BiomX Inc. (PHGE) 2024年年度報告「NYSE」.pdf

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1、 UNITED STATESSECURITIES AND EXCHANGE COMMISSIONWashington,D.C.20549 FORM 10-K 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 UNDER SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1934 For the t

2、ransition period from _ to _ Commission file number:0001-38762 BIOMX INC.(Exact name of registrant as specified in its charter)Delaware 82-3364020(State or other jurisdiction ofincorporation or organization)(I.R.S.EmployerIdentification No.)22 Einstein St.,Floor 4,Ness Ziona,Israel 7414003(Address o

3、f principal executive offices)(Zip Code)Registrants telephone number,including area code:+972 723942377 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,$0.0001 par value PHGE NYSE American Securities

4、 registered pursuant to Section 12(g)of the Act:None Indicate by check mark if the registrant is a well-known seasoned issuer,as defined in Rule 405 of the Securities Act.Yes No Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d)of the Exc

5、hange Act.Yes No Indicate by check mark whether the registrant(1)has filed all reports required by Section 13 or 15(d)of the Securities Exchange Act of 1934 during the preceding 12 months(or for such shorter period that the registrant was required to file such reports),and(2)has been subject to such

6、 filing requirements for the past 90 days.Yes No Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T(232.405 of this chapter)during the preceding 12 months(or for such shorter period th

7、at the registrant was required to submit such files).Yes No Indicate by check mark whether the registrant is a large accelerated filer,an accelerated filer,a non-accelerated filer,a smaller reporting company,or an emerging growthcompany.See the definitions of“large accelerated filer,”“accelerated fi

8、ler,”“smaller reporting company,”and“emerging growth company”in Rule 12b-2 of the ExchangeAct.Large accelerated filerAccelerated filerNon-accelerated filerSmaller reporting company Emerging Growth Company If an emerging growth company,indicate by check mark if the registrant has elected not to use t

9、he extended transition period for complying with any new or revised financialaccounting standards provided pursuant to Section 13(a)of the Exchange Act.Indicate by check mark whether the registrant has filed a report on and attestation to its managements assessment of the effectiveness of its intern

10、al control over financialreporting under Section 404(b)of the Sarbanes-Oxley Act(15 U.S.C.7262(b)by the registered public accounting firm that prepared or issued its audit report.If securities are registered pursuant to Section 12(b)of the Act,indicate by check mark whether the financial statements

11、of the registrant included in the filing reflect thecorrection of an error to previously issued financial statements.Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by any of theregistrants exec

12、utive officers during the relevant recovery period pursuant to 240.10D-1(b).Indicate by check mark whether the registrant is a shell company(as defined in Rule 12b-2 of the Exchange Act).Yes No On June 30,2024,the last day of the Registrants most recently completed second fiscal quarter,the aggregat

13、e market value of the Registrants shares of Common Stock heldby non-affiliates of the Registrant was$21,392,018 based on the closing sale price of the Registrants shares of Common Stock on June 28,2024(the last trading day of thefiscal quarter)of$3.36 per share.The price of the Registrants shares of

14、 Common Stock was retroactively adjusted to reflect a 1-for-10 reverse stock split,which took effect onAugust 26,2024.The number of shares outstanding of the Registrants shares of Common Stock as of March 20,2025 was 24,966,053.DOCUMENTS INCORPORATED BY REFERENCE Portions of the registrants definiti

15、ve proxy statement to be filed with the Securities and Exchange Commission pursuant to Regulation 14A under the Securities Exchange Actof 1934,as amended,relating to the registrants 2025 Annual Meeting of Stockholders are incorporated herein by reference into Part III of this Annual Report on Form 1

16、0-K.The definitive proxy statement will be filed with the Securities and Exchange Commission not later than 120 days after the registrants fiscal year ended December 31,2024.BIOMX INC.Annual Report on Form 10-K for the Year Ended December 31,2024 PART I ITEM 1.BUSINESS1 ITEM 1A.RISK FACTORS28 ITEM 1

17、B.UNRESOLVED STAFF COMMENTS70 ITEM 1C.CYBERSECURITY70 ITEM 2.PROPERTIES70 ITEM 3.LEGAL PROCEEDINGS70 ITEM 4.MINE SAFETY DISCLOSURES70PART II ITEM 5.MARKET FOR REGISTRANTS COMMON EQUITY,RELATED STOCKHOLDER MATTERS AND ISSUER PURCHASES OF EQUITYSECURITIES71 ITEM 6.RESERVED71 ITEM 7.MANAGEMENTS DISCUSS

18、ION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS72 ITEM 7A.QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK85 ITEM 8.FINANCIAL STATEMENTS AND SUPPLEMENTARY DATA85 ITEM 9.CHANGES IN AND DISAGREEMENTS WITH ACCOUNTANTS ON ACCOUNTING AND FINANCIAL DISCLOSURE85 ITEM 9A.CONTROLS

19、 AND PROCEDURES86 ITEM 9B.OTHER INFORMATION86 ITEM 9C.DISCLOSURE REGARDING FOREIGN JURISDICIONS THAT PREVENT INSPECTIONS86PART III ITEM 10.DIRECTORS,EXECUTIVE OFFICERS AND CORPORATE GOVERNANCE87 ITEM 11.EXECUTIVE COMPENSATION93 ITEM 12.SECURITY OWNERSHIP OF CERTAIN BENEFICIAL OWNERS AND MANAGEMENT A

20、ND RELATED STOCKHOLDER MATTERS98 ITEM 13.CERTAIN RELATIONSHIPS AND RELATED TRANSACTIONS,AND DIRECTOR INDEPENDENCE101 ITEM 14.PRINCIPAL ACCOUNTANT FEES AND SERVICES103PART IV ITEM 15.EXHIBITS AND FINANCIAL STATEMENT SCHEDULES104 ITEM 16.FORM 10-K SUMMARY106 i On March 15,2024,BiomX Inc.acquired Adapt

21、ive Phage Therapeutics,Inc.,a Delaware corporation,or APT,and such acquisition,or the Acquisition,pursuant to anagreement and plan of merger,or the Merger Agreement,by and among BiomX Inc.,APT,BTX Merger Sub I,Inc.,a Delaware corporation,and BTX Merger Sub II,LLC,aDelaware limited liability company.

22、References in this Annual Report on Form 10-K,or the Annual Report to the“Company,”“BiomX,”“we,”“us”or“our”mean BiomXInc.and its consolidated subsidiaries,including APT,unless otherwise expressly stated or the context indicates otherwise,provided,however,that the financial information asof and for t

23、he year ended December 31,2023 and other information as of a date before March 15,2024,unless noted specifically,does not include APT.References in thisAnnual Report to BiomX Ltd.mean BiomX Ltd.,our wholly owned Israeli subsidiary.The description of the Company herein describes the post Acquisition

24、Company andreflects the integration of APTs business.All share amounts included in this Annual Report have been retroactively adjusted to reflect a 1-for-10 reverse stock split,which took effect on August 26,2024.CAUTIONARY STATEMENT REGARDING FORWARD-LOOKING STATEMENTS This Annual Report contains f

25、orward-looking statements within the meaning of Section 27A of the Securities Act of 1933,as amended,or the Securities Act,andSection 21E of the Securities Exchange Act of 1934,as amended or the Exchange Act.The statements contained in this Annual Report that are not purely historical are forward-lo

26、oking statements.Forward-looking statements include statements about our expectations,beliefs,plans,objectives,intentions,assumptions and other statements that are nothistorical facts.Words or phrases such as“anticipate,”“believe,”“continue,”“estimate,”“expect,”“intend,”“may,”“ongoing,”“plan,”“poten

27、tial,”“predict,”“project,”“will”or similar words or phrases,or the negatives of those words or phrases,may identify forward-looking statements,but the absence of these words does not necessarily mean thata statement is not forward-looking.Examples of forward-looking statements in this Annual Report

28、include,but are not limited to,statements regarding our disclosureconcerning our operations,cash flows,financial position and also regarding our preclinical and clinical development plans,the safety,tolerability and efficacy of our phagetherapy and the conducting,design,aims and timing of its precli

29、nical and clinical studies and announcing results thereof.Forward-looking statements appear in a number of places in this Annual Report including,without limitation,in the sections entitled“Managements Discussion andAnalysis of Financial Conditions and Results of Operations,”and“Business.”The risks

30、and uncertainties include,but are not limited to:the ability to generate revenues,and raise sufficient financing to meet working capital requirements;the unpredictable timing and cost associated with our approach to developing product candidates using phage technology and potential success thereof;p

31、olitical,economic and military instability in the State of Israel,additional potential conflicts with other Middle Eastern countries and the continuation of theproposed judicial and other legislation reform by the Israeli government;political and economic instability,including,without limitation,due

32、 to natural disasters or other catastrophic events,such as the Russian invasion of Ukraine andworld sanctions on Russia,Belarus,and related parties,terrorist attacks,hurricanes,fire,floods,pollution and earthquakes;obtaining U.S.Food and Drug Administration,or FDA,acceptance of any non-U.S.clinical

33、trials of product candidates;our ability to enroll patients in clinical trials and achieve anticipated development milestones when expected;the ability to pursue and effectively develop new product opportunities and acquisitions and to obtain value from such product opportunities and acquisitions;pe

34、nalties and market withdrawal associated with any unanticipated problems with product candidates and failure to comply with labeling and other restrictions;general economic conditions,our current low stock price and other factors on our operations,the continuity of our business,including our preclin

35、ical and clinicaltrials,and our ability to raise additional capital;expenses associated with compliance with ongoing regulatory obligations and successful continuing regulatory review;market acceptance of our product candidates and ability to identify or discover additional product candidates;ii our

36、 ability to obtain high titers for specific phage cocktails necessary for preclinical and clinical testing;the availability of specialty raw materials and global supply chain challenges;the ability of our product candidates to demonstrate requisite,safety and efficacy for drug products,or safety,pur

37、ity and potency for biologics without causingadverse effects;the success of expected future advanced clinical trials of our product candidates;our ability to obtain required regulatory approvals;delays in developing manufacturing processes for our product candidates;competition from similar technolo

