1、UNITED STATESSECURITIES AND EXCHANGE COMMISSIONWashington,DC 20549_FORM 10-K_(Mark One)ANNUAL REPORT UNDER SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1934For the fiscal year ended September 30,2024TRANSITION REPORT UNDER SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1934For the tran
2、sition period from toCommission file number 001-38042_ARROWHEAD PHARMACEUTICALS,INC.(Exact name of registrant as specified in its charter)_Delaware46-0408024(State or other jurisdiction of incorporation or organization)(I.R.S.Employer Identification No.)(626)304-3400177 E.Colorado Blvd,Suite 700Pasa
3、dena,California 91105(Address and telephone number of principal executive offices)_Securities registered pursuant to Section 12(b)of the Exchange Act:Title of each classTrading Symbol(s)Name of each exchange on which registeredCommon Stock,$0.001 par valueARWRThe Nasdaq Global Select MarketSecuritie
4、s registered pursuant to Section 12(g)of the Exchange Act:NoneIndicate by a check mark if the registrant is a well-known seasoned issuer,as defined in Rule 405 of the Securities Act.Yes No Indicate by a check mark if the registrant is not required to file reports pursuant to Section 13 or 15(d)of th
5、e 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 registrant was required to file such reports),and(2)has been subject
6、 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 chapter)during the preceding 12 months(or for such shorter p
7、eriod that the registrantwas required to submit such files).Yes No Indicate by check mark whether the registrant is a large accelerated filer,an accelerated filer,a non-accelerated filer,a smaller reporting company,or an emerging growth company.See the definitions of“large accelerated filer,”“accele
8、rated filer,”“smaller reportingcompany”and“emerging growth company”in Rule 12b-2 of the Exchange Act.Large accelerated filerAccelerated filerNon-accelerated filerSmaller reporting companyEmerging growth companyIf an emerging growth company,indicate by check mark if the registrant has elected not to
9、use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a)of the Exchange Act.Indicate by check mark whether the registrant has filed a report on and attestation to its managements assessment of the effectiveness of its
10、internal control over financial reporting under Section 404(b)of the Sarbanes-Oxley Act(15 U.S.C.7262(b)by the registered publicaccounting firm that prepared or issued its audit report.Indicate by check mark whether the registrant is a shell company(as defined in Rule 12b-2 of the Act).Yes No If sec
11、urities are registered pursuant to Section 12(b)of the Act,indicate by check mark whether the financial statements of the registrant included in the filing reflect the correction of an error to previously issued financial statements.Indicate by check mark whether any of those error corrections are r
12、estatements that required a recovery analysis of incentive-based compensation received by any of the registrants executive officers during the relevant recovery period pursuant to 240.10D-1(b).The aggregate market value of issuers voting and non-voting outstanding common stock held by non-affiliates
13、 was approximately$3.0 billion based upon the closing stock price of issuers common stock on March 31,2024.Shares of common stock held by each officer anddirector and by each person who is known to own 10%or more of the outstanding common stock have been excluded in that such persons may be deemed t
14、o be affiliates of the Company.This determination of affiliate status is not necessarily a conclusive determination for otherpurposes.As of November 20,2024,124,434,442 shares of the issuers Common Stock were issued and outstanding.DOCUMENTS INCORPORATED BY REFERENCEPortions of the Definitive Proxy
15、Statement to be filed for Arrowhead Pharmaceuticals,Inc.s 2025 Annual Meeting of Stockholders are incorporated by reference into Part III hereof.PART IITEM 1.BUSINESS1ITEM 1A.RISK FACTORS32ITEM 1B.UNRESOLVED STAFF COMMENTS58ITEM 1C.CYBERSECURITY58ITEM 2.PROPERTIES59ITEM 3.LEGAL PROCEEDINGS60ITEM 4.M
16、INE SAFETY DISCLOSURES60PART IIITEM 5.MARKET FOR THE REGISTRANTS COMMON EQUITY,RELATED STOCKHOLDER MATTERS AND ISSUER PURCHASES OF EQUITY SECURITIES61ITEM 6.RESERVED62ITEM 7.MANAGEMENTS DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS62ITEM 7A.QUANTITATIVE AND QUALITATIVE DIS
17、CLOSURES ABOUT MARKET RISK71ITEM 8.FINANCIAL STATEMENTS AND SUPPLEMENTARY DATA72ITEM 9.CHANGES IN AND DISAGREEMENTS WITH ACCOUNTANTS ON ACCOUNTING AND FINANCIAL DISCLOSURE72ITEM 9A.CONTROLS AND PROCEDURES72ITEM 9B.OTHER INFORMATION73ITEM 9C.DISCLOSURE REGARDING FOREIGN JURISDICTIONS THAT PREVENT INS
18、PECTIONS75PART IIIITEM 10.DIRECTORS,EXECUTIVE OFFICERS,AND CORPORATE GOVERNANCE75ITEM 11.EXECUTIVE COMPENSATION75ITEM 12.SECURITY OWNERSHIP OF CERTAIN BENEFICIAL OWNERS AND MANAGEMENT AND RELATED STOCKHOLDER MATTERS75ITEM 13.CERTAIN RELATIONSHIPS,RELATED TRANSACTIONS AND DIRECTORS INDEPENDENCE75ITEM
19、 14.PRINCIPAL ACCOUNTANT FEES AND SERVICES75PART IVITEM 15.EXHIBITS AND FINANCIAL STATEMENT SCHEDULES76ITEM 16.FORM 10-K SUMMARY80SIGNATUREINDEX TO FINANCIAL STATEMENTS AND SCHEDULESF-1FORWARD-LOOKING STATEMENTSThis Annual Report on Form 10-K contains certain forward-looking statements within the me
20、aning of Section 27A of the Securities Act of 1933,as amended,and Section 21E of the SecuritiesExchange Act of 1934,as amended,and we intend that such forward-looking statements be subject to the safe harbors created thereby.For this purpose,any statements contained in this AnnualReport on Form 10-K
21、 except for historical information may be deemed to be forward-looking statements.Without limiting the generality of the foregoing,words such as“may,”“might,”“will,”“expect,”“believe,”“anticipate,”“goal,”“endeavor,”“strive,”“intend,”“plan,”“project,”“could,”“estimate,”“target,”“might,”“forecast,”or“
22、continue”or the negative of these words orother variations thereof or comparable terminology are intended to identify forward-looking statements.In addition,any statements that refer to projections of our future financial performance,trends in our business,or other characterizations of future events
23、 or circumstances are forward-looking statements.These forward-looking statements include,but are not limited to,statements aboutthe initiation,timing,progress and results of our preclinical studies and clinical trials,and our research and development programs;our expectations regarding regulatory a
24、pproval for andcommercial launch of plozasiran our expectations regarding the potential benefits of the partnership,licensing and/or collaboration arrangements and other strategic arrangements and transactionswe have entered into or may enter into in the future;our beliefs and expectations regarding
25、 the amount and timing of future milestone,royalty or other payments that could be due to or from thirdparties under existing agreements;and our estimates regarding future revenues,research and development expenses,capital requirements and payments to third parties.The forward-looking statements inc
26、luded herein are based on current expectations of our management based on available information and involve a number of risks and uncertainties,all ofwhich are difficult or impossible to predict accurately,and many of which are beyond our control.As such,our actual results and timing of certain even
27、ts may differ materially from the resultsdiscussed,projected,anticipated or indicated in any forward-looking statements.Forward-looking statements are not guarantees of future performance and our actual results of operations,financialcondition and cash flows may differ materially.Factors that may ca
28、use or contribute to such differences include,but are not limited to,those discussed in more detail in“Item 1.Business”and“Item1A.Risk Factors”of Part I and“Item 7.Managements Discussion and Analysis of Financial Condition and Results of Operations”of Part II of this Annual Report on Form 10-K.Reade
29、rs shouldcarefully review these risks,as well as the additional risks described in other documents we file from time to time with the Securities and Exchange Commission(the“SEC”).In light of the significantrisks and uncertainties inherent in the forward-looking information included herein,the inclus
30、ion of such information should not be regarded as a representation by us or any other person that suchresults will be achieved,and readers are cautioned not to place undue reliance on such forward-looking information.Statements made herein are as of the date of the filing of this Annual Report onFor
31、m 10-K with the SEC and should not be relied upon as of any subsequent date.Except as may be required by law,we disclaim any intent to revise the forward-looking statements contained hereinto reflect events or circumstances after the date hereof or to reflect the occurrence of unanticipated events.P
32、ART IUnless otherwise noted,(1)the term“Arrowhead”refers to Arrowhead Pharmaceuticals,Inc.,a Delaware corporation and its Subsidiaries,(2)the terms“Company,”“we,”“us,”and“our,”refer to the ongoing business operations of Arrowhead and its Subsidiaries,whether conducted through Arrowhead or a subsidia
33、ry of Arrowhead,(3)the term“Subsidiaries”refers to ArrowheadMadison Inc.(“Arrowhead Madison”),Arrowhead Australia Pty Ltd(“Arrowhead Australia”),and Visirna Therapeutics Inc.(“Visirna”)(4)the term“common stock”refers to Arrowheadscommon stock,(5)the term“preferred stock”refers to Arrowheads preferre
34、d stock and(6)the term“stockholder(s)”refers to the holders of Arrowhead common stock.ITEM 1.BUSINESSA.OverviewThe Company develops medicines that treat intractable diseases by silencing the genes that cause them.Using a broad portfolio of RNA chemistries and efficient modes of delivery,theCompanys
35、therapies trigger the RNA interference mechanism to induce rapid,deep and durable knockdown of target genes.The Companys most advanced candidate,plozasiran,has completed a Phase 3 study in patients with familial chylomicronemia syndrome(FCS)and expects to have its first commercial launchin 2025,prov
36、ided the United States Food and Drug Administration(the“FDA”)accepts the New Drug Application(“NDA”)for filing and after a successful review and subsequent approval.TheCompanys pipeline of 16 clinical stage investigational medicines range in development stage from Phase 1 to Phase 3.In addition,the
37、Company has a robust discovery stage pipeline which iscapable of generating multiple new clinical candidates each year.The Company endeavors to serve unmet medical needs and change lives leveraging the versatility of its proprietary RNAi-based technology.The Company is acutely aware of the urgent ne
38、edto develop solutions for the many diseases that have genetic targets that are otherwise undruggable by small molecules or biologics.To that end,the Company embraced its bold goal and strives tohave 20 individual drugs,either partnered or wholly owned,in clinical trials or on the market in 2025.RNA
39、 Interference and the Benefits of RNAi TherapeuticsRNA interference(“RNAi”)is a mechanism present in living cells that inhibits the expression of a specific gene,thereby affecting the production of a specific protein.RNAi-based therapeuticsmay leverage this natural pathway of gene silencing to targe
