ACAMPROSATE Efficacy Results from Three Pivotal Efficacy Trials Karl F. Mann, M.D. Professor and Chairman Director, Department of Addictive Behavior and Addiction Medicine Central Institute of Mental Health of Mannheim University of Heidelberg

ACAMPROSATE MAN-2 Pivotal European Efficacy Studies - Objective Compare the safety and efficacy of acamprosate versus placebo in maintaining long-term abstinence in alcohol-dependent outpatients following alcohol withdrawal. Source: ISE Section

ACAMPROSATE MAN-3 Number of: Study NameCentersSubjects*CountryDates of Study Pelc II12188Belgium/ France PRAMA 12272Germany Paille31538France TOTAL55998 Number of: Study NameCentersSubjects*CountryDates of Study Pelc II12188Belgium/ France PRAMA 12272Germany Paille31538France TOTAL55998 Pivotal European Efficacy Studies * ITT population Source: ISE Section

ACAMPROSATE MAN-4 CriterionPelc IIPRAMAPaille Double-blind, randomized, placebo-controlled Multicenter Acamprosate Dose-Levels,1332, , mg/day Treatment/Follow-up 3/--12/1212/6 Duration, months Site-specific psychosocial therapy CriterionPelc IIPRAMAPaille Double-blind, randomized, placebo-controlled Multicenter Acamprosate Dose-Levels,1332, , mg/day Treatment/Follow-up 3/--12/1212/6 Duration, months Site-specific psychosocial therapy Pivotal European Efficacy Studies: Study Design Features - General Source: ISE Section

ACAMPROSATE MAN-5 CriterionPelc IIPRAMAPaille Males and females Age, years DSM III/III-R for alcohol dependence In-patient detoxification Required abstinent period>5>14-< at Baseline, days CriterionPelc IIPRAMAPaille Males and females Age, years DSM III/III-R for alcohol dependence In-patient detoxification Required abstinent period>5>14-< at Baseline, days Pivotal European Study Design Features Entrance Criteria Source: ISE Section

ACAMPROSATE MAN-6 Methods for Collecting Drinking Data in Pivotal European Efficacy Studies Derived from an abstinence-oriented treatment tradition –Self-report of any alcohol consumption at each visit –Biochemical confirmation using at least one of the following: GGT, LFTs, MCV, CDT, breath/urine alcohol levels –Investigator’s Clinical Global Impression –Family member or other caretaker report (PRAMA and Paille) In case of discrepancies among data sources, the most negative outcome was assumed accurate. Derived from an abstinence-oriented treatment tradition –Self-report of any alcohol consumption at each visit –Biochemical confirmation using at least one of the following: GGT, LFTs, MCV, CDT, breath/urine alcohol levels –Investigator’s Clinical Global Impression –Family member or other caretaker report (PRAMA and Paille) In case of discrepancies among data sources, the most negative outcome was assumed accurate.

ACAMPROSATE MAN-7 Patient Disposition Pivotal European Efficacy Studies Source: ISE Section ACAMP (all doses)PlaceboTotal Randomized ITT (Treated)623 (>99%)375 (>99%) 998 (>99%) Completed Study335 (54%)147 (39%) 482 (48%) Discontinued Study288 (46%)228 (60%) 516 (52%) ACAMP (all doses)PlaceboTotal Randomized ITT (Treated)623 (>99%)375 (>99%) 998 (>99%) Completed Study335 (54%)147 (39%) 482 (48%) Discontinued Study288 (46%)228 (60%) 516 (52%)

ACAMPROSATE MAN-8 ACAMP (all doses)PlaceboTotal Discontinued Study288 (46%)228 (60%)516 (52%) Lost to Follow-up 87 (14%) 69 (18%) 156 (16%) Treatment Failure 93 (15%) 50 (13%) 143 (14%) Other 64 (10%) 81 (21%) 145 (14%) Patient Refusal 51 (8%)74 (20%)125 (12%) Improvement8 (<1%)5 (1%)13 (1%) “Other”5 (<1%)2 (<1%)7 (<1%) Adverse Event37 (6%)22 (6%)59 (6%) Death 6 (1%) 3 (1%)9 (1%) Protocol Violation1 (<1%)3 (1%)4 (<1%) ACAMP (all doses)PlaceboTotal Discontinued Study288 (46%)228 (60%)516 (52%) Lost to Follow-up 87 (14%) 69 (18%) 156 (16%) Treatment Failure 93 (15%) 50 (13%) 143 (14%) Other 64 (10%) 81 (21%) 145 (14%) Patient Refusal 51 (8%)74 (20%)125 (12%) Improvement8 (<1%)5 (1%)13 (1%) “Other”5 (<1%)2 (<1%)7 (<1%) Adverse Event37 (6%)22 (6%)59 (6%) Death 6 (1%) 3 (1%)9 (1%) Protocol Violation1 (<1%)3 (1%)4 (<1%) Reasons for Discontinuation Pivotal European Efficacy Studies Source: ISE Section