38、gies,products that are more effective,safer or more affordable than our product candidates or products that obtain marketingapproval before our product candidates;the impact of unfavorable pricing regulations,third-party reimbursement practices or healthcare reform initiatives on our ability to sell

39、 product candidates ortherapies profitably;protection of our intellectual property rights and compliance with the terms and conditions of current and future licenses with third parties;infringement on the intellectual property rights of third parties and claims for remuneration or royalties for assi

40、gned service invention rights;our ability to acquire,in-license or use proprietary rights held by third parties necessary to our product candidates or future development candidates;ethical,legal and social concerns about synthetic biology and genetic engineering that may adversely affect market acce

41、ptance of our product candidates;reliance on third-party collaborators;our ability to attract and retain key employees or to enforce the terms of noncompetition agreements with employees;the failure to comply with applicable laws and regulations other than drug manufacturing compliance;potential sec

42、urity breaches,including cybersecurity incidents;and other factors discussed in the section of this report entitled“Risk Factors”beginning on page 28.Forward-looking statements are subject to known and unknown risks and uncertainties and are based on our managements potentially inaccurate assumption

43、s thatcould cause actual results to differ materially from those expected or implied by the forward-looking statements.While these statements are based upon information available tous as of the filing date of this Annual Report,and while we believe such information forms a reasonable basis for such

44、statements,such information may be limited orincomplete,and our statements should not be read to indicate that we have conducted an exhaustive inquiry into,or review of,all potentially available relevant information.These statements are inherently uncertain and investors are cautioned not to unduly

45、rely upon these statements.Actual results could differ materially from those anticipated inforward-looking statements for many reasons,including the factors discussed in the section of this Annual Report entitled“Risk Factors”.Except as may be required byapplicable law,we undertake no obligation to

46、publicly revise any forward-looking statement to reflect circumstances or events after the date of this Annual Report or to reflectthe occurrence of unanticipated events.You should,however,review the factors and risks we describe in the reports we will file from time to time with the U.S.Securities

47、andExchange Commission,or the SEC,after the date of this Annual Report.iii RISK FACTORS SUMMARY The summary below provides an overview of many of the risks the Company faces,and a more detailed discussion of risks can be found in Item 1A.“Risk Factors”below.You should carefully consider these risks

48、and uncertainties when investing in our securities.The principal risks and uncertainties affecting our business include,but arenot limited to,the following:We are a clinical-stage company and have incurred losses since our inception.We anticipate that we will continue to incur significant expenses,a

49、nd we willcontinue to incur significant losses for the foreseeable future.We will need to raise additional capital in the future to support our operations which may not be available at terms that are favorable to us and might causesignificant dilution to our stockholders or increase our debt towards

50、 third parties.Our financial statements contain an explanatory paragraph regarding substantial doubt about our ability to continue as a going concern,which could prevent usfrom obtaining new financing on reasonable terms or at all.We are seeking to develop product candidates using phage technology,a

51、n approach for which it is difficult to predict the potential success and time and cost ofdevelopment.To our knowledge,no bacteriophage has thus far been approved as a drug in the United States or in the European Union.Our product candidates must undergo clinical testing which may fail to demonstrat

52、e the requisite safety and efficacy for drug products,or safety,purity,andpotency for biologics,and any of our product candidates could cause adverse effects,which would substantially delay or prevent regulatory approval and/orcommercialization.We have not completed composition development of our pr

53、oduct candidates.We intend to continue to rely on our BacteriOphage Lead to Treatment,or BOLT,proprietary product platform to develop our phage therapies.Our competitiveposition could be materially harmed if our competitors develop similar platforms and develop rival product candidates.Our limited o

54、perating history compared to the long cycle of development phage based products may make it difficult to evaluate the success of our business todate and to assess our future viability.We have never generated any revenue from product sales and may never be profitable or,if achieved,may not sustain pr

55、ofitability.Results from preclinical studies of our product candidates may not be predictive of the results of clinical trials or later stage clinical development.Our product candidates are subject to significant regulatory approval requirements,which could delay,prevent or limit our ability to mark

56、et or develop ourproduct candidates.Our relationships with healthcare providers,physicians and third-party payors will be subject to applicable anti-kickback,fraud and abuse and other healthcarelaws and regulations,which could expose us to criminal sanctions,civil penalties,contractual damages,reput

57、ational harm and other consequences.iv Even if we receive regulatory approval of any product candidates for therapeutic indications,we will be subject to ongoing regulatory compliance obligations andcontinued regulatory review which may result in significant additional expense.Additionally,any of ou

58、r product candidates,if approved,could be subject tolabeling and other restrictions and market withdrawal,and we may be subject to penalties if we fail to comply with regulatory requirements or experienceunanticipated problems with our product candidates.Any products that we may develop may become s

59、ubject to unfavorable pricing regulations,third-party reimbursement practices or healthcare reform initiatives,which could make it difficult for us to sell any product candidates or therapies profitably.Ongoing health care legislative and regulatory reform measures may have a material adverse effect

60、 on our business and results of operations.The license agreements we maintain are important to our business.If we or the other parties to our license agreements fail to adequately perform under the licenseagreements,or if we or they terminate the license agreements,the development,testing,manufactur

61、e,production and sale of our phage-based therapeutic productcandidates would be delayed or terminated,and our business would be adversely affected.We are dependent on patents and proprietary technology.If we fail to adequately protect this intellectual property or if we otherwise do not have exclusi

62、vity forthe marketing of our products,our ability to commercialize products could suffer.If we infringe the rights of third parties,we could be prevented from selling products,forced to pay damages and/or royalties,and forced to defend againstlitigation.We rely on trade secrets and other forms of no

63、n-patent intellectual property protection.If we are unable to protect our trade secrets,other companies may be ableto compete more effectively against us.Changes in trade policy,including the imposition of tariffs,may adversely affect our business,results of operations and financial condition.If we

64、are sued for infringing intellectual property rights of third parties or if we are forced to engage in an interference proceeding,it will be costly and time-consuming,and an unfavorable outcome in that litigation or interference would have a material adverse effect on our business.Third-party relati

65、onships are important to our business.If we are unable to maintain our collaborations or enter into new relationships,or if these relationships arenot successful,our business could be adversely affected.Our headquarters,research and development and other significant operations are located in Israel,

66、and,therefore,our results may be adversely affected bypolitical,economic and military instability in Israel,including the recent war with Hamas and other terrorist organizations from the Gaza Strip and other MiddleEastern countries.Our product candidates rely on the availability of specialty raw mat

67、erials,which may not be available to us on acceptable terms or at all.A significant number of shares of our Common Stock are subject to issuance upon exercise of outstanding warrants,pre-funded warrants and options orconversion of our Convertible Preferred Stock,which upon exercise or conversion may

68、 result in dilution to our security holders.The market price of our Common Stock and other securities may be volatile and fluctuate substantially,which could result in substantial losses for purchasers ofour Common Stock.Our success depends,in part,on our ability to retain key executives and to attr

69、act,retain and motivate qualified personnel.v PART I ITEM 1.BUSINESS Overview We are a clinical stage product discovery company developing products using both natural and engineered phage technologies designed to target and kill specificharmful bacteria associated with chronic diseases,such as cysti

70、c fibrosis,or CF and diabetic foot osteomyelitis,or DFO.Bacteriophage or phage are bacterial,species-specific,strain-limited viruses that infect,amplify and kill the target bacteria and are considered inert to mammalian cells.By utilizing proprietary combinations of naturally occurringphage and by c

71、reating novel phage using synthetic biology,we develop phage-based therapies intended to address both large-market and orphan diseases.Based on the urgency of treating the infection(whether acute or chronic),the susceptibility of the target bacteria to phage(e.g.the ability to identify a phage cockt

72、ailthat would target a broad range of bacterial strains)and other considerations,we offer two phage-based product types:(1)Fixed cocktail therapy in this approach a single product containing a fixed number of selected phages is developed to cover a wide range of bacterial strains,thus allowing treat

73、ment of broad patient populations with the same product.Fixed cocktails are developed using our proprietary BOLT platform,in which highthroughput screening,directed evolution,and bioinformatic approaches are leveraged to produce an optimal phage cocktail.(2)Personalized therapy in this approach a la

74、rge library of phages is developed,of which single optimal phages are personally matched to treat specific patients.Matching optimal phages with patients is carried out using a proprietary phage susceptibility testing,or PST,where multiple considerations are analyzedsimultaneously allowing for an ef

75、ficient screen of the phage library while maintaining short turnaround times.In our therapeutic programs,we focus on using phage therapy to target specific strains of pathogenic bacteria that are associated with diseases.Our phage-basedproduct candidates are developed utilizing our BOLT proprietary

76、research and development platform.The BOLT platform is unique,employing cutting edge methodologies andcapabilities across disciplines including computational biology,microbiology,synthetic engineering of phage and their production bacterial hosts,bioanalytical assaydevelopment,manufacturing and form

77、ulation,to allow agile and efficient development of natural or engineered phage combinations,or cocktails.The cocktail contains phagewith complementary features and is optimized for multiple characteristics such as broad target host range,ability to prevent resistance,biofilm penetration,stability a

78、nd ease ofmanufacturing.Our goal is to develop multiple products based on the ability of phage to precisely target harmful bacteria and on our ability to screen,identify and combine differentphage,both naturally occurring and created using synthetic engineering,to develop these treatments.Our Produc

79、t Pipeline The chart below identifies our product candidates pipeline,their current status and expected timing for upcoming milestones.We do not have any products approvedor available for sale,our product candidates are still in the preclinical and clinical development stages,and we have not generat

80、ed any revenue from product sales.Ongoing Programs BX004 Treatment of Cystic Fibrosis BX004 is our therapeutic phage product candidate under development for chronic pulmonary infections caused by Pseudomonas aeruginosa,or P.aeruginosa,a maincontributor to morbidity and mortality in patients with CF.