40、t and shut down specific disease-causing genes.Small molecule and antibody drugs have proven effective at inhibiting certain cell surface,intracellular,and extracellular targets.However,other drug targets have proven difficult to inhibitwith traditional drug-based and biologic therapeutics.Developin
41、g effective drugs for these targets would have the potential to address large underserved markets for the treatment of many diseases.Using the ability to specifically silence any gene,RNAi therapeutics may be able to address previously“undruggable”targets,unlocking the market potential of such targe
42、ts.1This figure depicts the mechanism by which gene silencing occurs.Double stranded RNAi triggers are introduced into a cell and are loaded into the RNA-induced silencing complex(“RISC”).The strands are then separated,leaving an active RISC/RNAi trigger complex.This complex can then pair with and d
43、egrade the complementary messenger RNAs(“mRNA”)and stop the productionof the target proteins.RNAi is a catalytic process,so each RNAi trigger can degrade mRNA hundreds of times,which results in a relatively long duration of effect for RNAi therapeutics.Key Benefits of RNAi as a Therapeutic Modality:
44、Silences the expression of disease associated genes;Potential to address any target in the transcriptome including previously“undruggable”targets;Rapid lead identification;High specificity;Opportunity to use multiple RNA sequences in one drug product for synergistic silencing of related targets;andR
45、NAi therapeutics are uniquely suited for personalized medicine through target and cell specific delivery and gene knockdown.Targeted RNAi Molecule(TRiM)PlatformThe Companys Targeted RNAi Molecule(TRiM)platform utilizes ligand-mediated delivery and is designed to enable tissue-specific targeting whil
46、e being structurally simple.Targeting hasbeen core to the Companys development philosophy and the TRiM platform builds on more than a decade of work on actively targeted drug delivery vehicles.The Companys scientists havediscovered ways to progressively“TRiM”away extraneous features and chemistries
47、and retain optimal pharmacologic activity.The TRiM platform is comprised of a highly potent RNA trigger identified using the Companys proprietary trigger selection rules and algorithms with the following components optimized,as needed,for each drug candidate:a high affinity targeting ligand;various
48、linker chemistries;structures that enhance pharmacokinetics;and highly potent RNAi triggers with sequence specificstabilization chemistries.Therapeutics developed with the TRiM platform offer several advantages:simplified manufacturing and reduced costs;multiple routes of administration;and potentia
49、l for improved safetybecause there are less metabolites from smaller molecules,thereby reducing the risk of intracellular buildup.The Company also believes that for RNAi to reach its true potential,it must target organsoutside the liver.The Company is leading this expansion with the TRiM platform,wh
50、ich has shown the potential to reach multiple tissues,including liver,lung,central nervous system(CNS),muscle,and adipose tissue.TMTMTMTMTMTM2RNA ChemistriesThe structure and chemistries of the oligonucleotide molecules used to trigger the RNAi mechanism can be tailored for optimal activity.The Comp
51、anys broad portfolio of RNA triggerstructures and chemistries,including some proprietary structures,enable the Company to optimize each drug candidate on a target-by-target basis and utilize the combination of structure andchemical modifications that yield the most potent RNAi trigger.As a component
52、 of the TRiM platform,the Companys design philosophy for RNA chemical modifications is to start with a structurally simple molecule and add only selective modificationand stabilization chemistries as necessary to achieve the desired level of target knockdown and duration of effect.The conceptual fra
53、mework for the stabilization strategy starts with a moresophisticated RNAi trigger screening and selection process that identifies potent sequences rapidly in locations that others may miss.B.PipelineThe Company is focused on developing innovative drugs for diseases with a genetic basis,typically ch
54、aracterized by the overproduction of one or more proteins that are involved with disease.The depth and versatility of the Companys RNAi technologies enables the Company to potentially address conditions in virtually any therapeutic area and pursue disease targets that are nototherwise addressable by
55、 small molecules and biologics.The Company is focused on bringing the promise of RNAi to address diseases outside of the liver,and its pipeline now includes diseasetargets in the liver,lung,central nervous system(CNS),muscle and adipose tissue.TM3Plozasiran(ARO-APOC3)Plozasiran(formerly ARO-APOC3)is
56、 designed to reduce production of Apolipoprotein C-III(apoC-III),a component of triglyceride rich lipoproteins(TRLs)including Very Low DensityLipoprotein(VLDL)and chylomicrons,a key regulator of triglyceride metabolism.The Company believes that knocking down the hepatic production of apoC-III may re
57、sult in reduced VLDLsynthesis and assembly,enhanced breakdown of TRLs,and better clearance of VLDL and chylomicron remnants.The Company is currently investigating plozasiran in one Phase 2 clinical trial andfour Phase 3 clinical trials.In the Phase 3 PALISADE trial in patients with familial chylomic
58、ronemia syndrome(FCS),plozasiran has met its primary endpoint of triglyceride reduction as well as allof its key(alpha controlled)secondary endpoints.The Company is currently in the process of seeking regulatory approval for plozasiran for the treatment of FCS.Hypertriglyceridemia:Elevated triglycer
59、ide levels are an independent risk factor for cardiovascular disease.Severely elevated triglycerides in patients with severe hypertriglyceridemia(SHTG)or familial chylomicronemia syndrome(FCS),a rare genetic disorder,can result in potentially fatal acute pancreatitis.Study Name:Study of ARO-APOC3 in
60、 Adults With DyslipidemiaA Phase 2 Open-Label Extension Study to Evaluate the Long-Term Safety and Efficacy of ARO-APOC3 in Adults With DyslipidemiaClinicalTrials.gov Identifier:NCT05413135Study Name:Study of ARO-APOC3 in Adults With FCS(PALISADE)A Phase 3 Study to Evaluate the Efficacy and Safety o
61、f ARO-APOC3 in Adults With Familial Chylomicronemia SyndromeClinicalTrials.gov Identifier:NCT05089084Study Name:Study of Plozasiran(ARO-APOC3)in Adults With Severe Hypertriglyceridemia(SHASTA-3)Double-blind,Placebo-controlled,Phase 3 Study to Evaluate the Efficacy and Safety of Plozasiran in Adults
62、With Severe HypertriglyceridemiaClinicalTrials.gov Identifier:NCT06347003Study Name:Study of Plozasiran in Adults With Severe Hypertriglyceridemia(SHASTA-4)Double-blind,Placebo-controlled,Phase 3 Study to Evaluate the Efficacy and Safety of Plozsiran in Adults With Severe HypertriglyceridemiaClinica
63、lTrials.gov Identifier:NCT06347016Study Name:Phase 3 Study of Plozasiran in Adults With Hypertriglyceridemia(MUIR-3)Double-blind,Placebo-controlled,Phase 3 Study to Evaluate the Efficacy and Safety of Plozasiran in Adults With HypertriglyceridemiaClinicalTrials.gov Identifier:NCT063471334Zodasiran(A
64、RO-ANG3)Zodasiran(formerly ARO-ANG3)is designed to reduce production of angiopoietin-like protein 3(ANGPTL3),a liver synthesized inhibitor of lipoprotein lipase and endothelial lipase.ANGPTL3 inhibition has been shown to lower serum LDL,serum and liver triglyceride and has genetic validation as a no
65、vel target for cardiovascular disease.The Company is currently investigatingzodasiran in two Phase 2b clinical trials.Dyslipidemia and Hypertriglyceridemia:Dyslipidemia and hypertriglyceridemia are risk factors for atherosclerotic coronary heart disease and cardiovascular events.Study Name:Study of
66、ARO-ANG3 in Adults With Mixed Dyslipidemia(ARCHES-2)A Double-blind,Placebo-controlled Phase 2b Study to Evaluate the Efficacy and Safety of ARO-ANG3 in Adults With Mixed DyslipidemiaClinicalTrials.gov Identifier:NCT04832971Study Name:Study of ARO-ANG3 in Participants With Homozygous Familial Hyperch
67、olesterolemia(HoFH)(GATEWAY)Phase 2 Study to Evaluate the Safety and Efficacy of ARO-ANG3 in Subjects with Homozygous Familial Hypercholesterolemia(HoFH)ClinicalTrials.gov Identifier:NCT05217667ARO-PNPLA3ARO-PNPLA3(formerly JNJ-75220795)is an investigational RNAi therapeutic designed to reduce liver
68、 expression of patatin-like phospholipase domain containing 3(PNPLA3)as a potentialtreatment for patients with metabolic-dysfunction associated steatohepatitis(MASH).PNPLA3 has strong genetic and preclinical validation as a driver of fat accumulation and damage in the livers ofpatients who carry the
69、 common I148M mutation.Former licensee Janssen Pharmaceuticals,Inc.investigated ARO-PNPLA3 in two Phase 1 clinical trials.MASH:MASH is a subgroup of steatotic liver disease(MASLD)in which hepatic cell injury and inflammation has developed over background steatosis.The I148M genetic variant in thePNP
70、LA3 gene is involved with the underlying pathophysiology and is a known risk factor for hepatic steatosis,steatohepatitis,elevated plasma liver enzyme levels,hepatic fibrosis andcirrhosis.The rising prevalence of MASH presents a significant health burden in many developed countries.ARO-INHBEARO-INHB
71、E is designed to reduce the hepatic expression of the INHBE gene and its secreted gene product,Activin E.INHBE is a promising genetically validated target in which loss-of-function INHBE variants in humans are associated with lower risk of obesity and metabolic diseases,such as type 2 diabetes.The C
72、ompany has filed for regulatory clearance to initiate a Phase 1/2aclinical trial of ARO-INHBE.ARO-RAGEARO-RAGE is designed to reduce production of the Receptor for Advanced Glycation End products(RAGE)as a potential treatment for various inflammatory pulmonary diseases.TheCompany is currently invest
73、igating ARO-RAGE in a Phase 1/2a clinical trial.Study Name:Study of ARO-RAGE in Healthy Subjects and Patients With Inflammatory Lung DiseaseA Phase 1/2a Study Evaluating the Effects of ARO-RAGE in Healthy Subjects and Patients With Inflammatory Lung DiseaseClinicalTrials.gov Identifier:NCT05276570AR
74、O-MUC5ACARO-MUC5AC is designed to reduce production of mucin 5AC(MUC5AC)as a potential treatment for various muco-obstructive pulmonary diseases.The Company is currently investigatingARO-MUC5AC in a phase 1/2a clinical trial.Study Name:Study of ARO-MUC5AC in Healthy Subjects and Patients With Muco-O
75、bstructive Lung DiseaseA Phase 1/2a Study to Evaluate the Effects of ARO-MUC5AC in Healthy Subjects and Patients with Muco-Obstructive Lung DiseaseClinicalTrials.gov Identifier:NCT052929505ARO-MMP7ARO-MMP7 is designed to reduce expression of matrix metalloproteinase 7(MMP7)as a potential treatment f
76、or Idiopathic Pulmonary Fibrosis(IPF).The Company is currently investigatingARO-MMP7 in a Phase 1/2a clinical trial.Study Name:Study of ARO-MMP7 Inhalation Solution in Healthy Subjects and Patients With Idiopathic Pulmonary FibrosisA Phase 1/2a Study Evaluating the Effects of ARO-MMP7 Inhalation Sol
77、ution in Healthy Subjects and Patients With Idiopathic Pulmonary FibrosisClinicalTrials.gov Identifier:NCT05537025ARO-DUX4ARO-DUX4 is designed to target the gene that encodes human double homeobox 4(DUX4)protein as a potential treatment for patients with facioscapulohumeral muscular dystrophy.Facios
