Efficacy and Safety of Extended-Release Injectable Naltrexone For the Treatment of Opioid Dependence Evgeny M. Krupitsky, MD 1 Ari Illeperuma, MS 2 David R. Gastfriend, MD 2 Bernard L. Silverman, MD 2 1 St Petersburg Bekhterev Research Psychoneurological Institute, St. Petersburg, Russia and St.-Petersburg Pavlov State Medical University, St. Petersburg, Russia 2 Alkermes Inc, Waltham, MA

Efficacy and Safety of Extended-Release Injectable Naltrexone (XR-NTX) for the Treatment of Opioid Dependence - Evgeny M. Krupitsky, MD Disclosures The study was funded by Alkermes, Inc. XR-NTX (Vivitrol ® ) was developed with support from National Institute on Drug Abuse Grant R43DA and National Institute on Alcohol Abuse and Alcoholism Grant N43AA Dr. Krupitsky has received funding as a consultant for Alkermes, Inc. Drs. Gastfriend and Silverman are full-time employees of Alkermes, Inc.

Background Heroin use is the leading cause of drug-related mortality and morbidity worldwide 1 Prescription opioid dependence is rapidly rising despite existing treatments: 1.Opioid maintenance/substitution pharmacotherapy (e.g., methadone or buprenorphine) Concerns: access, acceptability, diversion, illicit use and rising overdose deaths 2.Non-pharmacologic psychosocial treatment (halfway house or therapeutic community) Concerns: high rates of relapse 2,3 1 Darke et al, Drug Alcohol Rev 2007;26:49-54; 2 Dole VP. JAMA 1988;260: ; 3 Bell et al, Addiction. 2009;104:

Background 3.Antagonist pharmacotherapy with FDA-approved oral naltrexone Advantages: Blocks opioid receptors, is non-addicting and non-aversive Concerns: Is ineffective in practice, except with mandated, daily, supervised self-administration, e.g., recovering health professionals 4 Most studies report retention of <20% which is not superior to placebo 4,5 –In 1976, NIDA called for a long-acting opioid antagonist –Extended-release naltrexone (XR-NTX; Vivitrol ® ) was approved by the FDA for alcohol dependence in 2006 –Question: With XR-NTX treatment of opioid dependence, is there more to antagonism than µ-opioid receptor blockade, i.e., will the sustained benefits associated with recovery accrue? 4 McLellan et al. Components of successful addiction treatment. In: Graham AW et al (eds): Principles of Addiction Medicine, third edition. Chevy Chase: ASAM; 2003: ; 5 Minozzi et al. Cochrane Database of Systematic Reviews. (1):CD001333, 2006.

Study Objective and Methods Objective: To evaluate the efficacy and safety of XR-NTX for the treatment of opioid dependence Methods: Study conducted at 13 sites in Russia, July 2008 – Oct 2009 Protocol approved by ethics committees; written, informed consent obtained Patients were randomized (1:1) to 24 weeks of double-blind, parallel-group treatment with: –XR-NTX 380 mg (Vivitrol®) by IM injection every 4 weeks –Placebo injection The first dose was administered within 1 week of discharge Patients received biweekly Individual Drug Counseling guided by a treatment manual from psychiatrists (M.D.s) (Crits-Christoph et al, Arch Gen Psych 1999;56: )

Key Study Entry Criteria Male or female (non-pregnant; not nursing), age >18 years Meets DSM-IV-TR criteria for current opioid dependence Completed up to 30 days of inpatient treatment for opioid detoxification (patients screened during hospitalization) Not taking any opioid agonist (partial or full) for >7 days prior to first dose of study drug Negative naloxone challenge at randomization No evidence of hepatic failure, active hepatitis, or AIDS indicator disease No current diagnosis of psychosis, bipolar disorder or major depressive disorder with suicidal ideation, Negative drug test for cocaine and amphetamines, and no alcohol dependence in past 6 months, or current alcohol-use disorder

Efficacy and Safety Endpoints Primary Response profile for Weeks 5–24 of the rate of confirmed abstinence = retention + opioid-free weekly urine + no use by TLFB Secondary Visual Analog Scale (VAS) of opioid craving Relapse to opioid dependence (+Naloxone challenge test) Study retention Clinical Global Impression, Improvement scale (CGI-I) Safety assessments: adverse events, laboratory abnormalities, vital signs, ECGs and injection-site assessments

Efficacy and Safety Endpoints Exploratory SF-36v2™ Health Survey: Physical & Mental Health Component Summary Scores EQ-5D VAS self-assessment of overall health status Addiction Severity Index (ASI) Risk Assessment Battery (RAB; HIV risky behaviors)

Baseline Characteristics of Study Patients CharacteristicXR-NTX 380 mg N=126 Placebo N=124 Age, years, mean (SD)29.4 (±4.8)29.7 (±3.6) Male, N (%)113 (89.7%)107 (86.3%) White, N (%)124 (98.4%)124 (100%) Duration of opioid dependence, years, mean (SD)9.1 (±4.5)10.0 (±3.9) Opioid used in the 30 d prior to study treatment, N (%) Heroin Methadone Other opiates 111 (88.1%) 11 (8.7%) 21 (16.8%) 110 (88.7%) 18 (14.6%) 12 (9.8%) Days of pre-study inpatient detox, mean (SD)18 (±9)18 (±7) VAS-opioid craving score, mean (SD)18 (±23)22 (±24) HIV serology positive, N (%)51 (40.5%)52 (41.9%) Hepatitis C positive, N (%)108 (85.7%)114 (91.9%)

