THE 9th STAPLEFORD INTERNATIONAL ADDICTION CONFERENCE

1
THE 9th STAPLEFORD INTERNATIONAL ADDICTION
CONFERENCE Athens, Greece, May 24,
2008 INJECTABLE EXTENDED-RELEASE NALTREXONE FOR
ALCOHOL DEPENDENCE AN UPDATE David R.
Gastfriend MD, Robert Forman PhD, Elliot W.
Ehrich MD, Bernard L. Silverman MD Alkermes,
Inc., Cambridge Massachusetts, USA
david.gastfriend_at_alkermes.com
2
Oral Naltrexone Discontinuation Rates

• U.S. Dept of HHS/SAMHSA study (2004)1
• Pharmacy claims for NTX-PO in a plan with 1.5
  million insureds for 3 years (2000-2002)1
• Guidelines recommend treatment from 3-6 months to
  2 years1
• Approximately 50 did not refill even once
  despite having coverage1
• Two independent studies obtained similar
  discontinuation rates2,3

• References
• 1. Harris KM, et al. Psychiatr Serv. 200455221.
• 2. Hermos JA, et al. Alcohol Clin Exp Res.
  2004281229-1235.
• 3. Stephenson et al. American Academy of
  Addiction Psychiatry. 2006.

3
Oral Naltrexone Adherence in Alcohol Dependence

• Medstat MarketScan Insurance Claims Database
  (2000-2004)
• Over 5 million employees from 50 large national
  employers
• 1138 oral NTX patients
• 52 did not refill even once (Median 1 Rx)
• Only 14 filled prescriptions for 6 months

Nonadherent86
Adherent14
Stephenson et al., American Academy of Addiction
Psychiatry, 2006
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Oral Naltrexone Adherence in Alcohol Dependence
(continued)
Non-adherent patients were significantly more
likely to have

• Inpatient detoxification admissions
• Non-alcohol specific hospital admissions
• Non-alcohol specific ER visits
• No counseling participation

Stephenson et al., American Academy of Addiction
Psychiatry, 2006
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Pharmacotherapy for Alcohol Dependence
1
Based on a month with 30 days. References 1
. VIVITROL full Prescribing Information.
Alkermes, Inc. 2. Campral full Prescribing
Information. Merck Santé s.a.s. 3. ReVia full
Prescribing Information. Duramed Pharmaceuticals,
Inc. 4. Antabuse full Prescribing Information.
Odyssey Pharmaceuticals, Inc.
6
Development of XR-NTX

• Problem of nonadherence was well understood by
  19751
• The promise of naltrexone was undermined by
  nonadherence
• NIAAA and NIDA awarded grants that led to
  development of Medisorb technology
• XR-NTX uses the Medisorb extended-release
  properties, first introduced in Risperdal
  Consta

Medisorb is a registered trademark of Alkermes,
Inc. Risperdal Consta are registered trademarks
of Janssen Pharmaceutical. Reference 1. NIDA
Monograph, Narcotic Antagonists The Search for
Long-acting Preparations
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Phase III Safety Efficacy TrialRandomized,
double-blind, placebo-controlled study1-3
899 assessed for eligibility
624 DSM-IV alcohol-dependent patients
randomized Received 24-weeks treatment including
12 sessions of standardized psychosocial
support Multicenter 24 outpatient sites
Placebo Microspheres n209
XR-NTX 190 mg n210
XR-NTX 380 mg n205
134 received all 6 injections
130 received all 6 injections
137 received all 6 injections
64
63
65
128 completed trial
124 completed trial
126 completed trial
61
60
60

