Protalix BioTherapeutics, Inc. (PLX) 2023年年度報告「AMEX」.pdf

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1、Table of ContentsUNITED STATESSECURITIES AND EXCHANGE COMMISSIONWashington,D.C.20549FORM 10-KFOR ANNUAL AND TRANSITION REPORTS PURSUANT TO SECTIONS 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1934(Mark One)ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1934For the fi

2、scal year ended December 31,2023ORTRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1934For the transition period from to 001-33357(Commission file number)PROTALIX BIOTHERAPEUTICS,INC.(Exact name of registrant as specified in its charter)Delaware65-0643773State or ot

3、her jurisdictionof incorporation or organization(I.R.S.EmployerIdentification No.)2 University PlazaSuite 100Hackensack,NJ07601 (Address of principal executive offices)(Zip Code)(201)696-9345Registrants telephone number,including area codeSecurities registered pursuant to Section 12(b)of the Act:Tit

4、le of each class Trading Symbol(s)Name of each exchange on which registeredCommon stock,$0.001 par valuePLXNYSE AmericanSecurities registered pursuant to Section 12(g)of the Act:NoneIndicate by check mark if the registrant is a well-known seasoned issuer,as defined in Rule 405 of the Securities Act.

5、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 Act.Yes No Indicate by check mark whether the registrant(1)has filed all reports required to be filed by Section 13 or 15(d)of the Securities Exchange Act of 1934 during the

6、preceding 12 months(orfor such shorter period that the registrant was required to file such reports),and(2)has been subject to such filing requirements for the past 90 days.Yes No Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be su

7、bmitted pursuant to Rule 405 of Regulation S-T(232.405 of thischapter)during the preceding 12 months(or for such shorter period that the registrant was required to submit such files).Yes No Indicate by check mark whether the registrant is a large accelerated filer,an accelerated filer,a non-accelera

8、ted filer,a smaller reporting company,or an emerging growth company.Seedefinition of“large accelerated filer,”“accelerated filer,”“smaller reporting company,”and“emerging growth company”in Rule 12b-2 of the Exchange Act.Large accelerated filerAccelerated filerNon-accelerated filerSmaller reporting c

9、ompany Emerging growth companyIf an emerging growth company,indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accountingstandards provided pursuant to Section 13(a)of the Exchange Act.Indicate by check mark

10、whether the registrant has filed a report on and attestation to its managements assessment of the effectiveness of its internal control over financial reporting underSection 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 rep

11、ort.If securities are registered pursuant to Section 12(b)of the Act,indicate by check mark whether the financial statements of the registrant included in the filing reflect the correction of anerror to previously issued financial statements.Indicate by check mark whether any of those error correcti

12、ons are restatements that required a recovery analysis of incentive-based compensation received by any of the registrants executive officers during the relevant recovery period pursuant to 240.10D-1(b).Indicate by check mark whether the registrant is a shell company(as defined in Rule 12b-2 of the A

13、ct).Yes No The aggregate market value of the voting common stock held by non-affiliates of the Registrant as of June 30,2023 was approximately$139.3 million,based on the closing price for sharesof the Registrants common stock reported by the NYSE American for such date.On March 1,2024,approximately

14、73,052,124 shares of the Registrants common stock,par value$0.001 per share,were outstanding.DOCUMENTS INCORPORATED BY REFERENCEPortions of the registrants proxy statement related to its 2024 Annual Stockholders Meeting to be filed subsequently are incorporated by reference into Part III of this Ann

15、ual Report onForm 10-K.Except as expressly incorporated by reference,the registrants proxy statement shall not be deemed to be part of this report.Table of ContentsPROTALIX BIOTHERAPEUTICS,INC.2023 FORM 10-K ANNUAL REPORTTABLE OF CONTENTS PagePART ICautionary Statement Regarding Forward-Looking Stat

16、ements1Item 1.Business3Item 1A.Risk Factors33Item 1B.Unresolved Staff Comments59Item 1C.Cybersecurity59Item 2.Properties61Item 3.Legal Proceedings61Item 4.Mine Safety Disclosures61PART IIItem 5.Market for Registrants Common Equity,Related Stockholder Matters and Issuer Purchases of EquitySecurities6

17、2Item 6.Reserved62Item 7.Managements Discussion and Analysis of Financial Condition and Results of Operations63Item 7A.Quantitative and Qualitative Disclosures About Market Risk74Item 8.Financial Statements and Supplementary Data74Item 9.Changes in and Disagreements with Accountants on Accounting an

18、d Financial Disclosure74Item 9A.Controls and Procedures74Item 9B.Other Information76Item 9C.Disclosure Regarding Foreign Jurisdictions that Prevent Inspections76PART IIIItem 10.Directors,Executive Officers and Corporate Governance77Item 11.Executive Compensation77Item 12.Security Ownership of Certai

19、n Beneficial Owners and Management and Related Stockholder Matters77Item 13.Certain Relationships and Related Transactions,and Director Independence77Item 14.Principal Accountant Fees and Services77PART IVItem 15.Exhibits and Financial Statement Schedules78Item 16.Form 10-K Summary82Signatures83Tabl

20、e of ContentsPART IExcept where the context otherwise requires,the terms“we,”“us,”“our”or“the Company,”refer to the business ofProtalix BioTherapeutics,Inc.and its consolidated subsidiaries,and“Protalix”or“Protalix Ltd.”refers to the business ofProtalix Ltd.,our wholly-owned subsidiary and sole oper

21、ating unit.CAUTIONARY STATEMENT REGARDING FORWARD-LOOKING STATEMENTSThe statements set forth under the sections entitled“Business,”“Managements Discussion and Analysis of FinancialCondition and Results of Operations”and“Risk Factors,”and other statements included elsewhere in this Annual Reporton Fo

22、rm 10-K,particularly with respect to our plans and strategy for our business and related financing,include forward-looking statements within the meanings of Section 27A of the Securities Act of 1933,as amended,or the Securities Act,and Section 21E of the Securities Exchange Act of 1934,as amended,or

23、 the Exchange Act,including statements regardingexpectations,beliefs,intentions or strategies for the future.When used in this report,the terms“anticipate,”“believe,”“estimate,”“expect,”“can,”“continue,”“could,”“intend,”“may,”“plan,”“potential,”“predict,”“project,”“should,”“will,”“would”and other wo

24、rds or phrases of similar import,as they relate to our company,our subsidiaries or ourmanagement,are intended to identify forward-looking statements.We intend that all forward-looking statements be subjectto the safe-harbor provisions under the Private Securities Litigation Reform Act of 1995.These

25、forward-looking statementsare only predictions and reflect our views as of the date they are made with respect to future events and financialperformance,and we undertake no obligation to update or revise,nor do we have a policy of updating or revising,anyforward-looking statement to reflect events o

26、r circumstances after the date on which the statement is made or to reflect theoccurrence of unanticipated events,except as may be required under applicable law.Forward-looking statements aresubject to many risks and uncertainties that could cause our actual results to differ materially from any fut

27、ure resultsexpressed or implied by the forward-looking statements.Examples of the risks and uncertainties include,but are not limited to,the following:risks related to the commercialization of Elfabrio(pegunigalsidase alfa-iwxj),our approved product forthe treatment of adult patients with Fabry dise

28、ase;risks relating to Elfabrios market acceptance,competition,reimbursement and regulatory actions,including as a result of the boxed warning contained in the U.S.Food and Drug Administration,or FDA,approval receivedfor the product;the possible disruption of our operations due to the war declared by

29、 Israels security cabinet against theHamas terrorist organization located in the Gaza Strip,the military campaign against the Hezbollah and other terroristactivities and armed conflict,including as a result of the disruption of the operations of certain regulatory authorities and ofcertain of our su

30、ppliers,collaborative partners,licensees,clinical trial sites,distributors and customers;risks related to the regulatory approval and commercial success of our other product and productcandidates,if approved;risks related to our expectations with respect to the potential commercial value of our prod

31、ucts andproduct candidates;failure or delay in the commencement or completion of our preclinical studies and clinical trials,whichmay be caused by several factors,including:slower than expected rates of patient recruitment;unforeseen safety issues;determination of dosing issues;lack of effectiveness

32、 during clinical trials;inability to satisfactorily demonstrate non-inferiority to approved therapies;inability or unwillingness of medical investigators and institutional review boards tofollow our clinical protocols;inability to monitor patients adequately during or after treatment;and/or lack of

33、sufficientfunding to finance our clinical trials;delays in the approval or potential rejection of any applications we file with the FDA,EuropeanMedicines Agency,or EMA,or other health regulatory authorities for our other product candidates,and other risks relatingto the review process;Table of Conte

34、nts2risks associated with global conditions and developments such as supply chain challenges,theinflationary environment and tight labor market,and instability in the banking industry,which may adversely impact ourbusiness,operations and ability to raise additional financing if and as required and o

35、n terms acceptable to us;risks related to any transactions we may effect in the public or private equity markets to raise capital tofinance future research and development activities,general and administrative expenses and working capital;risks relating to our evaluation and pursuit of strategic par

36、tnerships;the risk that the results of our clinical trials will not support the applicable claims of safety or efficacyand that our product candidates will not have the desired effects or will be associated with undesirable side effects or otherunexpected characteristics;risks relating to our abilit

37、y to manage our relationship with our collaborators,distributors or partners,including,but not limited to,Pfizer Inc.,or Pfizer,and Chiesi Farmaceutici S.p.A.,or Chiesi;risks related to the amount and sufficiency of our cash and cash equivalents and short-term bankdeposits;risks relating to our abil

38、ity to make scheduled payments of the principal of,to pay interest on or torefinance our outstanding notes or any other indebtedness;risks relating to changes to interim,top-line or preliminary data from clinical trials that we announce orpublish;risks relating to the compliance by Fundao Oswaldo Cr

39、uz,or Fiocruz,an arm of the Brazilian Ministryof Health,or the Brazilian MoH,with its purchase obligations under our supply and technology transfer agreement,whichmay have a material adverse effect on us and may also result in the termination of such agreement;risk of significant lawsuits,including

40、stockholder litigation,which is common in the life sciences sector;our dependence on performance by third-party providers of services and supplies,including withoutlimitation,clinical trial services;the inherent risks and uncertainties in developing drug platforms and products of the type we aredeve

41、loping;the impact of development of competing therapies and/or technologies by other companies;risks related to our supply of drug products to Pfizer;potential product liability risks,and risks of securing adequate levels of related insurance coverage;the possibility of infringing a third-partys pat

42、ents or other intellectual property rights and the uncertaintyof obtaining patents covering our products and processes and successfully enforcing our intellectual property rights againstthird-parties;andrisks relating to changes in healthcare laws,rules and regulations in the United States or elsewh

43、ere.Given these uncertainties,you should not place undue reliance on these forward-looking statements.Companies in thepharmaceutical and biotechnology industries have suffered significant setbacks in advanced or late-stage clinical trials,even after obtaining promising earlier trial results or preli

44、minary findings for such clinical trials.Even if favorable testingdata is generated from clinical trials of a drug product,the FDA or foreign regulatory authorities may not accept or approvea marketing application filed by a pharmaceutical or biotechnology company for the drug product.Table of Conte

45、nts3These and other risks and uncertainties are detailed under the“Risk Factors”section of this Annual Report and aredescribed from time to time in the reports we file with the U.S.Securities and Exchange Commission,or the Commission.Item 1.BusinessWe are a commercial stage biopharmaceutical company

46、 focused on the development,production and commercialization ofrecombinant therapeutic proteins produced via our proprietary ProCellEx plant cell-based protein expression system.Weare the first and only company to gain FDA approval of a protein produced through plant cell-based expression insuspensi

47、on.Our unique expression system represents a new method for developing recombinant proteins in an industrial-scale manner.To date,we have successfully developed two commercial products.On May 5,2023,the European Commission,or EC,announced that it had approved the Marketing Authorization Application,

48、or MAA,for Elfabrio and on May 9,2023,theFDA announced that it had approved the Biologics License Application,or BLA,for Elfabrio(pegunigalsidase alfa-iwxj)injection BLA 761161,each for adult patients with a confirmed diagnosis of Fabry disease.Both approvals cover the1 mg/kg every two weeks dosage.

