Spyre Therapeutics, Inc. (SYRE) 2018年年度報告「NASDAQ」.pdf

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1、UNITED STATESSECURITIES AND EXCHANGE COMMISSIONWashington,DC 20549FORM 10-KANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1934For the fiscal year ended December 31,2018TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1934For the trans

2、ition period from to Commission file number 001-37722AEGLEA BIOTHERAPEUTICS,INC.(Exact name of Registrant as specified in its charter)Delaware 46-4312787(State or Other Jurisdiction ofIncorporation or Organization)(I.R.S.EmployerIdentification No.)901 S.MoPac ExpresswayBarton Oaks Plaza OneSuite 250

3、Austin,TX 78746(Address of Principal Executive Offices)(Zip Code)Registrants Telephone Number,including area code:(512)942-2935Securities registered pursuant to Section 12(b)of the Exchange Act:Title of Each Class Name of Each Exchange on Which RegisteredCommon Stock,$0.0001 Par Value Per Share The

4、Nasdaq Stock Market LLC(Nasdaq Global Market)Securities registered pursuant to Section 12(g)of the Exchange Act:NoneIndicate by check mark if the Registrant is a well-known seasoned issuer,as defined in Rule 405 of the Securities Act.Yes No Indicate by check mark if the Registrant is not required to

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

6、t was required to file such reports),and(2)has been subject to such filing requirements for the past 90 days.Yes No Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T(232.405 of this c

7、hapter)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 if disclosure of delinquent filers pursuant to Rule 405 of Regulation S-K is not contained herein,and will not be contained,to the best of Registrants

8、 knowledge,in definite proxy or information statements incorporated by reference in Part III of this Form 10-K or any amendment to this Form 10-K.Indicate by check mark whether the Registrant is a large accelerated filer,an accelerated filer,a non-accelerated filer,a smaller reporting company,or an

9、emerging growth company.See the definitions of“large accelerated filer,”“accelerated filer,”“smaller reporting company,”and“emerging growth company”in Rule 12b-2 of the Exchange Act.Large accelerated filer Accelerated filerNon-accelerated filerSmaller reporting companyEmerging growth companyIf an em

10、erging growth company,indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a)of the Exchange Act.Indicate by check mark whether the Registrant is a shell com

11、pany(as defined in Rule 12b-2 of the Exchange Act).Yes No The aggregate market value of the voting stock held by non-affiliates of the Registrant on June 30,2018(the last business day of the Registrants second fiscal quarter),based upon the closing price of$10.58 of the Registrants common stock as r

12、eported on The Nasdaq Global Market,was approximately$199.1 million.Indicate the number of shares outstanding of each of the issuers classes of common stock,as of the latest practicable date.Class Outstanding at March 1,2019Common stock,$0.0001 par value per share 28,819,900 sharesDOCUMENTS INCORPOR

13、ATED BY REFERENCEPortions of the Registrants Definitive Proxy Statement(“Proxy Statement”)relating to the 2019 Annual Meeting of Stockholders will be filed with the Commission within 120 days after the end of the Registrants 2018 fiscal year and is incorporated by reference into Part III of this Rep

14、ort.2TABLE OF CONTENTS PagePART IItem 1.Business.4Item 1A.Risk Factors.26Item 1B.Unresolved Staff Comments.66Item 2.Properties.66Item 3.Legal Proceedings.66Item 4.Mine Safety Disclosures.66PART IIItem 5.Market for Registrants Common Equity,Related Stockholder Matters and Issuer Purchases of Equity S

15、ecurities.67Item 6.Selected Financial Data.69Item 7.Managements Discussion and Analysis of Financial Condition and Results of Operations.72Item 7A.Quantitative and Qualitative Disclosures About Market Risk.82Item 8.Financial Statements and Supplementary Data.83Item 9.Changes in and Disagreements wit

16、h Accountants on Accounting and Financial Disclosure.107Item 9A.Controls and Procedures.107Item 9B.Other Information.108PART IIIItem 10.Directors,Executive Officers and Corporate Governance.109Item 11.Executive Compensation.109Item 12.Security Ownership of Certain Beneficial Owners and Management an

17、d Related Stockholder Matters.109Item 13.Certain Relationships and Related Transactions,and Director Independence.109Item 14.Principal Accountant Fees and Services.109PART IVItem 15.Exhibits and Financial Statement Schedules.110Item 16.Form 10-K Summary.112SIGNATURES.1133NOTE ABOUT FORWARD-LOOKING S

18、TATEMENTSThis Annual Report on Form 10-K,or Annual Report,contains forward-looking statements within the meaning of Section 21E of the Securities Exchange Act of 1934,as amended,or the Exchange Act,and section 27A of the Securities Act of 1933,as amended,or the Securities Act.All statements containe

19、d in this Annual Report other than statements of historical fact,including statements regarding our future results of operations and financial position,business strategy,market size,potential growth opportunities,nonclinical and clinical development activities,efficacy and safety profile of our prod

20、uct candidates,use of net proceeds from our public offerings,our ability to maintain and recognize the benefits of certain designations received by product candidates,the timing and results of nonclinical studies and clinical trials,commercial collaboration with third parties,and the receipt and tim

21、ing of potential regulatory designations,approvals and commercialization of product candidates,are forward-looking statements.The words“believe,”“may,”“will,”“potentially,”“estimate,”“continue,”“anticipate,”“predict,”“target,”“intend,”“could,”“would,”“should,”“project,”“plan,”“expect,”and similar ex

22、pressions that convey uncertainty of future events or outcomes are intended to identify forward-looking statements,although not all forward-looking statements contain these identifying words.These forward-looking statements are subject to a number of risks,uncertainties and assumptions,including tho

23、se described in Item 1A,“Risk Factors”and elsewhere in this Annual Report.Moreover,we operate in a very competitive and rapidly changing environment,and new risks emerge from time to time.It is not possible for our management to predict all risks,nor can we assess the impact of all factors on our bu

24、siness or the extent to which any factor,or combination of factors,may cause actual results to differ materially from those contained in any forward-looking statements we may make.In light of these risks,uncertainties,and assumptions,the forward-looking events and circumstances discussed in this Ann

25、ual Report may not occur and actual results could differ materially and adversely from those anticipated or implied in the forward-looking statements.You should not rely upon forward-looking statements as predictions of future events.Although we believe that the expectations reflected in the forward

26、-looking statements are reasonable,we cannot guarantee that the future results,levels of activity,performance or events and circumstances reflected in the forward-looking statements will be achieved or occur.We undertake no obligation to update publicly any forward-looking statements for any reason

27、after the date of this report to conform these statements to actual results or to changes in our expectations,except as required by law.You should read this Annual Report with the understanding that our actual future results,levels of activity,performance and events and circumstances may be material

28、ly different from what we expect.Unless the context indicates otherwise,as used in this Annual Report,the terms“Aeglea,”“the Company,”“we,”“us,”and“our”refer to Aeglea BioTherapeutics,Inc.,a Delaware corporation,and its subsidiaries taken as a whole,unless otherwise noted.“Aeglea”and all product can

29、didate names are our common law trademarks.This Annual Report contains additional trade names,trademarks and service marks of other companies,which are the property of their respective owners.We do not intend our use or display of other companies trade names,trademarks or service marks to imply a re

30、lationship with,or endorsement or sponsorship of us by,these other companies.4PART IITEM 1.BUSINESSOverviewWe are a biotechnology company that designs and develops innovative human enzyme therapeutics for patients with rare genetic diseases and cancer.We believe our novel approach of utilizing human

31、 enzymes offers advantages that provide a greater likelihood of clinical success and commercial adoption.Our drug-hunting capabilities in enzyme engineering,preclinical disease modeling,and drug development in both rare genetic disease and cancer allow us to identify and advance innovative opportuni

32、ties to address important unmet medical needs for the benefit of patients.Our programs and the decisions we make to progress assets into clinical studies are driven by the following considerations:-Potential for enhancement of human enzymatic activity-Ability to create novel human enzymatic activity

33、-Strong preclinical data and rationale-Limited or no competition-Meaningful commercial opportunities-Worldwide commercial rightsWe are a patient-focused organization conscious of the fact that people with a rare genetic disease or cancer have limited treatment options,and we recognize that their liv

34、es and well-being are highly dependent upon our efforts to develop improved therapies.For this reason,we are passionate about designing and developing novel therapeutics to address significant unmet medical need for rare genetic disease and cancer.Our StrategyOur goal is to build a world-class biote

35、chnology company dedicated to the discovery,development,and commercialization of human enzyme-based therapeutics that transform the lives of patients by addressing unmet medical needs in both rare genetic disease and cancer.To achieve that goal,we intend to:Successfully advance our lead product cand

36、idate,pegzilarginase,through clinical development.-For Arginase 1 Deficiency,we believe we have the only therapeutic in clinical development that addresses the underlying drivers of disease progression.Pegzilarginase is currently being evaluated in two ongoing clinical trials for Arginase 1 Deficien

37、cy,consisting of one Phase 1/2 clinical trial for the treatment of Arginase 1 Deficiency and one open label extension study for patients with Arginase 1 Deficiency.In December 2018,we announced the design of our global pivotal Phase 3 PEACE(Pegzilarginase Effect on Arginase 1 Deficiency Clinical End

38、points)trial with a primary endpoint of plasma arginine reduction and secondary endpoints which include assessments of clinical outcomes on mobility and adaptive behavior,safety and pharmacokinetics.We finalized the design of the PEACE trial to be a single,global pivotal trial based on FDA and EMA f

39、eedback.We expect to dose the first patient in the Phase 3 PEACE trial in the second quarter of 2019 and anticipate that topline data from the study will be available in the first quarter of 2021.Additional repeat dose data from our Phase 1/2 clinical trial of pegzilarginase in Arginase 1 Deficiency

40、 is expected in the first half of 2019.-For our oncology indications,pegzilarginase is currently being evaluated in two ongoing clinical trials,consisting of one Phase 1 clinical trial for the treatment of advanced solid tumors,and one Phase 1/2 combination clinical trial of pegzilarginase with Merc

