Efficacy and Safety of Extended-Release Injectable Naltrexone For the Treatment

of Opioid Dependence

Evgeny M. Krupitsky, MD1

Ari Illeperuma, MS2

David R. Gastfriend, MD2

Bernard L. Silverman, MD2

1St Petersburg Bekhterev Research Psychoneurological Institute, St. Petersburg, Russia and St.-Petersburg Pavlov State Medical University,

St. Petersburg, Russia2 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 R43DA013531 and National Institute on Alcohol Abuse and Alcoholism Grant N43AA001002.

• 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 worldwide1

• 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 relapse2,3

1 Darke et al, Drug Alcohol Rev 2007;26:49-54; 2Dole VP. JAMA 1988;260:3025-3129;3Bell et al, Addiction. 2009;104:1193-1200.

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 professionals4

• Most studies report retention of <20% which is not superior to placebo4,5

– 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?

4McLellan et al. Components of successful addiction treatment. In: Graham AW et al (eds): Principles of Addiction Medicine, third edition. Chevy Chase: ASAM; 2003: 429-442.;5Minozzi 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;56:493-502)

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

Characteristic XR-NTX 380 mgN=126

PlaceboN=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 ProfileCumulative % of Participants at Each Rate of WeeklyConfirmed 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 daysof 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. 45.3 for placebo (~half an SD below normal).

7.7

0.7

4.4

3.7

7.2

1.9

4.0

3.3

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1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

Mea

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AB

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XR-NTX (N=126/71)

Placebo (N=124/65)

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

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RAB: Drug Risk RAB: 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 Survey Mental 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 mgN=126

PlaceboN=124

Nasopharyngitis 9 (7.1%) 3 (2.4%)

Insomnia 8 (6.3%) 1 (0.8%)

Injection site pain 6 (4.8%) 1 (0.8%)

> 1 adverse event 63 (50.0%) 40 (32.3%)

> 1 severe adverse event 0 (0%) 0 (0%)

> 1 serious adverse event 3 (2.4%) 4 (3.2%)

Discontinued due to serious adverse event 0 (0%)* 2 (1.6%)

Liver function tests, mean change at endpoint ALT, IU/L AST, IU/L

+6.9+3.8

+5.6+6.7

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.