81、Enhanced resistance to antibiotics develops,particularly in CF patients,due to extensive drug use consisting ofprolonged and repeated broad-spectrum antibiotic courses often beginning in childhood,and leading to the appearance of multidrug-resistant strains.In preclinical in vitrostudies,BX004 was s

82、hown to be active against antibiotic resistant strains of P.aeruginosa and demonstrated the ability to penetrate biofilm,an assemblage of surface-associated microbial cells enclosed in an extracellular polymeric substance and one of the leading causes for antibiotic resistance.1 The Phase 1b/2a tria

83、l in CF patients with chronic respiratory infections caused by P.aeruginosa.was comprised of two parts.The study design was based onrecommendations from the Cystic Fibrosis Therapeutic Development Network.In February 2023,we announced positive results from Part 1 of the Phase 1b/2a trial evaluating

84、BX004.Part 1 evaluated the safety,tolerability,pharmacokinetics,orPK,and microbiologic activity of BX004 over a 7-day ascending treatment period in nine CF patients(7 on BX004,2 on placebo)with chronic P.aeruginosa pulmonaryinfection in a single ascending dose and multiple dose design.Results from P

85、art 1 of the Phase 1b/2a trial included the following findings:No safety events related to treatment with BX004 occurred;Mean P.aeruginosa colonyforming units,or CFU,at Day 15(compared to baseline):-1.42 log(BX004)vs.-0.28 log(placebo).This reduction was seen on top of standard of care inhaled antib

86、iotics;Phage were detected in all patients treated with BX004 during the dosing period,including in several patients up to Day 15(one week after end of therapy);no phage weredetected in patients receiving placebo;there was no evidence of treatment-related resistance to BX004 during or after treatmen

87、t,compared to placebo;and as expected due tothe short duration of treatment,there was no detectable effect on%predicted forced expiratory volume in 1 second,or FEV1.In November 2023,we announced positive topline results from Part 2 of the Phase 1b/2a trial evaluating BX004.The objectives of Part 2 o

88、f the Phase 1b/2a trial wereto evaluate the safety and tolerability of BX004 in a larger number of CF patients dosed for a longer treatment duration than Part 1 of the study,with the anticipation that thelonger treatment might result in greater effects than in the Part 1.In Part 2,34 CF patients wer

89、e randomized in a 2:1 ratio with 23 CF patients receiving BX004 and 11 patientsreceiving placebo via nebulization twice daily for 10 days.Key results from Part 2 of the Phase 1b/2a trial included the following findings:Study drug was safe and well-tolerated,with no related SAEs(serious adverse event

90、s)or related APEs(acute pulmonary exacerbations)to study drug.In the BX004 arm,3 out of 21(14.3%)patients with quantitative CFU at baseline converted to sputum culture negative for P.aeruginosa after 10 days oftreatment(including 2 patients after 4 days)compared to 0 out of 10(0%)in the placebo arm.

91、BX004 vs.placebo showed a positive clinical effect in a predefined subgroup of patients with reduced baseline lung function(FEV170%).Difference betweengroups at Day 17:relative FEV1 improvement of 5.67%(change from baseline+1.46 vs.-4.21)and+8.87 points in Cystic Fibrosis Questionnaire-Revised(CFQR)

92、respiratory symptom scale(change from baseline+2.52 vs.-6.35).In full population,BX004 vs.placebo P.aeruginosa levels were more variable in sputum,potentially driven by aligning initiation of study drug administrationwith the initiation of standard of care antibiotic treatment regimen.In a prespecif

93、ied subgroup of patients on standard of care inhaled antibiotics on continuousregimen,BX004 vs.placebo reduced sputum P.aeruginosa levels at Day 10:difference in change from baseline between groups of-2.8 log10 CFU/g sputum(change from baseline-2.91 vs-0.11),exceeding Part 1 results.Alternating/cycl

94、ing background antibiotic regimen likely associated with fluctuations in P.aeruginosa levels potentially confounding the ability to observe a P.aeruginosa reduction in this subgroup.During the study period,based on current available data,no evidence of treatment-related phage resistance was observed

95、 in patients treated with BX004 comparedto placebo.In August 2023,the FDA granted BX004 Fast Track designation for the treatment of chronic respiratory infections caused by P.aeruginosa bacterial strains in patientswith CF.In addition,in December 2023,BX004 received orphan drug designation from the

96、FDA.BiomX expects to initiate a randomized,double blind,placebo-controlled,multi-center Phase 2b study in CF patients with chronic P.aeruginosa pulmonary infectionsin the second quarter of 2025.The study is designed to enroll approximately 60 patients randomized at a 2:1 ratio to BX004 or placebo.Tr

97、eatment is expected to beadministered via inhalation twice daily for a duration of 8 weeks.The study is designed to monitor the safety and tolerability of BX004 and is designed to demonstrateimprovement in microbiological reduction of P.aeruginosa burden and evaluation of effects on clinical paramet

98、ers such as lung function measured by FEV1 and patientreported outcomes.BX004 Phase 2b topline results are anticipated in the first quarter of 2026.BiomX has been in communication with the FDA and additional regulatory agencies regarding the potential to use Real-World Evidence,or RWE,to explore the

99、 linkbetween P.aeruginosa reduction and improved clinical outcomes.RWE is clinical evidence on the usage,benefits,or risks of a medical product derived from real-world data,which includes sources such as electronic health records,claims data,patient registries,wearable devices,and observational stud

100、ies.We anticipate further discussion with theFDA and European Committee for Medicinal Products for Human Use,or CHMP,in 2025 to discuss our proposed plan to use RWE to support potential future regulatoryfilings.2 BX211 Treatment of Diabetic Foot Osteomyelitis(DFO)BX211 is a phage therapy for the tre

101、atment of DFO associated with Staphylococcus aureus,or S.aureus.The personalized phage treatment tailors a specific phageselected from a proprietary phage-bank according to the specific strain of S.aureus biopsied and isolated from each patient.DFO is a bacterial infection of the bone that usuallyde

102、velops from an infected foot ulcer and is a leading cause of amputation in patients with diabetes.We believe that scientific literature demonstrating the potential benefit intreating osteomyelitis using phage in animal models as well as numerous successful compassionate cases using phage therapy to

103、treat DFO patient support our approach ofusing phage therapy to treat DFO.The randomized,double-blind,placebo-controlled,multi-center phase 2 study investigating the safety,tolerability,and efficacy of BX211 for subjects with DFOassociated with S.aureus enrolled 41 subjects randomized at a 2:1 ratio

104、 to BX211 or placebo.BX211 or placebo is designed to be administered weekly,by topical andintravenous,or IV route at week 1 and by the topical route only at each of weeks 2-12.Over the 12-week treatment period,all subjects will be treated in accordance withstandard of care which includes antibiotic

105、treatment as appropriate.Readout of study topline results is expected at week 13 evaluating healing of the wound associated withosteomyelitis,and is expected in the first quarter of 2025.Non-CF Bronchiectasis,or NCFB NCFB is a chronic,progressive inflammatory lung disease characterized by permanent

106、dilation of the bronchi.Affecting over 1 million diagnosed patients across theUS,Europe,and Japan(according to Weycker,Chron Respir Dis.2017,Quint,European Respiratory Journal,2016,Ringshausen,European Respiratory Journal,2019,Henkle,Chest,2018,Asakura,American Journal of Respiratory and Critical Ca

107、re Medicine 2024,Insmed Commercial Presentation June 4th,2024),NCFB is caused by multipleetiologies but manifests with similar debilitating symptoms,including chronic cough,sputum production,and recurrent infections.Chronic P.aeruginosa infections in NCFBpatients are a main contributor to morbidity

108、and mortality in this disease.In preclinical in vitro studies,BX004 was shown to be active against antibiotic resistant strains of P.aeruginosa and demonstrated the ability to penetrate biofilm,an assemblage of surface-associated microbial cells enclosed in an extracellular polymeric substance and o

109、ne ofthe leading causes for antibiotic resistance.Pending positive data of BX004 in our CF Phase 2b study,we will explore the feasibility of a Phase 2 study in NCFB as an additional indication for BX004.National Institutes of Health,or NIH study in Cystic Fibrosis We are supporting a study conducted

110、 by the NIH and The Antibacterial Resistance Leadership Group targeting P.Aeruginosa infections in CF patients under FDAemergency Investigational New Drug,or eIND,allowance.The Phase 1b/2,multi-centered,randomized,double-blind,placebo-controlled trial is assessing the safety andmicrobiological activ

111、ity of a single IV dose of bacteriophage therapy in cystic fibrosis subjects colonized with P.aeruginosa.Programs on hold Prosthetic Joint Infections,or PJI Our personalized phage therapy for treating PJI targets multiple bacterial organisms such as Staphylococcus aureus,Staphylococcus epidermidis a

112、nd Enterococcusfaecium.This treatment was granted Orphan-drug designation by the FDA in July 2020.As of the date of this Annual Report,we have paused development efforts of thisprogram due to prioritizing resources towards our CF and DFO programs,and we cannot provide guidance on resuming its develo

113、pment.Discontinued programs BX005 Treatment of Atopic Dermatitis,or AD BX005 is our topical phage product candidate targeting Staphylococcus aureus,or S.aureus,a bacterium associated with the development and exacerbation ofinflammation in AD.S.aureus is more abundant on the skin of AD patients than

114、on the skin of healthy individuals and on lesional skin than non-lesional skin.It also increasesin abundance,becoming the dominant bacteria,when patients experience flares.By reducing the load of S.aureus,BX005 is designed to shift the skin microbiome compositionto its pre-flare state and potentiall

115、y provide a clinical benefit.In preclinical in vitro studies,BX005 was shown to eradicate over 90%of strains,including antibiotic resistantstrains,from a panel of S.aureus strains(120 strains isolated from skin of subjects from the U.S.and Europe).On April 8,2022,the FDA approved the CompanysInvesti

116、gational New Drug,or IND,application for BX005.In 2024,we discontinued the development of BX005,choosing instead to focus our resources on our Cystic Fibrosis and DFO programs.3 Our Strategy Our goal is to develop multiple products based on the ability of phage to precisely target harmful bacteria a

