IFU))J\. U.S. Food and Drug Administration
`
`Notice: Archived Document
`The content in this document is provided on the FDA's website for reference purposes
`only. This content has not been altered or updated since it was archived.
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`FDA PSYCHOPHARMACOLOGIC DRUGS ADVISORY
`COMMITTEE MEETING
`VIVITROL ® (naltrexone for extended-release injectable suspension)
`NDA 21-897
`
`16 September 2010
`
`Briefing Document/Background Package
`
`ADVISORY COMMITTEE BRIEFING MATERIALS:
`AVAILABLE FOR PUBLIC RELEASE
`
`Alkermes, Inc.
`852 Winter Street
`Waltham, MA 02451
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`TABLE OF CONTENTS
`ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................................. 8
`1.
`EXECUTIVE OVERVIEW ....... ................................................................................. 10
`2.
`OPIOID DEPENDENCE-AN OVERVIEW ........................................................... 15
`2.1.
`Prevalence ................................................................................................................... 16
`2.2.
`Mortality and Societal Impact ................................................................................... .16
`2.3.
`Current Opioid Dependence Treatment: Options and Needs .................................... .17
`3.
`DESCRIPTION OF VIVITROL ..................... ........................................................... 20
`3.1.
`Mechanism of Action ................................................................................................. 20
`3.2.
`Clinical Pharmacology ................................................................................................ 21
`3.2.1.
`VIVITROL Pharmacokinetics .................................... .............. .................................. 22
`3.2.2.
`VIVITROL Pharmacodynamics ..................................................................... ........... .24
`3.3.
`Dose Justification ........................................................................................................ 25
`VIVITROL OPIOID DEPENDENCE DEVELOPMENT PROGRAM .................... 27
`4.
`5.
`DESIGN OF THE ALK21 -013 EFFICACY STUDY. ............................................... 36
`5.1.
`Introduction ................................................................................................................. 36
`5.2.
`Patient Selection Criteria ............................................................................................ 37
`5.2. 1.
`Inclusion Criteria ............................................................................... ......................... 37
`5.2.2.
`Exclusion Criteria ................................................................................. ...................... 38
`5.3.
`Study Design ................................... ......................................................................... ... 39
`5.4.
`Evaluation Schedule ................................................................................................... 40
`5.5.
`ALK21-013 Outcome Measures ................................................................................ .43
`5.5.1.
`Primary Outcome Measure - Opioid-Free Response Profile .................................... .43
`5.5.2.
`Sample Size Considerations for the Primary Endpoint ............................................. .44
`5.5.3.
`Secondary Outcome Measures ................................................................................... 44
`5.5 .3.1.
`Key Secondary Endpoint: Treatment Retention ........................................................ .45
`5.5.3.2.
`Key Secondary Endpoint: Opioid Craving ................................................................ .45
`5.5.3.3.
`Secondary Endpoint: Self-Reported Opioid Use ....................................................... .45
`5.5.3.4.
`Secondary Endpoint: Positive Naloxone Challenge Test .......................................... .46
`Exploratory Outcome Measures ................................................................................ .46
`5.5.4.
`6.
`STUDY ALK21-013 EFFICACYRESULTS ........................................................... .47
`6.1.
`ALK21 -0 13: Efficacy Study Results ......................................................................... .48
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`6.1.1.
`6.1.2.
`6.1.3.
`6.1.3 .1.
`6.1.3.2.
`6.1.3.3.
`6.1.3.4.
`6.1.4.
`6.1.4.1.
`6.1.4.2.
`6.1.5.
`6.2.
`
`7.
`7.1.
`7.2.
`7.2.1.
`7.2.2.
`7.2.3.
`7.3.
`7.3.1.
`7.3.2.
`7.3.3.
`7.3.4.
`7.3.5.
`7.3.6.
`7.3 .6.1.
`7.3 .6.2.
`7.4.
`7.4.1.
`7.4.2.
`7.4.3.
