ACAMPROSATE Analysis of U.S.A. Multicenter Trial Results Barbara J. Mason, Ph.D. Professor, Department of Psychiatry and Behavioral Sciences Director, Division of Substance Abuse University of Miami School of Medicine Barbara J. Mason, Ph.D. Professor, Department of Psychiatry and Behavioral Sciences Director, Division of Substance Abuse University of Miami School of Medicine

ACAMPROSATE MAS-2 Acamprosate U.S.A. Multicenter Trial  Objectives  Study Design  Behavioral Therapy  Subjects  Study Results  Summary Acamprosate U.S.A and European Pivotal Trials Conclusions Acamprosate U.S.A. Multicenter Trial  Objectives  Study Design  Behavioral Therapy  Subjects  Study Results  Summary Acamprosate U.S.A and European Pivotal Trials Conclusions Overview of Presentation

ACAMPROSATE MAS-3 Objectives of the U.S.A. Multicenter Trial 1. Safety The FDA requested safety experience with acamprosate in the “typical” U.S.A. Outpatient with alcohol dependence, including those with:  Polysubstance abuse  No detoxification  No upper limit for liver function tests or serum creatinine  >65 years of age 1. Safety The FDA requested safety experience with acamprosate in the “typical” U.S.A. Outpatient with alcohol dependence, including those with:  Polysubstance abuse  No detoxification  No upper limit for liver function tests or serum creatinine  >65 years of age

ACAMPROSATE MAS-4 Objectives of the U.S.A. Multicenter Trial (continued) 2. Efficacy The sponsor sought to evaluate the efficacy of the standard 2 gram daily dose of acamprosate:  In a new 500 mg tablet strength  According to a new twice a day dosing schedule (two 500 mg tablets b.i.d.) Inclusion of an exploratory higher daily dose group in a smaller number of subjects:  3 gram daily dose, given as three 500 mg tablets b.i.d. 2. Efficacy The sponsor sought to evaluate the efficacy of the standard 2 gram daily dose of acamprosate:  In a new 500 mg tablet strength  According to a new twice a day dosing schedule (two 500 mg tablets b.i.d.) Inclusion of an exploratory higher daily dose group in a smaller number of subjects:  3 gram daily dose, given as three 500 mg tablets b.i.d.

ACAMPROSATE MAS-5 Approach to Understanding Efficacy in the U.S.A. Trial An efficacy evaluable (EFF) population was pre- specified and included those subjects who:  Took medication for 7 days to reach steady state  Were >75% compliant with medication  Did not have a positive urine test for illicit drugs at any study visit Standardized baseline measures of factors generally associated with alcoholism treatment outcome were collected (as potential covariates) An efficacy evaluable (EFF) population was pre- specified and included those subjects who:  Took medication for 7 days to reach steady state  Were >75% compliant with medication  Did not have a positive urine test for illicit drugs at any study visit Standardized baseline measures of factors generally associated with alcoholism treatment outcome were collected (as potential covariates)

ACAMPROSATE MAS-6 Pivotal European and U.S.A. Study Methods EuropeanU.S.A. Double-blindYesYes Placebo-controlledYesYes Random AssignmentYesYes DSM Criteria for Alcohol DependenceYesYes Excluded Current Substance AbusersYesNo Excluded >65 Years of AgeYesNo Detox RequiredYesNo Abstinent at BaselineYesNo Standardized Behavioral TherapyNoYes EuropeanU.S.A. Double-blindYesYes Placebo-controlledYesYes Random AssignmentYesYes DSM Criteria for Alcohol DependenceYesYes Excluded Current Substance AbusersYesNo Excluded >65 Years of AgeYesNo Detox RequiredYesNo Abstinent at BaselineYesNo Standardized Behavioral TherapyNoYes

ACAMPROSATE MAS-7 Drinking Data Collection Methods in Pivotal European and U.S.A. Trials Pelc IIPRAMAPailleU.S.A. Self-report elicited Yes Yes Yes Yes by alcoholism expert Written assurance Yes Yes Yes Yes of confidentiality Setting encouraged Yes Yes Yes Yes honest reporting (e.g., no legal ramifications) DiaryYes–YesYes Recall aids: Timeline follow back calendar – – – Yes Standard drinks – Yes YesYes Pelc IIPRAMAPailleU.S.A. Self-report elicited Yes Yes Yes Yes by alcoholism expert Written assurance Yes Yes Yes Yes of confidentiality Setting encouraged Yes Yes Yes Yes honest reporting (e.g., no legal ramifications) DiaryYes–YesYes Recall aids: Timeline follow back calendar – – – Yes Standard drinks – Yes YesYes

ACAMPROSATE MAS-8 One Standard Drink Equals 12 Grams of Pure Alcohol Beer  8 oz. Wine  4 oz. Hard Liquor (80 proof)  1 oz. Beer  8 oz. Wine  4 oz. Hard Liquor (80 proof)  1 oz.