78、capulohumeral Muscular Dystrophy:Facioscapulohumeral muscular dystrophy(FSHD)is an autosomal dominant disease associated with the failure to maintain complete epigeneticsuppression of DUX4 expression in differentiated skeletal muscle,leading to overexpression of DUX4,which is myotoxic and can lead t
79、o muscle degeneration.As DUX4 expression isrecognized as the cause of muscle pathology in FSHD patients,the Company believes that the selective targeting and knockdown of DUX4 using RNAi may prevent or reverse downstreammyotoxicity and lead to muscle repair and improvement in muscle function in pati
80、ents.There are currently no effective treatments specifically for FSHD.Study Name:Study of ARO-DUX4 in Adult Patients With Facioscapulohumeral Muscular Dystrophy Type 1A Phase1/2a Dose-Escalating Study to Evaluate the Safety,Tolerability,Pharmacokinetics,and Pharmacodynamics of ARO-DUX4 in Adult Pat
81、ients With Facioscapulohumeral MuscularDystrophy Type 1.ClinicalTrials.gov Identifier:NCT06131983ARO-DM1ARO-DM1 is designed to reduce expression of the dystrophia myotonica protein kinase(DMPK)gene.There is currently no approved disease-modifying therapy for type 1 myotonicdystrophy(DM1).Treatments
82、have focused on symptomatic management,including physical therapy,exercise,ankle-foot orthoses,wheelchairs,and other assistive devices.The Company iscurrently investigating ARO-DM1 in a Phase 1/2a clinical trial.Type 1 Myotonic Dystrophy:Type 1 myotonic dystrophy is an autosomal dominant,debilitatin
83、g,chronic progressive multisystem disorder characterized by an expansion of a highly unstableCUG in the DMPK gene.Patients with DM1 have muscle weakness and wasting,myotonia,cataracts,and often have cardiac conduction abnormalities,and may become physically disabledand have a shortened life span.Stu
84、dy Name:Study of ARO-DM1 in Subjects With Type 1 Myotonic DystrophyA Phase 1/2a Dose-Escalating Study to Evaluate the Safety,Tolerability,Pharmacokinetics,and Pharmacodynamics of ARO-DM1 in Subjects With Type 1 Myotonic Dystrophy Who Are 18to 65 YearsClinicalTrials.gov Identifier:NCT06138743ARO-ATXN
85、2ARO-ATXN2 is designed to reduce the expression of the ATXN2 gene as a potential treatment for spinocerebellar ataxia 2(SCA2).SCA2 is a progressive cerebellar ataxia with instability ofstance,speech and swallow disorder,pain,spasticity,and ocular signs,caused by gain of function of mutant expanded p
86、olyQ ATXN2 protein.The Company is currently investigating ARO-ATXN2 ina Phase 1 clinical trial.Study Name:Study of ARO-ATXN2 Injection in Adults With Spinocerebellar Ataxia Type 2A Phase 1 Placebo-Controlled Dose Escalating Study to Evaluate the Safety,Tolerability,Pharmacokinetics,and Pharmacodynam
87、ics of ARO-ATXN2 in Adult Subjects With SpinocerebellarAtaxia Type 2ClinicalTrials.gov Identifier:NCT06672445ARO-C3ARO-C3 is designed to reduce production of complement component 3(C3)as a potential therapy for patients with various complement mediated or complement associated renal diseases.TheComp
88、any is currently investigating ARO-C3 in a Phase 1/2a clinical trial.Complement-Mediated Renal Disease:A number of rare renal diseases result from uncontrolled activation of the alternative pathway of complement,leading to progressive glomerulardamage,proteinuria,hematuria,and impaired kidney functi
89、on,and often resulting in end-stage renal disease(ESRD).In addition,dysregulation of the alternativeexp6complement pathway has been shown to play a role in the pathogenesis and progression of disease in some of the more common glomerulopathies.Silencing C3 may be a therapeutic approachfor treatment
90、of these conditions.Study Name:Study of ARO-C3 in Adult Healthy Volunteers and Patients With Complement-Mediated Renal DiseaseA Phase 1/2a Dose-Escalating Study to Evaluate the Safety,Tolerability,Pharmacokinetics,and/or Pharmacodynamics of ARO-C3 in Adult Healthy Volunteers and in Adult Patients Wi
91、thComplement-Mediated Renal DiseaseClinicalTrials.gov Identifier:NCT05083364ARO-CFBARO-CFB is designed to reduce hepatic expression of complement factor B(CFB),which plays an important regulatory role in amplifying complement alternative pathway activation and hasbeen identified as a promising thera
92、peutic target.ARO-CFB is being developed as a potential treatment for complement mediated kidney diseases such as immunoglobulin A nephropathy(IgAN),which is the most common glomerular disease worldwide and carries a high lifetime risk of progression to end-stage renal disease.Additionally,ARO-CFB m
93、ay have clinical applications in non-renal diseases involving complement activation.The Company is currently investigating ARO-CFB in a Phase 1/2a clinical trial.Complement-Mediated Disease:A number of rare renal diseases result from uncontrolled activation of the alternative pathway of complement,l
94、eading to progressive glomerular damage,proteinuria,hematuria,and impaired kidney function,and often resulting in end-stage renal disease(ESRD).In addition,dysregulation of the alternative complement pathway has been shownto play a role in the pathogenesis and progression of disease in some of the m
95、ore common glomerulopathies.Silencing CFB may be a therapeutic approach for treatment of these conditions.Study Name:Study of ARO-CFB in Adult Healthy Volunteers and Patients With Complement-Mediated Kidney DiseaseA Phase 1/2a Dose-Escalating Study to Evaluate the Safety,Tolerability,Pharmacokinetic
96、s,and Pharmacodynamics of Single and Multiple Doses of ARO-CFB in Adult Healthy Volunteersand Adult Patients With Complement-Mediated Kidney DiseaseClinicalTrials.gov Identifier:NCT06209177Collaboration and License AgreementsGlaxosmithkline Intellectual Property(No.3)Limited(“GSK”)GSK-HSD License Ag
97、reementOn November 22,2021,GSK and the Company entered into an Exclusive License Agreement(the“GSK-HSD License Agreement”).Under the GSK-HSD License Agreement,GSK hasreceived an exclusive license for GSK-4532990(formerly ARO-HSD).The exclusive license is worldwide with the exception of greater China
98、.GSK is wholly responsible for all clinical developmentand commercialization of GSK-4532990 in its territory.GSK dosed the first patient in a Phase 2b trial in March 2023.GSK-4532990GSK-4532990(formerly ARO-HSD)is designed to reduce production of HSD17B13,a hydroxysteroid dehydrogenase involved in t
99、he metabolism of hormones,fatty acids and bile acids.Published human genetic data indicate that a loss of function mutation in HSD17B13 provides strong protection against metabolic-dysfunction associated steatohepatitis(MASH)cirrhosis andalcoholic hepatitis and cirrhosis.GSK is conducting Phase 2b c
100、linical trials in patients with MASH and alcohol-related liver disease(ALD).Metabolic-Dysfunction Associated Steatohepatitis:MASH is liver inflammation and damage caused by a buildup of fat in the liver.This can cause scarring of the liver and in advanced casescan lead to cirrhosis.Alcochol-related
101、liver disease(ALD)represents a spectrum of liver injury resulting from alcohol use,ranging from hepatic steatosis to more advances forms includingalcoholic hepatitis(AH),alcohol-associated cirrhosis(AC),and acute AH presenting as acute-on-chronic liver failure.Study Name:Phase 2b Study of GSK4532990
102、 in Adults With MASH(HORIZON)17-Hydroxysteroid Dehydrogenase Type 13 Minimization for the Treatment of MASH(HORIZON):A Double-Blind,Placebo-Controlled Phase 2b Study to Evaluate the Efficacy and Safetyof GSK4532990 in Adults With Pre-Cirrhotic Metabolic-Dysfunction Associated SteatohepatitisClinical
103、Trials.gov Identifier:NCT055833447GSK-HBV AgreementOn December 11,2023,the Company entered into an Amended and Restated License Agreement with GSK(the“GSK-HBV Agreement”)pursuant to which GSK received a worldwide,exclusivelicense to develop and commercialize daplusiran/tomligisiran(GSK5637608,former
104、ly JNJ-3989),the Companys third-generation subcutaneously administered RNAi therapeutic candidate beingdeveloped as a potential therapy for patients with chronic hepatitis B virus infection.GSK5637608 had previously been licensed to Janssen Pharmaceuticals,Inc.(“Janssen”)in October 2018.GSK iscurren
105、tly in the process of initiating a Phase 2 study of daplusiran/tomligisiran followed by bepirovirsen in patients with chronic hepatitis B.Study Name:A Study of Sequential Therapy With Daplusiran/Tomligisiran(DAP/TOM)Followed by Bepirovirsen in Participants Living With Chronic Hepatitis B(CHB)(B-UNIT
106、ED)A Phase 2b,Multi-centre,Randomized,Partially Placebo-controlled,Double-blind Study to Investigate the Safety and Efficacy of Sequential Therapy With Daplusiran/Tomligisiran Followedby Bepirovirsen in Participants With Chronic Hepatitis B Virus on Background Nucleos(t)Ide Analogue Therapy(B-United
107、)ClinicalTrials.gov Identifier:NCT06537414Takeda Pharmaceutical Company Limited(“Takeda”)On October 7,2020,Takeda and the Company entered into an Exclusive License and Co-Funding Agreement(the“Takeda License Agreement”).Under the Takeda License Agreement,Takedaand the Company co-develop the Companys
108、 Fazirsiran program(formerly TAK-999 and ARO-AAT),the Companys second-generation subcutaneously administered RNAi therapeutic candidatebeing developed as a treatment for liver disease associated with alpha-1 antitrypsin deficiency.Within the United States,fazirsiran,if approved,will be co-commercial
109、ized under a 50/50 profitsharing structure.Outside the United States,Takeda received an exclusive license to commercialize fazirsiran and will lead the global commercialization strategy,while the Company will be eligibleto receive tiered royalties of 20%to 25%on net sales.FazirsiranFazirsiran is a s
110、ubcutaneously administered RNAi therapeutic being developed as a treatment for liver disease associated with alpha-1 antitrypsin deficiency(AATD),which is a rare geneticdisorder that severely damages the liver and lungs of affected individuals.Fazirsiran is designed to reduce production of the mutan
111、t Z-AAT protein by silencing the AAT gene in order toprevent accumulation of Z-AAT in the liver,allow clearance of the accumulated Z-AAT protein,prevent repeated cycles of cellular damage,and possibly prevent or even reverse theprogression of liver fibrosis.Goal of Fazirsiran Treatment:The goal of F
112、azirsiran treatment is prevention and potential reversal of Z-AAT accumulation-related liver injury and fibrosis.Reduction of inflammatory Z-AAT protein,which has been clearly defined as the cause of progressive liver disease in AATD patients,is important as it is expected to halt the progression of
113、 liver disease and allow fibrotictissue repair.Alpha-1 Antitrypsin Deficiency(AATD):AATD is a genetic disorder associated with liver disease in children and adults,and pulmonary disease in adults.AAT is a circulating glycoproteinprotease inhibitor that is primarily synthesized and secreted by liver
114、hepatocytes.Its physiologic function is the inhibition of neutrophil protease to protect healthy lung tissues duringinflammation and prevent tissue damage.The most common disease variant,the Z mutant,has a single amino acid substitution that results in improper folding of the protein.The mutantprote
115、in cannot be effectively secreted and accumulates in globules in the hepatocytes.This triggers continuous hepatocyte injury,leading to fibrosis,cirrhosis,and increased risk ofhepatocellular carcinoma.Current Treatments:Individuals with the homozygous PiZZ genotype have severe deficiency of functiona