`7.5.
`
`Disposition of Patients ................................................................................................ 48
`Study Population ................................................. ........................................................ 49
`ALK21-013 Primary, Secondary and Exploratory Efficacy Results (PartA) ............ 51
`Primary Analysis of the Primary Endpoint.. ............................................................... 51
`Additional Analyses of the Primary Endpoint.. ..................................................... ..... 53
`Analyses of the Secondary Endpoints ........................................................................ 54
`Analysis of Exploratory Endpoints ............................................................................. 57
`Comparison of Results of Subpopulations ................................................................. 59
`ALK21-0 13 Prespecified Stratification Analysis ....................................................... 59
`ALK21 -0 13 Prespecified Subgroup Analyses ........................................................ .... 59
`Comparison ofEfficacy Results ofVIVITROL to Oral Naltrexone .......................... 59
`Supportive Evidence: ALK21 -006 (Final Results), ALK21-021 (Interim
`Results) and ALK21-013 Part B (Interim Results) ..................................................... 60
`VIVITROL SAFETY ................................................................................................. 62
`Clinical Trial Experience ............................................................................................ 65
`Adverse Events in the Pivotal Trial--ALK21-0 13 ...................................................... 65
`Serious Adverse Events .............................................................................................. 68
`Adverse Events Leading to Discontinuation .............................................................. 69
`Additional Safety Data from ALK21-013 (Part B) .................................................... 69
`Safety Topics of Special Interest ............................................................ .................... 70
`Suicide and Depression ............................................................................................... 70
`Injection Site Reactions ... ....................................................................................... .... 70
`Opioid Withdrawal ................................................ ..................................................... 71
`Opioid Overdose ......................................................................................................... 71
`Eosinophilic Pneumonia ............................................................................................. 71
`Hepatitis and Liver Disease ........................................................................................ 72
`Clinical Adverse Events of Hepatitis and/or Liver Disease ....................................... 72
`Liver Function Tests ................................................................................................... 72
`Other Clinical Laboratory Evaluations ....................................................................... 7 6
`Eosinophils ................................................................................................................. 76
`Platelets ....................................................................................................................... 76
`Serum Protein ............................................................................................................. 7 6
`Overall Safety Summary ............................................................................................. 76
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`8.
`
`8.1.
`8.2.
`8.3.
`8.4.
`9.
`9.1.
`9.1.1 .
`9.1.2.
`9.2.
`9.3.
`10.
`10.1.
`10.2.
`10.3.
`
`10.4.
`10.5.
`11.
`
`GENERALIZABILITY TO THE TREATMENT OF OPIOID
`DEPENDENCE IN THE UNITED STATES ............................... · .............................. 78
`Introduction .......................................... , ...................................................................... 78
`Opioid Dependence - Neuropharmacology and Pharmacokinetics ........................... 78
`Patient Population ....................................................................................................... 79
`Treatment Context ...................................................................................................... 80
`BENEFIT-TO-RISK PROFILE SUMMARY ............................................................ 81
`Summary of Expected Benefits .................................................................................. 81
`Impact oflncreased Rate of Abstinence ..................................................................... 82