49、Elfabrio was approved by the FDA with a boxed warning for hypersensitivityreactions/anaphylaxis,consistent with Enzyme Replacement Therapy(ERT)class labeling,and Warnings/Precautionsproviding guidance on the signs and symptoms of hypersensitivity and infusion-associated reactions seen in the clinica

50、lstudies as well as treatments to manage such events should they occur.The Warnings/Precautions formembranoproliferative glomerulonephritis(MPGN)alert prescribers to the possibility of MPGN and provide guidance forappropriate patient management.Overall,the FDA review team concluded that in the conte

51、xt of Fabry disease as a rare,serious disease with limited therapeutic options that may not be suitable to all individual patients,the benefit-risk ofElfabrio is favorable for the treatment of adults with confirmed Fabry disease.According to the EMA,overall,thebenefit/risk balance of Elfabrio is pos

52、itive in the claimed indication(Fabry disease).Elfabrio has also been approved formarketing in Great Britain,Switzerland and Israel.The FDA publicly released the internal review documents for Elfabrio.These documents provide previously unavailableadditional information regarding the basis for the FD

53、As May 2023 approval decision.In particular,the FDA determinedthat substantial evidence of effectiveness for Elfabrio in Fabry patients was established with one adequate and well-controlled study(our phase III clinical trial of Fabry Disease,Study PB-102-F01/02)with confirmatory evidence providedby

54、our phase III BALANCE clinical trial of PRX-102 for the treatment of Fabry disease,or the BALANCE study(alsoreferred to as Study PB-102-F20).The FDA review team also concluded that the BALANCE study met its primary efficacyendpoint,which assessed the annualized rate of change in eGFR(estimated glome

55、rular filtration rate)over 104 weeks.However,the FDA also determined that the results from the BALANCE study did not support a non-inferiority claim to thecomparator product due to the lack of data to support a non-inferiority margin.Our first product,Elelyso(taliglucerase alfa,except in Brazil wher

56、e it is marketed as BioManguinhos alfataliglicerase),an ERT for the treatment of patients with Gaucher disease was first approved by the FDA in May 2012 and is nowapproved for marketing in 23 markets including Brazil,Israel and others.In addition,we are developing PEGylated uricase,or PRX-115,for th

57、e treatment of severe gout,Long Acting(LA)DNase I,or PRX-119,for the treatment of NETs-related diseases,and a number of other technologies and preclinicalassets.Our proprietary ProCellEx platform is being used to manufacture both of our approved and marketed products as well asPRX-115 and PRX-119.Ou

58、r strategy moving forward is to develop proprietary recombinant proteins designed to address high,unmet needs in thegenetic and non-genetic rare disease space that are therapeutically superior to existing recombinant proteins currentlymarketed for the same indications.Consistent with this strategy,w

59、e have a number of product candidates in varying stagesof the clinical development process.Table of Contents4Product PipelineProCellEx:Our Proprietary Protein Expression SystemProCellEx is our proprietary platform used to produce and manufacture recombinant proteins through plant cell-basedexpressio

60、n in suspension.ProCellEx consists of a comprehensive set of proprietary technologies and capabilities,includingthe use of advanced genetic engineering and plant cell culture technology,enabling us to produce complex,proprietary andbiologically equivalent proteins for a variety of human diseases.Our

61、 protein expression system facilitates the creation andselection of high-expressing,genetically-stable cell lines capable of expressing recombinant proteins.We plan to executeon our strategy by developing tailored complex recombinant therapeutic proteins primarily produced through ProCellExwhile gen

62、etically engineering and/or chemically modifying the proteins pre-and/or post-production.We intend suchengineering and modifications to provide added clinical benefits by improving the biological characteristics(e.g.,glycosylation,half-life,immunogenicity)of the therapeutic proteins.Our ProCellEx te

63、chnology allows for many unique advantages,including:biologic optimization;an ability to handlecomplex protein expressions;flexible manufacturing with improvements through efficiencies,enhancements and/or rapidhorizontal scale-ups;a simplified production process;elimination of the risk of viral cont

64、aminations from mammaliancomponents;and intellectual property advantages.We developed ProCellEx based on our plant cell culture technology for the development,expression and manufacture ofrecombinant proteins which are the essential foundation of modern biotechnology.We develop new,recombinanttherap

65、eutic proteins by using the natural capability of agrobacterium to transfer a DNA fragment into the plantchromosome,allowing the genome of the plant cell to code for specific proteins of interest.The agrobacterium-mediatedtransformed cells are then able to produce specific proteins,which are extract

66、ed and purified and can be used as therapiesto treat a variety of diseases.We are the first and only company to gain FDA approval of a protein produced through plantcell-based expression,and with the recent approval of Elfabrio,we now have two commercial proteins produced throughour platform.Table o

67、f Contents5Our ProCellEx technology can be utilized to express complex therapeutic proteins belonging to different drug classes,suchas enzymes,hormones,monoclonal antibodies,cytokines and vaccines.The entire protein expression process,from initialnucleotide cloning to large-scale production of the p

68、rotein product,occurs under Current Good Manufacturing Practice-,orcGMP-,compliant,controlled processes.Our plant cell culture technology uses cells,such as carrot and tobacco(BY-2)cells,which undergo advanced genetic engineering and/or chemical modifications,and are grown on an industrial scale in

69、adisposable,flexible bioreactor system.Our system does not involve mammalian or animal-derived components ortransgenic field-grown or whole plants at any point in the production process.Cell growth,from initiating scale-up steps from a cell-bank through large-scale production takes place in a clean-

70、roomenvironment in flexible,sterile,custom-designed polyethylene bioreactors,and does not require the use of large stainless-steel bioreactors commonly used in mammalian-based systems for recombinant protein production.The ProCellEx reactorsare easy to use and maintain,allow for rapid horizontal sca

71、le-up and do not involve the risk of mammalian viralcontamination.Our bioreactors are well-suited for plant cell growth using a simple,inexpensive,chemically definedgrowth medium.The reactors,which are custom-designed and optimized for plant cell cultures,require low initial capitalinvestment and ar

72、e rapidly scalable at a low cost.Plant Cell Production AdvantagesProCellEx:Protalixs Differentiated Plant Cell Protein Expression PlatformTable of Contents6Business HighlightsWe have two commercial products,each of which is an ERT;Elelyso and Elfabrio.Our pipeline of product candidatesincludes PEGyl

73、ated uricase for the treatment of severe gout,Long Acting(LA)DNase I for the treatment of NETs andother technologies and preclinical assets.Elelyso(taliglucerase alfa)Elelyso for the treatment of Gaucher disease is currently approved and marketed in 23 countries including the UnitedStates,Australia,

74、Canada,Israel,Brazil,Russia and Turkey.In June 2012,the EMAs Committee for Medicinal Productsfor Human Use,or the CHMP,issued a positive opinion regarding the benefit of Elelyso but did not immediately grantmarketing authorization because of the ten-year market exclusivity granted to Vpriv(Takeda Sh

75、ire)in August 2010 forthe same condition,which was extended for an additional two years,and expired in August 2022.We have granted themarketing rights to Elelyso globally,excluding Brazil,to Pfizer through an exclusive licensing agreement.We maintain thedistribution rights to Elelyso in Brazil,where

76、 it is currently marketed as BioManguinhos alfataliglicerase,through theSupply and Technology Transfer Agreement,or the Brazil Agreement,we entered into on June 18,2013,with Fiocruz,anarm of the Brazilian MoH.In 2023,we generated$12.5 million from sales of Elelyso to Pfizer and$10.4 million fromsale

77、s of BioManguinhos alfataliglicerase to the Brazilian MoH.Elfabrio(pegunigalsidase alfa orPRX-102)Elfabrio for the treatment of adult patients with Fabry disease,is our proprietary,plant cell culture expressed enzyme,and achemically modified stabilized version of,the recombinant-Galactosidase-A prot

78、ein,a lysosomal enzyme.Elfabrio hasbeen approved by the FDA for marketing in the United States,the European Union,Great Britain,Switzerland and Israel.In 2023,we generated$17.5 million from sales of Elfabrio to Chiesi.Protalix Ltd.,our wholly-owned subsidiary,has entered into two exclusive licensing

79、 and supply agreements with Chiesi forElfabrio,one global excluding the United States and the second for the United States.Uricase(PRX-115)PEGylated Uricase(PRX-115)PRX-115 is our plant cell-expressed recombinant PEGylated Uricase(urate oxidase)a chemically modified enzymeunder development for the p

80、otential treatment of severe gout.Gout is the most common inflammatory arthritis,affecting anestimated 14.0 million adults in the United States,2.0 million in France,2.0 million in United Kingdom,0.7 million inItaly,1.5 million in Germany,0.7 million in Spain and over 190.0 million in China.An estim

81、ated approximately 5%of thegout population is considered to have chronic refractory disease.Gout results from sustained elevation of serum uratelevels(hyperuricaemia).Urate levels may increase due to diet,genetic predisposition and environmental factors leading tothe deposition of monosodium urate c

82、rystals,tophi,in joints,tendons and other tissues,which triggers recurrent episodes ofpronounced acute inflammation,known as gout flares.Gout leads to substantial morbidity,severe pain,reduced quality oflife,decreased physical function,increased healthcare costs,and lost economic productivity.Furthe

83、rmore,gout is stronglyassociated with a number of comorbidities,including hypertension,cardiovascular disease,renal impairment,diabetes,obesity,hyperlipidaemia and frequently in a combination known as the metabolic syndrome.PRX-119PRX-119 is our plant cell-expressed PEGylated recombinant human DNase

84、 I product candidate which we are designing tohave an elongated half-life in the circulation for the potential treatment of NETs-related diseases.NETs,or Neutrophilextracellular traps,are web-like structures released by activated neutrophils that trap and kill a variety of microorganisms.NETs are co

85、mposed of DNA,histones,antimicrobial and pro-inflammatory proteins.Excessive formation or ineffectiveclearance of NETs can cause different pathological effects.NETs formation has been observed in various autoimmune,inflammatory and fibrotic conditions,diverse forms of thrombosis,cancer and metastasi