116、l AAT leading to pulmonary disease and hepatocyte injury and liver disease.Lungdisease in this patient population is frequently treated with AAT augmentation therapy.However,augmentation therapy does nothing to treat liver disease,and there is no specific therapy forhepatic manifestations.There is a
117、 significant unmet need as liver transplant,with its attendant morbidity and mortality,is currently the only available treatment.Clinical Trials:Study Name:Study to Check the Safety of Fazirsiran and Learn if Fazirsiran Can Help People With Liver Disease and Scarring(Fibrosis)Due to an Abnormal Vers
118、ion of Alpha-1Antitrypsin Protein(REDWOOD)REDWOOD A Randomized,Double-blind,Placebo-Controlled,Phase 3 Study to Evaluate the Efficacy and Safety of fazirsiran in the Treatment of Alpha-1 Antitrypsin Deficiency-Associated Liver Disease With METAVIR Stage F2 to F4 FibrosisClinicalTrials.gov Identifier
119、:NCT056779718Study Name:An Extension Study to Learn About the Long-Term Safety of Fazirsiran and if Fazirsiran Can Help People With Alpha-1 Antitrypsin Liver DiseaseA Phase 3,Open-Label Extension Study to Evaluate the Long-Term Safety and Efficacy of fazirsiran in Participants With Alpha-1 Antitryps
120、in Deficiency-Associated Liver DiseaseClinicalTrials.gov Identifier:NCT05899673Study Name:Study to Learn About the Safety of Fazirsiran and if it Can Help People With Alpha-1 Antitrypsin Liver Disease With Mild Liver Scarring(Fibrosis)A Randomized,Double-Blind,Placebo-Controlled,Phase 3 Study to Eva
121、luate the Safety and Efficacy of Fazirsiran in the Treatment of Alpha-1 Antitrypsin Deficiency-Associated LiverDisease With METAVIR Stage F1 FibrosisClinicalTrials.gov Identifier:NCT06165341Amgen Inc.(“Amgen”)On September 28,2016,Amgen and the Company entered into two collaboration and license agree
122、ments and a common stock purchase agreement.Under the Second Collaboration andLicense Agreement(the“Olpasiran Agreement”),Amgen received a worldwide,exclusive license to the Companys novel RNAi olpasiran(previously referred to as AMG 890 or ARO-LPA)program.These RNAi molecules are designed to reduce
123、 elevated lipoprotein(a),which is a genetically validated,independent risk factor for atherosclerotic cardiovascular disease.Under theOlpasiran Agreement,Amgen is wholly responsible for clinical development and commercialization.In November 2022,Royalty Pharma Investments 2019 ICAV(“Royalty Pharma”)
124、and the Company entered into a Royalty Purchase Agreement(the“Royalty Pharma Agreement”).Inconsideration for the payments under the Royalty Pharma Agreement,Royalty Pharma is entitled to receive all royalties otherwise payable by Amgen to the Company under the Olpasiran Agreement.The Company remains
125、 eligible to receive up to an additional$485.0 million in remaining development,regulatory and sales milestone payments payable from Amgen and Royalty Pharma.OlpasiranOlpasiran is designed to reduce production of apolipoprotein A,a key component of lipoprotein(a),which has been genetically linked wi
126、th increased risk of cardiovascular diseases,independent of cholesterol and LDL levels.Amgen completed a Phase 2 clinical study evaluating the efficacy,safety,and tolerability of olpasiran in subjects with elevated levels of lipoprotein(a).Amgen reported Phase 2 clinical results at the American Hear
127、t Association(AHA)Scientific Sessions in November 2022 and simultaneously published in the New England Journal of Medicine.Amgen began evaluating olpasiran in a Phase 3 study to assess the impact of olpasiran on major cardiovascular events in participants with atherosclerotic cardiovascular disease
128、and elevatedlipoprotein(a),in a double-blind,randomized,placebo-controlled,multi center study in December 2022.Study Name:Olpasiran Trials of Cardiovascular Events and Lipoprotein(a)Reduction(OCEAN(a)-Outcomes TrialA Double-blind,Randomized,Placebo-controlled,Multicenter Study Assessing the Impact o
129、f Olpasiran on Major Cardiovascular Events in Participants With Atherosclerotic CardiovascularDisease and Elevated Lipoprotein(a)ClinicalTrials.gov Identifier:NCT05581303C.Intellectual Property and Other Key AgreementsThe Company controls approximately 667 issued patents(including 427 directed to RN
130、Ai trigger molecules;144 directed to targeting groups or targeting compounds;and one forhydrodynamic gene delivery),including European validations,and approximately 745 currently pending patent applications worldwide from 92 different patent families.The Companys patentapplications have been filed t
131、hroughout the world,including,in the United States,Argentina,ARIPO(Africa Regional Intellectual Property Organization),Australia,Brazil,Canada,Chile,China,Eurasian Patent Organization,Europe,GCC(Gulf Cooperation Council),Hong Kong,Israel,India,Indonesia,Iraq,Jordan,Japan,Lebanon,Mexico,New Zealand,O
132、API(African IntellectualProperty Organization),Peru,Philippines,Russian Federation,South Africa,Saudi Arabia,Singapore,South Korea,Thailand,Taiwan,Uruguay,Venezuela,and Vietnam.RNAi Triggers:The Company owns issued patents or has filed patent applications directed to RNAi trigger molecules,which ser
133、ve as the foundation of the Companys TRiM platform,andare targeted to reduce expression of various gene targets.However,the Company cannot guarantee that issued patents will be enforceable or provide adequate protection for the Company,or thatpending patent applications will result in issued patents
134、.These patents and patent applications include the following:TM9Patent GroupEstimated Year(s)of Expiration*AAT2035,2038ANGPTL32038APOC32035,2038ATXN22044C32043CFB2044COVID2043Cx432029DM12043DUX42041Factor 122036,2038FRP-12026HBV2032,2036,2037HIF1A2026HIF22034,2036,2040HRH12027HSD17B132039HSF12030,20
135、32KRAS2033LPA2036MARC12044MMP72042Mob-52027MUC5AC2042P2X32027PCSK92044PDtype42026PI4Kinase2028PNPLA32041RAGE(AGER)2042RRM22031SOD12043SYK2027TNF-2027,2028TSLP2044XDH2042-ENaC2028,2038-Catenin2033-ENaC2031,2040*Assuming issuance of any pending patent applications,and excluding any patent term adjustm
136、ents or patent term extensions.Delivery Technologies:The delivery technology-related patents and patent applications,which include components used in the Companys TRiM platform,have been filed and/or issued invarious jurisdictions worldwide including the United States,Argentina,Australia,Brazil,Cana
137、da,China,Eurasian Patent Organization,Europe(including validations in France,Germany,Italy,Spain,Switzerland,United Kingdom),GCC(Gulf Cooperation Council),Israel,India,Japan,Lebanon,Mexico,New Zealand,Philippines,Russia,South Africa,South Korea,Singapore,TM10Taiwan,and Uruguay.The Company also contr
138、ols a patent directed to hydrodynamic nucleic acid delivery that issued in the United States.However,the Company cannot guarantee that issuedpatents will be enforceable or provide adequate protection for the Company,or that pending patent applications will result in issued patents.These various grou
139、ps of patents and applicationsare set forth below:Patent GroupEstimated Year(s)of Expiration*Targeting ligands and other RNAi delivery and platform technologiesCNS Intrathecal Delivery Platform2043Adipose Delivery Platform2044Biologically cleavable linkers2036LDLR targeting2028Muscle delivery platfo
140、rm2041Peptide targeting(CPP-Arg)2028Peptide targeting(YM3-10H)2032Physiologically labile linkers2036PK/PD lipid modifiers2041RNAi agent design(5-phosphate mimic)2037Targeting groups(Galactose derivative ligands)2037Targeting groups(Galactose derivative trimer-PK)2031Targeting groups(v3/v5 integrin)2
141、034,2038,2039Targeting groups(v6 integrin)2037,2038,2041Transferrin targeting2028Trialkyne linkers2039Hydrodynamic deliveryThird iteration2024*Assuming issuance of any pending patent applications,and excluding any patent term adjustments or patent term extensions.The RNAi and drug delivery patent la
142、ndscapes are complex and rapidly evolving.As such,the Company may need to obtain additional patent licenses prior to commercialization of itscandidates.Please see“Risk Factors”in Part I,Item 1A of this Annual Report on Form 10-K.Acquisition of Assets from NovartisOn March 3,2015,Novartis and the Com
143、pany entered into an Asset Purchase and Exclusive License Agreement(the“RNAi Purchase Agreement”)pursuant to which the Company acquiredNovartiss RNAi assets and rights thereunder.Pursuant to the RNAi Purchase Agreement,the Company acquired or was granted a license to certain patents and patent appli
144、cations owned orcontrolled by Novartis related to RNAi therapeutics,was assigned Novartiss rights under a license from Alnylam Pharmaceuticals,Inc.(“Alnylam”)(the“Alnylam-Novartis License”)and acquired alicense to certain additional Novartis assets(the“Licensed Novartis Assets”).The patents acquired
145、 from Novartis include multiple patent families covering delivery technologies and RNAi-triggerdesign rules and modifications.The Licensed Novartis Assets include an exclusive,worldwide right and license,solely in the RNAi field,with the right to grant sublicenses through multiple tiersunder or with
146、 respect to certain patent rights and know how relating to delivery technologies and RNAi-trigger design rules and modifications.Under the assigned Alnylam-Novartis License,theCompany acquired a worldwide,royalty-bearing,exclusive license with limited sublicensing rights to existing and future Alnyl
147、am intellectual property(including intellectual property that cameunder Alnylams control on or before March 31,2016),excluding intellectual property concerning delivery technology,to research,develop and commercialize 30 undisclosed gene targets.Non-Exclusively Licensed Patent Rights from RocheOn Oc
148、tober 21,2011,the Company acquired the RNAi therapeutics business of Hoffmann-La Roche,Inc.and F.Hoffmann-La Roche Ltd.(collectively,“Roche”).The acquisition provided theCompany with two primary sources of value:11Broad freedom to operate with respect to key patents directed to the primary RNAi-trig
149、ger formats:canonical,unlocked nucleotide analogs(“UNA”),meroduplex,and dicer substratestructures;andA large team of scientists experienced in RNAi and oligonucleotide delivery.Pursuant to this acquisition,Roche assigned to the Company its entire rights under certain licenses including:the License a
150、nd Collaboration Agreement between Roche and Alnylam dated July8,2007;the Non-Exclusive Patent License Agreement between Roche and MDRNA,Inc.dated February 12,2009(“MDRNA License”);and the Non-Exclusive License Agreement between Rocheand City of Hope dated September 19,2011(collectively the“RNAi Lic
151、enses”).The RNAi Licenses include licenses to patents related to modifications of double-stranded oligonucleotides,including modifications to the base,sugar,or internucleoside linkage,nucleotidemimetics,and end modifications,which do not abolish the RNAi activity of the double-stranded oligonucleoti
152、des.Also included are patents relating to modified double-stranded oligonucleotides,such as meroduplexes described in U.S.Patent No.9,074,205 assigned to Marina Biotech(f/k/a MDRNA,Inc.),as well as U.S.Patent Nos.8,314,227,9,051,570,and 9,303,260 related to UNA.TheUNA patents were assigned by Marina
153、 Biotech to Arcturus Therapeutics,Inc.,but remain part of the MDRNA License.The RNAi Licenses further include patents related to dicer substrates and usesof the double-stranded oligonucleotides that function through the mechanism of RNA interference,such as described in City of Hopes U.S.Patent Nos.