117、nd on our ability to screen,identify and optimally combinedifferent phage,both naturally occurring and generated using synthetic engineering,to develop these treatments.We intend to continue to:Investigate clinical safety and efficacy of our lead phage-based product candidates to treat CF and DFO;Id

118、entify new pathogenic bacteria to be targeted by phage therapy for our existing indications and possible new indications;and Develop and partner microbiome-based biomarker tests,based on our proprietary XMarker platform,that can be used for disease diagnosis or as companiondiagnostics.Our phage disc

119、overy platform Our approach is driven by the convergence of several factors:a rapidly increasing understanding of phage,including the links between phage behaviors and theirgenomes;growing evidence that the presence of specific harmful bacteria may impact chronic diseases,such as CF,making them in p

120、rinciple,amenable to treatment withphage;and by a growing number of anecdotal reports from different academic centers of successful compassionate use of phage to treat seriously ill patients who wereunresponsive to other therapies.We believe our phage therapeutic product candidates have the potentia

121、l to treat conditions and diseases by precisely targeting pathogenicbacteria without disrupting elements of the healthy microbiota.Our phage-based product candidates,either fixed phage cocktails or personalized phage treatments,are developed utilizing our proprietary research and developmentplatform

122、s,named BOLT and PST.The BOLT,platform is unique,employing cutting edge methodologies and capabilities across disciplines including computational biology,microbiology,synthetic engineering of phage and their production bacterial hosts,bioanalytical assay development,manufacturing and formulation,to

123、allow agile and efficientdevelopment of natural or engineered phage combinations,or cocktails.The PST platform utilizes proprietary assays to allow us to screen extensive phage libraries in search of optimal phage for treatment of the specific target bacteriaisolated from a given patient.BOLT is des

124、igned to allow the rapid development of optimized phage cocktails.These cocktails may be comprised of naturally-occurring or synthetically engineeredphage.The cocktail contains phage with complementary features and is optimized for multiple characteristics such as broad target host range,ability to

125、prevent resistance,biofilm penetration,stability and ease of manufacturing.Pre-clinical development of the optimized phage cocktail is anticipated to require 1-2 years.We combine multiple technologies that originate from the laboratories of our scientific founders and that were developed internally.

126、Technologies that were developedby our scientific founders are described in leading scientific journals.One of our scientific founders,Professor Rotem Sorek,a Professor in the Department of MolecularGenetics at the Weizmann Institute of Science,or WIS,is a world leader in phage genomics and bacteria

127、l defense mechanisms.Another scientific founder,Professor EranElinav,a Professor in the Department of Immunology at the WIS,is an expert in investigating the link between the microbiome and human health and disease.Our thirdscientific founder,Professor Timothy K.Lu,is a world leader in synthetic bio

128、logy approaches to engineering gene circuits and phage,leading the Synthetic Biology Group inthe Department of Electrical Engineering and Computer Science and the Department of Biological Engineering at the Massachusetts Institute of Technology.In addition,through the acquisition of the privately he

129、ld Israel-based company,RondinX Ltd.in 2017,we gained access to high throughput genomic analyses techniques developed byProfessor Eran Segal,a leading computational biologist from the Department of Computer Science and Applied Mathematics at the WIS.The combination of the technologiesand expertise f

130、rom these leaders in each of their respective fields is critical in enabling us to focus on treating complex human diseases and conditions by precise manipulationof the microbiome.4 Additionally,we developed proprietary assays and screening technology for robust and high throughput testing PST.The P

131、ST platform combines state of the artautomation with advanced microbiology assays.The output is a reproducible conclusive decision for optimal phage matching,based on multiple factors,including success ofphage infection,suppression of resistant mutants,and antibiofilm activity.Manufacturing We have

132、developed manufacturing processes that utilize state-of-the-art industrial methods for the manufacturing of our product candidates.These processes aredesigned to comply with current Good Manufacturing Practice,or cGMP,with the appropriate scale to meet our clinical study needs,and to fulfill the req

133、uirements ofregulators for human studies.In February 2021,we consolidated our U.S.Good Manufacturing Practice,or GMP,manufacturing,testing and development into a 6,100 square feet space in ourGaithersburg facility and in March 2021,we moved into a new 6,500 square feet manufacturing facility in our

134、headquarters,in Ness Ziona,Israel.Both facilities were designedto produce clinical quantities of our product candidates required for early-stage clinical development with compliance suitable for this stage of development and to supporteIND.Currently,our use of these 2 facilities for GMP manufacturin

135、g has been put on hold while our in-house development activities continue to support our projects in otherways.The Ness Ziona facility,which has currently been put on hold but can resume GMP manufacturing,consists of two suites for drug substance phageproduction/development as well as formulation an

136、d final drug product production rooms to support topical,oral,inhaled and injectable phage-based products in a liquid,cream,semi-solid or dry form.We no longer expect to use our Gaithersburg facility for manufacturing.We currently operate a manufacturing model that combines in-house process developm

137、ent and testing with the flexibility to outsource to third-party development,manufacturing,testing,and logistics organizations,when needed.We maintain service agreements with multiple manufacturers,testing laboratories and a third-party logisticswarehouse for product candidate distribution.These ser

138、vice agreements are generally short-term in nature and can be extended or renewed.As such,for BX004,we haveengaged a third-party to supplement our in-house process development activities.We selected this organization based on its experience,capability,capacity and regulatorystatus.Manufacturing and

139、development projects are managed by a team of internal staff who assure compliance with the technical aspects and regulatory requirements of themanufacturing process.5 While we do not have a current need for a commercial scale manufacturing capacity,at the appropriate time we intend to evaluate buil

140、ding large scale cGMP internalmanufacturing capabilities,which may include expansion of our operations.Intellectual Property We strive to protect the proprietary technology that we believe is important to our business,including seeking and maintaining patent protection in the United Statesand intern

141、ationally for our product candidates and discovery platform.We also rely on trademarks,trade secrets,know-how,copyrights,continuing technological innovationand in-licensing opportunities to develop and maintain our proprietary position.For more information regarding the risks related to our intellec

142、tual property,see“Risk Factors Risks Related to our Licensed and Co-Owned Intellectual Property.”We plan to continue to expand our intellectual property estate by filing patent applications directed to formulations,related methods of treatment,methods ofmanufacture or identification from our ongoing

143、 development of our product candidates,as well as discovery based on our proprietary product platform.Our success willdepend on our ability to obtain and maintain patent and other proprietary protection for commercially important technology,inventions and know-how related to our business,defend,and

144、enforce any patents that we may obtain,preserve the confidentiality of our trade secrets and know-how and operate without infringing the valid and enforceablepatents and proprietary rights of third parties.Because patent applications in the United States and certain other jurisdictions are maintaine

145、d in secrecy for 18 months or potentially even longer,and becausepublication of discoveries in the scientific or patent literature often lags behind actual discoveries and patent application filings,we cannot be certain of the priority ofinventions covered by pending patent applications.Accordingly,

146、we may not have been the first to invent the subject matter disclosed in some of its patent applications or thefirst to file patent applications covering such subject matter,and we may have to participate in interference proceedings or derivation proceedings declared by the United StatesPatent and T

147、rademark Office,or USPTO,to determine priority of invention.Patent portfolio Our patent portfolio consists of owned patent applications,as well as both licensed and co-owned patent applications(that are also licensed).See“Risk Factors Risks Related to our Licensed and Co-Owned Intellectual Property.

148、”For some of these applications,prosecution has not started,and others are in the early stages ofprosecution in the United States and in selected jurisdictions outside of the United States.We solely own eight patent families.We co-own one US patent family with KeioUniversity in Tokyo,Japan,or Keio,o

149、ne international patent family(United States,Australia,Canada,European Patent Office national filings)with Yeda Research andDevelopment Company Limited,the technology transfer office of the WIS,or Yeda,and one international patent family(United States,Europe)with both Keio and Yeda.Wehave an exclusi

150、ve license from Yeda and Keio for these co-owned patent applications.We have exclusive licenses from Yeda or Keio for the rest of the patents and patentapplications in its portfolio.A significant portion of our portfolio is directed to CF,as well as product candidates relevant to programs which we h

151、ave stopped their development such as:AD,inflammatory bowel disease,or IBD,primary sclerosing cholangitis and colorectal cancer,or CRC,as well as to our bacterial target discovery and bacteriophage discoverytechnology platforms.Prosecution has yet to commence for most of the pending patent applicati

152、ons covering our product candidates.Prosecution is a lengthy process,duringwhich the scope of the claims initially submitted for examination by the USPTO are often significantly narrowed by the time they issue,if they issue at all.We expect this to bethe case with respect to our licensed and co-owne

153、d patent applications,described briefly below.6 In connection with the Acquisition,we further enhanced our intellectual property portfolio with the addition of APTs portfolio comprising of 7 issued or allowedpatents,19 patent families(including applications in United States,Europe,Australia,Canada,C

154、hina,India,Japan,Korea,Israel,Brazil,and South Africa).APTs patents andpatent applications consist of patents and patent applications with respect to pharmaceutical compositions and methods of treatment,methods of manufacture of suchcompositions and expire between June 2037 and October 2043.CF We so

155、lely own two patent families(one at pre-PCT stage and a second in national phase stage in United States,Australia,Canada,European Patent Office,Japan andChina)containing claims directed to pharmaceutical compositions comprising combinations of bacteriophage to treat chronic Pseudomonas lung infectio

156、ns,especially commonin CF patients,methods of use for these bacteriophage combinations,and methods of identifying patients who will respond to these bacteriophage combinations.Any UnitedStates patents issuing from the pending application covering our lead bacteriophage combination in this program,if

157、 issued,are expected to expire in 2042.Patent termadjustments or patent term extensions could result in later expiration dates.DFOAD We solely own one patent family(United States,Australia,Canada,European Patent Office and Japan)containing claims directed to pharmaceutical compositionscomprising com

158、binations of bacteriophage to treat staphylococcus aureus infections,common in patients with DFO and in AD patients,methods of use for these bacteriophagecombinations,and methods of identifying patients who will respond to these bacteriophage combinations.Any United States patents issuing from the p