86、s.According to scientific literature,animal studies have demonstrated that DNase I treatment reduce NETs toxicity.Our proprietary modified DNase I maypotentially enable effective treatment for these conditions.Table of Contents72023 and Recent Company DevelopmentsRecent DevelopmentsIn January 2024,t

87、he Israeli Ministry of Health granted principle approval of Elfabrio for adult patients witha confirmed diagnosis of Fabry disease.2023 DevelopmentsOn February 21,2023,we announced our participation in the 19th Annual WORLDSymposium 2023,which took place on February 22-26,2023 at the Hilton Orlando

88、in Orlando,Florida.We hosted an informational booth atthe symposium.On March 21,2023,the first patient was dosed in our phase I First-in-Human(FIH)clinical trial of PRX-115.Our decision to voluntarily delist our common stock from the Tel Aviv Stock Exchange took effect onMarch 22,2023.On May 5,2023,

89、we announced that the EC had granted marketing authorization to Elfabrio in the EuropeanUnion for the treatment of adult patients with Fabry disease.On May 10,2023,we announced that the FDA had approved Elfabrio in the United States for the treatmentof adult patients with Fabry disease.On June 28,20

90、23,we held our Annual Meeting of Stockholders at which our stockholders:(1)elected theseven persons nominated by our Board of Directors to serve as directors of our Company;(2)approved,on a non-binding,advisory basis,the compensation of our named executive officers;(3)approved,on a non-binding,advis

91、ory basis,oneyear as the frequency at which we will solicit stockholder approval of the compensation of our named executive officers;(4)adopted amendments to our Amended and Restated 2006 Stock Incentive Plan,as amended,to increase the number ofshares of common stock available under such plan from 8

92、,475,171 shares to 12,475,171 shares and to amend certain otherterms of the plan;and(5)ratified the appointment of Kesselman&Kesselman,Certified Public Accountants(Isr.),amember of PricewaterhouseCoopers International Limited,as our independent registered public accounting firm for thefiscal year en

93、ding December 31,2023.The meeting was adjourned until July 13,2023 to allow us to continue to solicitstockholder approval for the proposal to increase the amount of shares of common stock authorized for issuance under ourCertificate of Incorporation,as amended,or the Amended Charter,from 144,000,000

94、 shares to 185,000,000 shares.On July 13,2023,our stockholders approved an amendment to our Amended Charter to increase the amountof shares of common stock authorized for issuance thereunder from 144,000,000 shares to 185,000,000 shares.On August 15,2023,Chiesi announced that the UK Medicines and He

95、althcare products Regulatory Agency(MHRA)had granted marketing authorization for Elfabrio in Great Britain for long-term enzyme replacement therapy inadult patients with a confirmed diagnosis of Fabry disease.On September 11,2023,Swissmedic,the national authorization and supervisory authority for dr

96、ugs andmedical products in Switzerland,announced the approval of Elfabrio in Switzerland for long-term enzyme replacementtherapy in adult patients with a confirmed diagnosis of Fabry disease.On September 14,2023,Eliot Richard Forster,Ph.D.commenced his tenure as Chairman of our Board ofDirectors.Zee

97、v Bronfeld,the former Chairman of our Board retired for personal reasons,effective as of the same date.Table of Contents8Our Marketed ProductsElelyso for the Treatment of Gaucher DiseaseElelyso(taliglucerase alfa),our first commercial product,was approved by the FDA in 2012 for injection as an ERT f

98、or thelong-term treatment of adult patients with a confirmed diagnosis of type 1 Gaucher disease.In August 2014,the FDAapproved Elelyso for injection for pediatric patients.Elelyso is the first plant cell derived recombinant protein to beapproved by the FDA for the treatment of Gaucher disease and i

99、s now approved in 23 markets including the United States,Brazil,Israel and others.Gaucher disease,also known as glucocerebrosidase,or GCD,deficiency,is a rare genetic autosomal recessive disorder andone of the most common Lysosomal Storage Disorders,or LSDs,in the world.It is one of a group of disor

100、ders that affectspecific enzymes that normally break down fatty substances for reuse in the cells.If the enzymes are missing or do notwork properly,the substances can build up and become toxic.Gaucher disease occurs when a lipid called glucosylceramideaccumulates in the cells of the bone marrow,lung

101、s,spleen,liver,and sometimes the brain.Gaucher disease symptoms caninclude fatigue,anemia,easy bruising and bleeding,severe bone pain and easily broken bones,and distended stomach dueto an enlarged spleen and thrombocytopenia.Epidemiology of Gaucher disease varies;Recent literature provides thatprev

102、alence of Gaucher disease ranges from 0.70 to 1.75 per 100,000 in the general population.In people of AshkenaziJewish heritage,estimates of occurrence vary from approximately 1 in 400 to 1 in 850 people.The global market for Gaucher disease,that includes Sanofis Cerezyme,Shires Vpriv and Sanofis Cer

103、delga,amongothers,was$1.6 billion in 2023,is forecasted to be approximately$1.6 billion in 2024 and is forecasted to grow at aCAGR of approximately 1%from 2023-2029.The current standard of care for Gaucher disease is ERT,which is a medical treatment where recombinant enzymes areinjected into patient

104、s to replace the lacking or dysfunctional enzyme.In Gaucher disease,recombinant GCD is infused toreplace the mutated or deficient natural GCD enzyme.Elelyso is the only alternative ERT treatment of Gaucher disease toSanofi Genzymes Cerezyme and Takedas(Shire)Vpriv.Elfabrio for the Treatment of Fabry

105、 DiseaseElfabrio,our second commercial product,was approved by the EC for marketing in the EU and by the FDA for marketingin the United States in May 2023 for adult patients with Fabry disease.Both approvals cover the 1 mg/kg every two weeksdosage.Overall,the FDA review team concluded that in the co

106、ntext of Fabry disease as a rare,serious disease with limitedtherapeutic options that may not be suitable to all individual patients,the benefit-risk of Elfabrio is favorable for thetreatment of adults with confirmed Fabry disease.According to the EMA,overall,the benefit/risk balance of Elfabrio isp

107、ositive in the claimed indication(Fabry disease).The FDA publicly released the internal review documents for Elfabrio.These documents provide previously unavailable additional information regarding the basis for the FDAs May 2023approval decision.In particular,the FDA determined that substantial evi

108、dence of effectiveness for Elfabrio in Fabrypatients was established with one adequate and well-controlled study,our phase III clinical trial of Fabry disease,withconfirmatory evidence provided by the BALANCE study.The FDA review team also concluded that the BALANCE studymet its primary efficacy end

109、point,which assessed the annualized rate of change in eGFR(estimated glomerular filtrationrate)over 104 weeks.However,the FDA also determined that the results from the BALANCE study did not support a non-inferiority claim to the comparator product due to the lack of data to support the non-inferiori

110、ty margin.In August and September of 2023,Elfabrio was approved in Great Britain and Switzerland,respectively,and by the IsraeliMinistry of Health in January 2024,for long-term enzyme replacement therapy in adult patients with a confirmed diagnosisof Fabry disease.Fabry disease is a serious life-thr

111、eatening rare genetic disorder.Fabry patients lack or have low levels of-galactosidase-Aresulting in the progressive accumulation of abnormal deposits of a fatty substance called globotriaosylceramide,or Gb3,inblood vessel walls throughout their body.The ultimate consequences of Gb3 depositionTable

112、of Contents9range from episodes of pain and impaired peripheral sensation to end-organ failure,particularly of the kidneys,but also ofthe heart and the cerebrovascular system.Fabry disease occurs in one person per 40,000 to 60,000 males.The standard of care for Fabry disease is ERT.Currently,the ERT

113、s for Fabry disease are agalsidase alfa,agalsidase beta,and now Elfabrio.Through an ERT,the missing-galactosidase-A is replaced with a recombinant form of the protein viaintravenous,or IV,infusion once every two weeks.Fabry disease,if left untreated,will progress from a less severecondition to a mor

114、e serious one.It can have a significant impact on quality of life due to presence of serious,chronic anddebilitating complications,including cardiovascular and renal complications,and comorbid conditions such as pain canhave a significant impact on the psychological well-being of Fabry patients and

115、their social functioning.Fabry diseaseinvolves substantial reduction in life expectancy.Causes of death are most often cardiovascular disease and,to a lesserextent,cerebrovascular disease and renal disease.The life expectancy of Fabry patients is significantly shorter compared tothe general populati

116、on.Untreated male Fabry patients may experience shortened lifespans to approximately 50 years,and70 years for untreated female patients with Fabry disease.This represents a 20-and 10-year reduction of their respectivelifespans.The global market for Fabry disease,that includes agalsidase beta,Sanofis

117、 Fabrazyme,agalsidase alfa,Shires(acquiredby Takeda Pharmaceutical Company Limited)Replagal and Amicus Therapeutics Galafold,among others,is forecastedto be approximately$2.0 billion in 2023 and is forecasted to grow at a CAGR of 6.8%from 2023-2029 reachingapproximately$3.1 billion in annual sales a

118、t the end of the decade.Regulatory BackgroundOn November 9,2022,we,together with Chiesi,resubmitted to the FDA a BLA for PRX-102,the name we assigned toElfabrio internally prior to its approvals,for the potential treatment of adult patients with Fabry disease.The initial BLAfor PRX-102 was submitted

119、 to the FDA on May 27,2020 under the FDAs Accelerated Approval pathway,and thesubmission was subsequently accepted by the FDA and granted Priority Review designation.However,in April 2021,theFDA issued a complete response letter,or CRL,in response to the initial BLA.In preparation for the BLA resubm

120、ission,we and Chiesi participated in a Type A(End of Review)meeting with the FDA on September 9,2021.As part of themeeting minutes provided by the FDA,which included the preliminary comments and meeting discussion,the FDA,inprinciple,agreed that the data package proposed to the FDA for a BLA resubmi

121、ssion had the potential to support atraditional approval of PRX-102 for the treatment of Fabry disease.The data package in the BLA resubmission,given thechange in the regulatory landscape in the United States,included the final two-year analyses of our BALANCE study,whichwere completed in July 2022,

122、and long-term data from our open-label extension study of PRX-102 in adult patients treatedwith a 2 mg/kg every four weeks dosage of PRX-102.The initial BLA included a comprehensive set of preclinical,clinicaland manufacturing data compiled from our completed phase I/II clinical trial of PRX-102,inc

123、luding the related extensionstudy,interim clinical data from our phase III BRIDGE clinical trial of PRX-102 for the treatment of Fabry disease,or theBRIDGE study,and safety data from our then on-going clinical studies of PRX-102 in adult patients receiving 1 mg/kgevery two weeks.The CRL did not repo

124、rt any concerns relating to the potential safety or efficacy of PRX-102 in the submitted data package.In the CRL,the FDA noted that an inspection of our manufacturing facility in Carmiel,Israel,including the FDAssubsequent assessment of any related FDA findings,is required before the FDA can approve

125、 a new drug.Due to travelrestrictions during the COVID-19 pandemic,the FDA was unable to conduct the required pre-approval inspection duringthe review cycle.In addition to the foregoing,the FDA noted that agalsidase beta had recently been converted to fullapproval,a change in regulatory circumstance