Patient Disposition and Reasons for Withdrawal * * Two discontinuations (1.6%) were subsequently ruled to be due to adverse events by the U.S. FDA

Response Profile Cumulative % of Participants at Each Rate of Weekly Confirmed Abstinence: XR-NTX 380 mg vs. Placebo  Total abstinence (100% opioid-free weeks) during Weeks 5-24 was reported in 45 subjects (35.7%) in the XR-NTX group versus 28 subjects (22.6%) in placebo group (P=0.0224).

Retention: Kaplan-Meier Analysis of Time-to-Discontinuation Median days of treatment Median days of treatment  Median days on treatment was significantly longer for patients in the XR-NTX vs. placebo group: >168 days vs. 96 days in the placebo group (P=0.0042, log-rank test, adjusted for multiplicity)

Mean Change From Baseline in VAS-Opioid Craving Score  Baseline craving scores: XR-NTX = 18; Placebo = 22  XR-NTX patients showed a 50% reduction-from-baseline in VAS-craving vs. no change for placebo

Secondary and Exploratory Outcome Measures  During the 24-week treatment period, 1 participant on XR-NTX vs. 17 on placebo had a positive naloxone challenge test (indicating relapse to physiological dependence)

Improvement in Functional and Quality of Life Measures  Mean SF-36 physical component scores at Baseline were similar in the XR-NTX and placebo groups (50.4 vs. 50.7) and remained at or above U.S. norms (=50) at endpoint.  Mean SF-36 mental component scores were similar at Baseline (35.0 vs. 35.4), but at endpoint, the XR-NTX group had normalized to 50.4 vs for placebo (~half an SD below normal).

Baseline Week 24 Risk Assessment Battery (RAB): Baseline and LOCF-endpoint Scores * * P=0.006 P-value based on Van der Waerden test for XR-NTX vs. Placebo Less risky behavior RAB: Drug RiskRAB: Sex Risk Baseline Week 24

Functional and Quality of Life Endpoints: Overall Summary Functional / Quality of Life Endpoints Significant (P<0.05)Not Significant Addiction Severity Index (ASI)Drug use; Family/ Social status Medical, employment, legal, psych status; alcohol use SF-36 v2 Health SurveyMental Composite (mental health, role emotional, social functioning, vitality); Role physical Physical composite (except role physical) Euro-QOL (EQ-5D)VAS assessment of own health status; Usual activities Mobility, self-care, pain/ discomfort, anxiety/depression Risk Assessment Battery (RAB) Change from baseline for RAB Drug Risk and Overall score RAB Sex Risk score

Treatment-Emergent Adverse Events: Clinical Events With Incidence >5% and Incidence of Severe & Serious Events Adverse Event, N (%)XR-NTX 380 mg N=126 Placebo N=124 Nasopharyngitis9 (7.1%)3 (2.4%) Insomnia8 (6.3%)1 (0.8%) Injection site pain6 (4.8%)1 (0.8%) > 1 adverse event63 (50.0%)40 (32.3%) > 1 severe adverse event0 (0%) > 1 serious adverse event3 (2.4%)4 (3.2%) Discontinued due to serious adverse event0 (0%)*2 (1.6%) Liver function tests, mean change at endpoint ALT, IU/L AST, IU/L  In the XR-NTX group, 3 patients reported 4 SAEs consisting of infectious processes, e.g., AIDS/HIV or other infection.  In the Placebo group, 4 patients reported 5 SAEs: 2 infectious, 1 drug dependence, 1 psychotic disorder and 1 peptic ulcer. * Two XR-NTX patient discontinuations (1.6%) were subsequently ruled to be due to adverse events by the U.S. FDA

Conclusions In this first large scale, double-blind, placebo-controlled clinical trial of XR-NTX in opioid dependence, XR-NTX, in combination with drug counseling, was highly effective in: –Decreasing opioid use and facilitating sustained remission –Reducing opioid cravings –Preventing relapse to physical opioid dependence –Retaining opioid dependent patients in treatment –In addition, XR-NTX impacted broader recovery objectives of: Promoting abstinence Reducing risk behaviors Improving the mental component of quality of life, overall health status (on EQ-5D) and global clinical improvement

Study Limitations A possible limitation of this trial involves the generalizability of the Russian opioid dependent population. Another limitation is the substantial response in the placebo-plus-counseling treatment group which may have reduced the effect size of XR-NTX. Conclusions XR-NTX was generally well tolerated, with no previously unreported safety findings observed. Despite currently available treatments, more than half of the 1.6 million Americans suffering from this disease remain untreated and the global disease burden is growing. XR-NTX appears to offer an important alternative treatment strategy for the treatment of opioid dependence.