41、ks anti-PD-1 therapy,KEYTRUDA(pembrolizumab)for the treatment of patients with small cell lung cancer(SCLC).After determining the maximum tolerated dose in the Phase 1b combination study,we advanced to Phase 2 in December 2018 and dosed the first patients.We expect that topline data from open label

42、Phase 2 study will be available in the first half of 2020.5Target enzyme-based therapeutic opportunities within rare genetic disease and cancer where regulation of abnormal metabolism provides the potential for important medical benefits.Our focus is on rare genetic diseases and cancers where there

43、is a plausible link between disease development,progression,and metabolite levels including amino acids.Advancing to clinical development is gated by strong biological rationale and preclinical data.We favor diseases where there are meaningful potential commercial markets with limited or no current

44、competition and where potential therapy can transform patient outcomes.Concurrently develop and commercialize multiple product candidates.We are committed to the discovery and development of multiple product candidates of engineered human enzymes,as we believe this results in a diversified portfolio

45、,leverages organizational efficiencies,and utilizes economies of scale.This includes continually investing in our internal research capabilities to expand our portfolio.Develop and implement our precision medicine strategy to increase the probability of clinical success.An integral part of our produ

46、ct development programs is a precision medicine strategy designed to identify patient populations for subjects with the greatest potential to benefit from our metabolism focused approaches.In rare genetic disease this strategy is focused on identifying mis-diagnosed and undiagnosed patients.In the U

47、nited States,we continue to pursue avenues to improve disease state awareness and diagnosis of Arginase 1 Deficiency.In oncology,we are exploring biomarkers to identify patients with tumors sensitive to amino acid deprivation.We believe that targeting these patients will both enhance our ability to

48、detect evidence of clinical activity earlier in clinical development and improve the probability of treating their cancers effectively.Seek global approval and commercialization of our product candidates.We retain worldwide intellectual property rights to all of our product candidates.We intend to p

49、ursue clinical and regulatory programs for approval in the United States and internationally.Ultimately,our plan is to establish a multi-country commercial organization in rare genetic disease and seek commercial partnerships in select regional markets.In cancer,we plan to build a focused commercial

50、 organization in the United States and strategically evaluate partnership opportunities globally.Our FocusEnzyme-based Therapeutic Opportunities in MetabolismOur company was initially founded to develop therapeutics for diseases characterized by abnormal amino acid metabolism.We have broadened the s

51、cope of our metabolic focus,which we believe allows us to better leverage our enzyme engineering capabilities.Metabolism refers to fundamental chemical reactions that are critical to life-sustaining processes.Metabolism follows specific pathways that are comprised of various biochemical reactions ge

52、nerally catalyzed by proteins known as enzymes.Enzymes accelerate complex reactions and serve as key regulators of metabolic pathways by responding to changes in the cells environment or signals from other cells.An in-depth understanding of abnormal metabolic pathways is crucial to developing therap

53、ies that may address various disease states,including rare genetic diseases and cancer.Our core capability of exploiting these abnormal metabolic pathways has allowed us to develop engineered human enzyme therapies with the potential to reduce toxic levels of amino acids that may lead to novel,disea

54、se-modifying treatments for these rare genetic diseases.In addition,with our focus on the innovative field of cancer cell metabolism,we strive to leverage our engineered human enzyme product candidates to degrade the key nutrients needed for cancer cell survival and proliferation.The mechanism of ac

55、tion of our drugs also presents the potential for novel combination therapies when used together with existing or emerging standards of care.Background on Rare Genetic Disease and Arginase 1 DeficiencyThe incidence of a single metabolic abnormality typically occurs in fewer than one per 100,000 live

56、 births.While rare,most of these diseases have severe or life-threatening characteristics and many metabolic abnormalities are likely to be under-diagnosed.Current treatment options for these disorders are limited.While diet modification or nutrient 6supplementation can provide some benefit to patie

57、nts,several metabolic abnormalities have been treated successfully with enzyme therapy.We are targeting Arginase 1 Deficiency,a urea cycle disorder,with our lead product candidate,pegzilarginase.Arginase 1 Deficiency is a serious progressive disease with significant morbidity and early mortality.Thi

58、s disease is caused by deficiency of a key arginine metabolizing enzyme.This leads to two important harmful metabolic effects:(1)the accumulation of high levels of arginine and other arginine derived metabolites,and(2)an impairment of the urea cycle which leads to elevation of ammonia levels,especia

59、lly at times of stress.The high plasma arginine level is believed to be the key driver of the spasticity,developmental delays,and seizures that develop in early childhood and progress over time.The impairment of the urea cycle also means that these patients are at risk of episodic and sometimes pers

60、istent hyperammonemia,which causes irritability,nausea,and vomiting with potential to progress to brain swelling,encephalopathy,and death.There is currently no approved therapeutic agent specifically indicated for Arginase 1 Deficiency or effective treatment options for these patients.Current diseas

61、e management practice includes a medical diet with protein restriction and ammonia scavengers.Medical literature suggests that disease progression can be slowed with strict adherence to dietary protein restriction,which often includes the use of specially formulated supplements.Such dietary modifica

62、tion has been shown to partially reduce plasma arginine levels,but generally does not reach the range stipulated by medical guidelines.Therefore,this disease management approach is difficult to manage,unpalatable,and generally inadequate to treat the majority of patients.Ammonia-scavenging drugs suc

63、h as RAVICTI(glycerol phenylbutyrate)and BUPHENYL(sodium phenylbutyrate)are used to manage elevated ammonia levels.Liver transplantation has been reported to achieve normalization of arginine levels;however,this intervention is available only to a small fraction of patients and carries significant p

64、rocedural risk.The lack of a treatment option that directly address the cause of Arginase 1 Deficiency supports the need for a therapy that manages the harmful metabolic effects caused by accumulation of high levels of arginine and other arginine-derived metabolites(also referred to as guanidino com

65、pounds),as well as the accumulation of ammonia caused by the disease related slowing of the urea cycle.The development of an arginine reducing therapeutic introduced early in a patients life could potentially minimize the exposure to the neurotoxic effects of arginine,its metabolites,and ammonia,as

66、well as potentially enabling improved protein intake.Reduction of plasma arginine levels to below the recommended guidelines for an extended period during the pegzilarginase dosing schedule has the potential to slow or halt the progression of the disease,thereby offering the potential for more norma

67、l growth and development in these patients.Arginase 1 Deficiency is a rare disorder,and disease prevalence has not been established in the medical literature.Newborn screening data for two reliably detected urea cycle disorders allowed disease experts to estimate the incidence of Arginase 1 Deficien

68、cy at 1:950,000 births.Assuming a less than normal life span,we believe that at least 600 individuals in global addressable markets have Arginase 1 Deficiency.Presently,only 34 U.S.states and jurisdictions screen for Arginase 1 Deficiency,and screening in Europe is not universal.Because the symptoms

69、 of Arginase 1 Deficiency may overlap with other disorders such as cerebral palsy or epilepsy,the prevalence of Arginase 1 Deficiency may be underestimated in regions that do not mandate newborn screening for this disease.To date we have identified more than 170 patients in the major addressable mar

70、kets,primarily in the U.S.and Europe.Background on CancerCancer is the second-leading cause of death in the United States.The National Cancer Institute estimates that in 2018 there were approximately 1.7 million new cases and approximately 610,000 deaths from cancer in the United States.Cancer origi

71、nates from defects in the cells genetic code,or DNA,that disrupt the mechanisms that normally prevent uncontrolled cell growth.We believe that the altered metabolism of cancer cellsthe atypical uptake and breakdown of nutrients provides an opportunity to develop important new cancer treatments.Cance

72、r cells rapidly change how they take up and utilize nutrients.However,while cancer cell metabolic abnormalities fuel tumor growth and alter tumor immune response,they also expose vulnerabilities that can be targeted to selectively destroy tumor cells.It is our belief that depriving cancer cells of k

73、ey amino acids that are essential for cell survival and tumor growth will provide an effective treatment for some cancers,both as a single agent and in combination with existing or emerging standards of care.Enzyme-based therapies that degrade amino acids have shown clinical benefit in the treatment

74、 of cancer.For example,Oncaspar(pegaspargase)and Erwinaze(asparaginase Erwinia chrysanthemi)were approved as part of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia.Degrading the amino acid asparagine with Oncaspar(pegaspargase),an E.coli-derive

75、d L-asparaginase enzyme,in combination with chemotherapy generates much improved remission rates as compared with chemotherapy alone.Aeglea and other companies have also reported clinical responses with arginine degrading enzyme treatment in some cancers known to be 7arginine dependent.However,the c

76、linical impact reported by other third parties appear limited as the microbial-derived arginine-degrading enzyme elicited an immune response that appears to neutralize the activity of the drug and therefore may result in limited clinical utility.The use of microbial enzymes as human therapeutics is

77、often limited by an immune response to a foreign protein.We expect our enzyme product candidates,which are engineered from human proteins,may have more favorable drug-like properties and be less likely to elicit an immune response compared with microbial enzymes.This is supported by our experience w

78、ith pegzilarginase to date in our clinical programs compared to clinical trials reported in the medical literature with a bacterial-derived arginine depleting enzyme.We believe our approach may provide greater flexibility with respect to the target amino acids that can be addressed.Using pegzilargin

79、ase to enzymatically deplete extracellular arginine needed by some cancer cells provides an approach that,when used alone or in combination with existing or emerging standards of care,has the potential to be an effective treatment paradigm for cancer patients.Published literature suggests that a var

80、iety of cancers could potentially respond to amino acid deprivation,which offers us several potential targets for cancer treatment opportunities.Our Development ProgramsPegzilarginase OverviewOur lead product candidate,pegzilarginase,is an enhanced human arginase that enzymatically degrades the amin

81、o acid arginine.Pegzilarginase is a recombinant,human Arginase 1 enzyme with modifications that enhance the stability and arginine-degrading activity of the enzyme in human plasma,and we believe it may have a lower likelihood of immunogenicity in patients than bacterial arginine-degrading enzymes.Ou

82、r lead program,pegzilarginase,is in early clinical development for two indications.1.Arginase 1 Deficiency,which is a rare progressive autosomal recessive metabolic disease caused by a marked decrease in the activity of the native arginase 1 enzyme,which appears to play a key role in the degradation