126、s which had to be addressed in the resubmitted BLA for PRX-102.On February 7,2022,the PRX-102 MAA was submitted to,and subsequently validated by,the EMA.The submission wasmade after the October 8,2021 meeting we held,together with Chiesi,with the Rapporteur and Co-Rapporteur of the EMAregarding PRX-

127、102.At the meeting,we and Chiesi discussed the scope of the anticipated MAA submission for theEuropean Union,and the Rapporteur and Co-Rapporteur were generally supportive of the planned MAA submission.TheMAA submission included a comprehensive set of preclinical,clinical and manufacturing data comp

128、iled from ourcompleted and ongoing clinical studies evaluating PRX-102 as a potential alternative treatment for adult patients withFabry disease.The submission was supported by the 12month interim data analysis generated from our BALANCE study,which was released in June 2021.Data generated from the

129、completed BRIDGE study,the phase I/II clinical trial in naive oruntreated patients,and from the extension studies with 1 mg/kg every two weeks were also included in theTable of Contents10submission.In addition,the MAA included data from the completed 12month switchover phase III BRIGHT clinicaltrial

130、 of PRX-102 for the treatment of Fabry disease for adult patients with Fabry disease treated with the 2 mg/kg everyfour weeks dosage,or the BRIGHT study.As part of the EMA review process,we and Chiesi received the Day 120 list ofquestions in June 2022,and the full response package thereto was submit

131、ted to the EMA in September 2022(following a3-month clock-stop period).An essential portion of the response included the submission of the final analysis of the two-year BALANCE study(the final Clinical Study Report),and an interim analysis of the long-term,open-label extensionstudy of PRX-102 in ad

132、ult patients with Fabry disease treated with the 2 mg/kg every four weeks dosage.On February 24,2023,we,together with Chiesi,announced that the CHMP had adopted a positive opinion,recommending marketing authorization for PRX-102.The CHMP opinion was then referred for final action to the EC.Asdisclos

133、ed above,Elfabrio was subsequently approved by the EC for marketing in the EU and in the United States in May2023 for adult patients with Fabry disease.Both approvals cover the 1 mg/kg every two weeks dosage.Key Trials and DesignOur PRX-102 clinical development program was designed to show that PRX-

134、102 has a potential clinical benefit in all adultFabry patient populations when compared to the then marketed Fabry disease enzymes,agalsidase beta and agalsidase alfa.In preclinical studies,PRX-102 showed significantly longer half-life due to higher enzyme stability,enhanced activity inFabry diseas

135、e affected organs leading to reduction of the accumulated substrate and reduced immunogenicity,whichtogether can potentially lead to improved efficacy through increased substrate clearance and significantly lower formationof anti-drug antibodies,or ADAs.The phase III clinical program included three

136、individual studies;the BALANCE study,the BRIDGE study the BRIGHTstudy,all of which have been completed.In the phase III clinical program overall,two potential dosing regimens for PRX-102 were analyzed;1 mg/kg every two weeks,with the potential for improved efficacy and safety offering a potentialalt

137、ernative to existing enzyme replacement therapies,and 2 mg/kg every four weeks.The phase III program was precededby the phase I/II clinical trial,a dose range finding study in ERT-nave adult patients with Fabry disease,which wascompleted in 2016.Phase III BALANCE StudyThe BALANCE study(PB-102-F20,NC

138、T02795676)was a pivotal 24-month,randomized,double blind,active controlstudy of PRX-102 in adult Fabry patients with deteriorating renal function designed to evaluate the safety and efficacy of1 mg/kg of PRX-102 administered every two weeks compared to agalsidase beta.The Clinical Study Report for t

139、heBALANCE study was completed in July 2022.The final analysis confirmed the positive top-line results(announced inApril 2022)and favorable tolerability profile.A total of 78 patients who were previously treated with agalsidase beta for atleast one year with an eGFR slope at screening worse than-2 mL

140、/min/1.73 m2/year were enrolled in the study.Table of Contents11Patients were randomized on a 2:1 ratio for switching to PRX-102 or continuing on agalsidase beta.A total of 77 patientswere treated;52 with PRX-102 and 25 with agalsidase beta.Approximately 40%of the enrolled patients were female.Forty

141、-seven(90.4%)patients in the PRX-102 arm experienced at least one treatment-emergent adverse event(TEAE)compared to 24(96.0%)in the agalsidase beta arm.The number of events adjusted to 100 years of exposure is 572.36events for the PRX-102 arm and 816.85 events for the agalsidase beta arm.TEAEs were

142、reported for 21(40.4%)patients in the PRX-102 arm compared to 11(44.0%)in the agalsidase beta arm.Thenumber of treatment-related events adjusted to 100 years of exposure is 42.85 events for the PRX-102 arm and 152.91events for the agalsidase beta arm.Usage of infusion pre-medication was tapered down

143、 during the study,if possible,for all patients.At baseline,21(40.4%)patients in the PRX-102 arm used infusion premedication compared to 16(64.0%)in the agalsidase beta arm.At the end ofthe study,only three out of 47(6.4%)patients in the PRX-102 arm used infusion premedication compared to three out o

144、f24(12.5%)in the agalsidase beta arm.Even with this reduction in use of premedication,there were fewer reportedinfusion-related reactions with PRX-102:11(21.2%)patients in the PRX-102 arm experienced a total of 13 eventscompared to six(24.0%)patients experiencing a total of 51 events in the agalsida

145、se beta arm.The number of infusion-related reactions adjusted to 100 infusions is 0.5 for the PRX-102 arm and 3.9 for agalsidase beta arm.Assessment of immunogenicity,that is,the existence and development of anti PRX-102 antibodies or anti-agalsidase betaantibodies,in the study indicated that for th

146、e PRX-102 arm,18(34.6%)patients were ADA positive at baseline,of which17(94.4%)had neutralizing antibody activity.For the agalsidase beta arm,eight(32.0%)patients were ADA positive atbaseline,of which seven(87.5%)had neutralizing antibody activity.Only a small number of patients showed treatment-eme

147、rgent ADA.At the end of the two-year study,11(23.4%)patients that received PRX-102 were ADA positive,of whichseven(63.6%)had neutralizing antibody activity,while in the agalsidase beta arm six(26.1%)were ADA-positive and allsix(100%)had neutralizing antibody activity.There was little change in the p

148、ercentage of patients who were ADApositive,with a trend of reduction observed in the PRX-102 arm and stability in the agalsidase beta arm.The proportion ofpatients with neutralizing ADA decreased in the PRX-102 arm while it remained stable in the agalsidase beta arm.Out of the 78 randomized patients

149、,six patients discontinued the study:out of the five(9.4%)from the PRX-102 arm,onepatient withdrew consent prior to the first infusion,two discontinued due to personal reasons,and two due to adverseevents(one due to an unrelated adverse event and one due to a treatment related adverse event);one(4%)

150、patient from theagalsidase beta arm discontinued for personal reasons.There were no deaths in this study.Considering that in the trial patients in the PRX-102 arm were exposed for the first time to the novel enzyme,tolerabilitydata appear favorable for PRX-102 and in-line with what was observed in t

151、he previous clinical studies of PRX-102.Of the patients that completed the trial from both the PRX-102 and agalsidase beta treatment arms,69 opted,with theadvice of the treating physician,to receive PRX-102 1 mg/kg every two weeks in the long-term open-label extension studywhich is now sponsored by

152、Chiesi.The results of the direct,blinded comparison of PRX-102 to agalsidase beta,for the primary efficacy renal endpoints(i.e.,eGFR change,eGFR slope)and for the main secondary endpoints(e.g.,urine protein to creatinine ratio UPCR LVMI,MSSI,BPI)strongly suggest comparability in treatment effects be

153、tween the two treatments.At the same time a potentially favorable safety profile was identified based on lower rates of IRR,lower ADA positivity,and less premedication use in the PRX-102 arm compared to agalsidase beta.Overall,a positive benefit-risk balance wasconfirmed.Phase III BRIDGE StudyThe BR

154、IDGE study(PB-102-F30,NCT03018730)was a 12-month open-label,single arm switch-over study evaluating thesafety and efficacy of PRX-102,1 mg/kg infused every two weeks,in up to 22 Fabry patients previously treated withTable of Contents12agalsidase alfa for at least two years and on a stable dose for a

155、t least six months.In the study,patients were screened andevaluated over three months while continuing agalsidase alfa treatment.The study was completed in December 2019.Final results of the data generated in the BRIDGE study showed substantial improvement in renal function as measured bymean annual

156、ized eGFR slope in both male and female patients.Twenty of 22 patients completed the 12-month treatmentduration.Eighteen of the patients who completed the study opted to roll over to a long-term extension study and continueto be treated with PRX-102.In the study,the mean annualized eGFR slope of the

157、 study participants improved from-5.90 mL/min/1.73m2/year while on agalsidase alfa to-1.19 mL/min/1.73m2/year on PRX-102 in all patients.Male patientsimproved from-6.36 mL/min/1.73m2/year to-1.73mL/min/1.73m2/year and female patients improved from-5.03 mL/min/1.73m2/year to-0.21 mL/min/1.73m2/year.F

158、ollowing the switch to PRX-102,there was a decrease inpatients with progressing or fast progressing kidney disease which is consistent with the therapeutic goals for Fabrydisease,as identified by Christoph Wanner,et.al.,in 2019,and most patients achieved a stable status post-switch.PRX-102 was well-

159、tolerated in the BRIDGE study,with all adverse events being transient in nature without sequelae.Ofthe 22 patients enrolled in the BRIDGE study,the majority of TEAEs were mild or moderate in severity,with two patients(9.1%)withdrawing from the therapy due to hypersensitivity reaction that was resolv

160、ed.The most common moderateTEAEs were nasopharyngitis,headache and dyspnea.An immunogenicity assessment indicated that four out of 20 patients(20%)developed persistent ADAs over the course of the study,of which two had neutralizing activity.Of the patients that completed the trial,18 opted,with the

161、advice of the treating physician,to continue receiving PRX-1021 mg/kg every two weeks in a long-term open-label extension study which is now sponsored by Chiesi.Phase III BRIGHT StudyThe BRIGHT study(PB-102-F50,NCT03180840)was a multicenter,multinational open-label,switch-over study designedto evalu

162、ate the safety,efficacy and pharmacokinetics of treatment with 2 mg/kg of PRX-102 administered every four weeksfor 52 weeks(a total of 14 infusions).The study was completed in June 2020.The 2 mg/kg every four weeks dosage hasnot been approved by the EMA,FDA or any other jurisdiction.Enrollment in th

163、e study included 30 adult patients(24 males and 6 females)with mean(SD)age of 40.5(11.3)years,ranging from 19 to 58 years previously treated with a commercially available ERT(agalsidase beta or agalsidase alfa),forat least three years and on a stable dose administered every two weeks.To determine el

164、igibility for participation in thestudy,candidates were screened to identify and select Fabry patients with clinically stable kidney disease.The mostcommon Fabry disease symptoms at baseline were acroparesthesia,heat intolerance,angiokeratomas and hypohydrosis.Patients who matched the criteria were

165、enrolled in the study and switched from their current treatment of IV infusionsevery two weeks to 2 mg/kg of PRX-102 every four weeks for 12 months.Patients participating in the study wereevaluated,among other disease parameters,to determine if their kidney disease had not further deteriorated while