159、ending applicationcovering our lead bacteriophage combination in this program,if issued,are expected to expire in 2042.Patent term adjustments or patent term extensions could result in laterexpiration dates.Patent term The term of individual patents depends upon the legal term of the patents in the

160、countries in which they are obtained.In most countries in which we file patentapplications,including the United States,the base term is 20 years from the filing date of the earliest-filed non-provisional patent application from which the patent claimspriority.The term of a United States patent can b

161、e lengthened by patent term adjustment,which compensates the owner of the patent for administrative delays at the USPTO.Insome cases,the term of a United States patent is shortened by a terminal disclaimer that reduces its term to that of an earlier-expiring patent.The term of a United States patent

162、may be eligible for patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984,referred to as the Hatch-Waxman Act,to account for atleast some of the time the drug is under development and regulatory review after the patent is granted.With regard to a drug for whi

163、ch FDA approval is the first permittedmarketing of the active ingredient,the Hatch-Waxman Act allows for extension of the term of one United States patent that includes at least one claim covering the compositionof matter of such an FDA-approved drug,an FDA-approved method of treatment using the dru

164、g and/or a method of manufacturing the FDA-approved drug.The extendedpatent term cannot exceed the shorter of five years beyond the non-extended expiration of the patent or fourteen years from the date of the FDA approval of the drug,and apatent cannot be extended more than once or for more than a s

165、ingle product.During the period of extension,if granted,the scope of exclusivity is limited to the approvedproduct for approved uses.Some foreign jurisdictions,including Europe and Japan,have analogous patent term extension provisions,which allow for extension of the term of apatent that covers a dr

166、ug approved by the applicable foreign regulatory agency.In the future,if and when our product candidates receive FDA approval,we expect to apply,if appropriate,for patent term extension on patents directed to thoseproduct candidates,their methods of use and/or methods of manufacture.However,there is

167、 no guarantee that the applicable authorities,including the FDA in the United States,will agree with our assessment of whether such extensions should be granted,and if granted,the length of such extensions.7 Trade Secrets and Know-How In addition to patents,we rely on trade secrets and know-how to d

168、evelop and maintain our competitive position.We typically rely on trade secrets to protect aspects ofour business that are not amenable to,or that we do not consider appropriate for,patent protection.We protect trade secrets and know-how by establishing confidentialityagreements and invention assign

169、ment agreements with our employees,consultants,scientific advisors,contractors and collaborators.These agreements provide that allconfidential information developed or made known during the course of an individuals or entities relationship with us must be kept confidential during and after therelati

170、onship.These agreements also provide that all inventions resulting from work performed for us or relating to our business and conceived or completed during the period ofemployment or assignment,as applicable,shall be our exclusive property.In addition,we take other appropriate precautions,such as ph

171、ysical and technological securitymeasures,to guard against misappropriation of its proprietary information by third parties.Although we take steps to protect our proprietary information and trade secrets,including through contractual means with our employees and consultants,third partiesmay independ

172、ently develop substantially equivalent proprietary information and techniques or otherwise gain access to our trade secrets or disclose our technology.Thus,wemay not be able to meaningfully protect our trade secrets and benefit from the exclusive use thereof.For more information regarding the risks

173、related to our intellectualproperty,see“Risk Factors Risks Related to Our Licensed and Co-Owned Intellectual Property.”Competition The biotechnology and pharmaceutical industries are characterized by rapidly advancing technologies,strong competition and an emphasis on proprietary products.While we b

174、elieve that our technology,knowledge and experience provide us with competitive advantages,we face substantial competition from many different sources,including larger pharmaceutical companies with more resources.Specialty biotechnology companies,academic research institutions,governmental agencies,

175、as well as publicand private institutions are also potential sources of competitive products and technologies.We believe that the key competitive factors affecting the success of any of ourproduct candidates will include efficacy,safety profile,time to market,cost,level of promotional activity and i

176、ntellectual property protection.We are aware of a number of biotechnology companies developing bacteriophage products to treat diseases.To our knowledge,several biotechnology companies,suchas Locus Biosciences,Inc.,Armata Pharmaceuticals,Inc.and SNIPR Biome,as well as academic institutions,have disc

177、overy stage or clinical programs utilizing naturallyoccurring phage or synthetic biology approaches.In addition,we are aware of several investigational and marketed products to treat the indications that we are targeting withour product candidates,including,but not limited to:CF:Trikafta,Symdeco,Pul

178、mozyme,Tobramycin,Aztreonam DFO:TP-102 being developed by Technophage,a phage-based product being developed by Phaxiam Many of our competitors,either alone or with their strategic partners,have substantially greater financial,technical and human resources than ours and significantlygreater experienc

179、e in the discovery and development of product candidates,obtaining FDA and other regulatory approvals of products and the commercialization of thoseproducts.Accordingly,our competitors may be more successful than us in discovering product candidates,obtaining approval for such product candidates and

180、 achievingwidespread market acceptance.Our competitors products may be more effective,or more effectively marketed and sold,than any product we may commercialize and mayrender our product candidates obsolete or non-competitive before we can recover the expenses of developing and commercializing any

181、of our product candidates.We anticipatethat we will face intense and increasing competition as new drugs enter the market and advanced technologies become available.These third parties compete with us in recruiting and retaining qualified scientific,clinical,manufacturing,sales and marketing and man

182、agement personnel,establishing clinical trial sites and patient registration for clinical trials,as well as in acquiring technologies complementary to,or necessary for,our program.8 Sales and Marketing We intend to pursue the commercialization of our drug product candidates either by building intern

183、al sales and marketing capabilities or through collaborations withothers.Government Regulation Government authorities in the United States and other countries regulate,among other things,the research,development,testing,manufacture,quality control,approval,labeling,packaging,storage,record-keeping,p

184、romotion,advertising,distribution,post-approval monitoring and reporting,marketing and export and import of drugand biological products.Generally,before a new drug or biologic can be studied in human clinical trials or marketed,considerable data demonstrating its quality,safety,efficacy,purity,and/o

185、r potency must be obtained,organized into a format specific for each regulatory authority,submitted for review and approved by the regulatory authoritywhere the product is intended to be studied or marketed.U.S.Biological Product Development Process In the United States,the FDA regulates drugs under

186、 the Federal Food,Drug,and Cosmetic Act,or the FDCA,and its implementing regulations under the FDCA,thePublic Health Service Act,or the PHSA,and their implementing regulations.Both drugs and biologics are also subject to other federal,state and local statutes and regulations.The process of obtaining

187、 regulatory approvals and the subsequent compliance with appropriate federal,state and local statutes and regulations requires the expenditure ofsubstantial time and financial resources.Failure to comply with applicable U.S.requirements at any time during the product development,approval,or post-mar

188、keting processmay subject an applicant to administrative or judicial sanctions.These sanctions could include,among other actions,the FDAs refusal to approve pending applications,withdrawal of an approval or license revocation,a clinical hold,untitled or warning letters,product recalls or market with

189、drawals,product seizures,total or partial suspensionof production or distribution,injunctions,fines,refusals of government contracts,restitution,disgorgement and civil or criminal penalties.Any agency or judicial enforcementaction could have a material adverse effect on us.Certain of our current pro

190、duct candidates and future product candidates must be approved by the FDA through a Biologics License Application,or BLA,processbefore they may be legally marketed in the United States.The process generally involves the following.However,the new Trump administration may change or overhaulexisting dr

191、ug regulations,which would lead to additional time and money to comply with:Completion of extensive preclinical studies in accordance with applicable regulations,including studies conducted in accordance with GLP requirements,ifneeded;Submission to the FDA of an IND,which must become effective befor

192、e human clinical trials may begin;Approval by an institutional review board,or IRB,at each clinical trial site before each trial may be initiated;Performance of adequate and well-controlled human clinical trials in accordance with applicable IND regulations,good clinical practice,or GCP,requirements

193、and other clinical trial-related regulations to establish the safety,purity,potency and efficacy of the investigational product for each proposed indication;Submission to the FDA of a BLA;A determination by the FDA within 60 days of its receipt of a BLA to accept the application for review;Satisfact

194、ory completion of an FDA pre-approval inspection of the manufacturing facility or facilities where the biologic will be produced to assess compliancewith cGMP requirements to assure that the facilities,methods and controls are adequate to preserve the biologics identity,strength,quality and purity;9

195、 Potential FDA audit of the clinical trial sites that generated the data in support of the BLA;Payment of user fees for FDA review of the BLA(unless a fee waiver applies);and FDA review and approval of the BLA,including consideration of the views of any FDA advisory committee,prior to any commercial

196、 marketing or sale of thebiologic in the United States.Preclinical Studies and IND Preclinical studies include laboratory evaluation of product chemistry and formulation,as well as in vitro and animal studies to establish a rationale for therapeutic useand in some cases to assess the potential for a

197、dverse events.The conduct of preclinical studies is subject to federal regulations and requirements,including in some cases GLPregulations for safety/toxicology studies.An IND sponsor must submit the results of the preclinical tests,together with manufacturing information,analytical data,anyavailabl

198、e clinical data or literature and plans for clinical trials,among other things,to the FDA as part of an IND.An IND is a request for authorization from the FDA toadminister an investigational product to humans,and,must become effective before human clinical trials may begin.Some long-term preclinical

199、 testing may continue after theIND is submitted.An IND automatically becomes effective 30 days after receipt by the FDA,unless before that time,the FDA raises concerns or questions related to one ormore proposed clinical trials and places the trial on clinical hold.In such a case,the IND sponsor and

200、 the FDA must resolve any outstanding concerns before the clinical trialcan begin.As a result,submission of an IND may not result in the FDA allowing clinical trials to commence.Clinical Trials Clinical trials involve the administration of the drug or biological product candidate to healthy voluntee

201、rs or disease-affected patients under the supervision ofqualified investigators,generally physicians not employed by,or under,the trial sponsors control.Clinical trials are conducted under protocols detailing,among other things,the objectives of the clinical trial,dosing procedures,subject selection