ACAMPROSATE MAS-9 Pelc IIPRAMAPailleU.S.A. Biochemical confirmation Yes Yes Yes Yes GGT Yes Yes Yes Yes Transaminases Yes -- Yes -- MCV Yes Yes Yes -- Breathalyzer -- Yes -- Yes Alcohol in urine Yes Yes Collateral Informant--YesYesYes Time intervals assessed2 wks1-3 mo1-2 mo1 mo Pelc IIPRAMAPailleU.S.A. Biochemical confirmation Yes Yes Yes Yes GGT Yes Yes Yes Yes Transaminases Yes -- Yes -- MCV Yes Yes Yes -- Breathalyzer -- Yes -- Yes Alcohol in urine Yes Yes Collateral Informant--YesYesYes Time intervals assessed2 wks1-3 mo1-2 mo1 mo Drinking Data Collection Methods in Pivotal European and U.S.A. Trials (continued)

ACAMPROSATE MAS-10 Drinking Data Obtained in Pivotal European and U.S.A. Trials Pelc IIPRAMAPailleU.S.A. Abstinent/Non-abstinent Yes Yes Yes Yes Time to first drink Yes Yes Yes Yes No. of drinking days -- Yes Yes Yes Graduated frequency Yes Yes No. of grams per Yes -- Yes Yes drinking day Graduated quantity Yes Yes Yes -- Pelc IIPRAMAPailleU.S.A. Abstinent/Non-abstinent Yes Yes Yes Yes Time to first drink Yes Yes Yes Yes No. of drinking days -- Yes Yes Yes Graduated frequency Yes Yes No. of grams per Yes -- Yes Yes drinking day Graduated quantity Yes Yes Yes --

ACAMPROSATE MAS-11 Timeline Follow Back Method The U.S.A. trial used the Timeline Follow Back Method to obtain drinking data 1Developed as a continuous variable to assess controlled drinking rather than abstinence 2Provides variables that describe pattern of subject’s drinking beyond simpler quantity/frequency methods 3Limitation is more time to administer and increased burden on subject aCan cause increased attrition bIts self-monitoring nature can cause reduced drinking The U.S.A. trial used the Timeline Follow Back Method to obtain drinking data 1Developed as a continuous variable to assess controlled drinking rather than abstinence 2Provides variables that describe pattern of subject’s drinking beyond simpler quantity/frequency methods 3Limitation is more time to administer and increased burden on subject aCan cause increased attrition bIts self-monitoring nature can cause reduced drinking

ACAMPROSATE MAS Not Randomized 601 Randomized 260 Received Placebo Placebo 258 Received Acamprosate 2g/d 83 Received Acamprosate 3g/d U.S.A. Multicenter Study Schema 741 Patients Screened 2 Month Post-Treatment Follow-Up 98 Not Eligible 42 Declined Participation

ACAMPROSATE MAS-13 Manual-Guided Brief Intervention and Medication Compliance Procedures Goals: Abstinence and medication compliance Procedures:  Motivation enhancement strategies  Patient handouts about alcohol, tips for quitting, and self assessment of drinking  Treatment Goals Worksheet: Changes desired, reasons, steps, obstacles  Acamprosate Information Sheet  Treatment Progress Summary Goals: Abstinence and medication compliance Procedures:  Motivation enhancement strategies  Patient handouts about alcohol, tips for quitting, and self assessment of drinking  Treatment Goals Worksheet: Changes desired, reasons, steps, obstacles  Acamprosate Information Sheet  Treatment Progress Summary