`Specific Clinical Benefits ........................................................................................... 83
`Potential Risks ............................................................................................................ 84
`Summary of Benefits and Risks ................................................................................. 86
`APPENDICES ............................................................................................................ 87
`Approved Package Insert (for alcohol dependence) ................................................... 88
`Medication Guide ....................................................................................................... 91
`Guidance for Industry: Providing Clinical Evidence of Effectiveness for
`Human Drug and Biological Products ........................................................................ 94
`Statistical Analysis Plan-ALK21-013 .................................................................... 118
`Additional Data Tables ............................................................................................. 145
`REFERENCES ......................................................................................................... 159
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`LIST OF TABLES
`Summary of Efficacy: ALK21-013 Study .................................................................. 12
`Table 1:
`Table 2: NIDA Goals for Narcotic Agonist Development ...................................................... .19
`Table 3:
`Steady State Pharmacokinetic Parameters ofNaltrexone and 6~-naltrexol
`following VIVITROL (380 mg) and Oral Naltrexone (50 mg)
`Administration ............................................................................................................ 23
`Table 4: Overview ofVIVITROL Clinical Trials that Support the Opioid Dependence
`Indication .................................................................................................................... 29
`Table 5:
`Published Clinical Studies of Oral Naltrexone for Opioid Dependence .................... 31
`Study ALK21-013 Visit Assessments ....................................................................... .40
`Table 6:
`Patient Disposition-ALK21-013 .............................................................................. 49
`Table 7:
`Table 8: Demographics and Baseline Characteristics-ALK21-0 13 ....................................... 50
`Table 9: Opioid-Free Weeks Response Profile: Weeks 5-24 ................................................... 53
`Table 10: Percent Self-reported Opioid-Free Days (Part A) ...................................................... 56
`Table 11: VIVITROL Prescribing Information and Relevant Postmarketing Experience ......... 63
`Table 12: Overview of Adverse Events-ALK21-013 (Part A) ................................................ 66
`Table 13: Most Common1 Clinical Adverse Events-ALK21-013 (Part A) ............................. 67
`Table 14: Most Common 1 Laboratory Adverse Events- ALK21-013 (Part A) ........................ 67
`Table 15: Serious Adverse Events- ALK21-013 (Part A) ......................................................... 68
`Table 16: Summary of Select Liver Function Test Results--ALK21-013 (Part A) .................... 73
`Table 17: Changes in Select Liver Function Test Abnormalities from Baseline to Week
`24-ALK21-013 (Part A) ........................................................................................... 74
`Table 18: Response Profiles Based on the Rate of Opioid-Free Weeks during the Last
`20 Weeks of the Double-blind Period ........................................................................ 92
`Table 19: Days to Discontinuation during Part A (Full Analysis Set) ....................................... 93
`Table 20: Opioid Craving Scores during the Double-Blind Period-Summary by Visit
`with LOCF (F AS) ....................................................................................................... 93
`Incidence of Relapse to Physiologic Dependence (Part A) ........................................ 95
`Table 21:
`Table 22: Patients with a Positive Naloxone Challenge during the Double-Blind Period ......... 95
`Table 23: SF-36v2 Composite Scores ......................................................................................... 96
`Table 24: RAB Scale Scores ....................................................................................................... 97
`Table 25: CGI Scale Scores ........................................................................................................ 98
`Table 26: EQ-5D Health Questionnaire Responses to Five Domains ........................................ 99
`
`Table 27: EQ-5D Visual Analog Scale Assessment of Own Health State1 ............................• .102
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`Table 28: ASI Composite Scores .............................................................................................. l03