ACAMPROSATE MAN-9 Pivotal European Efficacy Studies: Demographic and Baseline Characteristics *Standard drink = 12 g pure alcohol Source: ISE Section CharacteristicPelc IIPaillePRAMAOverall % Male85%80%78%80% Mean age, years Mean weight, kg Mean duration of alcohol dep/abuse, years % >10 std. drinks*/day77%69%79%73% % Detox.100%100%100%100% % Abstinent (Baseline)99%100%100%>99% CharacteristicPelc IIPaillePRAMAOverall % Male85%80%78%80% Mean age, years Mean weight, kg Mean duration of alcohol dep/abuse, years % >10 std. drinks*/day77%69%79%73% % Detox.100%100%100%100% % Abstinent (Baseline)99%100%100%>99%

ACAMPROSATE MAN-10 ACAMPACAMP Placebo Pelc IIn = 63n = 63n = 62 (13 weeks)10.6 (0.5)11.2 (0.5)9.4 (0.6) PRAMA--n = 136n = 136 (48 weeks)32.2 (1.7) 26.1 (1.8) Paillen = 188n = 173n = 177 (52 weeks) 35.3 (1.4)37.7 (1.4) 31.6 (1.5) ACAMPACAMP Placebo Pelc IIn = 63n = 63n = 62 (13 weeks)10.6 (0.5)11.2 (0.5)9.4 (0.6) PRAMA--n = 136n = 136 (48 weeks)32.2 (1.7) 26.1 (1.8) Paillen = 188n = 173n = 177 (52 weeks) 35.3 (1.4)37.7 (1.4) 31.6 (1.5) Pivotal European Efficacy Studies Mean (S.E.) Study Drug Exposure in Weeks Source: ISE Section

ACAMPROSATE MAN-11 Pivotal European Efficacy Studies Mean Percent Medication Compliance ACAMPACAMP Placebo Pelc IIn = 55n = 53n = 49 (13 weeks)97%97%100% PRAMA--n = 118n = 109 (48 weeks)81%81% Paillen = 157n = 154n = 158 (52 weeks)82%88%83% ACAMPACAMP Placebo Pelc IIn = 55n = 53n = 49 (13 weeks)97%97%100% PRAMA--n = 118n = 109 (48 weeks)81%81% Paillen = 157n = 154n = 158 (52 weeks)82%88%83% Source: ISE Section

ACAMPROSATE MAN-12  Time to first drink –The number of days from the start of double-blind study medication to the estimated day of first consumption of any alcohol.  Rate of complete abstinence –Percent of patients completing the study without consuming any alcohol (relative to number of patients treated).  Cumulative Abstinence Duration, % – Estimated percent of abstinent time on study  Time to first drink –The number of days from the start of double-blind study medication to the estimated day of first consumption of any alcohol.  Rate of complete abstinence –Percent of patients completing the study without consuming any alcohol (relative to number of patients treated).  Cumulative Abstinence Duration, % – Estimated percent of abstinent time on study Pivotal European Efficacy Studies Definitions of Common Outcome Parameters Source: ISE Section

ACAMPROSATE MAN-13 Survival Estimate of Time to First Drink* - Pelc II Median time to 1st drink 3X longer in acamp 1998 vs placebo, p<0.001 * Dropout = failure Source: ISE Section

ACAMPROSATE MAN-14 Survival Estimate of Time to First Drink* - PRAMA * Dropout = failure Source: ISE Section Median time to 1st drink 3X longer in acamp vs placebo, p<

ACAMPROSATE MAN-15 Survival Estimate of Time to First Drink* - Paille Median time to 1st drink 2X longer in acamp 1998 mg vs placebo, p=0.005 * Dropout = failure Source: ISE Section

ACAMPROSATE MAN-16 European Pivotal Efficacy Studies Rate of Complete Abstinence 3 mos1 yr ** * * P .050; **P .010 Source: ISE Section **

ACAMPROSATE MAN-17 European Pivotal Efficacy Studies Median Percentage of Abstinent Days on Study (CAD%) ** * P .050; **P .010 Source: ISE Section **

ACAMPROSATE MAN-18 European Pivotal Efficacy Studies Primary Efficacy Variables - Summary  Time to First Drink, days –With acamprosate, median values 2 to 3 times longer than with placebo (P .005 for all 3 studies)  Complete Abstinence Rate, % –With acamprosate, times greater than with placebo (P .028 for all 3 studies)  Estimated Percentage of Abstinent Days (CAD%) –With acamprosate, greater percentage of study time in abstinent state (P .001 for all 3 studies)  Time to First Drink, days –With acamprosate, median values 2 to 3 times longer than with placebo (P .005 for all 3 studies)  Complete Abstinence Rate, % –With acamprosate, times greater than with placebo (P .028 for all 3 studies)  Estimated Percentage of Abstinent Days (CAD%) –With acamprosate, greater percentage of study time in abstinent state (P .001 for all 3 studies) Source: ISE Sections

ISBRA 15 th –18 th September 2004 Heidelberg, Germany Prof. Karl F. Mann, M.D. Chair in Addiction Research University of Heidelberg