ACAMPROSATE MAS-14 Minneapolis, MN Milwaukee, WI Cincinnati, OH Cleveland, OH South Burlington, VT Boston, MA Providence, RI New Haven, CT Farmington, CT New York, NY Buffalo, NY Pittsburgh, PA Charleston, SC Miami, FL Baltimore, MD Albuquerque, NM Los Angeles, CA Menlo Park, CA Oakland, CA Philadelphia, PA Houston, TX Acamprosate U.S.A. Multicenter Trial 21 Investigational Sites

ACAMPROSATE MAS-15 PlaceboACAMP 2g Age, years Range22 – 6923 – 72 Males65%70% White86%86% Lives alone17%21% Employed F/T59%53% Psychiatric history13%15% PlaceboACAMP 2g Age, years Range22 – 6923 – 72 Males65%70% White86%86% Lives alone17%21% Employed F/T59%53% Psychiatric history13%15% Acamprosate U.S.A. Multicenter Trial Patient Characteristics

ACAMPROSATE MAS-16 PlaceboACAMP 2g Clinical Global Impression (1-7) Alcohol Dependence Scale  2218%23% Parental Alcoholism 40%42% Drinking Days/Week Drinks/Drinking Day Heavy Drinking Years  2 Prior Detoxes28%32% PlaceboACAMP 2g Clinical Global Impression (1-7) Alcohol Dependence Scale  2218%23% Parental Alcoholism 40%42% Drinking Days/Week Drinks/Drinking Day Heavy Drinking Years  2 Prior Detoxes28%32% Acamprosate U.S.A. Multicenter Trial Baseline Clinical Characteristics

ACAMPROSATE MAS-17 PlaceboACAMP 2g Treatment Goal of Total Abstinence45%40% Medicated Detox10%12% PlaceboACAMP 2g Treatment Goal of Total Abstinence45%40% Medicated Detox10%12% Acamprosate U.S.A. Multicenter Trial Baseline Abstinence Parameters

ACAMPROSATE MAS-18 PlaceboACAMP 2g Marijuana79%72% Cocaine47%51% Psychedelics37%39% Stimulants36%34% Sedatives23%26% Opiates12%17% Heroin7%10% PlaceboACAMP 2g Marijuana79%72% Cocaine47%51% Psychedelics37%39% Stimulants36%34% Sedatives23%26% Opiates12%17% Heroin7%10% Acamprosate U.S.A. Multicenter Trial Lifetime Baseline Substance Use

ACAMPROSATE MAS-19 PlaceboACAMP 2g Cigarette Smoker45%47% Positive Urine for Cannabinoids6%8% PlaceboACAMP 2g Cigarette Smoker45%47% Positive Urine for Cannabinoids6%8% Acamprosate U.S.A. Multicenter Trial Baseline Consumption of Cigarettes and Marijuana

ACAMPROSATE MAS-20 PlaceboACAMP 2g (n = 260)(n = 258) Medication Compliance93%89% Weeks on Study % Completed55%41% Premature Termination45%59% Due to alcohol52%39% Due to adverse events5%4% PlaceboACAMP 2g (n = 260)(n = 258) Medication Compliance93%89% Weeks on Study % Completed55%41% Premature Termination45%59% Due to alcohol52%39% Due to adverse events5%4% Acamprosate U.S.A. Multicenter Trial Patient Disposition and Treatment Participation - Safety Population

ACAMPROSATE MAS-21 U.S.A. Primary Efficacy Results (ITT Population) for Originally Planned Analyses PlaceboACAMP 2g (n = 257) (n = 253) Abstinent at Baseline49%52% Weeks on Study Time to Relapse Any Drinking, days 4 4 Heavy Drinking, days1215 Complete Abstinence, %11 8 Cumulative Abstinence Duration Days % PlaceboACAMP 2g (n = 257) (n = 253) Abstinent at Baseline49%52% Weeks on Study Time to Relapse Any Drinking, days 4 4 Heavy Drinking, days1215 Complete Abstinence, %11 8 Cumulative Abstinence Duration Days %

ACAMPROSATE MAS-22 Baseline Factors Reliably Associated with Alcoholism Treatment Outcome  Psychiatric history –McLellan et al, 1983; Woody et al, 1984; Rounsaville et al, 1987; Project MATCH Research Group, 1997; Greenfield et al, 1998  Substance use –Hersh et al, 1998; Miller and Bennett, 1996; Caetano and Weisner, 1995; Grant and Pickering, 1996  Severity of alcohol dependence –Institute of Medicine, 1989  Psychiatric history –McLellan et al, 1983; Woody et al, 1984; Rounsaville et al, 1987; Project MATCH Research Group, 1997; Greenfield et al, 1998  Substance use –Hersh et al, 1998; Miller and Bennett, 1996; Caetano and Weisner, 1995; Grant and Pickering, 1996  Severity of alcohol dependence –Institute of Medicine, 1989