83、 of arginine as part of the urea cycle.2.Arginine dependent cancers,which demonstrate a potential vulnerability that leads to an increased dependency on extracellular argininePegzilarginase in Rare Genetic DiseasePEACE Global Pivotal Phase 3 Study of Pegzilarginase in Patients with Arginase 1 Defici

84、ency:In December 2018,we announced the design of our single,global pivotal Phase 3 PEACE trial to evaluate the safety and efficacy of pegzilarginase.The trial is believed to be the first-ever investigative therapy that addresses the high arginine levels that are the key drivers of this devastating d

85、isease for patients with Arginase 1 Deficiency.We designed the PEACE trial based on input from the FDA and EMA.We expect to dose the first patient in the PEACE trial in the second quarter of 2019 and anticipate that topline data from the Phase 3 PEACE study will be available in the first quarter of

86、2021.PEACE is a global,randomized,double-blind,placebo-controlled trial designed to assess the effects of treatment with pegzilarginase versus placebo over 24 weeks with a primary endpoint of plasma arginine reduction from baseline.The primary endpoint is intended to assess the effectiveness of pegz

87、ilarginase in lowering plasma arginine levels given the evidence that improved plasma arginine control has the potential to improve the clinical status and slow disease progression in patients with Arginase 1 Deficiency.Secondary endpoints will include mobility and adaptive behavior as assessments o

88、f clinically meaningful effects,in addition to safety and pharmacokinetics.The FDA and EMA indicated that data from this Phase 3 PEACE trial showing plasma arginine reduction in conjunction with improvements in clinically meaningful aspects of the disease may be sufficient to support a marketing app

89、lication for pegzilarginase in Arginase 1 Deficiency.We plan to enroll 30(pediatric and adult)patients with Arginase 1 Deficiency.Patients enrolled in the trial are randomized on a two-to-one basis to receive weekly infusions of pegzilarginase(0.1 mg/kg),or placebo for the double-blind treatment per

90、iod of 24 weeks.Dose adjustments during this period can be made to optimize plasma arginine control for levels outside the range of 50 to 150 M.Patients will be considered eligible for the PEACE trial during screening if they exhibit average plasma arginine of greater than 250 M,are greater than two

91、 years of age and have a deficit in at least one dimension of mobility or adaptive behavior.All assessments and dose adjustments will be conducted in a blinded fashion at pre-specified intervals.Patients will remain on current disease management for the duration of the Phase 3 PEACE trial.In additio

92、n to the primary endpoint of plasma arginine reduction,secondary endpoints in the Phase 3 PEACE trial will evaluate pegzilarginase relative to placebo through a multi-dimensional assessment of clinical response.A clinical 8responder is defined as a patient exhibiting improvement from baseline in mob

93、ility(2 Minute Walk Test or Functional Mobility Assessment)or adaptive behavior(Vineland Adaptive Behavior Scale).Additional secondary endpoints include a response rate for each individual assessment,the total number of mobility and adaptive behavior responses per patient and the proportion of patie

94、nts with plasma arginine below medical guidance of 200 M.Additional interim clinical data from our Phase 1/2 clinical trial reporting repeat dose administration of pegzilarginase is expected in the first half of 2019.Phase 1/2 Open Label Study of Pegzilarginase in Patients with Arginase 1 Deficiency

95、:We are conducting a Phase 1/2 clinical trial for the treatment of patients with Arginase 1 Deficiency to assess the safety and clinical activity of pegzilarginase.The Phase 1/2,multi-center,single-arm,open label trial of pegzilarginase enrolled 16 adult and pediatric patients with Arginase 1 Defici

96、ency in the United States,Canada,and Europe,exceeding the initial target of 10 patients.The Phase 1/2 dosing was completed in February 2019,with 14 patients completing 8 weeks of repeat dosing.The trial is investigating both single ascending doses(Part 1)and repeated dosing(Part 2).The primary endpo

97、int of the trial is safety and tolerability of intravenous administration of pegzilarginase in patients with Arginase 1 Deficiency.The trial also will evaluate the pharmacokinetic and pharmacodynamic effects of repeated doses of pegzilarginase on plasma arginine levels.Additionally,patients who comp

98、lete the repeat dose part of the Phase 1/2 trial are eligible to enroll in a long-term open label extension study.In October 2018,we announced new positive interim clinical data at the 2018 American Society of Human Genetics(ASHG)Conference from our ongoing Phase 1/2 trial of pegzilarginase in patie

99、nts with Arginase 1 Deficiency.We reported clinical improvements with repeat dose administration of pegzilarginase after only eight weeks,including consistent reduction of arginine and improvement in mobility or adaptive behavior.Pegzilarginase was generally well tolerated;most treatment-related adv

100、erse events were mild,and while investigators considered some of the hypersensitivity events as serious adverse events,they were generally manageable with standard measures and all patients continued study treatment.Additionally,we completed and exceeded our enrollment target with 16 patients in the

101、 Phase 1/2 clinical trial.If the data from our Phase 1/2 and open label extension trials are supportive,we may seek to accelerate our development plan for pegzilarginase by requesting to use established regulatory pathways,such as Breakthrough Therapy Designation.Regardless of whether we receive thi

102、s designation,we anticipate initiating a pivotal trial in the second quarter of 2019 and,if successful,we expect that this trial would support registration filing in the US and Europe.Phase 1/2 Open Label Extension Study to Evaluate the Long-Term Safety,Tolerability and Effects of Pegzilarginase in

103、Patients with Arginase 1 Deficiency Who Received Treatment in a Previous Study:After completing the repeat dose portion of the Phase 1/2 study and at least four weeks of post-treatment observation,patients are allowed to continue treatment with pegzilarginase by enrolling in a long-term open label e

104、xtension study.This study is expected to provide important insights into the longer term clinical effects of reducing plasma arginine.In December 2017,we announced the initiation of this study with the recruitment of two patients who had previously completed the repeat dose phase(Part 2)of the previ

105、ous study.Currently,10 patients have enrolled in the long-term open label extension study,and we expect to enroll 13 patients by the second quarter of 2019.Regulatory Designations:We have obtained orphan drug designation from the FDA and EMA,as well as Fast Track Designation from the FDA,for pegzila

106、rginase for the treatment of patients with Arginase 1 Deficiency.In addition,we announced in October 2018 that the FDA granted a rare pediatric disease designation for pegzilarginase for the treatment of Arginase 1 Deficiency.This designation by the FDA confirms our eligibility to receive a rare ped

107、iatric disease priority review voucher upon approval of a qualifying biologics license application for pegzilarginase if completed before October 1,2022.Pegzilarginase in CancerBackground Biology:We are developing pegzilarginase to target arginine-dependent cancers.Arginine is considered a semi-esse

108、ntial amino acid because,under conditions such as enhanced proliferation,tissue injury,or stress,cells are unable to make enough arginine and are therefore dependent on an extracellular source.The role of arginine and its metabolites in cancer has been studied extensively in preclinical models with

109、demonstrated effects,including enhancement of tumor growth and cellular proliferation.Conversely,restriction of dietary arginine attenuates tumor growth in experimental tumor models.Many types of cancers lack the ability to synthesize intracellular arginine due to lack of expression of argininosucci

110、nate synthase1(ASS1),argininosuccinate lyase(ASL),or ornithine transcarbamoylase(OTC),which are enzymes in the urea cycle.As a result,these cancers depend on extracellular arginine without which they may exhibit 9reduced protein synthesis and proliferation,and undergo autophagy and/or apoptosis,esta

111、blishing a correlation between their inability to synthesize arginine and vulnerability to arginine deprivation.Based on data from our preclinical studies and the published scientific and medical literature,arginase 1 degrades arginine to ornithine and urea.Ornithine cannot be used to make arginine

112、by cancer cells that lack expression of OTC,ASS or ASL.Pezilarginase is intended to target cancer cells that depend on extracellular arginine by depriving the cells of the amino acid that is essential for cell survival and tumor growth.We believe pegzilarginase has the potential to provide an effect

113、ive treatment option in combination with existing or emerging standards of care for patients with some cancers.Diagnostic Potential:As documented in scientific and medical literature and from our own preclinical research,the lack of expression of any one or more of the enzymes OTC,ASS1 or ASL in tum

114、or cells has been shown to be associated with cancer cell sensitivity to arginine depletion.Our preclinical research has focused on the reduction or loss of expression of ASS1 as the predominant cause of tumor arginine dependence.We found that low or no expression of ASS1 in nonclinical patient deri

115、ved xenograft models of melanoma or SCLC can result in sensitivity to arginine depletion by pegzilarginase.Phase 1/2 Combination Trial in Patients with SCLC:In the first quarter of 2018,we initiated an open label Phase 1b clinical collaboration with Merck to evaluate the combination of pegzilarginas

116、e with Mercks anti-PD1 therapy,pembrolizumab,for the treatment of patients with SCLC that relapsed or progressed after platinum-based chemotherapy.The primary objectives in Phase 1b were to determine the safety and recommended dose of pegzilarginase to be used in combination with pembrolizumab in Ph

117、ase 2.In March 2019,we announced the Phase 1b topline data from 16 patients enrolled across three cohorts.The recommended Phase 2 dose was established at 0.27 mg/kg/week of pegzilarginase in combination with pembrolizumab.Of nine patients in Phase 1b treated at the recommended Phase 2 dose,three pat

118、ients had stable disease at 9 weeks,one partial response was observed,and three patients remained on treatment as of the data cutoff.The safety profile was consistent with pegzilarginase monotherapy observations.We initiated enrollment in open label Phase 2 in December 2018 with topline data expecte

119、d in the first half of 2020.The Phase 2 primary objective is objective response rate(ORR),and secondary objectives include safety,clinical benefit rate,time to response,duration of response,progression free survival(PFS),and overall survival.Phase 1 Dose Escalation Trial of Pegzilarginase in Patient

120、s with Advanced Solid Tumors:In October 2015,we initiated the Phase 1 open label,multiple dose,dose escalation clinical trial in patients with advanced solid tumors.The primary objective of dose-escalation is to determine the maximum tolerated dose,and secondary objectives are to evaluate the safety