166、 beingtreated with the four-week dosing regimen as measured by eGFR and for lyso-Gb3 levels as a Fabry biomarker,as well asother parameters.In addition,participating patients were evaluated to assess the safety and tolerability of PRX-102.The final results from the BRIGHT study indicate that 2 mg/kg

167、 of PRX-102 administered by intravenous infusion everyfour weeks was well tolerated,and Fabry disease assessed by eGFR slope and plasma lyso-Gb3 was stable throughoutPRX-102 treatment in adult Fabry patients.None of the patients without ADAs at screening developed treatment-inducedADAs following the

168、 switch to PRX-102 treatment.All 30 patients received at least one dose of PRX-102,and 29 patients completed the one-year study.Of these 29 patients,28 received the intended regimen of 2 mg/kg every four weeks throughout the entire study,while one patient was switchedto 1 mg/kg PRX-102 every two wee

169、ks per protocol at the 11th infusion.One patient withdrew from the study after the firstinfusion due to a traffic accident.First infusions of PRX-102 were administered under controlled conditions at the investigation site.Based on the protocol-specified criteria,patients were able to receive their P

170、RX-102 infusions at a home care setup once the applicableInvestigator and Sponsor Medical Monitor agreed that it was safe to do so.Safety and efficacy exploratory endpoints wereassessed throughout the 52-week study.Table of Contents13Overall,33 of 183 total TEAEs reported in nine(30.0%)of the patien

171、ts were considered treatment related;all were mild ormoderate in severity and the majority were resolved at the end of the study.There were no serious or severe treatment-related TEAEs and no TEAEs led to death or study withdrawal.Of the treatment-related TEAEs,27 were infusion-relatedreactions(IRRs

172、)and the remainder were single events of diarrhea,erythema,fatigue,influenza-like illness,increases urineprotein/creatinine ratio,and urine positive for white blood cells.The 27 IRRs were reported in five(16.7%)patients,allmale.All IRRs occurred during the infusion or within two hours post-infusion;

173、no events were recorded between two and24 hours post-infusion.The study suggests that Fabry patients who are currently receiving ERT every two weeks may be successfully transitionedto PRX-102 2 mg/kg every four weeks as an effective and tolerable alternative treatment option.Additional long term dat

174、ais being collected as part of the ongoing long term extension study(PB-102-F51,NCT03614234)of the 2 mg/kg PRX-102every four weeks dose.Following a survey of participants using the Quality of Life EQ-5D-5L questionnaire,responses indicate that patientperception of their own health remained high and

175、stable throughout the 52-week study duration,with overall health mean(SE)scores of 78.3(3.1)and 82.1(2.9)at baseline and Week 52,respectively,in a 0 to 100 scale.Using the short-formBrief Pain Inventory,or,questionnaire,approximately 75%of study participants had an improvement or no change inaverage

176、 pain severity at Week 52(compared to baseline).The short-form BPI interference items also remained stableduring the study.Pain-related results indicate that there was no increase and/or relapse in pain.No Fabry clinical eventswere reported during the study.Of the patients that completed the trial,2

177、9 opted,with the advice of the treating physician,to continue receiving PRX-1022 mg/kg every four weeks in a long-term open-label extension study which is now sponsored by Chiesi.Two of suchpatients are being treated with 1 mg/kg every two weeks dosage.Phase I/II StudyThe phase I/II clinical trial o

178、f PRX-102(NCT01678898)was a worldwide,multi-center,open-label,dose ranging studydesigned to evaluate the safety,tolerability,pharmacokinetics,immunogenicity and efficacy parameters of PRX-102 inadult patients with Fabry disease.It was completed in 2015.We initiated the phase III study after PRX-102,

179、in preclinical studies,showed significantly longer half-life due to higherenzyme stability,enhanced activity in Fabry disease affected organs leading to reduction of the accumulated substrate andreduced immunogenicity,which together can potentially lead to improved efficacy through increased substra

180、te clearanceand significantly lower formation of ADAs.Sixteen adult,nave Fabry patients(9 male and 7 female)completed the phase I/II study,each in one of three dosinggroups,0.2 mg/kg,1 mg/kg and 2 mg/kg.Each patient received IV infusions of PRX-102 every two weeks for 12 weeks,with efficacy follow-u

181、p after six-month and twelve-month periods.The overall results demonstrate that PRX-102 reachesthe affected tissue and reduces kidney Gb3 inclusions burden and lyso-Gb3 in the circulation.A high correlation was foundbetween the two Fabry disease biomarkers,reduction of kidney Gb3 inclusions and the

182、reduction of plasma lyso-Gb3 oversix months of treatment.Data was recorded at 24 months from 11 patients who completed 12 months of the long-term open-label extension trial thatsucceeded the phase I/II study.Patients who did not continue in the extension trial included female patients who became orp

183、lanned to become pregnant and therefore were unable to continue in accordance with the study protocol and patients whorelocated to a location where treatment was not available under the clinical study.Results show that lyso-Gb3 levels decreased approximately 90%from baseline.Renal function remained

184、stable with meaneGFR levels of 108.02 and 107.20 at baseline and 24 months,respectively,with a modest annual eGFR slope of-2.1.Animprovement across all the gastrointestinal symptoms evaluated,including severity and frequency of abdominal pain andfrequency of diarrhea,was noted.Cardiac parameters,inc

185、luding LVM,LVMI and EF,remained stable with no cardiacfibrosis development detected.In conclusion,an improvement of over 40%in disease severity was shown as measured bythe Mainz Severity Score Index,or MSSI,a score compiling the different elements of the disease severityTable of Contents14including

186、neurological,renal and cardiovascular parameters.In addition,an improvement was noted in each of theindividual parameters of the MSSI.The majority of adverse events were mild-to-moderate in severity,and transient in nature.During the first 12 months oftreatment,only three of 16 patients(less than 19

187、%)formed ADAs of which two of these patients(less than 13%)hadneutralizing antibodies.Importantly,however,the ADAs turned negative for all three of these patients following 12 monthsof treatment.The ADA positivity effect had no observed impact on the safety,efficacy or continuous biomarker reduction

188、of PRX-102.Of the patients who completed the trial,10 patients opted to continue receiving PRX-102 in an open-label,60-monthextension study under which all patients were switched to receive 1 mg/kg of the drug,the selected dose for our BALANCEand BRIDGE studies.Extension StudiesPatients who complete

189、d the BALANCE,BRIDGE and BRIGHT studies,and the extension of the phase I/II study,wereoffered the opportunity to continue PRX-102 treatment in one of two long-term open-label extension studies.Overall,126subjects who participated in our PRX-102 clinical program initially opted,with the advice of the

190、 treating physician,toenroll in one of our long-term,open label,extension studies of PRX-102:97 patients in the 1 mg/kg every two weeksextension study(PB-102-F60,NCT03566017)(10 subjects who completed an extension study from the phase I/II study,18subjects who completed the BRIDGE study;69 subjects

191、who completed the BALANCE study),and 29 subjects whocompleted the BRIGHT study in the 2 mg/kg every four weeks extension study(PB-102-F51,NCT03614234).Two of thesubjects in the PB-102-F51 study are being treated with 1 mg/kg every two weeks.As of March 1,2023,sponsorship of thetwo extension studies

192、was transferred to Chiesi,and Chiesi is now administering the open-label extension studies.Over time,and as Elfabrio is approved for marketing in different jurisdictions,participants switch-out of the open-labelextension studies.Most of them have transferred to a commercial setting;others withdraw f

193、or other reasons.Pediatric FLY StudyThe pediatric FLY study,to be sponsored by Chiesi with our collaborative efforts,is currently in the start-up phase.Thestudy is planned to be a multi-center,open-label trial to assess the safety,pharmacodynamics,efficacy andpharmacokinetics of Elfabrio in patients

194、 from two years to less than 18 years of age with confirmed Fabry disease.Thedesign of the study is based on the Initial Pediatric Study Plan(iPSP)agreed to with the FDA and the paediatricinvestigation plan(PIP)for Elfabrio,which has been accepted,as amended,by the Paediatric Committee(PDCO)of theEM

195、A.Japanese RISE StudyChiesi is currently enrolling patients in its Japanese RISE clinical trial of PRX-102 for the treatment of Fabry disease inJapan.PEGylated Uricase(PRX-115)PRX-115 is our recombinant PEGylated uricase(urate oxidase)a chemically modified enzyme under development for thepotential t

196、reatment of severe gout patients.The uricase enzyme converts uric acid to allantoin,which is easily eliminatedthrough urine and does not exist naturally in humans.This recombinant enzyme,expressed via our ProCellEx system,isdesigned to lower uric acid levels and improve clinical manifestation of the

197、 disease while having low immunogenicity andincreased half-life of the drug in the blood.Pre-clinical data demonstrates long half-life,reduced immunogenic risk andhigh specific activity which supports the potential of PRX-115 to be a safe and effective treatment for patients with gout.One-month mult

198、iple dosing toxicity studies in two species and 6-month multiple dosing toxicity study in one species wereconducted to support single and multiple dose studies is humans.A phase I First in Human(FIH)single ascending dose(SAD)double-blind,placebo-controlled study designed to evaluatethe safety,pharma

199、cokinetics,pharmacodynamics(reduction of uric acid)and immunogenicity of PRX-115 in patients withelevated uric acid levels(NCT05745727)was commenced in March 2023.The study is being conducted atTable of Contents15New Zealand Clinical Research(NZCR)under the New Zealand Medicines and Medical Devices

200、Safety Authority(MedSafe)and the Health and Disability Ethics Committee(HDEC)guidelines.Fifty-six patients with no previousexposure to PEGylated uricase have been enrolled in the study.We anticipate announcing preliminary results in the secondquarter of 2024.Gout is the most common inflammatory arth

201、ritis,affecting an estimated 14.0 million adults in the United States,2.0 millionin France,2.0 million in United Kingdom,0.7 million in Italy,1.5 million in Germany,0.7 million in Spain and over 190.0million in China.An estimated approximately 5%of the gout population is considered to have chronic r

202、efractory disease.The risk of gout increases with age,and it is thus more common in ageing populations.Gout results from sustainedelevation of serum urate levels(hyperuricaemia).Urate levels may increase due to diet,genetic predisposition andenvironmental factors leading to the deposition of monosod

203、ium urate crystals andor tophi in joints,tendons and othertissues,which triggers recurrent episodes of pronounced acute inflammation,known as gout flares.Gout leads tosubstantial morbidity,severe pain,reduced quality of life,decreased physical function,increased healthcare costs,and losteconomic pro

204、ductivity.Furthermore,gout is strongly associated with a number of comorbidities,including hypertension,cardiovascular disease,renal impairment,diabetes,obesity,hyperlipidaemia and frequently in a combination known as themetabolic syndrome.Severe gout is generally described as a state of gout in whi

205、ch there is a presence of monosodium urate crystals with any ofthe following:frequent recurrent gout flares,chronic gouty arthritis,subcutaneous tophi or disease elements of gout seenvia imaging.Currently available urate-lowering therapies,can be effective in treating gout.However,low adherence,unde