ACAMPROSATE MAS-23 Baseline Factors Reliably Associated with Alcoholism Treatment Outcome (continued)  Psychosocial support (e.g., full-time employment, marital status) –McLellan et al, 1983; Institute of Medicine, 1989  Readiness to Change –DiClemente and Hughes, 1990; Project MATCH Research Group, 1997  Treatment goal of complete abstinence –Polich et al, 1980; Hall et al, 1990; O’Malley et al, 1992; Rohsenow et al, 2000  Treatment compliance –Mattson et al, 1998; Volpicelli et al, 1997  Psychosocial support (e.g., full-time employment, marital status) –McLellan et al, 1983; Institute of Medicine, 1989  Readiness to Change –DiClemente and Hughes, 1990; Project MATCH Research Group, 1997  Treatment goal of complete abstinence –Polich et al, 1980; Hall et al, 1990; O’Malley et al, 1992; Rohsenow et al, 2000  Treatment compliance –Mattson et al, 1998; Volpicelli et al, 1997

ACAMPROSATE MAS-24 Acamprosate U.S.A. Multicenter Trial Covariates Applied Uniformly Across Outcome Measures  Baseline CGI severity (1-7)  Treatment goal (total abstinence versus not)  Readiness to Change (precontemplation, contemplation, and action)  Psychiatric history (present or not)  Addiction index (Fagerström Score x Illicit Drug Use Index)  Treatment exposure (Study drug duration [wks] x Compliance [%]) / 100  Baseline values (analyses of change from baseline)  Baseline CGI severity (1-7)  Treatment goal (total abstinence versus not)  Readiness to Change (precontemplation, contemplation, and action)  Psychiatric history (present or not)  Addiction index (Fagerström Score x Illicit Drug Use Index)  Treatment exposure (Study drug duration [wks] x Compliance [%]) / 100  Baseline values (analyses of change from baseline)

ACAMPROSATE MAS-25 Acamprosate U.S.A. Multicenter Trial Case Report Form Question for Treatment Goal What is your treatment goal? ÿTotal abstinence ÿTotal abstinence but I realize a slip is possible ÿOccasional use ÿTemporary abstinence ÿRegular use but quantity controlled ÿNo goal What is your treatment goal? ÿTotal abstinence ÿTotal abstinence but I realize a slip is possible ÿOccasional use ÿTemporary abstinence ÿRegular use but quantity controlled ÿNo goal 

ACAMPROSATE MAS-26 PlaceboACAMP 2gACAMP 3gTotal Safety ITT EFF MITT MEFF PlaceboACAMP 2gACAMP 3gTotal Safety ITT EFF MITT MEFF EFF MEFF MITT MITT ITT U.S.A. Trial Patient Subgroups

ACAMPROSATE MAS-27 PlaceboACAMP 2g ITT * EFF * MITT * MEFF * PlaceboACAMP 2g ITT * EFF * MITT * MEFF * Cumulative Abstinence Duration (%) with Covariates * p < 0.05 for 2g vs placebo

ACAMPROSATE MAS-28 PlaceboACAMP 2g ITT EFF MITT * MEFF * PlaceboACAMP 2g ITT EFF MITT * MEFF * Cumulative Abstinence Duration (%) with Covariates Treatment + Follow-up Phase * p < 0.05 for 2g vs placebo

ACAMPROSATE MAS-29 ACAMP 2g vs Placebo ACAMP 2g vs Placebo Good ResponsePoor Response ITT * EFF1.80*0.44* MITT * MEFF2.72*0.18* ACAMP 2g vs Placebo ACAMP 2g vs Placebo Good ResponsePoor Response ITT * EFF1.80*0.44* MITT * MEFF2.72*0.18* Odds Ratios with Covariates of Good Response (CAD  90%) and Poor Response (CAD  10%) * p < 0.05 for 2g vs placebo