121、,tolerability,and pharmacokinetic profile of pegzilarginase.The inclusion criteria include patients with locally advanced or metastatic solid tumors that failed to respond to or progressed under standard treatment,could not tolerate standard therapies,or for which no standard therapy exists.In Decem

122、ber 2017,we reported topline results of the dose escalation trial in which 40 patients were enrolled.The maximum tolerated dose was established at 0.33 mg/kg weekly by intravenous infusion,based on observations of reversible rash and reversible tremor at 0.40 mg/kg/week.Two dose-limiting toxicities(

123、DLT)were observed:failure to thrive and maculopapular rash.Other treatment-related serious or Grade 3/4 adverse events(AEs)that were not DLTs per protocol,including those that occurred after the DLT window,were hypophosphatemia,anemia(developed from a Grade 1 baseline),neutropenia(developed from a G

124、rade 1 baseline),tremor,weakness,and transient hypertension.Treatment-related AEs in 10%or more of patients included nausea,stomatitis/mouth sores,fatigue,vomiting,rash,decreased appetite,and diarrhea,which were primarily Grades 1 or 2.Other serious adverse events,including death,occurred on study b

125、ut were not considered related to pegzilarginase treatment.Most patients discontinued due to disease progression,and only one patient discontinued due to an adverse event that was considered related to pegzilarginase(tremor).Clinical proof of mechanism was demonstrated,with a rapid and sustained red

126、uction of plasma arginine to levels substantially less than the normal range in cancer patients.Additionally,preliminary evidence suggesting clinical activity was observed in two patients with forms of melanoma who had stable disease longer than 12 weeks while receiving pegzilarginase.Upon completio

127、n of the dose escalation in patients with advanced solid tumors,we initiated three separate cohort expansions of patients with SCLC,uveal melanoma,and cutaneous melanoma.These cancer types were selected because nonclinical studies and the medical literature suggested that a significant fraction of p

128、atients are expected to have cancers that are dependent on extracellular arginine.The primary endpoint of each cohort expansion is to assess the safety of pegzilarginase in patients with each tumor type.Secondary endpoints include the assessment of pharmacokinetics,pharmacodynamics and clinical resp

129、onse.We plan to also use the data to inform the viability of companion diagnostic development,which has the potential to enrich patient populations with the greatest likelihood of clinical success.10In March 2019,we announced the completion of enrollment to three separate cohort expansions of patien

130、ts with heavily pre-treated SCLC,uveal melanoma,and cutaneous melanoma,with clinical data expected to be submitted for publication later in 2019.We previously presented interim clinical data at the European Society for Medical Oncology(ESMO)2018 Congress in October 2018,demonstrating that pegzilargi

131、nase monotherapy resulted in anti-tumor activity in heavily pre-treated patients with advanced uveal and cutaneous melanoma.Across the two advanced melanoma cohorts,28 patients were enrolled with one confirmed partial response observed and eight patients with stable disease at 8 weeks.Three patients

132、 experienced treatment-related,Grade 3 serious adverse events,including asthenia and failure to thrive,vomiting and dehydration.For the SCLC cohort,no objective responses and no new safety findings were observed in the 13 heavily-pretreated patients in the single agent expansion arm,which completed

133、enrollment in December 2018.Anti-tumor activity appeared greater in melanomas lacking argininosuccinate synthetase 1(ASS1)expression,which is consistent with preclinical studies that suggest tumors lacking ASS1 expression are dependent on extracellular arginine for survival.Additionally,pegzilargina

134、se was shown to rapidly and sustainably deplete plasma arginine.The results,combined with preclinical evidence of synergy with immune checkpoint inhibitors,support further clinical evaluation of pegzilarginase in immunotherapy combinations.Preclinical PipelineAEB4104 in Patients with HomocystinuriaA

135、EB4104 is a novel recombinant human enzyme that degrades the amino acid homocysteine and its oxidized form homocystine.Aeglea is developing AEB4104 for the treatment of patients with cystathionine beta synthase(CBS)deficiency,also known as Classical Homocystinuria.Homocystinuria is an inherited diso

136、rder of methionine metabolism caused by mutations in CBS and other genes leading to elevated levels of plasma and tissue homocysteine and homocystine,which affect multiple organ systems and cause early mortality.Current disease management,which includes dietary protein(methionine)restriction,vitamin

137、s,and betaine supplementation,is insufficient to effectively control the more severe forms of the disease.In October 2018,we announced preclinical efficacy data on our AEB4104 homocystinuria program at the 2018 American Society of Human Genetics(ASHG)Conference,demonstrating that AEB4104 improved su

138、rvival and correction of disease-related abnormalities in a preclinical model of homocystinuria.AEB4104 decreased homocysteine and homocystine levels in the plasma,including the cystathionine beta synthase(CBS)deficient model(CBS-/-)and the high methionine diet-induced model of homocystinuria.Treatm

139、ent with AEB4104 prevented early mortality,stopped disease progression,and reversed liver pathology in the cystathionine beta synthase(CBS)deficient model(CBS-/-).We believe homocystinuria represents a viable market opportunity with significant unmet medical need,which we plan to address by continui

140、ng our preclinical development of AEB4104.Given the severity of the disease,the limitations of current disease management approaches,and the data demonstrating improved survival in a preclinical model of the disease,Aeglea initiated IND-enabling activities and is progressing manufacturing,pharmacolo

141、gy and other activities to support preclinical toxicology studies and advancement towards clinical trials.We anticipate filing an IND or CTA in the first quarter of 2020.AEB5100 in Patients with CystinuriaAEB5100 is a novel recombinant human enzyme that degrades plasma cystine and cysteine.Aeglea is

142、 developing AEB5100 for the treatment of patients with cystinuria,a rare genetic disease characterized by frequent and recurrent kidney stone formation requiring multiple procedural interventions,and by an increased risk of chronic kidney disease.Cystinuria occurs due to genetic mutations in amino a

143、cid transporters that lead to increased amounts of cystine in the urine.This results in high cystine concentrations in the urine and formation of kidney stones.In October 2018,we announced preclinical efficacy data on our AEB5100 cystinuria therapeutic program at the 2018 American Society of Nephrol

144、ogy(ASN)Conference,demonstrating that AEB5100 lowered blood levels of cystine,decreased the amount of cystine in the urine and reduced both cystine crystal and kidney stone formation in a preclinical model of cystinuria.Given the compelling preclinical data and the limitations of current disease man

145、agement approaches,Aeglea initiated IND-enabling activities and is progressing manufacturing,pharmacology and other activities to support preclinical toxicology studies and advancement towards clinical trials.We anticipate filing an IND or CTA in the second half of 2020.11AEB3103AEB3103 is an engine

146、ered human enzyme that targets the degradation of the amino acid cysteine/cystine.Initial efficacy testing in preclinical models demonstrated significant depletion of glutathione and significantly increased levels of ROS in HMVP2 prostate cancer cells.AEB2109AEB2109 is an engineered human enzyme tha

147、t targets the degradation of the amino acid methionine.Earlier work from our enzyme engineering program has been presented in the scientific literature describing activity in an animal tumor model.We believe AEB2109 provides us with the opportunity to exploit a tumor vulnerability not yet successful

148、ly exploited for therapeutic benefit.We plan to continue our preclinical development efforts for AEB2109 and,if appropriate,proceed to IND-enabling studies with a development candidate from this program.Intellectual PropertyOur success depends in part on our ability to obtain and maintain patents an

149、d other forms of intellectual property rights,including in-licenses of intellectual property rights of others,for our product candidates,methods used to manufacture our product candidates and methods for treating patients using our product candidates,as well as our ability to preserve our trade secr

150、ets,to prevent third parties from infringing upon our proprietary rights and to operate without infringing upon the proprietary rights of others.As of December 31,2018,we are the owner of seven U.S.patents,expiring between 2029 and 2032,absent any extensions;three patents of which are directed to th

151、e compositions or methods of preparing pegzilarginase,and three patents of which are directed to compositions of methionine-gamma lyase enzymes,methods of treatment using the enzymes,nucleic acids encoding the enzymes,or methods of identifying the enzymes.One U.S.patent is to arginase variants other

152、 than pegzilarginase.As of December 31,2018,we are the owner of three U.S.patent applications that include methods of treatment that can use pegzilarginase.As of December 31,2018,we are the owner of one U.S.patent application that includes methionine-gamma-lyase enzymes that can include AEB2109 havi

153、ng L-methionine degrading activity.As of December 31,2018,we are also the owner of three pending U.S.patent provisional applications that include methods of treatment that can use pegzilarginase.As of December 31,2018,we also controlled two U.S.patents and five U.S.patent applications,exclusively li

154、censed to us by the Board of Regents of The University of Texas System,or the University.The two U.S.patents include compositions,methods of treatment,or nucleic acids encoding the compositions that include AEB2109.One U.S.patent application is directed to cystathionine-gamma-lyase variants other th

155、an AEB2109.One U.S.patent application is directed to a method of treatment that include using AEB2109.Three of the U.S.patent applications include compositions or methods of treatment that include AEB3103.One U.S.application includes enzyme variants and methods of treatment using the enzyme variants

156、 that can include AEB4104.As of December 31,2018,we also controlled one U.S.provisional patent application that includes compositions that include AEB5100.Any patents and patents issuing from the foregoing licensed U.S.patent applications are expected to expire between 2034 to 2038,absent any adjust

157、ments or extensions.As of December 31,2018,we owned a total of eight patents and five patent applications in foreign jurisdictions variously including:Australia,Canada,China,Europe,Japan,Hong Kong,Taiwan,and South Korea.As of December 31,2018,we are the owner of two PCT applications.Any issued forei

158、gn patents or patents issuing from these foreign patent applications,are expected to expire between 2029 and 2038,absent any adjustments or extensions.These owned foreign patent applications and patents include compositions of pegzilarginase or methods of using pegzilarginase to treat cancer or argi

159、nine 1 deficiency,or compositions and methods of using methionine-gamma-lyase enzyme variants.As of December 31,2018,we also controlled one Europe patent,three PCT applications,and thirteen pending foreign patent applications in Australia,Canada,China,Europe,Israel,Japan and South Korea,which are al