154、8,084,599,8,658,356,8,691,786,8,796,444,8,809,515,and 9,518,262.D.Government RegulationGovernment authorities in the United States,at the federal,state,and local levels,and in other countries and jurisdictions,including the European Union(“EU”),extensively regulate,amongother things,the research,dev
155、elopment,testing,product approval,manufacture,quality control,manufacturing changes,packaging,storage,recordkeeping,labeling,promotion,advertising,sales,distribution,marketing,and import and export of drugs and biologic products.All of the Companys current product candidates are expected to be regul
156、ated as drugs.The processes for obtainingregulatory approval in the United States and in foreign countries and jurisdictions,along with compliance with applicable statutes and regulations and other regulatory authorities both pre-and post-commercialization,are a significant factor in the production
157、and marketing of the Companys products and its R&D activities and require the expenditure of substantial time and financial resources.Review and Approval of Drugs in the United StatesThe FDA and other government entities regulate drugs under the Federal Food,Drug,and Cosmetic Act(the“FDCA”),the Publ
158、ic Health Service Act,and the regulations promulgated underthose statutes,as well as other federal and state statutes and regulations.Failure to comply with applicable legal and regulatory requirements in the United States at any time during the productdevelopment process,approval process,or after a
159、pproval,may subject us to a variety of administrative or judicial sanctions,such as a delay in approving or refusal by the FDA to approve pendingapplications,withdrawal of approvals,delay or suspension of clinical trials,issuance of warning letters and other types of regulatory letters,product recal
160、ls,product seizures,total or partialsuspension of production or distribution,injunctions,fines,civil monetary penalties,refusals of or debarment from government contracts,exclusion from the federal healthcare programs,restitution,disgorgement of profits,civil or criminal investigations by the FDA,U.
161、S.Department of Justice,State Attorneys General,and/or other agencies,False Claims Act suits and/or other litigation,and/orcriminal prosecutions.An applicant seeking approval to market and distribute a new drug in the United States must typically undertake the following:(1)completion of preclinical
162、laboratory tests,which may include animal and in vitro studies,and formulation studies in compliance with the FDAs good laboratory practice(“GLP”)regulations;(2)submission to the FDA of an Investigational New Drug application(“IND”)for human clinical testing,which must become effective without FDA o
163、bjection before human clinical trialsmay begin;(3)approval by an independent institutional review board(“IRB”),representing each clinical site before each clinical trial may be initiated;(4)performance of adequate and well-controlled human clinical trials in accordance with the FDAs current good cli
164、nical practice(“cGCP”)regulations,to establish the safety and effectivenessof the proposed drug product for each indication for which approval is sought;(5)preparation and submission to the FDA of an NDA;(6)satisfactory review of the NDA by an FDA advisory committee,where appropriate or if applicabl
165、e;12(7)satisfactory completion of one or more FDA inspections of the manufacturing facility or facilities at which the drug product,and the active pharmaceutical ingredient or ingredients thereof,are produced to assess compliance with current good manufacturing practice(“cGMP”)regulations and to ass
166、ure that the facilities,methods,and controls are adequate to ensure the productsidentity,strength,quality,and purity;(8)payment of user fees,as applicable,and securing FDA approval of the NDA;and(9)compliance with any post-approval requirements,such as any Risk Evaluation and Mitigation Strategies(“
167、REMS”)or post-approval studies required by the FDA.Preclinical Studies and an INDPreclinical studies can include in vitro and animal studies to assess the potential for adverse events and,in some cases,to establish a rationale for therapeutic use.The conduct of preclinicalstudies is subject to feder
168、al regulations and requirements,including GLP regulations.Other studies include laboratory evaluation of the purity,stability and physical form of the manufactured drugsubstance or active pharmaceutical ingredient and the physical properties,stability and reproducibility of the formulated drug or dr
169、ug product.An IND sponsor must submit the results of thepreclinical tests,together with manufacturing information,analytical data,any available clinical data or literature and plans for clinical studies,among other things,to the FDA as part of an IND.Some preclinical testing,such as longer-term toxi
170、city testing,animal tests of reproductive adverse events and carcinogenicity,may continue after the IND is submitted.An IND automaticallybecomes effective 30 days after receipt by the FDA,unless before that time the FDA raises concerns or questions related to a proposed clinical trial and places the
171、 trial on clinical hold.In such a case,the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin.As a result,submission of an IND may not result in the FDA allowing clinical trials tocommence.Following commencement of a clinical trial under an IND,the FDA
172、may place a clinical hold on that trial.A clinical hold is an order issued by the FDA to the sponsor to delay a proposedclinical investigation or to suspend an ongoing investigation.A partial clinical hold is a delay or suspension of only part of the clinical work requested under the IND.For example
173、,a specific protocolor part of a protocol is not allowed to proceed,while other protocols may do so.No more than 30 days after imposition of a clinical hold or partial clinical hold,the FDA will provide the sponsor awritten explanation of the basis for the hold.Following issuance of a clinical hold
174、or partial clinical hold,an investigation may only resume after the FDA has notified the sponsor that theinvestigation may proceed.The FDA will base that determination on information provided by the sponsor correcting the deficiencies previously cited or otherwise satisfying the FDA that theinvestig
175、ation can proceed.Human Clinical Studies in Support of an NDAClinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators in accordance with cGCP requirements,which include,among other things,the requirement that all res
176、earch subjects provide their informed consent in writing before their participation in any clinical trial.Clinical trials are conducted under written studyprotocols detailing,among other things,the objectives of the study,the parameters to be used in monitoring safety and the effectiveness criteria
177、to be evaluated.A protocol for each clinical trial andany subsequent protocol amendments must be submitted to the FDA as part of the IND.In addition,an IRB representing each institution participating in the clinical trial must review and approve theplan for any clinical trial before it commences at
178、that institution,and the IRB must conduct continuing review and reapprove the study at least annually.The IRB must review and approve,amongother things,the study protocol and informed consent information to be provided to study subjects.An IRB must operate in compliance with FDA regulations.Informat
179、ion about certain clinical trialsmust be submitted within specific timeframes to the National Institutes of Health for public dissemination on its ClinicalTrials.gov website.Human clinical trials are typically conducted in three sequential phases,which may overlap or be combined:Phase 1:The product
180、candidate is initially introduced into healthy human subjects or patients with the target disease or condition and tested for safety,dosage tolerance,absorption,metabolism,distribution,excretion and,if possible,to gain an early indication of its effectiveness.Phase 2:The product candidate is adminis
181、tered to a limited patient population to identify possible adverse effects and safety risks,to preliminarily evaluate the efficacy of the product forspecific targeted diseases and to determine dosage tolerance and optimal dosage.Phase 3:The product candidate is administered to an expanded patient po
182、pulation,generally at geographically dispersed clinical trial sites,in well-controlled clinical trials to generate enoughdata to statistically evaluate the efficacy and safety of the product for approval,to establish the overall risk-benefit profile of the product,and to provide adequate information
183、 for the labeling ofthe product.13Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and more frequently if serious adverse events occur.Phase 1,Phase 2,and Phase 3clinical trials may not be completed successfully within any specified period,
184、or at all.Furthermore,the FDA or the sponsor may suspend or terminate a clinical trial at any time on various grounds,including a finding that the research subjects are being exposed to an unacceptable health risk.Similarly,an IRB can suspend or terminate approval of a clinical trial at its institut
185、ion,or an institutionit represents,if the clinical trial is not being conducted in accordance with the IRBs requirements or if the drug has been associated with unexpected serious harm to patients.The FDA will typicallyinspect one or more clinical sites in late-stage clinical trials to assure compli
186、ance with cGCP and the integrity of the clinical data submitted.A sponsor may choose,but is not required,to conduct a foreign clinical study under an IND.When a foreign clinical study is conducted under an IND,all IND requirements must be met unlesswaived.When the foreign clinical study is not condu
187、cted under an IND,the sponsor must ensure that the study complies with certain FDA regulatory requirements in order to use the study as supportfor an IND or application for marketing approval or licensure,including that the study was conducted in accordance with cGCP,including review and approval by
188、 an independent ethics committeeand use of proper procedures for obtaining informed consent from subjects,and the FDA is able to validate the data from the study through an onsite inspection if the FDA deems such inspectionnecessary.The cGCP requirements encompass both ethical and data integrity sta
189、ndards for clinical studies.Submission of an NDA to the FDAAssuming successful completion of required clinical testing and other requirements,the results of the preclinical and clinical studies,together with detailed information relating to the productschemistry,manufacture,controls and proposed lab
190、eling,among other things,are submitted to the FDA as part of an NDA requesting approval to market the drug product for one or more indications.Under federal law,the submission of most NDAs is additionally subject to an application user fee,currently approximately$4.3 million for fiscal year 2025,for
191、 applications requiring clinical data,and the sponsor of an approved NDA is also subject to an annual program fee,currently approximately$0.4 million for fiscal year 2025.These fees are adjusted annually.Under certain circumstances,the FDA will waive the application fee for the first human drug appl
192、ication that a small business,defined as a company with less than 500 employees,includingemployees of affiliates,submits for review.An affiliate is defined as a business entity that has a relationship with a second business entity if one business entity controls,or has the power to control,the other
193、 business entity,or a third-party controls,or has the power to control,both entities.In addition,an application to market a prescription drug product that has received orphan designation isnot subject to a prescription drug user fee unless the application includes an indication for other than the ra
194、re disease or condition for which the drug was designated.The FDA conducts a preliminary review of an NDA within 60 days of its receipt and informs the sponsor by the 74th day after the FDAs receipt of the submission to determine whether theapplication is sufficiently complete to permit substantive
195、review.The FDA may request additional information rather than accept an NDA for filing.In this event,the application must be resubmittedwith the additional information.The resubmitted application is also subject to review before the FDA accepts it for filing.Once the submission is accepted for filin
196、g,the FDA begins an in-depthsubstantive review.The FDA has agreed to specified performance goals in the review process of NDAs.Most such applications are meant to be reviewed within ten months from the date of filing,and most applications for“priority review”products are meant to be reviewed within
197、six months of filing.The review process may be extended by the FDA for three additional months to considernew information or clarification provided by the applicant to address an outstanding deficiency identified by the FDA following the original submission.Before approving an NDA,the FDA typically
198、will inspect the facility or facilities where the product is manufactured.The FDA will not approve an application unless it determines that themanufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required s