206、rdosing and disease progression that cause high patient burden require new,effective and safe therapies to treat these severe,underserved gout patients.To date,two variants of recombinant uricases are approved for marketing:(i)Krystexxa(pegloticase)for treatment ofchronic gout refractory to conventi

207、onal therapy(gout patients who have contraindication/failure of other lowering uric acidtreatments)and(ii)Elitek,indicated for the treatment of tumor lysis syndrome but not gout.Both have a black boxwarning for anaphylaxis and other major side-effects.In particular,89%of patients treated with Kryste

208、xxa developed animmunogenic response associated with a failure to maintain normalization of serum uric acid levels over a 6-month therapycycle.The FDA label of krystexxa was amended in 2022 to include co-treatment of metrotrexate to prolong efficacy andincreases tolerability in patients with refract

209、ory gout.Krystexxa is no longer marketed in the European Union.The ECwithdrew the marketing authorization for Krystexxa in 2016 at the request of the marketing authorization holder whichnotified the EC of its decision not to market the product in the European Union for commercial reasons.We believe

210、thatnew effective,safe therapies are needed to treat severe gout,chronic refractory and uncontrolled gout,regardless oftreatment history.PRX-119PRX-119 is our plant cell-expressed PEGylated recombinant human DNase I product candidate being designed to elongatehalf-life in the circulation for NETs-re

211、lated diseases.NETs,Neutrophil extracellular traps,are web-like structures,releasedby activated neutrophils that trap and kill a variety of microorganisms.NETs are composed of DNA,histones,antimicrobial and pro-inflammatory proteins.Excessive formation or ineffective clearance of NETs can cause diff

212、erentpathological effects.NETs formation has been observed in various autoimmune,inflammatory and fibrotic conditions,diverse forms of thrombosis,cancer and metastasis.According to scientific literature,animal studies have demonstratedthat DNase treatment reduces NETs toxicity.Our proprietary modifi

213、ed DNase I design for long and customizedsystemically circulating in the bloodstream,may potentially enable effective treatment of these conditions.The administration of PRX-119 resulted in a decrease in circulating of DNA levels and significantly enhanced the survivalof mice in both a CLP-induced s

214、epsis model and an ARDS model.Intellectual PropertyWe have a robust patent portfolio,which is a key element of our overall strategy.We work to continually enhance,strengthen,and protect our intellectual property and now hold a broad portfolio of approximately 90 patents globally,including in Europe,

215、the United States,Israel and additional countries worldwide.Our patents are designed to protect ourTable of Contents16proprietary technology,proprietary products and product candidates,and their methods of use.Additionally,we haveapproximately 50 pending patent applications.During the year ended Dec

216、ember 31,2023,we received the following:New patents in each of New Zealand and the Russian Federation for the patent family named“TherapeuticRegimen For The Treatment of Fabry Using Stabilized Alpha-galactosidase,adding to the single previouslygranted patent in such family.A new patent in Brazil for

217、 the patent family named“DNase I Polypeptides,Polynucleotides Encoding Same,Methods of Producing DNase I and uses thereof in Therapy,adding to the two previously granted patents in suchfamily.A new patent in Brazil for the patent family named“Nucleic Acid Construct for Expression of Alpha-Galactosid

218、ase in Plants and Plant Cells,”adding to the nine previously granted patents in such family.New patents in each of the USA,New Zealand,Israel and South Africa for the patent family named“ModifiedDNase and uses thereof,”adding to the three previously granted patents in such family.Our competitive pos

219、ition and future success depend,in part,on our ability,and that of our licensees,to obtain and leveragethe intellectual property rights covering our product candidates,know-how,methods,processes and other technologies,toprotect our trade secrets,to prevent others from using our intellectual property

220、 and to operate without infringing on theintellectual property rights of third parties.We seek to protect our competitive position by filing United States,EuropeanUnion,Israeli and other foreign patent applications covering our technology,including both new technology andimprovements to existing tec

221、hnology.Our patent strategy includes obtaining patents on methods of production,compositions of matter and methods of use.We also rely on know-how,continuing technological innovation,licensing andpartnership opportunities to develop and maintain our competitive position.Our outstanding 7.50%Senior S

222、ecured Convertible Notes due 2024,or the 2024 Notes,are guaranteed by our subsidiariesand secured by perfected liens on all of our material assets,primarily consisting of our intellectual property assets,including a stock pledge of our foreign subsidiaries in favor of the holders of outstanding 2024

223、 Notes.As of December 31,2023,our patent portfolio consisted of several patent families(consisting of patents and/or patentapplications)covering our technology,protein expression methodologies and system and product candidates,as follows:Production of High MannoseProteins in Plant Culture/PCT/Il2004

224、 000181N/AJapan,Israel,Canada,RussianFederation,Mexico,India,Australia,South Africa,Republic ofKorea,Singapore,Europe,HongKong,Ukraine,China,USA,Brazil2024(1)(3)Plant Cell/Tissue CulturingDevice,System andMethod/PCT/Il2005/000228N/AIsrael2025Large Scale DisposableBioreactor/PCT/Il2008/000614N/AAustr

225、alia,Canada,China,Europe,Hong Kong,India,Israel,Republicof Korea,Russian Federation,Singapore,South Africa,USA,Brazil2028(2)Stabilized Alpha-galactosidase anduses thereof/PCT/Il2011/000209BrazilCanada,South Africa,RussianFederation,Singapore,Israel,India,New Zealand,Republic of Korea,Australia,2031(

226、3)Patent Name/Int.App.No.Global PendingJurisdictionsGranted JurisdictionsNominalExpiryTable of Contents17China,Japan,USA,Europe,Hong Kong,India,BrazilNucleic Acid Construct forExpression of Alpha-galactosidasein Plants and Plant Cells/PCT/Il2011/000719N/AIndia,China,Republic of Korea,Japan,Israel,Eu

227、rope,Hong Kong,USA,Brazil2024(2)Therapeutic Regimen For TheTreatment of Fabry UsingStabilized Alpha-galactosidase/PCT/Il2018/050018USA,Europe,Brazil,Japan,Canada,Australia,Chile,Israel,Republic of Korea,China,Mexico,Hong KongSouth Africa,New Zealand,RussianFederation2038Dry Powder Formulations ofDNa

228、se 1/PCT/Il2013/050094N/AIsrael,USA2033DNase I Polypeptides,Polynucleotides Encoding Same,Methods of Producing DNase Iand uses thereof in Therapy/PCT/Il2013/050097N/AEurope,Israel,Brazil2033Inhalable Liquid Formulations ofDNase I/PCT/Il2013/050096N/AIsrael,USA2033Modified DNase and uses thereof/PCT/

229、Il2016/050003Europe,Canada,China,Hong KongUSA,Australia,Mexico,Israel,New Zealand,South Africa2036Use of Plant Cells Expressing aTNF Alpha Polypeptide Inhibitorin Therapy/PCT/IL2014/050231N/AIsrael2034Removal of Constructs fromTransformed Cells/PCT/IL2019/051266USA,Israel,Japan,NewZealand,AustraliaN

230、/AN/ALong-ActingDNase/PCT/IL2021/051207Canada,Israel,USA,Japan,Europe,Hong Kong,Republicof Korea,ChinaN/AN/ADicer-Like Knock-Out Plant Cells/PCT/IL2021/051194Israel,USA,Japan,Europe,Hong Kong,Republic ofKorea,ChinaN/AN/AModified Uricase and UsesThereof/PCT/IL2021/051305Japan,Canada,Brazil,USA,Israel

231、,Mexico,Europe,Republic of Korea,ChinaN/AN/AMethods of treating diseasesassociated with elevated uric acidN/AN/AN/A(1)Patent granted in Australia expires in 2029.(2)Patent granted in the United States expires in 2032.(3)PTE/SPC applications were submitted for some of the patents.We are aware of U.S.

232、patents,and corresponding international counterparts of such patents,owned by third parties thatcontain claims covering methods of producing glucocerebrosidase.We do not believe that,if any claim of infringementwere to be asserted against us based upon such patents,taliglucerase alfa would be found

233、to infringe any valid claim undersuch patents.However,there can be no assurance that a court would find in our favor or that,if we choose or are requiredto seek a license to any one or more of such patents,a license would be available to us on acceptable terms or at all.In April 2005,Protalix Ltd.en

234、tered into a license agreement with Icon Genetics AG,or Icon,pursuant to which wereceived an exclusive worldwide license to develop,test,use and commercialize Icons technology to express certainproteins in our ProCellEx protein expression system.We are also entitled to a non-exclusive worldwide lice

235、nse to makeand have made other proteins expressed by using Icons technology.As consideration for the license,we are obligated tomake royalty payments equal to varying low,single-digit percentages of net sales of products by us,our affiliates,or anyTable of Contents18sublicensees under the agreement.

236、In addition,we are obligated to make milestone payments equal to$350,000,in theaggregate,for each product developed under the license,upon the achievement of certain milestones.Our license agreement with Icon remains in effect until the earlier of the expiration of the last patent under the agreemen

237、tor,if all of the patents under the agreement expire,20 years after the first commercial sale of any product under theagreement.Icon may terminate the agreement upon written notice to us that we are in material breach of our obligationsunder the agreement and we are unable to remedy such material br

238、each within 30 days after we receive such notice.Further,Icon may terminate the agreement in connection with certain events relating to a wind up or bankruptcy,if wemake a general assignment for the benefit of our creditors,or if we cease to conduct operations for a certain period.Iconmay also termi

239、nate the exclusivity granted to us by written notice if we fail to reach certain milestones within a designatedperiod of time.Notwithstanding the termination date of the agreement,our obligation to pay royalties to Icon under theagreement may expire prior to the termination of the agreement,subject

240、to certain conditions.CompetitionThe biotechnology and pharmaceutical industries are characterized by rapidly evolving technology and significantcompetition.Competition from numerous existing companies and others entering the fields in which we operate is intenseand expected to increase.Most of thes

241、e companies have substantially greater research and development,manufacturing,marketing,financial,technological personnel and managerial resources than we do.In addition,many specializedbiotechnology companies have formed collaborations with large,established companies to support research,developmen

242、tand commercialization of products that may be competitive with our current and future product candidates andtechnologies.Acquisitions of competing companies by large pharmaceutical or biotechnology companies could furtherenhance such competitors financial,marketing and other resources.Academic inst

243、itutions,governmental agencies andother public and private research organizations are also conducting research activities and seeking patent protection andmay commercialize competitive products or technologies on their own through collaborations with pharmaceutical andbiotechnology companies.With re

244、spect to Gaucher disease,we face competition primarily from two ERTs,Sanofi Genzymes Cerezyme and Takedas(Shire)Vpriv.In addition,Actelion markets a small molecule drug for the treatment of mild to moderate Type 1 Gaucherdisease(Zavesca or miglustat),an oral treatment approved by the FDA only for pa

245、tients for whom ERT is not a therapeuticoption.In addition,Sanofi Genzyme markets a small molecule oral drug,Cerdelga,approved for Gaucher patients withcertain CYP2D6 metabolizer status.We are aware of other treatments and gene therapies in early clinical development andlater stage clinical developm