160、so exclusively licensed to us by the University.The controlled foreign Europe patent includes cystathionine-gamma-lyase variants,their formulations and use in treatment in cancer and includes AEB2109.The controlled foreign patent applications include compositions and their use in treatment that can

161、include AEB2109 or AEB3103.One PCT application includes compositions that can include AEB4104.Any foreign patent and foreign patents issuing from these controlled foreign applications are expected to expire between 2034 and 2038,absent any adjustments or extensions.Patents may extend for varying per

162、iods according to the date of patent filing or grant and the legal term of patents in various countries where patent protection is obtained.The actual protection afforded by a patent,which can vary from 12country to country,depends on the type of patent,the scope of its coverage and the availability

163、 of legal remedies in the country.We also use other forms of protection,such as trademark,copyright and trade secret protection,to protect our intellectual property,particularly where we do not believe patent protection is appropriate or obtainable.We aim to take advantage of all of the intellectual

164、 property rights that are available to us and believe that this comprehensive approach will provide us with proprietary positions for our product candidates,where available.We also protect our proprietary information by requiring our employees,consultants,contractors and other advisors to execute no

165、ndisclosure and assignment of invention agreements upon commencement of their respective employment or engagement.In addition,we also require confidentiality or service agreements from third parties that receive our confidential information or materials.LicensingOn December 24,2013,two of our wholly

166、-owned subsidiaries,AECase,Inc.,or AECase,and AEMase,Inc.,or AEMase,entered into license agreements with the University under which the University has granted to AECase and AEMase exclusive,worldwide,sublicenseable licenses.The University granted to AECase a license under a patent application relati

167、ng to the right to use,develop,manufacture,and market technology related to our AEB3103 product candidate.The University granted to AEMase license under a patent relating to the right to use technology related to our AEB2109 product candidate.In January 2017,we entered into an Amended and Restated P

168、atent License Agreement,or the Restated License,with the University which consolidated the two license agreements dated December 24,2013,revised certain obligations,and licensed additional patent applications to Aeglea.We have also entered into amendments to the Restated License in August 2017,Decem

169、ber 2017,and December 2018 to license additional patent applications.With respect to each product candidate covered by the Restated License,we could be required to pay the University up to$6.4 million in milestone payments based on the achievement of certain development milestones,including clinical

170、 trials and regulatory approvals,the majority of which are due upon the achievement of later development milestones,including a$5.0 million payment due on regulatory approval of a product and a$0.5 million payment payable on final regulatory approval of a product for a second indication.In addition,

171、we are required to pay the University a low single digit royalty on worldwide-net sales of products covered under the Restated License,together with a revenue share on non-royalty consideration received from sublicensees.The rate of the revenue share ranges from 6.5%to 25%,depending on the date the

172、sublicense agreement is signed.The term of the Restated License continues until the expiration of the last to expire of the patents licensed thereunder.The University may terminate the agreement under certain circumstances,including for a breach by us that is not cured within 30 or 60 days of notice

173、(depending on the type of breach),or if we or any of our affiliates or sublicensees participate in any proceeding to challenge the licensed patent rights(unless,with respect to sublicensees,we terminate the applicable sublicense).As of December 31,2018,we have paid$0.1 million under these license ag

174、reements.In connection with the above license agreements,we and each of our wholly-owned subsidiaries also entered into a Sponsored Research Agreement,or SRA,with the University on December 24,2013,which was subsequently amended.Pursuant to the SRA,we agreed to sponsor research to be conducted at th

175、e laboratory of Professor George Georgiou at the University related to the systemic depletion of amino acids for cancer therapy,and enzyme replacement for the treatment of patients having inborn metabolic defects.The SRA expired on August 31,2018.For the year ended December 31,2018,we paid$0.2 milli

176、on to the University under the SRA.Grant AgreementIn June 2015,we entered into a Cancer Research Grant Contract,or the Grant Contract,with the Cancer Prevention and Research Institute of Texas,or CPRIT,under which CPRIT awarded us a grant not to exceed$19.8 million to be used to develop novel cancer

177、 treatments by exploiting the unique metabolism of cancer cells.The contract ended in May 2018 with the full$19.8 million in grant proceeds collected and recognized as revenue under the Grant Contract.Pursuant to the Grant Contract,we granted to CPRIT a non-exclusive,irrevocable,royalty-free,perpetu

178、al,worldwide license to any technology and intellectual property resulting from the grant-funded activities and any other intellectual property that is owned by us and necessary for the exploitation of the technology and intellectual property resulting from the grant-funded activities,or the Project

179、 Results,for and on behalf of CPRIT and other governmental entities and agencies of the State of Texas and private or independent institutions of higher education located in Texas for education,research and other non-commercial purposes only.The terms of the Grant Contract require that we pay tiered

180、 royalties in the low-to mid-single digit percentages on revenues from sales and licenses of products or services that are based upon,utilize,are developed from or materially incorporate Project Results.Such royalties reduced to less than one percent after 13a mid-single-digit multiple of the grant

181、funds have been repaid to CPRIT in royalties.Such royalties are payable for so long as we have marketing exclusivity or patents covering the applicable product or service(or twelve years from first commercial sale of such product or service in certain countries if there is no such exclusivity or pat

182、ent protection).If we abandon patent applications or patents covering Project Results in certain major market countries,CPRIT can,at its own cost,take over the prosecution and maintenance of such patents and is granted a non-exclusive,irrevocable,royalty-free,perpetual license with right to sublicen

183、se in such country to the applicable Project Results.We are required to use diligent and commercially reasonable efforts to commercialize at least one commercial product or service or otherwise bring to practical application the Project Results.If CPRIT notifies us of our failure with respect to the

184、 foregoing,and such failure is not owing to material safety concerns,then,at CPRITs option,the applicable Project Results would be transferred to CPRIT and CPRIT would be granted a non-exclusive license to any other intellectual property that is owned by us and necessary for the exploitation of the

185、Project Results,and CPRIT,at its own cost,can commercialize products or services that are based upon,utilize,are developed from or materially incorporate Project Results.CPRITs option is subject to our ability to cure any failures identified by CPRIT within 60 days and a requirement to negotiate in

186、good faith with us with respect to an alternative commercialization strategy for a period of 180 days.CompetitionWhile we believe that our preclinical development experience and scientific knowledge provide us with competitive advantages,we face potential competition from many different sources,incl

187、uding major pharmaceutical companies,specialty pharmaceutical companies,biotechnology companies,and ultimately biosimilar and generic drug companies.Recent advances in gene-based medicine,such as gene therapy have resulted in market approvals of DNA and RNA-based therapeutics in certain rare genetic

188、 diseases.However,no gene therapy drugs have yet to demonstrate clinical success in the type of complex diseases targeted by our research approach with novel enzyme therapeutics.Any product candidates that we successfully develop and commercialize will compete with existing therapies and new therapi

189、es that may become available in the future.The acquisition or licensing of pharmaceutical products is also very competitive,and a number of more established companies,which have acknowledged strategies to license or acquire products,may have competitive advantages as may other emerging companies tak

190、ing similar or different approaches to product acquisitions.These established companies may have a competitive advantage over us due to their size,cash flows,and institutional experience.We compete in the segments of the pharmaceutical,biotechnology and other related markets that address rare geneti

191、c disease and cancer.Rare genetic disease.With respect to pegzilarginase for Arginase 1 Deficiency,there are currently no approved therapeutics that address the underlying cause of the disease and we are not aware of any other therapeutics that do so in clinical development.It is possible that compe

192、titors may produce,develop,and commercialize therapeutics,or utilize other approaches to treat Arginase 1 Deficiency.The current medical management of patients with Arginase 1 Deficiency includes dietary protein restriction,essential amino acid supplementation,and ammonia scavengers,which appears to

193、 slow the disease progression in some cases.Ammonia scavengers such as Horizon Pharmas RAVICTI(glycerol phenylbutyrate)and BUPHENYL(sodium phenylbutyrate)are used for the management of elevated blood ammonia in urea cycle disorders in combination with dietary approaches.Erytech Pharma announced a po

194、tential collaboration to explore preclinical development of an Arginase 1 Deficiency candidate.Cancer.With respect to our oncology product candidates,we compete with other companies that pursue a cancer metabolism approach,as well as companies that employ more common methods of treating patients suc

195、h as surgery,radiation and drug therapy.These drug therapies include chemotherapy,hormone therapy and targeted drugs,including biologic products such as engineered antibodies.There are a variety of available drug therapies marketed for cancer.In many cases,these drugs are administered in combination

196、 to enhance efficacy.Our product candidates may compete with many such therapies whether used in combination with or as an adjunct to other cancer therapies.Some of the currently approved drug therapies are branded and subject to patent protection,and others are available on a generic basis.Many of

197、these approved drugs are well-established therapies and are widely accepted by physicians,patients and third-party payors.In general,although there has been considerable progress over the past few decades in the treatment of cancer and the currently marketed therapies provide benefits to many patien

198、ts,most of these therapies are limited to some extent in their efficacy and frequency of adverse events,and none are successful in treating all patients.As a result,the level of morbidity and mortality from cancer remains high.In addition to currently marketed therapies,there are also a number of me

199、dicines in late-stage clinical development to treat cancer.While there are currently no approved drugs targeting tumor arginine dependence,we are aware of a 14number of compounds that are in clinical development and enrolling patients with solid and hematological malignancies,including Polaris Group

200、s microbial ADI-PEG 20 and Athenexs pegylated native human arginase 1.Additionally,Calithera Biosciences is targeting a therapy that inhibits arginase 1 as an immune modulator.These medicines in development may provide efficacy,safety,convenience and other benefits that are not provided by currently

201、 marketed therapies.As a result,they may provide significant competition for our product candidate pegzilarginase.Many of our competitors may have significantly greater financial resources and expertise in research and development,manufacturing,nonclinical testing,conducting clinical trials,obtainin

202、g regulatory approvals and marketing approved medicines than we do.Mergers and acquisitions in the pharmaceutical and biotechnology industries may result in even more resources being concentrated among a smaller number of our competitors.These competitors also compete with us in recruiting and retai