199、pecifications.Additionally,beforeapproving an NDA,the FDA will typically inspect one or more clinical sites to assure compliance with cGCP.The FDA also may require submission of a REMS plan to mitigate any identified or suspected serious risks.The REMS plan could include medication guides,physician
200、communication plans,assessment plans,and elements to assure safe use,such as restricted distribution methods,patient registries,or other risk minimization tools.The FDA is required to refer an application for a novel drug to an advisory committee or explain why such referral was not made.Typically,a
201、n advisory committee is a panel of independentexperts,including clinicians and other scientific experts,that reviews,evaluates and provides a recommendation as to whether the application should be approved and under what conditions.TheFDA is not bound by the recommendations of an advisory committee,
202、but it considers such recommendations carefully when making decisions.14The FDAs Decision on an NDAOn the basis of the FDAs evaluation of the NDA and accompanying information,including the results of the inspection of the manufacturing facilities,the FDA may issue an approval letter ora complete res
203、ponse letter.An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications.A complete response letter generallyoutlines the deficiencies in the submission and may require substantial additional testing or information in order for the
204、 FDA to reconsider the application.If and when those deficiencies have beenaddressed to the FDAs satisfaction in a resubmission of the NDA,the FDA will issue an approval letter.The FDA has committed to reviewing such resubmissions in two or six months depending onthe type of information included.Eve
205、n with submission of this additional information,the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.If the FDA approves a product,it may limit the approved indications for use for the product,require that contraindications,warnings or precautions
206、 be included in the product labeling,requirethat post-approval studies be conducted to further assess the drugs safety after approval,require testing and surveillance programs to monitor the product after commercialization,or impose otherconditions,including distribution restrictions or other risk m
207、anagement mechanisms,including REMS,which can materially affect the potential market and profitability of the product.Afterapproval,the FDA may seek to prevent or limit further marketing of a product based on the results of post-market studies or surveillance programs.Some types of changes to the ap
208、proved product,such as adding new indications,manufacturing changes and additional labeling claims,are subject to further testing requirements and FDA review and approval.The product may also be subject to official lot release,meaning that the manufacturer is required to perform certain tests on eac
209、h lot of the product before it is released for distribution.If theproduct is subject to official lot release,the manufacturer must submit samples of each lot,together with a release protocol showing a summary of the history of manufacture of the lot and the resultsof all of the manufacturers tests p
210、erformed on the lot,to the FDA.The FDA may in addition perform certain confirmatory tests on lots of some products before releasing the lots for distribution.Finally,the FDA will conduct laboratory research related to the safety and effectiveness of drug products.Under the Orphan Drug Act,the FDA ma
211、y grant orphan drug designation to a drug intended to treat a rare disease or condition,which is generally a disease or condition that affects fewer than200,000 individuals in the United States,or more than 200,000 individuals in the United States and for which there is no reasonable expectation tha
212、t the cost of developing and making available in theUnited States a drug for this type of disease or condition will be recovered from sales in the United States for that drug.Orphan drug designation entitles the applicant to incentives such as grantfunding towards clinical study costs,tax advantages
213、,and waivers of FDA user fees.Orphan drug designation must be requested before submitting an NDA,and both the drug and the disease orcondition must meet certain criteria specified in the Orphan Drug Act and FDAs implementing regulations at 21 C.F.R.Part 316.The granting of an orphan drug designation
214、 does not alter thestandard regulatory requirements and process for obtaining marketing approval.Safety and effectiveness of a drug must be established through adequate and well-controlled studies.After the FDA grants orphan drug designation,the identity of the therapeutic agent and its potential or
215、phan use are disclosed publicly by the FDA.If a product that has orphan drug designationsubsequently receives the first FDA approval for the disease for which it has such designation,the product is entitled to orphan product exclusivity,which means that the FDA may not approve anyother application t
216、o market the same drug for the same indication,except in very limited circumstances,for seven years.Orphan drug exclusivity does not prevent the FDA from approving a differentdrug for the same disease or condition,or the same drug for a different disease or condition.The FDAs interpretation of the s
217、cope of orphan drug exclusivity may change.The FDAs longstanding interpretation of the Orphan Drug Act is that exclusivity is specific to the orphanindication for which the drug was actually approved.As a result,the scope of exclusivity has been narrow and protected only against competition from the
218、 same“use or indication”rather than thebroader“disease or condition.”In the September 2021 case Catalyst Pharmaceuticals,Inc.v.FDA,a federal circuit court set aside the FDAs narrow interpretation and ruled that orphan drugexclusivity covers the full scope of the orphan-designated disease or conditio
219、n regardless of whether the drug obtains approval only for a narrower use.The decision concerned amifampridine,a drugused to treat Lambert-Eaton myasthenic syndrome(LEMS).Depending on how the FDA applies the decision beyond this case,it may limit which drugs can receive exclusivity orphan drug.Exped
220、ited Review and Accelerated Approval ProgramsA sponsor may seek approval of its product candidate under programs designed to accelerate the FDAs review and approval of NDAs.For example,Fast Track Designation may be granted toa drug intended for treatment of a serious or life-threatening disease or c
221、ondition and data demonstrate its potential to address unmet medical needs for the disease or condition.The key benefits ofFast Track Designation are the eligibility for priority review,rolling review(submission of portions of an application before the complete marketing application is submitted),an
222、d acceleratedapproval,if relevant15criteria are met.The FDA may grant the NDA a priority review designation,which sets the target date for FDA action on the application at six months after the FDA accepts the application for filing.Priority review is granted where there is evidence that the proposed
223、 product would be a significant improvement in the safety or effectiveness of the treatment,diagnosis,or prevention of a seriouscondition.Priority review designation does not change the scientific/medical standard for approval or the quality of evidence necessary to support approval.The FDA may appr
224、ove an NDA under the accelerated approval program if the drug treats a serious condition,provides a meaningful advantage over available therapies,and demonstrates aneffect on either(1)a surrogate endpoint that is reasonably likely to predict clinical benefit,or(2)on a clinical endpoint that can be m
225、easured earlier than irreversible morbidity or mortality,that isreasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit,taking into account the severity,rarity,or prevalence of the condition and the availability or lack ofalternative treatments.Post-ma
226、rketing studies or completion of ongoing studies after marketing approval are generally required to verify the drugs clinical benefit in relationship to the surrogateendpoint or ultimate outcome in relationship to the clinical benefit.Under the Food and Drug Omnibus Reform Act of 2022(“FDORA”),the F
227、DA may require,as appropriate,that such studies beunderway prior to approval or within a specific time period after the date of approval for a product granted accelerated approval.The FDA also has increased authority for expedited procedures towithdraw approval of a product or indication approved un
228、der accelerated approval if the sponsor fails to conduct the required post-marketing studies or if such studies fail to verify the predictedclinical benefit.In addition,the FDA currently requires as a condition for accelerated approval pre-approval of promotional materials,which could adversely impa
229、ct the timing of the commerciallaunch of the product.In addition,the Food and Drug Administration Safety and Innovation Act of 2012(“FDASIA”)established the Breakthrough Therapy designation.A sponsor may seek FDA designation of itsproduct candidate as a breakthrough therapy if the drug is intended,a
230、lone or in combination with one or more other drugs,to treat a serious or life-threatening disease or condition and preliminaryclinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints,such as substantial
231、 treatment effectsobserved early in clinical development.If a drug is designated as breakthrough therapy,FDA will provide more intensive guidance on the drug development program and expedite its review.Post-Approval RequirementsDrugs manufactured or distributed pursuant to FDA approvals are subject
232、to pervasive and continuing regulation by the FDA,including,among other things,requirements relating torecordkeeping,periodic reporting,product sampling and distribution,advertising and promotion and reporting of adverse experiences with the product.After approval,most changes to the approvedproduct
233、,such as adding new indications or other labeling claims,are subject to prior FDA review and approval.There also are continuing,annual user fee requirements for any marketed products andthe establishments at which such products are manufactured,as well as new application fees for supplemental applic
234、ations with clinical data.In addition,drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and state agenciesand are subject to periodic unannounced inspections by the FDA and these state agenc
235、ies for compliance with cGMP requirements.Changes to the manufacturing process are strictly regulated andoften require prior FDA approval before being implemented.FDA regulations also require investigation and correction of any deviations from cGMP and impose reporting and documentationrequirements
236、upon the sponsor and any third-party manufacturers that the sponsor may decide to use.Accordingly,manufacturers must continue to expend time,money,and effort in the area ofproduction and quality control to maintain cGMP compliance.Once an approval is granted,the FDA may withdraw the approval if comp
237、liance with regulatory requirements and standards is not maintained or if problems occur after the product reaches themarket.Later discovery of previously unknown problems with a product,including adverse events or problems with manufacturing processes of unanticipated severity or frequency,or failu
238、re tocomply with regulatory requirements,may result in revisions to the approved labeling to add new safety information;imposition of post-market studies or clinical trials to assess new safety risks;orimposition of distribution or other restrictions under a REMS program.Other potential consequences
239、 include,among other things:restrictions on the marketing or manufacturing of the product,complete withdrawal of the product from the market or product recalls;fines,warning,untitled,or it has come to our attention letters,or holds on post-approval clinical trials;refusal of the FDA to approve pendi
240、ng NDAs or supplements to approved NDAs,or suspension or revocation of product license approvals;product seizure or detention,or refusal to permit the import or export of products;orinjunctions or the imposition of civil or criminal penalties.16The FDA strictly regulates marketing,labeling,advertisi
241、ng and promotion of products that are placed on the market.Drugs may be promoted only for the approved indications and inaccordance with the provisions of the approved label.The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses,and a company
242、 that is foundto have improperly promoted off-label uses may be subject to significant liability.In addition,the distribution of prescription pharmaceutical products is subject to the Prescription Drug Marketing Act(“PDMA”),which regulates the distribution of drugs and drug samples atthe federal lev
243、el and sets minimum standards for the registration and regulation of drug distributors by the states.Both the PDMA and state laws limit the distribution of prescription pharmaceuticalproduct samples and impose requirements to ensure accountability in distribution.Abbreviated New Drug Applications fo
244、r Generic DrugsIn 1984,with passage of the Drug Price Competition and Patent Term Restoration Act of 1984(commonly referred to as the“Hatch-Waxman Amendments”)amending the FDCA,Congressauthorized the FDA to approve generic drugs that are the same as drugs previously approved by the FDA under the NDA