`Table 29: Percent ofOpioid-Free Weeks, Weeks 5-24 ........................................... ................ .104
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`LIST OF FIGURES
`Figure 1: Prevalence ofOpioid Dependence in the United States, 2002-2008 ........................ .16
`Figure 2: Poisoning Deaths due to Opioid Analgesics; United States 1999- 2006 .................. 17
`Figure 3:
`Illustration of Drug Release from VIVITROL Microspheres .................................... 20
`Figure 4: Competitive Antagonism by Naltrexone Shifts the Concentration-Response
`Curve of an Opioid Agonist to the Right.. .................................................................. 21
`Figure 5: Naltrexone Plasma Concentrations at Steady State following 380 mg IM
`VIVITROL Administration (Dose 4 of 4; Mean ±SD; N=10 ALK21-005) ............... 22
`Figure 6: Study Timeline-ALK21-013 .................................................................................... 36
`Figure 7: Study ALK21-013 Primary Analysis: Opioid-free Weeks Response Profile,
`Weeks 5-24 ................................................ , ............................................................... 53
`Figure 8: Study ALK21-013-Percent ofOpioid-Free Patients, by Week (Full
`Analysis Set) ............................................................................................................... 54
`Figure 9: Time to Discontinuation: Part A (Full Analysis Set) .................................................. 55
`Figure 10: Opioid Craving Score, Mean Change from Baseline using Last Observation
`Carried Forward (LOCF), Full Analysis Set .............................................................. 56
`Figure 11: Quality of Life Improvements with VIVITROL ........................................................ 58
`Figure 12: Edish Plot: Evaluation ofDrug-Induced Serious Hepatotoxicity: ALK21-013 ......... 75
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`CNS
`CSAT
`CSR
`CYP 450
`DAWN
`DHHS
`DSM-IV
`DSM-IV-TR
`
`ABBREVIATIONS AND DEFINITIONS OF TERMS
`Definition
`Term
`AE
`adverse event
`AIDS
`acquired immune deficiency syndrome
`ALT
`alanine aminotransferase
`ANOVA
`analysis of variance
`ASI
`Addiction Severity Index
`AST
`aspartate aminotransferase
`area under the curve
`AUC
`Beck Depression Inventory
`BDI
`BMI
`body mass index
`CFR
`Code ofFederal Regulations
`clinical global improvement
`CGI
`maximum plasma concentration
`central nervous system
`Center for Substance Abuse Treatment
`clinical study report
`Cytochrome P450
`Drug Abuse Warning Network
`Department of Health and Human Services
`Diagnostic and Statistical Manual of Mental Disorders, 4th Edition
`Diagnostic and Statistical Manual of Mental Health Disorders, 41h Edition- Text
`Revision
`electrocardiogram
`Euro-QOL Health Questionnaire-S Domains
`full analysis set
`Food and Drug Administration
`good clinical practice(s)
`gamma-glutamyl transferase
`human immunodeficiency virus
`International Conference on Harmonisation
`Individual Drug Counseling
`intramuscular(ly)
`injection site reaction
`intravenous(ly)
`interactive voice response system
`levo-alpha-acetylmethadol
`
`ECG
`EQ-5D
`FAS
`FDA
`GCP
`GGT
`HIV
`ICH
`IDC
`IM
`ISR
`IV
`IVRS
`LAAM
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`Term
`LFT
`LOCF
`MADRS
`MedDRA
`NDA
`NIDA
`NIH
`NSDUH
`NTX
`PI
`PD
`PK
`PLG
`PSUR
`QOL
`QT [interval]
`RAB
`REMS
`SAE
`SAMHSA
`SAP
`SD
`sNDA
`soc
`
`TEAE
`TLFB
`ULN
`us
`VAS
`WHO
`
`Definition
`liver function test
`last observation carried forward
`Montgomery-Asberg Depression Rating Scale
`Medical Dictionary for Regulatory Activities
`New Drug Application
`National Institute on Drug Abuse
`National Institutes of Health
`National Survey on Drug Use and Health
`naltrexone
`principal investigator
`pharmacodynamic( s)
`pharmacokinetic( s)
`poly lactide-co-glycolide
`Periodic Safety Update Report
`quality oflife
`the time between the beginning of the QRS complex and the end of the T-wave
`Risk Assessment Battery
`risk evaluation and mitigation strategy
`serious adverse event
`Substance Abuse and Mental Health Services Administration
`statistical analysis plan
`standard deviation
`supplemental New Drug Application
`system order class
`half-life
`treatment-emergent adverse event
`Timeline FollowBack
`upper limit of normal
`United States
`visual analog scale
`World Health Organization
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`EXECUTIVE OVERVIEW
`1.
`VIVITROL was approved in 2006 by the FDA as an extended-release formulation of naltrexone
`for the treatment of alcohol dependence in patients who are able to abstain from alcohol in an
`outpatient setting prior to initiation of treatment. VIVITROL is administered by intramuscular
`(IM) injection once per month. A copy of the current approved VIVITROL package insert is
`provided in Appendix Section 1 0.1 .