203、ning qualified scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials,as well as in acquiring technologies complementary to,or necessary for,our programs.Smaller or early stage companies may also prove to be significant competitors,part

204、icularly through collaborative arrangements with large and established companies.The key competitive factors affecting the success of all of our product candidates,if approved,are likely to be their efficacy,safety,convenience,price,the effectiveness of assays or tests that are essential to identify

205、ing an appropriate patient population,which we refer to as companion diagnostics,in guiding the use of related therapeutics,the level of biosimilar competition and the availability of reimbursement from government and other third-party payors.ManufacturingWe currently contract with third parties for

206、 the manufacturing and testing of our product candidates for nonclinical and clinical studies and intend to do so for future studies as well.We may qualify additional manufacturers to provide potential alternative sources for the active pharmaceutical ingredient and fill-and-finish services for pegz

207、ilarginase as the compound progresses through clinical development,prior to seeking marketing approval from FDA.We believe we have sufficient supplies of pegzilarginase for our ongoing and currently expected Phase 1/2 clinical trial to evaluate the combination of pegzilarginase with pembrolizumab fo

208、r the treatment of patients with small cell lung cancer and the Phase 3 pivotal trial in conjunction with the open label extension study for the treatment of patients with Arginase 1 Deficiency.The Diosynth AgreementIn November 2018,we entered into a master services agreement(Diosynth Agreement)with

209、 Fujifilm Diosynth Biotechnologies UK Limited,Fujifilm Diosynth Biotechnologies Texas,LLC,and Fujifilm Diosynth Biotechnologies U.S.A.,Inc.(collectively,Fujifilm).Under the Diosynth Agreement,Fujifilm provides research,development,testing and manufacturing services of certain of our products,which a

210、re or will be designated as programs pursuant to scope of work agreements.The fees for such services are or will be set out in each scope of work agreement.We may pay additional fees in consideration of certain research and development and technical consultancy services in relation to the procuremen

211、t,testing and management of consumables,subcontracted work(including delivery of material to and from such subcontractors),process-specific equipment(including installation and qualification thereof),modifications and special waste.Either party may terminate the Diosynth Agreement by giving six mont

212、hs written notice to the other party,provided there are no uncompleted programs existing at the date such notice is given,or upon material breach.We may also be required to pay Fujifilm cancellation fees in the event that we decide to terminate any scope of work prior to its completion,calculated as

213、 a percentage of the fees payable under the applicable scope of work agreement.Additionally,upon providing written notice,we may cancel certain stages or programs for convenience,and Fujifilm may terminate for certain unforeseen technical errors.Government Regulation and Product ApprovalGovernment a

214、uthorities in the United States,at the federal,state and local level,and in other countries and jurisdictions,including the European Union,extensively regulate,among other things,the research,development,testing,manufacture,quality control,approval,packaging,storage,recordkeeping,labeling,advertisin

215、g,promotion,distribution,marketing,post-approval monitoring and reporting,and import and export of pharmaceutical products.The processes for obtaining regulatory approvals in the United States and in foreign countries and jurisdictions,along with subsequent compliance with applicable statutes and re

216、gulations and other regulatory authorities,require the expenditure of substantial time and financial resources.15FDA approval processIn the United States,pharmaceutical products are subject to extensive regulation by the United States Food and Drug Administration,or the FDA.The Federal Food,Drug,and

217、 Cosmetic Act,or the FDC Act,and other federal and state statutes and regulations,govern,among other things,the research,development,testing,manufacture,storage,recordkeeping,approval,labeling,promotion and marketing,distribution,post-approval monitoring and reporting,sampling,and import and export

218、of pharmaceutical products.Biological products used for the prevention,treatment,or cure of a disease or condition of a human being are subject to regulation under the FDC Act,except the section of the FDC Act which governs the approval of new drug applications,or NDAs.Biological products are approv

219、ed for marketing under provisions of the Public Health Service Act,or PHSA,via a Biologics License Application,or BLA.However,the application process and requirements for approval of BLAs are very similar to those for NDAs,and biologics are associated with similar approval risks and costs as drugs.F

220、ailure to comply with applicable U.S.requirements may subject a company to a variety of administrative or judicial sanctions,such as clinical hold,FDA refusal to approve pending NDAs or BLAs,warning or untitled letters,product recalls,product seizures,total or partial suspension of production or dis

221、tribution,injunctions,fines,civil penalties,and criminal prosecution.Biological product development for a new product or certain changes to an approved product in the United States typically involves preclinical laboratory and animal tests,the submission to the FDA of an investigational new drug app

222、lication,or IND,which must become effective before clinical testing may commence,and adequate and well-controlled clinical trials to establish the safety and effectiveness of the drug for each indication for which FDA approval is sought.Satisfaction of FDA pre-market approval requirements typically

223、takes many years and the actual time required may vary substantially based upon the type,complexity,and novelty of the product or disease.Preclinical tests include laboratory evaluation of product chemistry,formulation,and toxicity,as well as animal trials to assess the characteristics and potential

224、 safety and efficacy of the product.The conduct of some preclinical tests must comply with federal regulations and requirements,including good laboratory practices.The results of preclinical testing are submitted to the FDA as part of an IND along with other information,including information about p

225、roduct chemistry,manufacturing and controls,and a proposed clinical trial protocol.Long term preclinical tests,such as animal tests of reproductive toxicity and carcinogenicity,may continue after the IND is submitted.A 30-day waiting period after the submission of each IND is required prior to the c

226、ommencement of clinical testing in humans.If the FDA has neither commented on nor questioned the IND within this 30-day period,the clinical trial proposed in the IND may begin.Clinical trials involve the administration of the investigational biologic to healthy volunteers or patients under the super

227、vision of a qualified investigator.Clinical trials must be conducted:(i)in compliance with federal regulations;(ii)in compliance with good clinical practice,or GCP,an international standard meant to protect the rights and health of patients and to define the roles of clinical trial sponsors,administ

228、rators,and monitors;as well as(iii)under protocols detailing the objectives of the trial,the parameters to be used in monitoring safety,and the effectiveness criteria to be evaluated.Each protocol involving testing on U.S.patients and subsequent protocol amendments must be submitted to the FDA as pa

229、rt of the IND.The FDA may order the temporary,or permanent,discontinuation of a clinical trial at any time,or impose other sanctions,if it believes that the clinical trial either is not being conducted in accordance with FDA requirements or presents an unacceptable risk to the clinical trial patient

230、s.The trial protocol and informed consent information for patients in clinical trials must also be submitted to an institutional review board,or IRB,for approval.An IRB may also require the clinical trial at the site to be halted,either temporarily or permanently,for failure to comply with the IRBs

231、requirements,or may impose other conditions.Clinical trials to support BLAs for marketing approval are typically conducted in three sequential phases,but the phases may overlap.In Phase 1,the initial introduction of the biologic into healthy human subjects or patients,the product is tested to assess

232、 safety,metabolism,pharmacokinetics,pharmacological actions,side effects associated with increasing doses,and,if possible,early evidence on effectiveness.Phase 2 usually involves trials in a limited patient population to determine the effectiveness of the drug or biologic for a particular indication

233、,dosage tolerance,and optimal dosage,and to identify common adverse effects and safety risks.If a compound demonstrates evidence of effectiveness and an acceptable safety profile in Phase 2 evaluations,Phase 3 trials are undertaken to obtain the additional information about clinical efficacy and saf

234、ety in a larger number of patients,typically at geographically dispersed clinical trial sites,to permit the FDA to evaluate the overall benefit-risk relationship of the drug or biologic and to provide adequate information for the labeling of the product.In most cases,the FDA requires two adequate an

235、d well-controlled Phase 3 clinical trials to demonstrate the efficacy of the biologic.A single Phase 3 trial with other confirmatory evidence may be sufficient in rare instances where the trial is a large multicenter trial demonstrating internal consistency and a statistically very persuasive findin

236、g of a clinically meaningful effect on mortality,irreversible morbidity or prevention of a disease with a potentially serious outcome and confirmation of the result in a second trial would be practically or ethically impossible.16In addition,the manufacturer of an investigational drug in a Phase 2 o

237、r Phase 3 clinical trial for a serious or life-threatening disease is required to make available,such as by posting on its website,its policy on evaluating and responding to requests for expanded access to such investigational drug.After completion of the required clinical testing,a BLA is prepared

238、and submitted to the FDA.FDA approval of the BLA is required before marketing of the product may begin in the United States.The BLA must include the results of all preclinical,clinical,and other testing and a compilation of data relating to the products pharmacology,chemistry,manufacture,and control

239、s.The cost of preparing and submitting a BLA is substantial.The submission of most BLAs is additionally subject to a substantial application user fee,and the applicant under an approved BLA is also subject to an annual program fee for each prescription product.Beginning in fiscal year 2018,this annu

240、al program fee replaces the annual product and established fees.These fees are typically increased annually.The FDA has 60 days from its receipt of a BLA to determine whether the application will be accepted for filing based on the agencys threshold determination that it is sufficiently complete to

241、permit substantive review.Once the submission is accepted for filing,the FDA begins an in-depth review.The FDA has agreed to certain performance goals in the review of BLAs.Most such applications for standard review biologic products are reviewed within ten months of the date the FDA files the BLA;m

242、ost applications for priority review biologics are reviewed within six months of the date the FDA files the BLA.Priority review can be applied to a biologic that the FDA determines has the potential to treat a serious or life-threatening condition and,if approved,would be a significant improvement i

243、n safety or effectiveness compared to available therapies.The review process for both standard and priority review may be extended by the FDA for three additional months to consider certain late-submitted information,or information intended to clarify information already provided in the submission.T

244、he FDA may also refer applications for novel biologic products,or biologic products that present difficult questions of safety or efficacy,to an advisory committeetypically a panel that includes clinicians and other expertsfor review,evaluation,and a recommendation as to whether the application shou

245、ld be approved.The FDA is not bound by the recommendation of an advisory committee,but it generally follows such recommendations.Before approving a BLA,the FDA will typically inspect one or more clinical sites to assure compliance with GCP.Additionally,the FDA will inspect the facility or the facili