245、 provisions of the statute.To obtain approval of a generic drug,an applicantmust submit an abbreviated new drug application(“ANDA”)to the agency.In support of such applications,a generic manufacturer may rely on the preclinical and clinical testing previouslyconducted for a drug product previously a
246、pproved under an NDA,known as the reference listed drug(“RLD”).To reference that information,however,the ANDA applicant must demonstrate,andthe FDA must conclude,that the generic drug does,in fact,perform in the same way as the RLD it purports to copy.Specifically,in order for an ANDA to be approved
247、,the FDA must find that thegeneric version is identical to the RLD with respect to the active ingredients,the route of administration,the dosage form,and the strength of the drug.However,an applicant may submit an ANDAsuitability petition to request the FDAs prior permission to submit an abbreviated
248、 application for a drug that differs from the RLD in route of administration,dosage form,or strength,or for a drugthat has one different active ingredient in a fixed combination drug product(i.e.,a drug product with multiple active ingredients).At the same time,the FDA must also determine that the g
249、eneric drug is“bioequivalent”to the innovator drug.Under the statute,a generic drug is bioequivalent to a RLD if the rate and extentof absorption of the generic drug do not show a significant difference from the rate and extent of absorption of the RLD.Upon approval of an ANDA,the FDA indicates that
250、 the generic product is“therapeutically equivalent”to the RLD and it assigns a therapeutic equivalence rating to the approved generic drug in its publication“Approved Drug Products with Therapeutic EquivalenceEvaluations,”also referred to as the“Orange Book.”Physicians and pharmacists consider the t
251、herapeutic equivalence rating to mean that a generic drug is fully substitutable for the RLD.In addition,by operation of certain state laws and numerous health insurance programs,the FDAs designation of a therapeutic equivalence rating often results in substitution of the generic drug without thekno
252、wledge or consent of either the prescribing physician or patient.Under the Hatch-Waxman Amendments,the FDA may not approve an ANDA until any applicable period of nonpatent exclusivity for the RLD has expired.The FDCA provides a period offive years of data exclusivity for NDAs containing a new chemic
253、al entity.In cases where such exclusivity has been granted,an ANDA may not be filed with the FDA until the expiration of five yearsunless the submission is accompanied by a Paragraph IV certification,in which case the applicant may submit its application four years following the original product app
254、roval.The FDCA alsoprovides for a period of three years of exclusivity if the NDA includes reports of one or more new clinical investigations,other than bioavailability or bioequivalence studies,that were conducted byor for the applicant and are essential to the approval of the application.This thre
255、e-year exclusivity period often protects changes to a previously approved drug product,such as a new dosage form,route of administration,combination or indication.Hatch-Waxman Patent Certification and the 30 Month StayUpon approval of an NDA or a supplement thereto,NDA sponsors are required to list
256、with the FDA each patent with claims that cover the applicants product or a method of using the product.Each of the patents listed by the NDA sponsor is published in the Orange Book.When an ANDA applicant files its application with the FDA,the applicant is required to certify to the FDAconcerning an
257、y patents listed for the referenced product in the Orange Book,except for patents covering methods of use for which the ANDA applicant is not seeking approval.Specifically,the applicant must certify with respect to each patent that:the required patent information has not been filed;the listed patent
258、 has expired;the listed patent has not expired,but will expire on a particular date and approval is sought after patent expiration;orthe listed patent is invalid,unenforceable or will not be infringed by the new product.17A certification that the new product will not infringe the already approved pr
259、oducts listed patents or that such patents are invalid or unenforceable is called a Paragraph IV certification.If theapplicant does not challenge the listed patents or indicate that it is not seeking approval of a patented method of use,the ANDA application will not be approved until all the listed
260、patents for thereferenced product have expired.If the ANDA applicant has provided a Paragraph IV certification to the FDA,the applicant must also send notice of the Paragraph IV certification to the NDA andpatent holders once the ANDA has been accepted for filing by the FDA.The NDA and patent holder
261、s may then initiate a patent infringement lawsuit in response to the notice of the Paragraph IVcertification.The filing of a patent infringement lawsuit within 45 days after the receipt of a Paragraph IV certification automatically prevents the FDA from approving the ANDA until the earlier of30 mont
262、hs after the receipt of the Paragraph IV certification,expiration of the patent,settlement of the lawsuit or a decision in the infringement case that is favorable to the ANDA applicant.505(b)(2)New Drug ApplicationsAs an alternative path to FDA approval for modifications to formulations or uses of p
263、roducts previously approved by the FDA pursuant to an NDA,an applicant may submit an NDA underSection 505(b)(2)of the FDCA.Section 505(b)(2)was enacted as part of the Hatch-Waxman Amendments and permits the filing of an NDA where at least some of the information required forapproval comes from studi
264、es not conducted by,or for,the applicant,and for which the applicant has not obtained a right of reference.If the 505(b)(2)applicant can establish that reliance on theFDAs previous findings of safety and effectiveness is scientifically and legally appropriate,it may eliminate the need to conduct cer
265、tain preclinical studies or clinical trials of the new product.TheFDA may also require companies to perform additional bridging studies or measurements,including clinical trials,to support the change from the previously approved reference drug.The FDA maythen approve the new drug candidate for all,o
266、r some,of the label indications for which the reference drug has been approved,as well as for any new indication sought by the 505(b)(2)applicant.To the extent that a Section 505(b)(2)applicant is relying on studies conducted for an already approved product,the applicant is required to certify to th
267、e FDA concerning any patents listed forthe approved product in the Orange Book to the same extent that an ANDA applicant would.As a result,approval of a 505(b)(2)NDA can be stalled until all the listed patents claiming the referencedproduct have expired,until any non-patent exclusivity,such as exclu
268、sivity for obtaining approval of a new chemical entity,listed in the Orange Book for the referenced product has expired,and,inthe case of a Paragraph IV certification and subsequent patent infringement suit,until the earlier of 30 months,settlement of the lawsuit or a decision in the infringement ca
269、se that is favorable to theSection 505(b)(2)applicant.Pediatric Studies and ExclusivityUnder the Pediatric Research Equity Act of 2003,an NDA or supplement thereto must contain data that are adequate to assess the safety and effectiveness of the drug product for the claimedindications in all relevan
270、t pediatric subpopulations,and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.With the enactment ofFDASIA,sponsors must also submit pediatric study plans prior to the assessment data.Those plans must contain an outline of the propose
271、d pediatric study or studies the applicant plans to conduct,including study objectives and design,any deferral or waiver requests,and other information required by regulation.The applicant,the FDA,and the FDAs internal review committee must thenreview the information submitted,consult with each othe
272、r,and agree upon a final plan.The FDA or the applicant may request an amendment to the plan at any time.The FDA may,on its own initiative or at the request of the applicant,grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults,or full orpa
273、rtial waivers from the pediatric data requirements.Additional requirements and procedures relating to deferral requests and requests for extension of deferrals are contained in FDASIA.Unlessotherwise required by regulation,the pediatric data requirements do not apply to products with orphan designat
274、ion.Pediatric exclusivity is another type of non-patent marketing exclusivity in the United States and,if granted,provides for the attachment of an additional six months of marketing protection tothe term of any existing regulatory exclusivity,including the non-patent and orphan exclusivity.This six
275、-month exclusivity may be granted if an NDA sponsor submits pediatric data that fairlyrespond to a written request from the FDA for such data.The data do not need to show the product to be effective in the pediatric population studied;rather,if the clinical trial is deemed to fairlyrespond to the FD
276、As request,the additional protection is granted.If reports of requested pediatric studies are submitted to and accepted by the FDA within the statutory time limits,whateverstatutory or regulatory periods of exclusivity or patent protection cover the product are extended by six months.This is not a p
277、atent term extension,but it effectively extends the regulatory periodduring which the FDA cannot accept or approve another application.Patent Term Restoration and ExtensionA patent claiming a new drug product may be eligible for a limited patent term extension under the Hatch-Waxman Amendments.Those
278、 Amendments permit a patent restoration of up to fiveyears for patent term lost during product18development and the FDA regulatory review.The restoration period granted is typically one-half the time between the effective date of an IND and the submission date of a NDA,plus the timebetween the submi
279、ssion date of a NDA and ultimate approval.Patent term restoration cannot be used to extend the remaining term of a patent past a total of 14 years from the products approval date.Only one patent applicable to an approved drug product is eligible for the extension,and the application for the extensio
280、n must be submitted prior to the expiration of the patent in question.The U.S.Patent and Trademark Office reviews and approves the application for any patent term extension or restoration in consultation with the FDA.Review and Approval of Drugs in the European Union and United KingdomIn order to ma
281、rket any pharmaceutical product outside of the United States,a company must also comply with numerous and varying regulatory requirements of other countries andjurisdictions governing,among other things,research and development,testing,manufacturing,quality control,safety,efficacy,labeling,clinical
282、trials,marketing authorization,packaging,storage,record keeping,reporting,export and import,advertising,marketing and other promotional practices involving pharmaceutical products,as well as commercial sales,distribution,authorization,approval and post-approval monitoring and reporting of its produc
283、ts.Whether or not a company obtains FDA approval for a pharmaceutical product,the company would need to obtain the necessaryapprovals by the comparable foreign regulatory authorities before it can commence clinical trials or marketing of the pharmaceutical product in those countries or jurisdictions
284、.The approval processultimately varies between countries and jurisdictions and can involve additional product testing and additional administrative review periods.The time required to obtain approval in other countriesand jurisdictions might differ from and be longer than that required to obtain FDA
285、 approval.Regulatory approval in one country or jurisdiction does not ensure regulatory approval in another,but afailure or delay in obtaining regulatory approval in one country or jurisdiction may negatively impact the regulatory process in others.The United Kingdom(“UK”)formally left the EU on Jan
286、uary 31,2020(“Brexit”)and EU laws now only apply to the UK in respect of Northern Ireland as laid out in the Protocol on Irelandand Northern Ireland.The EU and the UK have agreed on a trade and cooperation agreement(“TCA”)which includes provisions affecting the life sciences sector(including on cust
287、oms and tariffs).There are some specific provisions concerning pharmaceuticals,including the mutual recognition of Good Manufacturing Practice(“GMP”)and issued GMP documents.The TCA does not,however,contain wholesale mutual recognition of UK and EU pharmaceutical regulations and product standards.Th
288、e UK government has enacted the Medicines and Medical Devices Act 2021.The purpose of the act is to enable the existing regulatory frameworks in relation to human medicines andclinical trials of human medicines,among others,to be updated.The powers under the act may only be exercised in relation to
289、specified matters and must safeguard public health.The Medicines and Medical Devices Act 2021 supplements the UK Medical Devices Regulations 2002(“UK Regulations”),which are based on the EU Medical Devices Directive as amendedto reflect the UKs post-Brexit regulatory regime.Notably,the UK Regulation