`VIVITROL was approved by FDA as a Section 505(b)(2) NDA, meaning that it was approved
`on the basis of:
`•
`the submitted VIVITROL clinical trial data;
`•
`the published literature related to the safety and efficacy of oral naltrexone; and
`•
`the prior determination of safety and effectiveness of oral naltrexone as evidenced by
`the approved NDA for oral naltrexone.
`The purpose of the supplemental NDA (sNDA) under review is to obtain an additional
`indication-the treatment of opioid dependence (ie, an Efficacy Supplement). As with the
`original NDA for VIVITROL for the alcohol dependence indication, this sNDA was submitted
`pursuant to Section 505(b )(2) by which Alkermes is relying on the clinical studies described in
`the supplemental application (ALK21-013, ALK21-006, ALK21-006-EXT, ALK21-004, and
`preliminary data from the ongoing ALK21-021 study) as well the previous FDA determination
`of safety and effectiveness of oral naltrexone and published literature for the opioid indication.
`This document summarizes the safety and efficacy data that support the pending Efficacy
`Supplement. Section 2 includes some background information on opioid dependence, and a
`description of the medical need for a new treatment option. Section 3 provides a description of
`the VIVITROL microsphere and a brief discussion of its mechanism of action, clinical
`pharmacology, pharmacokinetics (PK), pharmacodynamics (PD), and dose justification. An
`overview of the VIVITROL clinical development program is provided in Section 4. A detailed
`description of the pivotal efficacy study design is provided in Section 5. In Section 6 there is a
`discussion of the efficacy results from study ALK21-013, supportive data from US studies
`ALK21 -006 and its extension (ALK21-006-EXT), and preliminary data from ongoing studies
`(ALK21-021 and Part B of the ALK21-013 study). Safety is covered in Section 7, and a
`discussion ofthe generalizability ofVIVITROL program to the US population is in Section 8. A
`description of the VIVITROL risk/benefit profile in the opioid-dependent population is provided
`in Section 9.
`Opioid addiction is a serious and growing problem associated with rising mortality. A recent
`publication from SAMHSA indicates the rate of opioid addiction continues to rise at an alarming
`rate [Substance Abuse and Mental Health (SAMHSA) Data Archive 2009]. Alkermes is
`continuing to develop medications to treat this and other addiction disorders.
`While some patients are being treated for opioid dependence with the currently available
`products, many patients remain untreated. Two current therapies, methadone (a 11-opioid
`agonist) and buprenorphine (a partial!l-opioid agonist), produce physical dependence
`themselves. While effective, they are controlled substances with limited distribution and are
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`subject to abuse and diversion as well as posing risks for respiratory and CNS depression. The
`third available option, oral naltrexone, is an opioid antagonist and is effective, although
`compliance with daily administration in this population is a well described issue.
`As many patients in the US with opioid dependence do not receive treatment, additional options
`are needed. A safe and effective long-acting opioid antagonist may represent an important
`alternative with meaningful public health impact. Naltrexone for extended-release injectable
`suspension (VIVITROL) was designed to deliver therapeutic levels ofnaltrexone for one month.
`This aspect offers significant advantages over existing therapies. Indeed, the FDA designated
`the VIVITROL sNDA for "priority review," the criteria for which is: "The drug product, if
`approved, would be a significant improvement compared to marketed products."
`VIVITROL is a non-scheduled, non-narcotic, non-addictive medication administered by health
`care professionals via a once-per-month long-acting IM injection. Abuse and diversion are not
`issues as it provides no euphoria, its effects cannot be boosted and it has no street value.
`VIVITROL poses no risk for CNS or respiratory depression and is not associated with
`withdrawal symptoms when discontinued.
`The IM delivery route ensures that the patient has received the medication. This provides direct
`assurance of treatment adherence for the patient, the patient's family members, and the health
`care providers.