246、ties at which the biologic product is manufactured.The FDA will not approve the product unless compliance with current good manufacturing practice,or cGMP,is satisfactory and the BLA contains data that provide substantial evidence that the biologic is safe,pure,potent and effective in the intended i

247、ndication.After the FDA evaluates the BLA and the manufacturing facilities,it issues either an approval letter or a complete response letter.A complete response letter generally outlines the deficiencies in the submission and may require substantial additional testing,or information,in order for the

248、 FDA to reconsider the application.If,or when,those deficiencies have been addressed to the FDAs satisfaction in a resubmission of the BLA,the FDA will issue an approval letter.The FDA has committed to reviewing such resubmissions in two or six months depending on the type of information included.An

249、 approval letter authorizes commercial marketing of the biologic with specific prescribing information for specific indications.As a condition of BLA approval,the FDA may require a risk evaluation and mitigation strategy,or REMS,to help ensure that the benefits of the biologic outweigh the potential

250、 risks.REMS can include medication guides,communication plans for healthcare professionals,and elements to assure safe use,or ETASU.ETASU can include,but are not limited to,special training or certification for prescribing or dispensing,dispensing only under certain circumstances,special monitoring,

251、and the use of patient registries.The requirement for a REMS can materially affect the potential market and profitability of the product.Moreover,product approval may require substantial post-approval testing and surveillance to monitor the products safety or efficacy.Once granted,product approvals

252、may be withdrawn if compliance with regulatory standards is not maintained or problems are identified following initial marketing.Changes to some of the conditions established in an approved application,including changes in indications,labeling,or manufacturing processes or facilities,require submis

253、sion and FDA approval of a new BLA or BLA supplement before the change can be implemented.A BLA supplement for a new indication typically requires clinical data similar to that in the original application,and the FDA uses the same procedures and actions in reviewing BLA supplements as it does in rev

254、iewing BLAs.17Fast track designation and accelerated approvalThe FDA is required to facilitate the development,and expedite the review,of biologics that are intended for the treatment of a serious or life-threatening disease or condition for which there is no effective treatment and which demonstrat

255、e the potential to address unmet medical needs for the condition.Under the fast track program,the sponsor of a new biologic candidate may request that the FDA designate the candidate for a specific indication as a fast track biologic concurrent with,or after,the filing of the IND for the candidate.T

256、he FDA must determine if the biologic candidate qualifies for fast track designation within 60 days of receipt of the sponsors request.Under the fast track program and FDAs accelerated approval regulations,the FDA may approve a biologic for a serious or life-threatening illness that provides meaning

257、ful therapeutic benefit to patients over existing treatments based upon a surrogate endpoint that is reasonably likely to predict clinical benefit,or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality,that is reasonably likely to predict an effect on irrever

258、sible morbidity or mortality or other clinical benefit,taking into account the severity,rarity,or prevalence of the condition and the availability or lack of alternative treatments.In clinical trials,a surrogate endpoint is a measurement of laboratory or clinical signs of a disease or condition that

259、 substitutes for a direct measurement of how a patient feels,functions,or survives.Surrogate endpoints can often be measured more easily or more rapidly than clinical endpoints.A biologic candidate approved on this basis is subject to rigorous post-marketing compliance requirements,including the com

260、pletion of Phase 4 or post-approval clinical trials to confirm the effect on the clinical endpoint.Failure to conduct required post-approval trials,or confirm a clinical benefit during post-marketing trials,will allow the FDA to withdraw the biologic from the market on an expedited basis.All promoti

261、onal materials for biologic candidates approved under accelerated regulations are subject to prior review by the FDA.In addition to other benefits such as the ability to use surrogate endpoints and engage in more frequent interactions with the FDA,the FDA may initiate review of sections of a fast tr

262、ack products BLA before the application is complete.This rolling review is available if the applicant provides,and the FDA approves,a schedule for the submission of the remaining information and the applicant pays applicable user fees.However,the FDAs time period goal for reviewing an application do

263、es not begin until the last section of the BLA is submitted.Additionally,the fast track designation may be withdrawn by the FDA if the FDA believes that the designation is no longer supported by data emerging in the clinical trial process.Breakthrough therapy designationThe FDA is also required to e

264、xpedite the development and review of the application for approval of biological products that are intended to treat a serious or life-threatening disease or condition where preliminary clinical evidence indicates that the biologic may demonstrate substantial improvement over existing therapies on o

265、ne or more clinically significant endpoints.Under the breakthrough therapy program,the sponsor of a new biologic candidate may request that the FDA designate the candidate for a specific indication as a breakthrough therapy concurrent with,or after,the filing of the IND for the biologic candidate.Th

266、e FDA must determine if the biological product qualifies for breakthrough therapy designation within 60 days of receipt of the sponsors request.Orphan drug designationUnder the Orphan Drug Act,the FDA may grant orphan drug designation to biological products intended to treat a rare disease or condit

267、iongenerally a disease or condition that affects fewer than 200,000 individuals in the United States,or if it affects more than 200,000 individuals in the United States,there is no reasonable expectation that the cost of developing and making a product available in the United States for such disease

268、 or condition will be recovered from sales of the product.Orphan drug designation must be requested before submitting a BLA.After the FDA grants orphan drug designation,the generic identity of the biological product and its potential orphan use are disclosed publicly by the FDA.Orphan drug designati

269、on does not convey any advantage in,or shorten the duration of,the regulatory review and approval process.The first BLA applicant to receive FDA approval for a particular active moiety to treat a particular disease with FDA orphan drug designation is entitled to a seven-year exclusive marketing peri

270、od in the United States for that product for that indication.During the seven-year exclusivity period,the FDA may not approve any other applications to market a biological product containing the same principal molecular structural features for the same disease,except in limited circumstances,such as

271、 a showing of clinical superiority to the product with orphan drug exclusivity.A product is clinically superior if it is safer,more effective or makes a major contribution to patient care.Orphan drug exclusivity does not prevent the FDA from approving a different drug or biological product for the s

272、ame disease or condition,or the same biological product for a different disease or condition.Among the other benefits of orphan drug designation are tax credits for certain research and a waiver of the BLA user fee.18Rare pediatric disease priority review voucher programUnder the Rare Pediatric Dise

273、ase Priority Review Voucher program,FDA may award a priority review voucher to the sponsor of an approved marketing application for a product that treats or prevents a rare pediatric disease.The voucher entitles the sponsor to priority review of one subsequent marketing application.A voucher may be

274、awarded only for an approved rare pediatric disease product application.A rare pediatric disease product application is an NDA or BLA for a product that treats or prevents a serious or life-threatening disease in which the serious or life-threatening manifestations primarily affect individuals aged

275、from birth to 18 years;in general,the disease must affect fewer than 200,000 such individuals in the U.S.;the NDA or BLA must be deemed eligible for priority review;the NDA or BLA must not seek approval for a different adult indication(i.e.,for a different disease/condition);the product must not con

276、tain an active ingredient that has been previously approved by FDA;and the NDA or BLA must rely on clinical data derived from studies examining a pediatric population such that the approved product can be adequately labeled for the pediatric population.Before NDA or BLA approval,FDA may designate a

277、product in development as a product for a rare pediatric disease,but such designation is not required to receive a voucher.To receive a rare pediatric disease priority review voucher,a sponsor must notify FDA,upon submission of the NDA or BLA,of its intent to request a voucher.If FDA determines that

278、 the NDA or BLA is a rare pediatric disease product application,and if the NDA or BLA is approved,FDA will award the sponsor of the NDA or BLA a voucher upon approval of the NDA or BLA.FDA may revoke a rare pediatric disease priority review voucher if the product for which it was awarded is not mark

279、eted in the U.S.within 365 days of the products approval.The voucher,which is transferable to another sponsor,may be submitted with a subsequent NDA or BLA and entitles the holder to priority review of the accompanying NDA or BLA.The sponsor submitting the priority review voucher must notify FDA of

280、its intent to submit the voucher with the NDA or BLA at least 90 days prior to submission of the NDA or BLA and must pay a priority review user fee in addition to any other required user fee.FDA must take action on an NDA or BLA under priority review within six months of receipt of the NDA or BLA.Th

281、e Rare Pediatric Disease Priority Review Voucher program was reauthorized in the 21st Century Cures Act,allowing a product that is designated as a product for a rare pediatric disease prior to October 1,2020 to be eligible to receive a rare pediatric disease priority review voucher upon approval of

282、a qualifying NDA or BLA prior to October 1,2022.Disclosure of clinical trial informationSponsors of clinical trials of FDA-regulated products,including biological products,are required to register and disclose certain clinical trial information.Information related to the product,patient population,p

283、hase of investigation,trial sites and investigators,and other aspects of the clinical trial is then made public as part of the registration.Sponsors are also obligated to discuss the results of their clinical trials after completion.Disclosure of the results of these trials can be delayed in certain

284、 circumstances for up to two years after the date of completion of the trial.Competitors may use this publicly available information to gain knowledge regarding the progress of development programs.Pediatric informationUnder the Pediatric Research Equity Act,or PREA,NDAs or BLAs or supplements to ND

285、As or BLAs must contain data to assess the safety and effectiveness of the biological product for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the biological product is safe and effective.The FDA

286、may grant full or partial waivers,or deferrals,for submission of data.Unless otherwise required by regulation,PREA does not apply to any biological product for an indication for which orphan designation has been granted.Additional controls for biologicsTo help reduce the increased risk of the introd

287、uction of adventitious agents and related process impurities,the PHSA emphasizes the importance of manufacturing controls for products whose attributes cannot be precisely defined.The PHSA also provides authority to the FDA to immediately suspend licenses in situations where there exists a danger to

288、 public health,to prepare or procure products in the event of shortages and critical public health needs,and to authorize the creation and enforcement of regulations to prevent the introduction or spread of communicable diseases in the United States and between states.19After a BLA is approved,the p

289、roduct may also be subject to official lot release as a condition of approval.As part of the manufacturing process,the manufacturer is required to perform certain tests on each lot of the product before it is released for distribution.If the product is subject to official release by the FDA,the manu