• No oral naltrexone lead-in

References 1. Garbutt JC, et al.
JAMA. 20052931617-1625. 2. Volpicelli JR, et
al. Combining Medication and Psychosocial
Treatments for Addictions The BRENDA Approach.
2001. 3. Data on file. Alkermes, Inc.
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Patient Characteristics
1,2
Subset Analysis
HDD heavy drinking days. 34 indicated a goal
of treatment that was other than complete
abstinence.
References 1. Garbutt JC, et al.
JAMA. 20052931617-1625.2. OMalley SS, et al.
J Clin Psychopharmacol. 200727507-512.
9
Reduction in Heavy Drinking1 (N624)
XR-NTX 380 mg vs. placebo in the 6-month trial
Median heavy drinking days (HDD) per
month Baseline 19 In-treatment 6.0
PBO 3.1 XR-NTX A 48 benefit vs.
PBO(plt.002)
Reference 1. Garbutt et al., JAMA 2005
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XR-NTX Onset of Efffect (N624)
Median No. of Drinks/Day
Data on file. Alkermes, Inc.
11
Changes in GGT Levels
Placebo (N209)
XR-NTX (N205)
Martin, et al. Annual meeting of the American
Psychiatric Association, 2005 (abstract).
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(Gromov et al., AMERSA 2008)
Placebo XR-NTX XR-NTX
Placebo XR-NTX XR-NTX
190 mg 380 mg
190 mg 380 mg
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Quality of Life SF-36 Change From BL
Mental Component Summary
Physical Component Summary
20
20
P lt 0.001 vs Baseline P lt 0.05 XR-NTX 380 vs PBO
15
15
10
10
5
5
Mean Change from Baseline
Mean Change from Baseline
0
0
-5
-5
380 mg
Placebo
380 mg
Placebo
-10
-10
BL
28
56
84
112
140
168
BL
28
56
84
112
140
168
Day
Day
Subjects (n)
Kranzler. Annual Meeting of the American
Psychiatric Association, 2005 (abstract).
Data on File, Alkermes, Inc.
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Reduction in Heavy Drinking Is Sustained1
Among patients receiving XR-NTX 380 mg or placebo
in the 6-month trial
XR-NTX vs. PBO
Open Label Extension
Patients switched from PBO to XR-NTX 380 mg
(N60)
Patients continuing on XR-NTX (N115)
Reference 1. Data on file. Alkermes, Inc.
15
(OBrien et al., ASAM 2008)
N74Mean Duration XR-NTX 3.7 yrs
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XR-NTX 380 mg Response
1

• Among patients who were abstinent for 7 days
  prior to treatment initiation

• Prolongs initial abstinence
• Maintains 6-month abstinence
• Dose response observed

Post-injection phase
XR-NTX 380 mg (N17)
XR-NTX 190 mg (N26)
Placebo (N19)
Reference 1. Ciraulo DA, et al. J Clin
Psychiatry. 200869190-195.
17
XR-NTX 380 mg ResponseAmong patients who were
abstinent for 4 or more days prior to treatment
initiation
1
Post-injection phase
XR-NTX 380 mg (N28)
Placebo (N28)
Reference 1. OMalley SS, et al. J Clin
Psychopharmacol. 200727507-512.
18
XR-NTX 380 mg Response
1
Among patients who were abstinent for 4 or more
days prior to treatment initiation
XR-NTX prolongs initial abstinence
Post-injection phase
XR-NTX 380 mg (N28)
Placebo (N28)
Reference 1. OMalley SS, et al. J Clin
Psychopharmacol. 200727507-512.
19
XR-NTX 380 mg Response
1
Among patients who were abstinent for 4 or more
days prior to treatment initiation
XR-NTX prolongs initial abstinence
Nearly 3 times more patients abstinent at 6
months
Post-injection phase
XR-NTX 380 mg (N28)
Placebo (N28)
Reference 1. OMalley SS, et al. J Clin
Psychopharmacol. 200727507-512.
20
XR-NTX 380 mg Response
1
Among patients who were abstinent for 4 or more
days prior to treatment initiation
XR-NTX prolongs initial abstinence
Nearly 3 times more patients abstinent at 6
months
Dose response observed
Post-injection phase
XR-NTX 380 mg (N28)
XR-NTX 190 mg (N26)
Placebo (N28)
Reference 1. OMalley SS, et al. J Clin
Psychopharm. 200727507-512.
21
Reduction in Holiday Drinking1
Among patients who were abstinent for 4 or more
days prior to treatment initiation
Placebo(N27)
Placebo(N27)
XR-NTX 380 mg (N27)
XR-NTX 380 mg (N27)
Similar findings were observed among patients who
were abstinent 7 days prior to treatment
initiation (n53). Reference 1. Bohn MJ. Poster
presented at Annual Meeting of the American
Psychiatric Association May 19-24, 2007 San
Diego, CA.
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NTX-PO XR-NTX Adherence in Schizophrenia with
Alcohol Dependence (Batki et al., RSA 2007)
N10 N5
Bonferoni-corrected pairwise comparisons
revealed 1) significantly higher medication
adherence in the injectable group for mo 1 (p
lt.05), 2) trends toward significance at month 3
(p.09).
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XR-NTX Feasibility in Urban Primary Care
Preliminary Analysis (Lee JD, et al.
NYU/Bellevue ASAM 2008)
(N 38)
Treatment retention to date
Treatment retention to date
Treatment retention to date
Treatment retention to date
31 of 38 eligible patients received first
injection
16 of 23 patients in study gt5wks received second
injection
13 of 17 subjects in study gt8wks received third
injection
31 of 38 eligible patients received first
injection
16 of 23 patients in study gt5wks received second
injection
13 of 17 subjects in study gt8wks received third
injection
31 of 38 eligible patients received first
injection
16 of 23 patients in study gt5wks received second
injection
13 of 17 subjects in study gt8wks received third
injection
31 of 38 eligible patients received first
injection
16 of 23 patients in study gt5wks received second
injection
13 of 17 subjects in study gt8wks received third
injection
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Important Safety Information1
Reference 1. VIVITROL full Prescribing
Information. Alkermes, Inc.
28
Important Safety Information1