ACAMPROSATE MAS-30 ACAMP 2g vs Placebo ITT1.43 EFF1.64 MITT1.67 MEFF2.15* ACAMP 2g vs Placebo ITT1.43 EFF1.64 MITT1.67 MEFF2.15* Odds Ratios with Covariates of Complete Abstinence During the Last Visit (Treatment Phase) Interval [LOCF] * p < 0.05 for 2g vs placebo

ACAMPROSATE MAS-31 PlaceboACAMP 2g ITT EFF MITT * MEFF * PlaceboACAMP 2g ITT EFF MITT * MEFF * Percent Reduction (Relative to Baseline) in Drinks per Week on Study with Covariates * p < 0.05 for 2g vs placebo

ACAMPROSATE MAS-32 PlaceboACAMP 2g Baseline Mean (IU/L) Endpoint Mean (IU/L) Mean Change from Baseline (IU/L) PlaceboACAMP 2g Baseline Mean (IU/L) Endpoint Mean (IU/L) Mean Change from Baseline (IU/L) Normal Range: Females 5 – 49 IU/L; Males 7 – 64 IU/L Change from Baseline GGT at Treatment Phase Endpoint

ACAMPROSATE MAS-33 Acamprosate U.S.A. Multicenter Trial Overall Summary Acamprosate U.S. study results support: External validity: 81% of screened patients were randomized Safety Acceptability: >88% medication compliance Acamprosate U.S. study results support: External validity: 81% of screened patients were randomized Safety Acceptability: >88% medication compliance

ACAMPROSATE MAS-34 Acamprosate U.S.A. Multicenter Trial Overall Summary Acamprosate U.S. study results support: Efficacy, controlling for baseline variables and treatment exposure, and especially in patients with a goal of abstinence: Increased cumulative abstinence duration Increased likelihood of good response Decreased likelihood of poor response Increased likelihood of abstinence at termination Other changes relative to pre-treatment status: – less alcohol consumption – normalization of GGT Acamprosate U.S. study results support: Efficacy, controlling for baseline variables and treatment exposure, and especially in patients with a goal of abstinence: Increased cumulative abstinence duration Increased likelihood of good response Decreased likelihood of poor response Increased likelihood of abstinence at termination Other changes relative to pre-treatment status: – less alcohol consumption – normalization of GGT

ACAMPROSATE MAS-35 Conclusions from Acamprosate U.S.A. and European Pivotal Trials 1. Acamprosate, 2 grams per day, showed beneficial and clinically relevant effects on abstinence outcomes in almost 2000 alcohol-dependent outpatients who participated in double-blind, placebo- controlled trials of up to 1 year in duration. 2. Acamprosate, 2 grams per day, showed sustained efficacy, for post-treatment periods of up to 1 year, relative to placebo. 1. Acamprosate, 2 grams per day, showed beneficial and clinically relevant effects on abstinence outcomes in almost 2000 alcohol-dependent outpatients who participated in double-blind, placebo- controlled trials of up to 1 year in duration. 2. Acamprosate, 2 grams per day, showed sustained efficacy, for post-treatment periods of up to 1 year, relative to placebo.

ACAMPROSATE MAS-36 Conclusions from Acamprosate U.S.A. and European Pivotal Trials 3. To optimize acamprosate treatment outcome, patients should be motivated to have abstinence as their treatment goal. –US data suggest that acamprosate does not induce abstinence in unmotivated drinkers. –The US data suggest that it may not be necessary to undergo formal detoxification in order to obtain therapeutic benefit from acamprosate, provided patients are motivated to have abstinence as their treatment goal. 3. To optimize acamprosate treatment outcome, patients should be motivated to have abstinence as their treatment goal. –US data suggest that acamprosate does not induce abstinence in unmotivated drinkers. –The US data suggest that it may not be necessary to undergo formal detoxification in order to obtain therapeutic benefit from acamprosate, provided patients are motivated to have abstinence as their treatment goal.

ACAMPROSATE MAS-37 Conclusions from Acamprosate U.S.A. and European Pivotal Trials 4. High rates of compliance support the acceptability of acamprosate and the b.i.d. and t.i.d. dosing schedules 5. Long term beneficial effects of acamprosate are evident across a range of countries, clinical settings, and behavioral therapies 4. High rates of compliance support the acceptability of acamprosate and the b.i.d. and t.i.d. dosing schedules 5. Long term beneficial effects of acamprosate are evident across a range of countries, clinical settings, and behavioral therapies