the FDCA,a pharmaceutical manufacturer may file an abbreviated new drug appli

317、cation(an ANDA)seeking approval of a generic version of an approved innovator product.Under the Hatch-Waxman Amendments,a manufacturer may also submit an NDA under section 505(b)(2)of the FDCA that references the FDAs prior approval of the innovator product.A 505(b)(2)NDA product may be for a new or

318、 improved version of the original innovator product.The Hatch-Waxman Amendments also provide for certain periods of regulatory exclusivity,which preclude FDA approval(or in some circumstances,FDA filing and review)of an ANDA or 505(b)(2)NDA.In addition to the benefits of regulatory exclusivity,an in

319、novator NDA holder may have patents claiming the active ingredient,product formulation or an approved use of the drug,which would be listed with the product in the FDA publication“Approved Drug Products with Therapeutic Equivalence Evaluations,”known as the Orange Book.If there are patents listed in

320、 the Orange Book for a product,a generic or 505(b)(2)applicant that seeks to market its product before expiration of the patents must include in their applications what is known as a“Paragraph IV”certification,challenging the validity or enforceability,or claiming non-infringement,of the listed pate

321、nt or patents.Notice of the certification must be given to the patent owner and NDA holder and if,within 45 days of receiving notice,either the patent owner or NDA holder sues for patent infringement,approval of the ANDA or 505(b)(2)NDA is stayed for up to 30 months.Accordingly,if any of our future

322、drug candidates are approved,competitors could file ANDAs for generic versions of these products or 505(b)(2)NDAs that reference our products.If there are patents listed for such drug products in the Orange Book,those ANDAs and 505(b)(2)NDAs would be required to include a certification as to each li

323、sted patent indicating whether the ANDA applicant does or does not intend to challenge the patent.We cannot predict which,if any,patents in our current portfolio or patents we may obtain in the future will be eligible for 50listing in the Orange Book,how any generic competitor would address such pat

324、ents,whether we would sue on any such patents or the outcome of any such suit.We may not be successful in securing or maintaining proprietary patent protection for products and technologies we develop or license,despite expending a significant amount of resources that could have been focused on othe

325、r areas of our business.Moreover,if any of our owned or in-licensed patents that are listed in the Orange Book are successfully challenged by way of a Paragraph IV certification and subsequent litigation,the affected product could immediately face generic competition and its sales would likely decli

326、ne rapidly and materially.Even if we are able to commercialize any drug candidates,such products may become subject to unfavorable pricing regulations or third-party coverage and reimbursement policies,which would harm our business.The regulations that govern marketing approvals,pricing and reimburs

327、ement for new products vary widely from country to country.Some countries require approval of the sale price of a product before it can be marketed.In many countries,the pricing review period begins after marketing approval is granted.In some foreign markets,prescription pharmaceutical pricing remai

328、ns subject to continuing governmental control even after initial approval is granted.As a result,we might obtain marketing approval for a drug candidate in a particular country,but then be subject to price regulations that delay our commercial launch of the drug candidate,possibly for lengthy time p

329、eriods,and negatively impact the revenues we are able to generate from the sale of the drug candidate in that country,potentially to the point of unviability.Adverse pricing limitations may hinder our ability to recoup our investment in one or more drug candidates,even if our drug candidates obtain

330、marketing approval.Our ability to successfully commercialize any drug candidates,whether as a single agent or in combination,will also depend in part on the extent to which coverage and reimbursement for these drug candidates and related treatments is available from government authorities,private he

331、alth insurers and other organizations.Government authorities and third-party payors,such as private health insurers and health maintenance organizations,decide which medications they will pay for and establish reimbursement levels.It is difficult to predict at this time what government authorities a

332、nd third-party payors may decide with respect to coverage and reimbursement for our programs(if approved).A primary trend in the U.S.healthcare industry and elsewhere is cost containment.Government authorities,particularly in the European Union,and third-party payors have attempted to control costs

333、by limiting coverage and the amount of reimbursement for particular products and requiring substitutions of generic products and/or biosimilars.Increasingly,third-party payors are scrutinizing the prices charged for drugs.We cannot be sure that coverage will be available for any drug candidate that we commercialize and,if coverage is available,the level of reimbursement.These government authoritie