202、 and exclusion criteria,and the parameters to be used to monitor subject safety and efficacy,includingstopping rules that assure a clinical trial will be stopped if certain adverse events should occur.Each protocol and any amendments to the protocol must be submitted to theFDA as part of the IND.Cli

203、nical trials must be conducted and monitored in accordance with the FDAs regulations comprising the GCP requirements,including the requirementthat all research subjects provide informed consent.Further,each clinical trial must be reviewed and approved by an IRB at or servicing each institution at wh

204、ich the clinicaltrial will be conducted.An IRB is charged with protecting the welfare and rights of study participants and considers such items as whether the risks to individuals participatingin the clinical trials are minimized and are reasonable in relation to anticipated benefits.The IRB also ap

205、proves the form and content of the informed consent that must besigned by each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed.There are also requirements governing the reporting ofongoing clinical trials and completed clinical trial resu

206、lts to public registries.Information about certain clinical trials,including clinical trial results,must be submitted withinspecific timeframes for publication on the www.clinicaltrials.gov website.Clinical trials generally are conducted in three sequential phases,known as Phase 1,Phase 2 and Phase

207、3,and may overlap.Phase 1 clinical trials generally involve a small number of healthy volunteers or disease-affected patients who are initially exposed to a single dose and thenmultiple doses of the product candidate.The primary purpose of these clinical trials is to assess the metabolism,pharmacolo

208、gic action,side effect tolerability andsafety of the product candidate.10 Phase 2 clinical trials generally involve studies in disease-affected patients to evaluate proof of concept and/or determine the dosing regimen(s)for subsequentinvestigations.At the same time,safety and sometimes further pharm

209、acokinetic and pharmacodynamic information is collected,possible adverse effects and safetyrisks are identified and a preliminary evaluation of efficacy is conducted.Phase 3 clinical trials generally involve a large number of patients at multiple sites and are designed to provide the data necessary

210、to demonstrate the effectivenessof the product for its intended use,its safety in use and to establish the overall benefit/risk relationship of the product and provide an adequate basis for labelingfor new drugs.Post-approval trials,sometimes referred to as Phase 4 clinical trials,may be conducted a

211、fter initial marketing approval.These trials are conducted to gain additionalexperience from the treatment of patients in the intended therapeutic indication.In certain instances,the FDA may mandate the performance of Phase 4 clinical trials as acondition of approval of a BLA.Progress reports detail

212、ing the results of the clinical trials,among other information,must be submitted at least annually to the FDA and written IND safety reports mustbe submitted to the FDA and the investigators for serious and unexpected suspected adverse events,findings from other studies or animal or in vitro testing

213、 that suggest asignificant risk for human subjects and any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigatorbrochure.It is possible for Phase 1,Phase 2,Phase 3 and other types of clinical trials not to be completed succ

214、essfully within a specified period,if at all.The FDA or the sponsormay suspend or terminate a clinical trial at any time on various grounds,including a finding that the patients are being exposed to an unacceptable health risk.Similarly,an IRBcan suspend or terminate approval of a clinical trial at

215、its institution if the clinical trial is not being conducted in accordance with the IRBs requirements or if the testedbiological product has been associated with unexpected serious harm to patients.Additionally,some clinical trials are overseen by an independent group of qualified expertsorganized b

216、y the clinical trial sponsor,or the Data Safety Monitoring Board.This group provides authorization for whether a trial may move forward at designated check pointsbased on access to certain data from the trial.Concurrent with clinical trials,companies may complete additional animal studies and also m

217、ust develop additional information about the chemistry and physicalcharacteristics of the biologic as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.The manufacturingprocess must be capable of consistently producing quality batc

218、hes of the product and,among other things,companies must develop methods for testing the identity,strength,quality and purity of the final product.Additionally,appropriate packaging must be selected and tested,and stability studies must be conducted to demonstrate that the productcandidates do not u

219、ndergo unacceptable deterioration over their shelf life.11 FDA Review Process Following completion of the clinical trials,data are analyzed to assess whether the investigational product is safe and effective for the proposed indicated use or usesand also meets the regulatory requirements for potency

220、 and purity.The results of preclinical studies and clinical trials are then submitted to the FDA as part of a BLA,alongwith proposed labeling,chemistry and manufacturing information to ensure product quality and other relevant data.The BLA is a request for approval to market the biologicalproduct fo

221、r one or more specified indications and must contain proof of safety,purity and potency.The application may include both negative and ambiguous results ofpreclinical studies and clinical trials,as well as positive findings.Data may come from company-sponsored clinical trials intended to test the saf

222、ety and efficacy of a productsuse or from a number of alternative sources,including studies initiated by investigators.To support marketing approval,the data submitted must be sufficient in quality andquantity to establish the safety and efficacy in the intended indication,purity and potency of the

223、investigational product to the satisfaction of the FDA.FDA approval of a BLAmust be obtained before a biologic may be marketed in the United States.Under the Prescription Drug User Fee Act,or PDUFA,as amended,each BLA must be accompaniedby a user fee.The FDA adjusts the PDUFA user fees on an annual

224、basis.Fee waivers or reductions are available in certain circumstances,including a waiver of the applicationfee for the first application filed by a small business.Additionally,no user fees are assessed on BLAs for products designated as orphan drugs,unless the product also includes anon-orphan indi

225、cation.The FDA reviews all submitted BLAs before it accepts them for filing and may request additional information rather than accept the BLA for filing.The FDA mustmake a decision on accepting a BLA for filing within 60 days of receipt,and such a decision could include a refusal to file by the FDA.

226、Once the submission is accepted forfiling,the FDA begins an in-depth review of the BLA.Under the goals and policies agreed to by the FDA under PDUFA,the FDA has 10 months,from the filing date,in whichto complete its initial review of an original BLA and respond to the applicant,and 6 months from the

227、 filing date of an original BLA designated for priority review.The FDAdoes not always meet its PDUFA goal dates for standard and priority BLAs,and the review process is often extended by FDA requests for additional information orclarification.Before approving a BLA,the FDA will conduct a pre-approva

228、l inspection of the manufacturing facilities for the new product to determine whether they comply withcGMP requirements.The FDA will not approve the product unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements andadequate to assure consistent

229、production of the product within required specifications.The FDA also may audit data from clinical trials to ensure compliance with GCPrequirements.Additionally,the FDA may refer applications for novel products or products which present difficult questions of safety or efficacy to an advisory commit

230、tee,typically a panel that includes clinicians and other experts,for review,evaluation and a recommendation as to whether the application should be approved and under whatconditions,if any.The FDA is not bound by recommendations of an advisory committee,but it considers such recommendations when mak

231、ing decisions on approval.The FDAlikely will reanalyze the clinical trial data,which could result in extensive discussions between the FDA and the applicant during the review process.After the FDA evaluates a BLA,it will issue an approval letter,or a Complete Response Letter.An approval letter autho

232、rizes commercial marketing of the biologicwith specific prescribing information for specific indications.A Complete Response Letter indicates that the review cycle of the application is complete and the application willnot be approved in its present form.A Complete Response Letter usually describes

233、all the specific deficiencies in the BLA identified by the FDA.The Complete ResponseLetter may require additional clinical data and/or other significant and time-consuming requirements related to clinical trials,preclinical studies or manufacturing.If aComplete Response Letter is issued,the applican

234、t may either resubmit the BLA,addressing all the deficiencies identified in the letter,or withdraw the application.Even if suchdata and information are submitted,the FDA may decide that the BLA does not satisfy the criteria for approval.Data obtained from clinical trials are not always conclusive an

235、dthe FDA may interpret data differently than the sponsors interpretation of the same data.Orphan Drug Designation Under the Orphan Drug Act of 1983,or the Orphan Drug Act,the FDA may grant orphan designation to a drug or biological product intended to treat a rare disease orcondition,which is genera

236、lly a disease or condition that affects fewer than 200,000 individuals in the United States,or more than 200,000 individuals in the United States andfor which there is no reasonable expectation that the cost of developing and making the product available in the United States for this type of disease

237、 or condition will berecovered from sales of the product.Orphan drug designation for a biological product must be requested before submitting a BLA.After the FDA grants orphan drugdesignation,the identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA.orphan

238、drug designation does not convey any advantage in orshorten the duration of the regulatory review and approval process.12 Orphan drug designation entitles a party to financial incentives such as opportunities for grant funding towards clinical trial costs,tax advantages and user-fee waivers.If a pro

239、duct that has orphan designation subsequently receives the first FDA approval for the disease or condition for which it has such designation,the product is entitled toorphan drug exclusivity,which means that the FDA may not approve any other applications to market the same drug for the same indicati

240、on for seven years from the date ofsuch approval,except in limited circumstances,such as a showing of clinical superiority to the product with orphan exclusivity by means of greater effectiveness,greater safetyor providing a major contribution to patient care,or in instances of drug supply issues.Co

241、mpetitors,however,may receive approval of either a different product for the sameindication or the same product for a different indication but that could be used off-label in the orphan indication.Orphan drug exclusivity also could block the approval of oneof our products for seven years if a compet

242、itor obtains approval before we do for the same product,as defined by the FDA,for the same indication we are seeking approval,orif our product is determined to be contained within the scope of the competitors product for the same indication or disease.If one of our products designated as an orphan d

243、rugreceives marketing approval for an indication broader than that which is designated,it may not be entitled to orphan drug exclusivity.In December 2023,BX004,receivedorphan drug designation from the FDA.Expedited Development and Review Programs The FDA has a fast-track program that is intended to

244、expedite or facilitate the process for reviewing new drugs and biologics that meet certain criteria.Specifically,new drugs and biologics are eligible for fast-track designation if they are intended to treat a serious or life-threatening condition and preclinical or clinical data demonstrate thepoten

245、tial to address unmet medical needs for the condition.Fast track designation applies to the combination of the product and the specific indication for which it is beingstudied.Any product submitted to the FDA for marketing,including under a fast-track program,may be eligible for other types of FDA p

246、rograms intended to expeditedevelopment and review,such as priority review and accelerated approval.A product is eligible for priority review if it treats a serious or life-threatening condition and,ifapproved,would provide a significant improvement in safety and effectiveness compared to available