290、s do not include any of the revisions that have been made by the EU Medical Devices Regulation(EU)2017/745,which,since May 26,2021,applies in all EU member states.The UKs Medicines and Healthcare products Regulatory Agency(“MHRA”)conducted a comprehensive consultation in 2021 on proposals to develop
291、 a new UK regime for medical devicesin the UK.The proposals include more closely aligning definitions for medical devices and in vitro medical devices with internationally recognized definitions and changing the classification ofmedical devices according to levels or risk.The proposals are intended
292、to improve patient and public safety and increase the appeal of the UK market.Core aspects of the new regime are planned tocome into force on July 1,2025,with strengthened post-market surveillance proposals to be introduced ahead of this in 2023.Under the Medical Devices(Amendment)(Great Britain)Reg
293、ulations 2023,CE marked European medical devices will continue to be accepted for sale in the UK until 2028 or 2030(depending on the type of device).Drug and Biologic Development ProcessThe conduct of clinical trials in the EU is governed by the EU Clinical Trials Regulation(EU)No.536/2014(“CTR”)whi
294、ch entered into force on January 31,2022.The CTR replaced theClinical Trials Directive 2001/20/EC,(Clinical Trials Directive)and introduced a complete overhaul of the existing regulation of clinical trials for medicinal products in the EU.Under the former regime,which will expire after a transition
295、period of one or three years,respectively,as outlined below in more detail,before a clinical trial can be initiated,it must beapproved in each EU member state where there is a site at which the clinical trial is to be conducted.The approval must be obtained from two separate entities:the National Co
296、mpetent Authority(“NCA”),and one or more Ethics Committees.The NCA of the EU member states in which the clinical trial will be conducted must authorize the conduct of the trial,and the independent EthicsCommittee must grant a19positive opinion in relation to the conduct of the clinical trial in the
297、relevant EU member state before the commencement of the trial.Any substantial changes to the trial protocol or other informationsubmitted with the Clinical Trial Applications(“CTA”)must be submitted to or approved by the relevant NCA and Ethics Committees.Under the current regime all suspected unexp
298、ected seriousadverse reactions to the investigated drug that occur during the clinical trial must be reported to the NCA and to the Ethics Committees of the EU member state where they occur.A more unified procedure applies under the new CTR.A sponsor is able to submit a single application for approv
299、al of a clinical trial through a centralized EU clinical trials portal,the ClinicalTrials Information System(“CTIS”).One national regulatory authority(the reporting EU member state proposed by the applicant)takes the lead in validating and evaluating the application,andconsults and coordinates with
300、the other concerned EU member states.If an application is rejected,it may be amended and resubmitted through the CTIS.If an approval is issued,the sponsor may startthe clinical trial in all concerned EU member states.However,a concerned EU member state may in limited circumstances declare an“opt-out
301、”from an approval and prevent the clinical trial frombeing conducted in such EU member state.The CTR also aims to streamline and simplify the rules on safety reporting and introduces enhanced transparency requirements such as mandatorysubmission of a summary of the clinical trial results to the CTIS
302、.The CTR includes a three-year transition period.Member states will work in CTIS immediately after the system has gone live.SinceJanuary 31,2023,submission of initial CTA via CTIS is mandatory and CTIS serves as the single entry point for submission of clinical trial-related information and data.By
303、January 31,2025,allongoing trials approved under the former Clinical Trials Directive will need to comply with the CTR and have to be transitioned to CTIS.Under both the former regime and the new CTR,national laws,regulations,and the applicable GCP and Good Laboratory Practice standards must also be
304、 respected during the conduct of thetrials,including the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use guidelines on GCP,and the ethical principles that have their origin in theDeclaration of Helsinki.During the development of a medicinal product
305、,the European Medicines Agency(“EMA”)and national regulators within the EU provide the opportunity for dialogue and guidance on thedevelopment program.At the EMA level,this is usually done in the form of scientific advice,which is given by the Committee for Medicinal Products for Human Use(“CHMP”)on
306、 therecommendation of the Scientific Advice Working Party(“SAWP”).A fee is incurred with each scientific advice procedure,but is significantly reduced for designated orphan medicines.Advice fromthe EMA is typically provided based on questions concerning,for example,quality(chemistry,manufacturing an
307、d controls testing),nonclinical testing and clinical studies,and pharmacovigilanceplans and risk-management programs.Advice is not legally binding with regard to any future Marketing Authorization Application(“MAA”)of the product concerned.Marketing Authorization ProceduresIn the EU and in Iceland,N
308、orway and Liechtenstein(together the European Economic Area or“EEA”),after completion of all required clinical testing,pharmaceutical products may only beplaced on the market after obtaining a Marketing Authorization(“MA”).To obtain an MA of a drug under EU regulatory systems,an applicant can submit
309、 a MAA through,amongst others,acentralized or decentralized procedure.The centralized procedure provides for the grant of a single MA by the European Commission(“EC”)that is valid for all EU member states and,after respective national implementingdecisions which must be rendered within 30 days,in th
310、e three additional member states of the EEA.The centralized procedure is compulsory for specific pharmaceutical products,including formedicines developed by means of certain biotechnological processes,products designated as orphan pharmaceutical products,advanced therapy pharmaceutical products and
311、pharmaceutical productswith a new active substance indicated for the treatment of certain diseases(AIDS,cancer,neurodegenerative disorders,diabetes,auto-immune and viral diseases).For pharmaceutical productscontaining a new active substance not yet authorized in the European Economic Area before May
312、 20,2004 and indicated for the treatment of other diseases,pharmaceutical products that constitutesignificant therapeutic,scientific or technical innovations or for which the grant of a MA through the centralized procedure would be in the interest of public health at EU level,an applicant mayvolunta
313、rily submit an application for a marketing authorization through the centralized procedure.Under the centralized procedure,the CHMP established at the EMA is responsible for conducting the initial assessment of a drug.The CHMP is also responsible for several post-authorizationand maintenance activit
314、ies,such as the assessment of modifications or extensions to an existing marketing authorization.Under the centralized procedure,the timeframe for the evaluation of an MAAby the EMAs CHMP is,in principle,210 days from receipt of a valid MAA.However,this timeline excludes clock stops,when additional
315、written or oral information is to be provided by theapplicant in response to questions asked by the CHMP,so the overall process typically takes a year or more,unless the application is eligible for an accelerated assessment.Accelerated assessmentmight be granted by the CHMP in exceptional cases when
316、 a pharmaceutical product is expected to be of major public health interest,particularly from the point of therapeutic innovation.On request,the CHMP can reduce the time frame to 150 days if the applicant provides sufficient justification20for an accelerated assessment.The CHMP will provide a positi
317、ve opinion regarding the application only if it meets certain quality,safety and efficacy requirements.However,the EC has finalauthority for granting the MA within 67 days after receipt of the CHMP opinion.The decentralized procedure permits companies to file identical MA applications for a pharmace
318、utical product to the competent authorities in various EU member states simultaneously if suchpharmaceutical product has not received marketing approval in any EU member state before.This procedure is available for pharmaceutical products not falling within the mandatory scope of thecentralized proc
319、edure.The competent authority of a single EU member state,known as the reference EU member state,is appointed to review the application and provide an assessment report.Underthis procedure,an applicant submits an application based on identical dossiers and related materials,including a draft summary
320、 of product characteristics,and draft labeling and package leaflet,to thereference EU member state and concerned EU member states.The reference EU member state prepares a draft assessment report and drafts of the related materials within 120 days after receipt of avalid application.Subsequently,each
321、 concerned EU member state must decide whether to approve the assessment report and related materials.If an EU member state cannot approve the assessment report and related materials on the grounds of potential serious risk to public health,the disputed points are subject to a dispute resolutionmech
322、anism and may eventually be referred to the EC,whose decision is binding for all EU member states.All new MAAs must include a Risk Management Plan(“RMP”),describing the risk management system that the company will put in place and documenting measures to prevent or minimizethe risks associated with
323、the product.RMPs are continually modified and updated throughout the lifetime of the medicine as new information becomes available.New RMPs are required to besubmitted(i)at the request of EMA or a national competent authority,or(ii)whenever the risk-management system is modified,especially as the re
324、sult of new information being received that maylead to a significant change to the benefit-risk profile or as a result of an important pharmacovigilance or risk-minimization milestone being reached.The regulatory authorities may also imposespecific obligations as a condition of the MA.Since October
325、20,2023,all RMPs for centrally authorized products are published by the EMA subject to only limited redactions.Marketing Authorizations have an initial duration of five years.After these five years,the authorization may subsequently be renewed on the basis of a reevaluation of the risk-benefit balan
326、ce.Once renewed,the MA is valid for an unlimited period unless the EC or the national competent authority decides,on justified grounds relating to pharmacovigilance,to proceed with only oneadditional five-year renewal.Applications for renewal must be made to the EMA at least nine months before the f
327、ive-year period expires.Data and Market Exclusivity in the European UnionAs in the United States,it may be possible to obtain a period of market and/or data exclusivity in the EU that would have the effect of postponing the entry into the marketplace of acompetitors generic,hybrid or biosimilar prod
328、uct(even if the pharmaceutical product has already received an MA)and prohibiting another applicant from relying on the MA holderspharmacological,toxicological and clinical data in support of another MA for the purposes of submitting an application,obtaining MA or placing the product on the market.N
329、ew Chemical Entities(“NCE”)approved in the EU qualify for eight years of data exclusivity and ten years of marketing exclusivity.The overall ten-year period can be extended to a maximum of eleven years if,during thefirst eight years of those ten years,the marketing authorization holder obtains an au
330、thorization for one or more new therapeutic indications which,during the scientific evaluation prior to theirauthorization,are deemed to bring a significant clinical benefit in comparison with existing therapies.The data exclusivity period begins on the date of the products first MA in the EU.After
331、eight years,a generic product application may be submitted and generic companies may rely on theMA holders data.However,a generic product cannot launch until two years later(or a total of 10 years after the first MA in the EU of the innovator product),or three years later(or a total of 11years after
332、 the first MA in the EU of the innovator product)if the MA holder obtains MA for a new indication with significant clinical benefit within the eight-year data exclusivity period.Additionally,another noncumulative one-year period of data exclusivity can be added to the eight years of data exclusivity
333、 where an application is made for a new indication for a well-establishedsubstance,provided that significant preclinical or clinical studies were carried out in relation to the new indication.Another year of data exclusivity may be added to the eight years,where a changeof classification of a pharmaceutical product has been authorized on the basis of significant pre-trial tests or clinical trials(
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