290、facturer submits samples of each lot of product to the FDA together with a release protocol showing a summary of the history of manufacture of the lot and the results of all of the manufacturers tests performed on the lot.The FDA may also perform certain confirmatory tests on lots of some products,s

291、uch as viral vaccines,before releasing the lots for distribution by the manufacturer.In addition,the FDA conducts laboratory research related to the regulatory standards on the safety,purity,potency,and effectiveness of biological products.As with drugs,after approval of biologics,manufacturers must

292、 address any safety issues that arise,are subject to recalls or a halt in manufacturing,and are subject to periodic inspection after approval.Patent term restorationAfter approval,owners of relevant drug or biologic patents may apply for up to a five year patent extension.The allowable patent term e

293、xtension is calculated as half of the drugs testing phasethe time between IND application and NDA or BLA submissionand all of the review phasethe time between NDA or BLA submission and approval up to a maximum of five years.The time can be shortened if FDA determines that the applicant did not pursu

294、e approval with due diligence.The total patent term after the extension may not exceed 14 years.For patents that might expire during the application phase,the patent owner may request an interim patent extension.An interim patent extension increases the patent term by one year and may be renewed up

295、to four times.For each interim patent extension granted,the post-approval patent extension is reduced by one year.The director of the U.S.PTO must determine that approval of the drug covered by the patent for which a patent extension is being sought is likely.Interim patent extensions are not availa

296、ble for a drug or biologic for which an NDA or BLA has not been submitted.BiosimilarsThe Biologics Price Competition and Innovation Act of 2009,or BPCIA,creates an abbreviated approval pathway for biological products shown to be highly similar to or interchangeable with an FDA-licensed reference bio

297、logical product.Biosimilarity sufficient to reference a prior FDA-approved product requires that there be no differences in conditions of use,route of administration,dosage form,and strength,and no clinically meaningful differences between the biological product and the reference product in terms of

298、 safety,purity,and potency.Biosimilarity must be shown through analytical trials,animal trials,and a clinical trial or trials,unless the Secretary of Health and Human Services waives a required element.A biosimilar product may be deemed interchangeable with a prior approved product if it meets the h

299、igher hurdle of demonstrating that it can be expected to produce the same clinical results as the reference product and,for products administered multiple times,the biologic and the reference biologic may be switched after one has been previously administered without increasing safety risks or risks

300、 of diminished efficacy relative to exclusive use of the reference biologic.The first biosimilar was approved by FDA in 2015,and no interchangeable products have been approved under the BPCIA.Complexities associated with the larger,and often more complex,structures of biological products,as well as

301、the process by which such products are manufactured,pose significant hurdles to implementation,which is still being evaluated by the FDA.A reference biologic is granted 12 years of exclusivity from the time of first licensure of the reference product,and no application for a biosimilar can be submit

302、ted for four years from the date of licensure of the reference product.The first biologic product submitted under the abbreviated approval pathway that is determined to be interchangeable with the reference product has exclusivity against a finding of interchangeability for other biologics for the s

303、ame condition of use for the lesser of(i)one year after first commercial marketing of the first interchangeable biosimilar,(ii)18 months after the first interchangeable biosimilar is approved if there is no patent challenge,(iii)eighteen months after resolution of a lawsuit over the patents of the r

304、eference biologic in favor of the first interchangeable biosimilar applicant,or(iv)42 months after the first interchangeable biosimilars application has been approved if a patent lawsuit is ongoing within the 42-month period.Post-approval requirementsOnce a BLA is approved,a product will be subject

305、to certain post-approval requirements.For instance,the FDA closely regulates the post-approval marketing and promotion of biologics,including standards and regulations for direct-to-consumer advertising,off-label promotion,industry-sponsored scientific and educational activities and promotional acti

306、vities involving the internet.Biologics may be marketed only for the approved indications and in accordance with the provisions of the approved labeling.20Adverse event reporting and submission of periodic reports is required following FDA approval of a BLA.The FDA also may require post-marketing te

307、sting,known as Phase 4 testing,REMS,and surveillance to monitor the effects of an approved product,or the FDA may place conditions on an approval that could restrict the distribution or use of the product.In addition,quality control,biological product manufacture,packaging,and labeling procedures mu

308、st continue to conform to cGMPs after approval.Biologic manufacturers and certain of their subcontractors are required to register their establishments with the FDA and certain state agencies.Registration with the FDA subjects entities to periodic unannounced inspections by the FDA,during which the

309、agency inspects manufacturing facilities to assess compliance with cGMPs.Accordingly,manufacturers must continue to expend time,money,and effort in the areas of production and quality-control to maintain compliance with cGMPs.Regulatory authorities may withdraw product approvals or request product r

310、ecalls if a company fails to comply with regulatory standards,if it encounters problems following initial marketing,or if previously unrecognized problems are subsequently discovered.FDA regulation of companion diagnosticsIf use of an in vitro diagnostic is essential to safe and effective use of a d

311、rug or biologic product,then the FDA generally will require approval or clearance of the diagnostic,known as a companion diagnostic,at the same time that the FDA approves the therapeutic product.The FDA has generally required in vitro companion diagnostics intended to select the patients who will re

312、spond to cancer treatment to obtain a pre-market approval,or PMA,for that diagnostic simultaneously with approval of the therapeutic.The review of these in vitro companion diagnostics in conjunction with the review of a cancer therapeutic involves coordination of review by the FDAs Center for Drug E

313、valuation and Research and by the FDAs Center for Devices and Radiological Health.Approval and clearance of a companion diagnostic also requires a high level of coordination between the drug or biologic manufacturer and device manufacturer,if different companies.The PMA process,including the gatheri

314、ng of clinical and preclinical data and the submission to and review by the FDA,can take several years or longer.It involves a rigorous premarket review during which the applicant must prepare and provide the FDA with reasonable assurance of the devices safety and effectiveness and information about

315、 the device and its components regarding,among other things,device design,manufacturing and labeling.PMA applications are subject to a substantial application fee,which is typically increased annually.In addition,PMAs must generally include the results from extensive preclinical and adequate and wel

316、l-controlled clinical trials to establish the safety and effectiveness of the device for each indication for which FDA approval is sought.In particular,for a diagnostic,the applicant must demonstrate that the diagnostic has adequate sensitivity and specificity,has adequate specimen and reagent stabi

317、lity,and produces reproducible results when the same sample is tested multiple times by multiple users at multiple laboratories.As part of the PMA review,the FDA will typically inspect the manufacturers facilities for compliance with the Quality System Regulation,or QSR,which imposes elaborate testi

318、ng,control,documentation and other quality assurance requirements.PMA approval is not guaranteed,and the FDA may ultimately respond to a PMA submission with a not approvable determination based on deficiencies in the application and require additional clinical trial or other data that may be expensi

319、ve and time-consuming to generate and that can substantially delay approval.If the FDAs evaluation of the PMA application is favorable,the FDA typically issues an approvable letter requiring the applicants agreement to specific conditions,such as changes in labeling,or specific additional informatio

320、n,such as submission of final labeling,in order to secure final approval of the PMA.If the FDA concludes that the applicable criteria have been met,the FDA will issue a PMA for the approved indications,which can be more limited than those originally sought by the applicant.The PMA can include post-a

321、pproval conditions that the FDA believes necessary to ensure the safety and effectiveness of the device,including,among other things,restrictions on labeling,promotion,sale and distribution.After a device is placed on the market,it remains subject to significant regulatory requirements.Medical devic

322、es may be marketed only for the uses and indications for which they are cleared or approved.Device manufacturers must also register their establishment(s),including payment of an annual establishment registration fee,and list their device(s)with the FDA.A medical device manufacturers manufacturing p

323、rocesses and those of its suppliers are required to comply with the applicable portions of the QSR,which cover the methods and documentation of the design,testing,production,processes,controls,quality assurance,labeling,packaging and shipping of medical devices.Domestic facility records and manufact

324、uring processes are subject to periodic unscheduled inspections by the FDA.The FDA also may inspect foreign facilities that export products to the United States.21Other U.S.healthcare laws and compliance requirementsIn the United States,our activities are potentially subject to regulation by various

325、 federal,state and local authorities in addition to the FDA,including but not limited to,the Centers for Medicare and Medicaid Services,or CMS,other divisions of the U.S.Department of Health and Human Services(e.g.,the Office of Inspector General),the U.S.Department of Justice,or DOJ,and individual

326、U.S.Attorney offices within the DOJ,and state and local governments.For example,sales,marketing and scientific/educational grant programs must comply with the anti-fraud and abuse provisions of the Social Security Act,the false claims laws,the privacy provisions of the Health Insurance Portability a

327、nd Accountability Act,or HIPAA,and similar state laws,each as amended.The federal Anti-Kickback Statute prohibits,among other things,any person or entity,from knowingly and willfully offering,paying,soliciting or receiving any remuneration,directly or indirectly,overtly or covertly,in cash or in kin

328、d,to induce or in return for purchasing,leasing,ordering or arranging for the purchase,lease or order of any item or service reimbursable under Medicare,Medicaid or other federal healthcare programs.The term remuneration has been interpreted broadly to include anything of value.The Anti-Kickback Sta

329、tute has been interpreted to apply to arrangements between pharmaceutical manufacturers on one hand and prescribers,purchasers,and formulary managers on the other.There are a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution.The exceptions

330、and safe harbors are drawn narrowly and practices that involve remuneration that may be alleged to be intended to induce prescribing,purchasing or recommending may be subject to scrutiny if they do not qualify for an exception or safe harbor.Failure to meet all of the requirements of a particular ap

331、plicable statutory exception or regulatory safe harbor does not make the conduct per se illegal under the Anti-Kickback Statute.Instead,the legality of the arrangement will be evaluated on a case-by-case basis based on a cumulative review of all of its facts and circumstances.Our practices may not i

332、n all cases meet all of the criteria for protection under a statutory exception or regulatory safe harbor.Additionally,the intent standard under the Anti-Kickback Statute was amended by the Affordable Care Act,or ACA,to a stricter standard such that a person or entity no longer needs to have actual

333、knowledge of the statute or specific intent to violate it in order to have committed a violation.In addition,the ACA codified case law that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal False Claims Act(discussed below).The civil monetary penalties statute imposes penalties aga