`The mechanism of action makes it suitable for patients who have medical contraindications or
`are philosophically opposed to agonist therapy, are strongly motivated to become abstinent or
`have not had sufficient duration or severity of opioid dependence to meet criteria for agonist
`maintenance therapy. VIVITROL is also uniquely suitable for patients whose employment or
`professional license prohibits agonist treatment eg, health care professionals, transportation
`workers, public safety officials, and military personnel.
`Alkermes has conducted several VIVITROL clinical trials (see Section 4) including a large
`250-patient placebo-controlled clinical study in opioid dependence (ALK21-0 13). The ALK21-
`013 study results are compelling and robust and demonstrate a consistent pattern of clinical
`efficacy for maintaining opioid abstinence, increasing retention in treatment, reduction in craving
`for opioids, and protecting against re-establishment of opioid physical dependence. This study,
`taken with the results and experience accumulated throughout the entire VIVITROL
`development program and many years of experience with oral naltrexone, demonstrates the
`safety and effectiveness of this product for the treatment of opioid addiction.
`As noted above, the subject of the September 161
`h Advisory Committee meeting is the sNDA that
`has been submitted by Alkermes to revise the labeling of VIVITROL to include an indication to
`treat patients with opioid dependence. Specifically, we understand that the Division is seeking
`advice from the Advisory Committee concerning the results of the pivotal clinical study
`submitted by Alkermes (ALK21-013) and whether it provides substantial clinical evidence of
`safety and effectiveness. The review Division asked Alkermes to comment on the following two
`points in this briefing package:
`• Does the single pivotal clinical study (ALK21-013) have the ability to provide
`substantial clinical evidence of safety and efficacy?
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`• Can the clinical data from the ALK21-013 study conducted in Russia be extrapolated
`to the intended US population?
`We believe that the answers to the above two questions are yes.
`Substantial Evidence
`ALK21-0 13 is an 18-month randomized, multi-center, study conducted in 2 parts: a 6-month
`parallel group, placebo-controlled efficacy evaluation (Part A) followed by a 12-month open-
`label safety extension (Part B). The ALK21 -0 13 clinical study enrolled patients with opioid
`dependence identified by DSM-IV-TR criteria- see Section 5 for more details.
`The lead investigator, Dr. Evgeny Krupitsky, is an established expert in the field of opioid
`dependence research and treatment (see Section 5 for more details). The clinical sites where
`study ALK21 -0 13 was conducted were qualified and experienced. The staffs at those sites
`received training and ongoing supervision and monitoring with regard to the study protocol. The
`protocol employed at these sites is similar to that which would be employed in the US in terms of
`design, diagnostic and measurement tools, psychosocial therapy, endpoints, and data analyses.
`The study protocol and Statistical Analysis Plan were reviewed with and found acceptable by
`FDA.
`The study was rigorously conducted and independently monitored. Study ALK21-013, as all
`Alkermes clinical trials, was conducted according to the principles of Good Clinical Practice, the
`Declaration of Helsinki and Consolidated Guidelines approved by ICH. The study complied
`with FDA and ICH rules governing 'informed consent' and 'institutional (ethics committee)
`review. ' The study was monitored by a Contract Research Organization and independently
`audited by Alkermes. The study was inspected by FDA investigators who found no deficiencies
`in the conduct of the study.
`The results of the study are robust. The primary endpoint-opioid-free week response profile-
`was statistically and clinically significant (p=0.0002)-see Section 6. All pre-specified key-
`secondary and secondary endpoints-retention in treatment (p=0.0042), opioid craving
`(p<0.0002), positive naloxone challenge test (p=0.0154), and self-reported opioid use
`(p=0.0004), were statistically and clinically significant (see Table 1).