246、ent for the treatment of Gaucher disease.With respect to Fabry disease,we face competition primarily from Sanofi Genzyme(Fabrazyme),Takeda(Replagal)andAmicus(Galafold).In addition,we are aware of other late clinical stage,early clinical stage and experimental drugs thatare being developed by other c

247、ompanies for the treatment of Fabry disease.With respect to severe gout,we face competition from Horizon Therapeutics Public Limited Company(Krsytexxa),whichis indicated for treatment of chronic gout in adult patients refractory to conventional therapy.In addition,we are aware ofother clinical stage

248、,early clinical stage and experimental refractory or chronic gout treatments.For example,we are awareof a product candidate for chronic refractory gout that recently completed a phase III clinical trial and has met the primaryendpoints of the trial,and of another product candidate that is the subjec

249、t of a phase II clinical trial for hyperuricemia ingout patients with advanced CKD.We also face potential competition to our ProCellEx system from companies that are developing other platforms for the expression of recombinant therapeutic pharmaceuticals.We are aware of companies that are developing

250、 alternative technologies to develop and produce therapeutic proteins in anticipation of the expiration of certain patent claims covering marketed proteins.A number of companies have developed or are developing alternative expression technologies.Examples include Crucell N.V.s(acquired by Johnson&Jo

251、hnson)expression system based on human-cell technology,Dyadic International Inc.s expression system based on a fungus,Pfenex Inc.s(acquired by Ligand Pharmaceuticals Incorporated)bacteria-based expression system,and others.Companies developing alternate plant-based technologies include iBio,Inc.,Med

252、icago,Inc.,and eleva.Unlike ProCellEx,these alternate technologies are not cell-based.These companies base their product development on transgenic plants or whole plants.Table of Contents19Agreements and PartnershipsElelyso PfizerWe have licensed to Pfizer the global rights to Elelyso in all markets

253、,excluding Brazil,pursuant to an Amended andRestated Exclusive License and Supply Agreement,or the Amended Pfizer Agreement,which we entered into with Pfizerin October 2015 to amend and restate our initial Exclusive License and Supply Agreement with Pfizer,or the PfizerAgreement.Pursuant to the Amen

254、ded Pfizer Agreement,Pfizer retains 100%of revenue and reimburses 100%of directcosts.For the first 10-year period after the execution of the Amended Pfizer Agreement,we have agreed to sell drugsubstance to Pfizer for the production of Elelyso,subject to certain terms and conditions,and Pfizer mainta

255、ins the right toextend the supply period for up to two additional 30-month periods,subject to certain terms and conditions.In asubsequent amendment,we agreed that after the completion of the first 10-year supply period,the supply term wouldautomatically extend for a five-year period.Any failure to c

256、omply with our supply commitments may subject us tosubstantial financial penalties.The Amended Pfizer Agreement includes customary provisions regarding cooperation forregulatory matters,patent enforcement,termination,indemnification and insurance requirements.We retain distributionrights to taligluc

257、erase alfa in Brazil.Elelyso Fundao Oswaldo Cruz(Fiocruz)Elelyso,marketed as BioManguinhos alfataliglicerase in Brazil,is commercialized in Brazil through the Brazil Agreementwith Fiocruz,which became effective in January 2014.Gaucher patients in Brazil are entitled to receive ERT paid for bythe Bra

258、zilian MoH.The Brazilian MoH clinical treatment guidelines(PCDT)state that BioManguinhos alfataliglicerase isthe therapy of choice for newly diagnosed patients.BioManguinhos alfataliglicerase is currently estimated to be used byapproximately 25%of Gaucher patients in Brazil.The Brazil Agreement prov

259、ides for a staged technology transfer which is intended to transfer to Fiocruz the capacity andskills required for the Brazilian government to construct its own manufacturing facility,at its sole expense,and to producea sustainable,high-quality,and cost-effective supply of BioManguinhos alfataliglic

260、erase.Fiocruz has not satisfied certainpurchase commitments under the Brazil Agreement.Accordingly,we and Fiocruz discuss on a continuous basis,potentialsteps to maximize sales of BioManguinhos alfataliglicerase sales to the Brazilian MoH.Elfabrio(pegunigalsidase alfaPRX-102)Chiesi FarmaceuticiWe ha

261、ve entered into two exclusive global licensing and supply agreements for PRX-102 for the treatment of Fabry diseasewith Chiesi;the Exclusive License and Supply Agreement dated as of October 17,2017,made by and betweenProtalix Ltd.and Chiesi,or the Chiesi Ex-US Agreement,and the Exclusive License and

262、 Supply Agreement dated as ofJuly 23,2018,made by and between Protalix Ltd.and Chiesi,or the Chiesi US Agreement.The Chiesi Ex-US Agreementand the Chiesi US Agreement are referred to herein collectively as the Chiesi Agreements.Under the agreements,Protalix Ltd.has received$50.0 million in upfront p

263、ayments and development cost reimbursements of$45 million,and isentitled to more than$1.0 billion in potential milestone payments tiered payments for drug product purchased from ProtalixLtd.equal to 15%-35%(ex-US)and 15%-40%(US),depending on the amount of annual net sales in the applicableterritorie

264、s.Under the Chiesi Ex-US Agreement,we granted to Chiesi an exclusive license for all markets outside of the United Statesto commercialize PRX-102.Chiesi made an upfront payment to Protalix Ltd.of$25.0 million in connection with theexecution of the agreement,and Protalix Ltd.was entitled to additiona

265、l payments of up to$25.0 million in developmentcosts in the aggregate,capped at$10.0 million per year.Protalix Ltd.is also eligible to receive additional payments of up toa maximum of$320.0 million,in the aggregate,in regulatory and commercial milestone payments.Protalix Ltd.agreed tomanufacture all

266、 of the PRX-102 needed for all purposes under the agreement,subject to certain exceptions,and Chiesi willpurchase PRX-102 from Protalix Ltd.,subject to certain terms and conditions.Chiesi is required to make tiered paymentsof 15%to 35%of its net sales,depending on the amount of annual sales,as consi

267、deration for the supply of PRX-102.The exclusive license to develop and commercialize PRX-102 in the United States were granted to Chiesi under the ChiesiUS Agreement.Protalix Ltd.received an upfront,non-refundable,non-creditable payment of$25.0 million fromTable of Contents20Chiesi and was entitled

268、 to additional payments of up to a maximum of$20.0 million to cover development costs for PRX-102,capped at$7.5 million per year.Protalix Ltd.is also eligible to receive additional payments of up to a maximum of$760.0 million,in the aggregate,in regulatory and commercial milestone payments.Chiesi ag

269、reed to make tiered paymentsof 15%to 40%of its net sales under the Chiesi US Agreement to Protalix Ltd.,depending on the amount of annual sales,subject to certain terms and conditions,as consideration for product supply.On May 13,2021,we signed a binding term sheet with Chiesi amending the Chiesi Ag

270、reements in order to provide ourcompany with near-term capital.Chiesi agreed to make a$10.0 million payment to us before the end of the second quarterof 2021 in exchange for a$25.0 million reduction in a longer term regulatory milestone payment provided in the ChiesiEX-US Agreement.All other regulat

271、ory and commercial milestone payments remain unchanged.We received the paymentin June 2021.We also agreed to negotiate certain manufacturing related matters.On August 29,2022,we entered into the F/F Agreement and the Letter Agreement.Under the F/F Agreement,we agreed tosupply Chiesi with drug substa

272、nce for PRX-102 and,following relevant technology and technical information transferactivities,Chiesi has agreed,among other things,to provide us with commercial fill/finish services for PRX-102,includingto support the anticipated global launch of PRX-102.The F/F Agreement will expire December 31,20

273、25,unless terminatedearlier in accordance with its terms and may be extended by mutual agreement in writing for an additional period of sevenyears.The Letter Agreement changed the obligations of both us and Chiesi under the Chiesi Agreements with respect to,among other things,the evaluation,selectio

274、n and establishment of an initial alternate source of commercial fill/finishservices for PRX-102.In addition,the Letter Agreement amended certain provisions of the Chiesi Agreements to reflectthe appointment of Chiesi as a supplier to our company of commercial fill/finish services and the potential

275、establishment ofan initial alternate source of commercial fill/finish services.ManufacturingWe use our current manufacturing facility in Carmiel,Israel,which has approximately 14,700 sq/ft of clean rooms builtaccording to industry standards,to manufacture drug substance for Elfabrio and Elelyso for

276、commercial purposes and,withrespect to Elfabrio,in connection with clinical trials.We maintain an approximately 3,400 sq/ft pilot plant for proteindevelopment and to manufacture supplies for clinical trials(phase I and phase II).Elelyso,Elfabrio and our drug productcandidates must be manufactured in

277、 a clean environment and in compliance with cGMPs set by the FDA and other relevantforeign regulatory authorities.We intend to use our manufacturing space to produce all of the drug substance needed inconnection with the clinical trials for our other product candidates.In 2017,the FDA approved the s

278、upplemental New Drug Application(sNDA)we submitted to allow us to convert ourmanufacturing facility from a single dedicated product facility to a multi-product facility.This conversion allows us torealize potentially significant operational savings.Our facilitys current capacity can serve all of our

279、 current and expectedcommercial and clinical needs.Our manufacturing facilities are subject to inspections by various regulatory authorities from time to time.We haveundergone successful inspections by the FDA,the Irish Medicines Board(under the EMAs centralized marketingauthorization procedure),the

280、 Brazilian National Health Surveillance Agency(ANVISA),the Israeli Ministry of Health,theTurkish Ministry of Health,the Australian Therapeutic Goods Administration(TGA)and Health Canada.Our current facility in Israel was granted“Approved Enterprise”status,and we have elected to participate in the al

281、ternativebenefits program.Our facility is located in a top priority location,or“Zone A,”location,and,therefore,our income fromthe Approved Enterprise will be tax exempt in Israel for a 10-year period,commencing with the year in which we firstgenerate taxable income from the relevant Approved Enterpr

282、ise and after we use our net operating loss carryforwards,orNOLs.We expect to be entitled to similar tax benefits for a number of years thereafter.To remain eligible for these taxbenefits,we must continue to meet certain conditions,and if we increase our activities outside of Israel,for example,byfu

283、ture acquisitions,such increased activities generally may not be eligible for inclusion in Israeli tax benefit programs.Inaddition,our technology is subject to certain restrictions with respect to the transfer of technology and manufacturingrights.Table of Contents21Raw Materials and SuppliersWe bel

284、ieve that the raw materials that we require throughout the manufacturing process of Elfabrio and Elelyso,and ourcurrent and potential drug product candidates,are widely available from numerous suppliers and are generally consideredto be generic industrial biological supplies.We rely on a single,appr

285、oved supplier for certain materials relating to thecurrent expression of our proprietary biotherapeutic proteins through ProCellEx.We have identified additional suppliers formost of the materials required for the production of our product candidates.Development and regulatory approval of our pharmac

286、eutical products are dependent upon our ability to procure activeingredients(DS)and certain packaging materials from sources approved by the FDA and other regulatory authorities.TheFDA and other regulatory approval processes require manufacturers to specify their proposed suppliers of activeingredie