247、therapies.The FDA will attempt to direct additional resources to theevaluation of an application for a new drug or biologic designated for priority review in an effort to facilitate the review.A product may also be eligible for accelerated approval if it treats a serious or life-threatening conditio

248、n and demonstrates an effect on a surrogate endpoint that isreasonably likely to predict clinical benefit or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality,or IMM,that is reasonably likely topredict an effect on IMM or other clinical benefit.As a conditi

249、on of approval,the FDA generally requires that a sponsor of a drug or biologic receiving accelerated approvalperform adequate and well-controlled post-marketing clinical trials to demonstrate clinical benefit.Products receiving accelerated approval may be subject to expeditedwithdrawal procedures if

250、 such clinical trials fail to verify the predicted clinical benefit or if the sponsor fails to conduct such trials in a timely manner.Additionally,a drug or biologic may be eligible for designation as a breakthrough therapy if the product is intended,alone or in combination with one or more otherdru

251、gs or biologics,to treat a serious or life-threatening condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement overcurrently approved therapies on one or more clinically significant endpoints.The benefits of breakthrough therapy designation incl

252、ude the same benefits as fast-trackdesignation,plus intensive guidance from the FDA to ensure an efficient drug development program.Even if a product qualifies for one or more of these programs,the FDA may later decide that the product no longer meets the conditions for qualification or the timeperi

253、od for FDA review or approval may not be shortened.Furthermore,fast track designation,priority review,accelerated approval and breakthrough therapy designation donot change the standards for approval,but may expedite the development or approval process.13 Pediatric Information Under the Pediatric Re

254、search Equity Act of 2003,or PREA,a BLA or supplement to a BLA must contain data to assess the safety and efficacy of the biologic for theclaimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is sa

255、fe andeffective.The FDA may grant deferrals for submission of pediatric data or full or partial waivers.A sponsor who is planning to submit a marketing application for a drug thatincludes a new active ingredient,new indication,new dosage form,new dosing regimen or new route of administration must su

256、bmit an initial Pediatric Study Plan,or PSP,within 60 days of an end-of-Phase 2 meeting or,if there is no such meeting,as early as practicable before the initiation of the Phase 3 or Phase 2/3 study.The initial PSP mustinclude an outline of the pediatric study or studies that the sponsor plans to co

257、nduct,including study objectives and design,age groups,relevant endpoints and statisticalapproach,or a justification for not including such detailed information,and any request for a deferral of pediatric assessments or a full or partial waiver of the requirement toprovide data from pediatric studie

258、s along with supporting information.The FDA and the sponsor must reach an agreement on the PSP.A sponsor can submit amendments to anagreed-upon initial PSP at any time if changes to the pediatric plan need to be considered based on data collected from preclinical studies,early phase clinical trials

259、and/or otherclinical development programs.Post-marketing Requirements Following approval of a new product,the manufacturer and the approved product are subject to continuing regulation by the FDA,including,among other things,monitoring and record-keeping activities,reporting of adverse experiences,c

260、omplying with promotion and advertising requirements,which include restrictions on promotingproducts for unapproved uses or patient populations(known as“off-label use”)and limitations on industry-sponsored scientific and educational activities.Although physiciansmay prescribe legally available produ

261、cts for off-label uses,manufacturers may not market or promote such uses.Prescription drug and biologic promotional materials must besubmitted to the FDA in conjunction with their first use.Further,if there are any modifications to the biologic,including changes in indications,labeling or manufactur

262、ingprocesses or facilities,the applicant may be required to submit and obtain FDA approval of a new BLA or BLA supplement,which may require the development of additionaldata or preclinical studies and clinical trials.The FDA may also place other conditions on approvals including the requirement for

263、a Risk Evaluation and Mitigation Strategy,or REMS,to assure the safe use of theproduct.If the FDA concludes a REMS is needed,the sponsor of the BLA must submit a proposed REMS.The FDA will not approve the BLA without an approved REMS,ifrequired.A REMS could include medication guides,physician commun

264、ication plans or elements to assure safe use,such as restricted distribution methods,patient registriesand other risk minimization tools.Any of these limitations on approval or marketing could restrict the commercial promotion,distribution,prescription or dispensing ofproducts.Newly discovered or de

265、veloped safety or effectiveness data may require changes to a products approved labeling,including the addition of new warnings andcontraindications,and also may require the implementation of other risk management measures,including a REMS or the conduct of post-marketing studies to assess a newlydi

266、scovered safety issue.Product approvals may be withdrawn for non-compliance with regulatory standards or if problems occur following initial marketing.FDA regulations require that products be manufactured in specific approved facilities and in accordance with cGMP regulations,which require,among oth

267、er things,quality control and quality assurance,the maintenance of records and documentation and the obligation to investigate and correct any deviations from cGMP.Manufacturersand other entities involved in the manufacture and distribution of approved drugs or biologics are required to register the

268、ir establishments with the FDA and certain stateagencies,and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP requirements and other laws.Accordingly,manufacturers must continue to expend time,money and effort in the area of production an

269、d quality control to maintain cGMP compliance.The discovery of violativeconditions,including failure to conform to cGMP regulations,could result in enforcement actions,and the discovery of problems with a product after approval may result inrestrictions on a product,manufacturer or holder of an appr

270、oved BLA,including recall.14 Biosimilars and Exclusivity An abbreviated approval pathway for biological products shown to be biosimilar to,or interchangeable with,an FDA licensed reference biological product was createdby the Biologics Price Competition and Innovation Act of 2009.This amendment to t

271、he PHSA,in part,attempts to minimize duplicative testing.Biosimilarity,which requiresthat the biological product be highly similar to the reference product notwithstanding minor differences in clinically inactive components and that there be no clinicallymeaningful differences between the product an

272、d the reference product in terms of safety,purity and potency,can be shown through analytical studies,animal studies and aclinical trial or trials.Interchangeability requires that a biological product be biosimilar to the reference product and that the product can be expected to produce the same cli

273、nical results asthe reference product in any given patient and,for products administered multiple times to an individual,that the product and the reference product may be alternated orswitched after one has been previously administered without increasing safety risks or risks of diminished efficacy

274、relative to exclusive use of the reference biological productwithout such alternation or switch.A reference biological product is granted 12 years of data exclusivity from the time of first licensure of the product,and the FDA will not accept an application for abiosimilar or interchangeable product

275、 based on the reference biological product until four years after the date of first licensure of the reference product.“First licensure”typically means the initial date the particular product at issue was licensed in the United States.Date of first licensure does not include the date of licensure of

276、(and a newperiod of exclusivity is not available for)a biological product if the licensure is for a supplement for the biological product or for a subsequent application by the same sponsoror manufacturer of the biological product(or licensor,predecessor in interest,or other related entity)for a cha

277、nge(not including a modification to the structure of the biologicalproduct)that results in a new indication,route of administration,dosing schedule,dosage form,delivery system,delivery device or strength,or for a modification to thestructure of the biological product that does not result in a change

278、 in safety,purity,or potency.Pediatric exclusivity is another type of regulatory market exclusivity in the United States,available under the Best Pharmaceuticals for Children Act by way of itsapplication to biologics through the Biologics Price Competition and Innovation Act.Pediatric exclusivity,if

279、 granted,adds six months to existing regulatory exclusivity periods,which must be in place in order for pediatric exclusivity to apply.This six-month exclusivity may be granted based on the voluntary completion of a pediatric trial inaccordance with an FDA issued“Written Request”for such a trial,alt

280、hough FDA may issue such a Written Request at the request of the sponsor.Companion Diagnostics We may employ companion diagnostics to identify the most suitable phage to treat a specific patient under our personalized phage treatments and to help moreaccurately identify patients sensitive to our pha

281、ge cocktails,during our clinical trials and potentially also in connection with the commercialization of our product candidatesthat we are developing or may in the future develop.Companion diagnostics can identify patients who are most likely to benefit from a particular therapeutic product;identify

282、patients likely to be at increased risk for serious side effects as a result of treatment with a particular therapeutic product;or monitor response to treatment with a particulartherapeutic product for the purpose of adjusting treatment to achieve improved safety or effectiveness.Companion diagnosti

283、cs are regulated as medical devices by the FDAand,as such,require either clearance or approval prior to commercialization.The level of risk combined with available controls to mitigate risk determines whether acompanion diagnostic device requires Premarket Approval Application approval or is cleared

284、 through the 510(k)premarket notification process.For a novel therapeutic productfor which a companion diagnostic device is essential for the safe and effective use of the product,the companion diagnostic device should be developed and approved or510(k)-cleared contemporaneously with the therapeutic

285、.The use of the companion diagnostic device will be stipulated in the labeling of the therapeutic product.15 Government Regulation Outside of the United States In addition to regulations in the United States,we will be subject to a variety of regulations in other jurisdictions governing,among other

286、things,clinical trials of drugproducts as well as the approval,manufacture and distribution of our product candidates.Because biologically sourced raw materials are subject to unique contamination risks,their use may be restricted in some countries.Whether or not we obtain FDA approval for a product

287、 candidate,we must obtain the requisite approvals from regulatoryauthorities in foreign countries prior to the commencement of clinical trials or marketing of the product in those countries.If we fail to comply with applicable foreignregulatory requirements,we may be subject to,among other things,fi

288、nes,suspension or withdrawal of regulatory approvals,product recalls,seizure of products,operatingrestrictions and criminal prosecution.Clinical Trials Certain countries outside of the United States have a regulatory process similar to the U.S process that requires the submission of a clinical trial

289、 application much likethe IND prior to the commencement of human clinical trials.In the European Union,for example,a clinical trial application,or CTA,must be submitted for each clinical trial ina centralized manner to the relevant national health authority and an independent ethics committee in eac

290、h country in which the trial is to be conducted through a single EUportal for harmonized assessment,much like the FDA and an IRB,respectively.CTAs must be accompanied by an investigational medicinal product dossier with supportinginformation prescribed by the Clinical Trials Regulation(and correspon

291、ding national laws of the member states)and further detailed in applicable guidance documents.Oncethe CTA is approved in accordance with the European Commission and each countrys requirements,the clinical trial may proceed.A similar process to the one described forthe European Union is required in I

292、srael for initiation of clinical trials.The requirements and process governing the conduct of clinical trials vary from country to country.In allcases,the clinical trials must be conducted in accordance with GCP and the applicable regulatory requirements and the ethical principles that have their or

293、igin in theDeclaration of Helsinki.Approval Process In order to market our products,we must obtain a marketing approval for each product and comply with numerous and varying regulatory requirements.The approvalprocedure varies among countries and can involve additional testing in comparison to the t

294、esting carried out for the U.S.approval.The time required to obtain approval inforeign countries may differ substantially from that required to obtain FDA approval.Clinical trials conducted in one country may not be accepted by regulatory authorities inother countries.The regulatory approval process

295、 outside the United States generally is subject to all of the same risks associated with obtaining FDA approval.In addition,inmany countries outside the United States,it is required that the product be approved for reimbursement before the product can be approved for sale in that country.To obtain m

296、arketing approval of a medicinal product under the European Union regulatory system,an applicant must submit a marketing authorization application,orMAA,under either a centralized or a decentralized procedure.The decentralized procedure is based on a collaboration among the member states selected by

297、 the applicant.Inessence,the applicant chooses a lead member state that will carry out the scientific assessment of the MAA and review the product information.The other member states mustrecognize the outcome of such assessment and review except in case of a“serious potential risk to public health.”