`Table 1:
`Summary of Efficacy: ALK21-013 Study
`
`Endpoint
`Primary Endpoint
`Rate of opioid-free weeks during the last 20 weeks of Part A
`Secondary Endpoints
`Key Secondary: Retention in treatment
`Key Secondary: Opioid craving score
`Positive naloxone challenge test
`Self-reported opioid use
`
`P-Value (VIVITROL vs Placebo)
`
`p = 0.0002
`
`p = 0.0042
`p < 0.0002
`p = 0.0154
`p = 0.0004
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`The primary and secondary endpoint results are further supported by the analysis of exploratory
`endpoints that provide further perspective of the impact, clinical significance and consequence of
`treatment with VIVITROL-
`see Section 6.1.3.4.
`According to the FDA Guidance, Providing Clinical Evidence of Effectiveness for Human Drugs
`and Biological Product (Appendix Section 10.3), the ALK21-013 clinical study possesses the
`characteristics that provide adequate support for an effectiveness claim:
`It is a large, multi-center trial
`•
`- No single center provided a disproportionately large fraction of patients.
`No single investigator or site was disproportionately responsible for the favorable
`effect.
`• Analysis of the results reveals consistency across key patient subsets.
`• Significant results across multiple endpoints involving different events were:
`-
`The ALK21-013 study included several important, prospectively identified
`primary and secondary endpoints some of which represent a beneficial but
`different effect. According to the guidance, "Where a study shows statistically
`persuasive evidence of an effect on more than one endpoint, the internal weight of
`evidence ofthe study is enhanced."
`• Statistically persuasive findings were seen:
`-
`The low p-values obtained across all primary and secondary endpoints indicate
`that the results are inconsistent with the null hypothesis of no treatment effect.
`The validity of the results of ALK21-0 13 is supported by the known and established mechanism
`of action ofnaltrexone as a 11-opioid receptor antagonist. Based on the pathophysiology of the
`disease and the known mechanism of action of naltrexone in interrupting that pathophysiology, it
`is very reasonable to accept the results of study ALK21 -0 13 as demonstrating substantial
`evidence of effectiveness. In addition, there is extensive evidence of the safety and efficacy of
`oral naltrexone for the treatment of opioid dependence, although it is well known that
`compliance is an issue. It has been accepted by the addiction community that "naltrexone works,
`if you can get the patient to take it"-see Section 6.1.5.
`The results of study ALK21-0 13 are supported by the results of two open-label studies ALK21-
`006/EXT, a long term, Phase 3 study in alcohol-, opioid- and mixed alcohol- opioid-dependent
`patients and ALK21 -021, a 2 year, Phase 3 study in health care professionals. These studies are
`supportive based on the observed retention in treatment (see Section 6.2). Retention in treatment
`is an important indicator of successful treatment of opioid-dependence. The longer a patient
`remains in therapy the better the chances of prolonged recovery. ALK21-006 enrolled N=121
`patients with opioid dependence and mixed opioid- and alcohol dependence. Over 50%
`remained on treatment with VIVITROL at 6 months, and >30% remained at 12 months.
`ALK21-021 enrolled N=38 patients; emerging data suggest similar good retention in treatment.
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`Extrapolation to the Treatment of Opioid Dependence in the United States
`There is significant evidence to indicate that the existing body of data with VIVITROL can be
`extrapolated to clinical treatment of opioid dependence in the US - see Section 8 for further
`details.
`Based on the ICH E5 Guidance, the following properties ofVIVITROL make it less likely
`exposure is influence by ethnic factors:
`• dose-linear pharmacokinetics
`• naltrexone is not metabolized by the CYP enzyme system.
`In addition, the following factors indicate that the results of the VIVITROL opioid program can
`indeed be generalized to the treatment of opioid dependence in the US:
`• The underlying neuropharmacologic mechanism of opioid dependence and the
`mechanism of action of naltrexone- competitive )..L-opioid blockade - are well
`characterized and operative irrespective of region, country, culture, or treatment
`context.
`• The patient population studied in the VIVITROL program is directly relevant to the
`treatment of opioid dependence in the US. All patients studied met DSM-IV-TR
`criteria for opioid dependence. Importantly, there are strong para