287、nts(which is not relevant to our company),intermediate material and certain packaging materials in theirapplications.From time to time,we intend to continue to identify alternative approved suppliers to ensure the uninterruptedsupply of necessary raw materials.Government RegulationsU.S.Drug Developm

288、ent ProcessThe FDA regulates drugs under the U.S.Federal Food,Drug,and Cosmetic Act,or the FFDCA,and its implementingregulations.Drugs are also subject to other federal,state and local statutes and regulations.Biologics are subject toregulation by the FDA under the FFDCA,the Public Health Service Ac

289、t,and related regulations and other federal,stateand local laws and regulations.Biological products include a wide variety of products including vaccines,blood and bloodcomponents,gene therapies,tissue and proteins.Unlike most prescription products made through chemical processes,biological products

290、 generally are made from human and/or animal materials.To be lawfully marketed in interstatecommerce,a biologic product must be the subject of a BLA issued by the FDA on the basis of a demonstration that theproduct is safe,pure and potent,and that the facility in which the product is manufactured me

291、ets standards to assure thatthe product continues to be safe,pure and potent.The FDA has developed,and is continuously updating,the requirementswith respect to cell and gene therapy products and has issued documents concerning the regulation of cellular and tissue-based products.Manufacturers of cel

292、l and tissue-based products must comply with the FDAs current good tissue practices,or cGTP,which are FDA regulations that govern the methods used in,and the facilities and controls used for,themanufacture of such products.The primary intent of the cGTP requirements is to ensure that cell and tissue

293、-based productsare manufactured in a manner designed to prevent the introduction,transmission and spread of communicable disease.The process of obtaining regulatory approvals and ensuring compliance with appropriate federal,state and local statutesand regulations in the United States,and foreign sta

294、tutes and regulations,requires the expenditure of substantial time andfinancial resources.Failure to comply with the applicable U.S.requirements at any time during the product developmentprocess,approval process,or after approval,may subject an applicant to administrative or judicial sanctions.These

295、sanctions could include the FDAs refusal to approve pending applications,withdrawal of an approval,a clinical hold,warning letters,product recalls,product seizures,product detention,total or partial suspension of production ordistribution,injunctions,fines,refusals of government contracts,restitutio

296、n,disgorgement or civil or criminal penalties.The process required by the FDA before a biological product or drug may be marketed in the United States generallyinvolves the following:Completion of preclinical laboratory tests,animal studies and formulation studies according to Good LaboratoryPractic

297、es or other regulations;Submission to the FDA of an investigational new drug application,or IND,which must become effective beforehuman clinical trials may begin;Performance of adequate and well-controlled clinical trials according to Good Clinical Practices,or GCP,toestablish the safety and efficac

298、y of the proposed biological product or drug for its intended use;Table of Contents22Submission to the FDA of a BLA for a new biological product or a new drug application,or NDA,for a newdrug;Satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the drug i

299、sproduced to assess compliance with cGMP to assure that the facilities,methods and controls are adequate topreserve the drugs or biologics identity,strength,quality and purity;andFDA review and approval of the BLA or NDA.All clinical trials must be conducted under the supervision of one or more qual

300、ified investigators in accordance with GCPregulations.These regulations include the requirement that all subjects participating in the clinical trial provide theirinformed consent regarding the trial.Further,an institutional review board,or IRB,must review and approve the plan forany clinical trial

301、before it commences at any institution.An IRB considers,among other things,whether the risks toindividuals participating in the trials are minimized and are reasonable in relation to anticipated benefits.The IRB alsoapproves the information regarding the clinical trial and the consent form that must

302、 be provided to each clinical trialsubject,or his or her legal representative,and must monitor the clinical trial until completed.Once an IND is in effect,eachnew clinical protocol and any amendments to the protocol must be submitted to the FDA for review,and to the IRBs forapproval.Human clinical t

303、rials are typically conducted in three sequential phases that may overlap or be combined:Phase I.The product is initially introduced into healthy human subjects and tested for safety,dosage tolerance,absorption,metabolism,distribution and excretion.In the case of some products for severe or life-thr

304、eateningdiseases,especially when the product may be too inherently toxic to ethically administer to healthy volunteers,the initial human testing may be conducted in patients having the specific disease.Phase II.Phase II clinical trials involve investigations in a limited patient population to identi

305、fy possible adverseeffects and safety risks,to preliminarily evaluate the efficacy of the product for specific targeted diseases and todetermine dosage tolerance and the optimal dosage and schedule.Phase III.Phase III clinical trials are undertaken to further evaluate dosage,clinical efficacy and sa

306、fety in anexpanded patient population at geographically dispersed clinical trial sites.These trials are intended to establishthe overall risk/benefit ratio of the product and provide an adequate basis for regulatory approval and productlabeling.Post-approval studies,also called Phase IV trials,may b

307、e conducted after initial marketing approvals.These studies areused to obtain additional experience from the treatment of patients in the intended therapeutic indication and may berequired by the FDA as part of the approval process.Progress reports detailing the results of the clinical trials must b

308、e submitted at least annually to the FDA and safety reportsmust be submitted to the FDA and the investigators for serious and unexpected side effects.Phase I,Phase II and Phase IIItesting may not be completed successfully within any specified period,if at all.The FDA or the trial sponsor may suspend

309、or terminate a clinical trial at any time on various grounds,including a finding that the study subjects or patients are beingexposed to an unacceptable health risk.Similarly,an IRB can suspend or terminate approval of a clinical trial at itsinstitution if the clinical trial is not being conducted i

310、n accordance with the IRBs requirements or if the product candidatehas been associated with unexpected serious harm to patients.Concurrent with clinical trials,companies usually complete additional animal studies and must also develop additionalinformation about the chemistry and physical characteri

311、stics of the product and finalize a process for manufacturing theproduct in commercial quantities in accordance with cGMP requirements.The manufacturing process must be capable ofconsistently producing quality batches of the product candidate and,among other things,the manufacturer must developmetho

312、ds for testing the identity,strength,quality and purity of the final product.Additionally,appropriate packaging mustbe selected and tested and stability studies must be conducted to demonstrate that the applicable product candidate does notundergo unacceptable deterioration over its shelf life.Table

313、 of Contents23The results of product development,preclinical studies and clinical trials,along with descriptions of the manufacturingprocess,analytical tests conducted on the product candidate,proposed labeling and other relevant information,aresubmitted to the FDA as part of an NDA or BLA,requestin

314、g approval to market the product.The submission of an NDA orBLA is subject to the payment of substantial user fees which may be waived under certain limited circumstances.The testing and approval processes require substantial time and effort,and may not result in an approval on a timely basis,if at

315、all.The FDA may refuse to approve a BLA or NDA if the applicable regulatory criteria are not satisfied or mayrequire additional clinical data or other data and information.Generally,it takes one to three years to obtain approval.Ifquestions arise during the FDA review process,approval may take a sig

316、nificantly longer period of time.If a product receives regulatory approval,the approval may be significantly limited to specific diseases and dosages or theindications for use may otherwise be limited,which could restrict the commercial value of the product.Further,the FDAmay require that certain co

317、ntraindications,warnings or precautions be included in the product labeling.In addition,theFDA may require Phase IV testing which involves clinical trials designed to further assess a drugs or biologics safety andeffectiveness after BLA or NDA approval and may require testing and surveillance progra

318、ms to monitor the safety ofapproved products that have been commercialized.Orphan Drug DesignationUnder the Orphan Drug Act of 1983,the FDA may grant orphan drug designation to drugs and biological productsintended to treat a rare disease or condition,which is generally a disease or condition that a

319、ffects fewer than 200,000individuals in the United States or that affects more than 200,000 persons in the United States but that sales in the UnitedStates are not expected to recover the costs of developing and marketing a treatment drug.Orphan product designationdoes not convey any advantage in,or

320、 shorten the duration of,the regulatory review and approval process.Among thebenefits of orphan drug designation are possible funding and tax savings to support clinical trials,other financial incentivesand a waiver of the marketing application user fee.If a product that has orphan designation subse

321、quently receives the first FDA approval for the disease or condition for whichit has such designation,the product is entitled to orphan product exclusivity,which means that the FDA may not approveany other applications to market the same treatment for the same indication for seven years,except in li

322、mitedcircumstances,such as(i)the drugs orphan designation is revoked;(ii)its marketing approval is withdrawn;(iii)theorphan exclusivity holder consents to the approval of another applicants product;(iv)the orphan exclusivity holder isunable to assure the availability of a sufficient quantity of drug

323、;or(v)a showing of clinical superiority to the product withorphan exclusivity by a competitor product.Competitors,however,may receive approval of different products for theindication for which the orphan product has exclusivity or obtain approval for the same product but for a differentindication fo

324、r which the orphan product has exclusivity.Orphan drug status in the European Union has similar but notidentical benefits in the European Union.Patent Term Restoration and Marketing ExclusivityDepending upon the timing,duration and specifics of FDA marketing approval of our product candidates,some o

325、f our U.S.patents may be eligible for limited patent term extension under the Drug Price Competition and Patent Term RestorationAct of 1984,commonly referred to as the Hatch-Waxman Amendments.The Hatch-Waxman Amendments permit a patentrestoration term of up to five years as compensation for patent t

326、erm lost during product development and the FDAregulatory review process.However,patent term restoration cannot extend the remaining term of a patent beyond a total of14 years from the products approval date.The patent term restoration period is generally one-half the time between(a)theeffective dat

327、e of an IND and the submission date of a BLA or an NDA plus(b)the time between the submission date of aBLA or an NDA and the approval of that application.Only one patent applicable to an approved drug is eligible for theextension and the extension must be requested prior to expiration of the patent.

328、The U.S.Patent and Trademark Office,orUSPTO,in consultation with the FDA,reviews and approves the application for any patent term extension or restoration.We anticipate that we will apply for restorations of the patent term for certain of patents covering our product candidates.Table of Contents24Fa

329、st Track DesignationThe FDA has a fast track program that is designed to facilitate the development and expedite the review of drugs to treatserious conditions and fill an unmet medical need,the purpose being to make important new drugs available to patientsearlier.A drug candidate that receives Fas

330、t Track designation from the FDA is eligible for some or all of the following:more frequent meetings with the FDA to discuss the drugs development plan and ensure collection of appropriate dataneeded to support drug approval;more frequent written communication from the FDA about such things as the d

331、esign ofthe proposed clinical trials;eligibility for the FDAs Accelerated Approval and Priority Review,if relevant criteria are met;and eligibility for Rolling Review,which allows a drug company to submit completed sections of its BLA or NDA forreview by the FDA,rather than waiting until every secti

332、on of the BLA or NDA is completed before the entire applicationcan be reviewed.BLA or NDA review usually does not begin until the drug company has submitted the entire applicationto the FDA.We used the Rolling Review option for our taliglucerase alfa NDA,which we completed in April 2010.Accelerated

333、ApprovalSection 901 of the U.S.Food and Drug Administration Safety Innovations Act amends the FFDCA to allow the FDA tobase Accelerated Approval for drugs for serious conditions that fill an unmet medical need on whether the drug has aneffect on a surrogate or an intermediate clinical endpoint.A surrogate endpoint used for Accelerated Approval is a marker;that is,a laboratory measurement,radiograp