• XR-NTX is contraindicated in patients receiving
  or dependent on opioids, in acute opioid
  withdrawal, and in those who have failed the
  naloxone challenge test or have a positive urine
  screen for opioids and in those with previous
  hypersensitivity to naltrexone, PLG,
  carboxymethylcellulose, or any other components
  of the diluent.
• Patients must be opioid free for a minimum of
  7-10 days before treatment. Attempts to overcome
  opioid blockade due to XR-NTX may result in fatal
  overdose. In prior opioid users, use of opioids
  after discontinuing XR-NTX may result in fatal
  overdose because patients may be more sensitive
  to lower doses of opioids. Patients requiring
  reversal of the XR-NTX blockade for pain
  management should be monitored by appropriately
  trained personnel in a setting equipped for
  cardiopulmonary resuscitation.
• Consider the diagnosis of eosinophilic pneumonia
  if patients develop progressive dyspnea and
  hypoxemia. Injection site reactions not
  improving may require prompt medical attention.
  Alcohol-dependent patients, including those
  taking XR-NTX, should be monitored for the
  development of depression or suicidal thinking.
  Caution is recommended in administering XR-NTX to
  patients with moderate to severe renal
  impairment.
• The most common adverse events associated with
  XR-NTX in clinical trials were nausea, vomiting,
  headache, dizziness, asthenic conditions and
  injection site reactions.

Reference 1. VIVITROL full Prescribing
Information. Alkermes, Inc.
29
Tolerability Profile

• During clinical trials, treatment with XR-NTX
  was generally well tolerated
• Tolerability profile is based on more than 900
  patients treated with XR-NTX1
• The adverse events in the majority of patients
  were mild or moderate in intensity1
• Discontinuation rates due to adverse events1
• 9 in patients treated with XR-NTX
• 7 in patients treated with placebo

Reference 1. VIVITROL full Prescribing
Information. Alkermes, Inc.
30
Most Common Adverse Events1
Occurring in gt10 of patients

• Injection site reactions (ISRs) included
  tenderness, induration, pain, and pruritus. The
  dropout rate due to ISRs was 3.
• Nausea was usually mild, occurred in the first
  month, and lasted a few days. The dropout rate
  due to nausea was 2.

Reference 1. VIVITROL full Prescribing
Information. Alkermes, Inc.
31
Safety and Tolerability

• Serious adverse events occurred at a rate similar
  to patients receiving placebo injections1
• 5.4 on XR-NTX 380 mg vs 7.2 on placebo
• Most common serious adverse event (SAE) was
  inpatient hospitalization for detoxification
• Other SAEs seen on XR-NTX2
• 2 cases of pneumonia (one confirmed case of
  eosinophilic)
• 1 case of injection site induration requiring
  excision
• No significant increase in mean AST or ALT
  levels1
• The safety profile of patients treated with
  XR-NTX concomitantly with antidepressants was
  similar to that of patients taking XR-NTX without
  antidepressants2

References 1. Garbutt JC, et al.
JAMA. 20052931617-1625. 2. VIVITROL full
Prescribing Information. Alkermes, Inc
32
XR-NTX Randomized, Open-Label, Repeat-Dose Safety
Study

• (Kampman et al., APA 2008)

33
Patient Demographics
34
Summary of AEs
35
Most Common AEs (5)
Adverse events occurring in 5 of patients
36
Injection Site Reactions

37
Overriding Blockade in Rats(Dean et al., Pharm
Biochem Behav 2008)

• Baseline Reference untreated rats, placed on a
  hot plate. Fentanyl 0.1 mg/kg hydrocodone 8
  mg/kg produce mean response latency (MRL) to
  rear paw lick of 60 sec.
• In XR-NTX treated rats, morphine produced 36
  46 MRL at 90 mg/kg on days 4 19 and 96 MRL at
  45 mg/kg on day 39.
• Fentanyl 2.0 mg/kg produced 100 MRL on days 4
  19 and 0.5 mg/kg produced 100 MRL on day 39.
• Hydrocodone 80 mg/kg produced 69, 80 100 MRL
  on days 4, 19 39.
• Compared to placebo, these doses did not further
  depress respiration or alter locomotor activity.
• XR-NTX blockade can be overcome in rats with
  higher doses of opioids without further affecting
  respiration or locomotor activity.