298、The decentralized procedure results in the grant of a nationalmarketing authorization in each selected country.That procedure is available for all medicinal products unless they fall into the mandatory scope of the centralized procedure.In practice,it is used for OTC,not highly innovative products,g

299、eneric products and,increasingly,for biosimilars.The centralized procedure provides for the grant of a single marketing authorization by the European Commission that is valid for all European Union member states.The centralized procedure is compulsory for certain medicinal products,including for med

300、icinal products produced by certain biotechnological processes,products designatedas orphan medicinal products,advanced therapy medicinal products,or ATMPs,and products with a new active substance and indicated for the treatment of certain diseases.For products with a new active substance and indica

301、ted for the treatment of other diseases,products that are highly innovative or for which a centralized process is in theinterest of patients,the centralized procedure is optional.16 Under the centralized procedure,the CHMP,the main scientific committee established at the European Medicines Agency,or

302、 EMA,is responsible for conducting thescientific assessment of the future medicinal product.The CHMP is also responsible for several post-authorization and maintenance activities,such as the assessment ofmodifications or extensions to an existing marketing authorization.The maximum timeframe for the

303、 evaluation of an MAA is 210 days,excluding clock stops.The EuropeanCommission grants or refuses the marketing authorization,following a procedure that involves representatives of the member states.The European Commissions decision is inaccordance with the CHMP scientific assessment except in very r

304、are cases.Pursuant to Regulation(EC)1394/2007,specific rules apply to ATMPs,a category that is comprised of gene therapy medical products,somatic cell therapy medicinalproducts,and tissue-engineered medicinal products.Those rules have triggered the adoption of guidelines on manufacturing,clinical tr

305、ials and pharmacovigilance that adapt thegeneral regulatory requirements to the specific characteristics of ATMPs.Regulation(EC)1394/2007 introduced a“hospital exemption”,which authorizes hospitals to developATMP for their internal use without having obtained a marketing authorization and to complyi

306、ng with European Union pharmaceutical law.The hospital exemption,which is inessence a compounded ATMP,has been transposed in all Member States,sometimes in such a way that the ATMPs under the hospital exemption are competitive alternatives toATMPs with marketing authorization.The broad use of the ho

307、spital exemption by national hospitals led the European Commission to discuss with the Member States a morereasonable application of the hospital exemption that would not undermine the common legal regime for ATMP.Marketing authorization is valid for five years in principle and the marketing authori

308、zation may be renewed after five years on the basis of a re-evaluation of the risk-benefit balance by the EMA or the competent authority of the authorizing member state.To this end,the marketing authorization holder must provide the EMA or thecompetent authority with a consolidated version of the fi

309、le in respect of quality,safety and efficacy,including all variations introduced since the marketing authorization wasgranted,at least six months before the marketing authorization ceases to be valid.Once renewed,the marketing authorization is valid for an unlimited period,unless theEuropean Commiss

310、ion or the national competent authority decides,on justified grounds relating to pharmacovigilance,to proceed with one additional renewal.Anyauthorization which is not followed by the actual placing of the medicinal product on the European Union market(in case of centralized procedure)or on the mark

311、et of theauthorizing member state within three years after authorization ceases to be valid(the so-called sunset clause).Orphan Designation Countries other than the United States have adopted a specific legal regime to support the development and marketing of drugs and biologics for rare diseases.Fo

312、r example,in the European Union,Regulation 141/2000 organizes the grant of orphan drug designations to promote the development of products that are intendedfor the diagnosis,prevention or treatment of life threatening or chronically debilitating conditions affecting not more than 5 in 10,000 persons

313、 in the European Economic Area(the European Union,plus Iceland,Liechtenstein and Norway),or EEA,(or where it is unlikely that the development of the medicine would generate sufficient return to justifythe investment)and for which no satisfactory method of diagnosis,prevention or treatment has been a

314、uthorized or,if a method exists,the product would be of significantbenefit to those affected.The EMAs Committee for Orphan Medicinal Products,or COMP,examines if the orphan criteria are met and gives opinions thereon,and the orphanstatus is granted by the European Commission.The meeting of the crite

315、ria for orphan designation is examined again by the COMP at the time of approval of the medicinalproduct,which typically occurs several years after the grant of the orphan designation.If the criteria for orphan designation are no longer met at that time,the EuropeanCommission withdraws the orphan st

316、atus.In the European Union,orphan drug designation entitles the sponsor to financial incentives such as reduction of fees or fee waivers and to ten years of marketexclusivity granted following medicinal product approval.Market exclusivity precludes the EMA or a national regulatory authority from val

317、idating another MAA,and theEuropean Commission or a national regulatory authority from granting another marketing authorization,for a same or similar medicinal product and a same therapeuticindication,for that time period.This 10-year period may be reduced to six years if the orphan drug designation

318、 criteria are no longer met,including where it is shown that theproduct is sufficiently profitable not to justify maintenance of market exclusivity.The orphan exclusivity may be lost vis-vis another medicinal product in cases themanufacturer is unable to assure sufficient quantity of the medicinal p

319、roduct to meet patient needs or if that other product is proved to be clinically superior to the approvedorphan product.A drug is clinically superior if it is safer,more effective or makes a major contribution to patient care.Orphan drug designation must be requested beforesubmitting a MAA.Orphan dr

320、ug designation does not convey any advantage in,or shorten the duration of,the regulatory review and approval process,and it does not affordany regulatory exclusivity until a marketing authorization is granted.17 Expedited Development and Approval Mechanisms are in place in many jurisdictions that a

321、llow an earlier approval of the drug so that it reaches patients with unmet medical needs earlier.The EuropeanUnion,for example,has instituted several expedited approval mechanisms including two mechanisms that are specific to the centralized procedure:the accelerated approval:the EMA may reduce the

322、 maximum timeframe for the evaluation of an MAA from 210 days to 150 days when the future medicinalproduct is of major interest from the point of view of public health,in particular from the viewpoint of therapeutic innovation.the conditional marketing authorization:as part of its marketing authoriz

323、ation process,the European Commission may grant marketing authorizations on the basisof less complete data than is normally required.A conditional marketing authorization may be granted when the CHMP finds that,although comprehensive clinical data referring to the safety and efficacy of themedicinal

324、 product have not been supplied,all the following requirements are met:the risk/benefit balance of the medicinal product is positive;it is likely that the applicant will be in a position to provide the comprehensive clinical data;unmet medical needs will be addressed;and the benefit to public health

325、 of the immediate availability on the market of the medicinal product concerned outweighs the risk inherent in the fact that additionaldata is still required.The granting of a conditional marketing authorization is typically restricted to situations in which only the clinical part of the application

326、 is not yet fully complete.Incomplete preclinical or quality data may however be accepted if duly justified and only in the case of a product intended to be used in emergency situations in response topublic health threats.Conditional marketing authorizations are valid for one year,on a renewable bas

327、is.The conditions to which approval is subject will typically require the holder tocomplete ongoing trials or to conduct new trials with a view to confirming that the benefit-risk balance is positive and to collect pharmacovigilance data.Once the conditions towhich the marketing authorization is sub

328、ject are fulfilled,the conditional marketing authorization is transformed into a regular marketing authorization.If,however,theconditions are not fulfilled with the timeframe set by EMA,the conditional marketing authorization ceases to be renewed.The EMA has also implemented the so-called“PRIME”(PRI

329、ority MEdicines)status in order support the development and accelerate the approval of complexinnovative medicinal products addressing an unmet medical need.PRIME status enables early dialogue with the relevant EMA scientific committees and,possibly,some payorsand thus reinforces the EMAs scientific

330、 and regulatory support.It also opens accelerated assessment of the MAA as PRIME status,is normally reserved for medicinal productsthat may benefit from accelerated assessment,i.e.,medicines of major interest from a public health perspective,in particular from a therapeutic innovation perspective.Fi

331、nally,all medicinal products(i.e.decentralized and centralized procedures)may benefit from an MA“under exceptional circumstances.”This marketingauthorization is close to the conditional marketing authorization as it is reserved to medicinal products to be approved for severe diseases or unmet medica

332、l needs and theapplicant does not hold the complete data set legally required for the grant of a marketing authorization.However,unlike the conditional marketing authorization,the applicantdoes not have to provide the missing data and will never have to.The risk-benefit of the medicinal product is r

333、eviewed annually.As a result,although the MA“underexceptional circumstances”is granted definitively,the risk-benefit balance of the medicinal product is reviewed annually and the marketing authorization is withdrawn in casethe risk-benefit ratio is no longer favorable.18 Pediatrics Mandatory testing in the pediatric population is required in more and more jurisdictions.The European Union has enact