1. Optimizing the Management Of Alcohol Dependence New Therapeutic Options Toronto and Vancouver, September 6, 2007 Prof. I. Pelc (M.D., Ph. D.) Université Libre de Bruxelles Lab of Psychological Medicine, Alcohology and Drug addictions

2. Campral ® A Novel Agent in the Treatment of Alcohol Dependence

3. Campral Global Timelines Early 1980’s - Acamprosate, a synthetic molecule, was developed for alcohol dependence 1987 - Authorized for marketing in France 1995 - Re-launched by Merck Santé 1996 to 1998 - Launched in European countries 2004 - Launched in the US 2007 - Registration and launch in Canada

4. Campral ® Understanding The Neurobiology Of Alcohol Dependence & Campral’s Mechanism Of Action

5. Acamprosate Structural similarity with amino-acids and other gluR ligands for NMDARs and GluRs N-acetylhomotaurine

6. Neuro-pharmacological basis of ethanol withdrawal and Campral mechanism of action Acute effects of ethanol Adaptation to chronic alcoholisation Ethanol withdrawal Potentiation of neuroinhibitory receptors (Taurine, GABA) Inhibition of neuroexcitatory receptors (Glutamate, Aspartate) Downregulation Upregulation Neuronal hyperexcitability Glutamate release + Inh Exc Inh Exc Inh Exc Ref: De Witte - Littleton

7. Neuro-pharmacological basis of ethanol withdrawal and Campral mechanism of action Acute effects of ethanol Adaptation to chronic alcoholisation Ethanol withdrawal Craving - Cues Potentiation of neuroinhibitory receptors (Taurine, GABA) Inhibition of neuroexcitatory receptors (Glutamate, Aspartate) Downregulation Upregulation Neuronal hyperexcitability Glutamate release Ref: De Witte - Littleton Campral ® + - - Inh Exc

11. EFFECTS OF CAMPRAL ® ON VOLUNTARY ALCOHOL CONSUMPTION Voluntary consumption (ml) Free-choice paradigm (days)

12. WITHDRAWAL Motility / Rat / 12h Ref: De Witte P < 0.05

13. SUCCESSIVE WITHDRAWAL Successive Withdrawal % Lost animals Log-Rank test p=0.0001 Dahchour A., De Witte P: Acamprosate reduces mortality during repeated experimental withdrawal in rats Alcoologie Addict.,2001,23.3:437-440

14. Dead Alive Alcohol Withdrawal + Acamprosate (200 mM) Control Alcohol Withdrawal Acamprosate reduces brain damage during alcohol withdrawal in rats Cell necrosis in cultured rat hippocampal slices revealed with propidium iodide. Ref.: J. Littleton, M. Prendergast 10 day alcohol exposure (50 or 100 mM) 1 day of withdrawal (staining of dead cells)

15. Campral and Animal Models  No effect on non-alcohol-preferring and non-dependent animals  Abolishes the alcohol dependence in dependent animals (Alcohol Consumption and Alcohol Deprivation Effect)  Abolishes the alcohol withdrawal (glutamate release and motility)  Keeps dependent animals alive during multiple successive withdrawals (neuroprotective properties) Ref: De Witte; Spanagel; Koob

16. Campral ® Clinical Studies

17. Material COMBINED DATA ANALYSIS 11 Double blind, placebo controlled multicentre studies 8 European countries 3 338 alcohol dependent patients Mean Age42.8 years ± 9.3 Sex: female19% Mean MAST score31.8 ± 10.9 Mean CAGE score3.5 ± 0.76

18. B, 96 F, 85S, 93 B, 92G, 96F, 95 A, 96 S, 98I, 00 UK, 00SP, 01I, 97NL, 97 P, 97B, 97 F, 95 G, 96 A, 96 P, 97 NL, 97 B, 97 I, 97 UK, 00 I, 00 S, 93G, 96S, 98P, 97NL, 97B, 97I, 97I, 00D30D90D180D360 Days to First Drink: TFR Cumulative Abstinence Duration (%) CAD Rate of Total Abstinence (%): CAP Campral European Double-Blind Trials and Drinking Behavior Drinks per week 0 5 10 15 20 25 0 10 20 30 40 50 60 70 80 20 10 30 40 50 60 0 0 40 80 120 160 15 placebo-controlled treatment studies

19. Rates of Continuous Abstinence Days Survival analysis %Abstinence rate (no alcohol consumption) Continuous Abstinence Measures: time to first relapse absolute abstinence Comment: this method does not take subsequent abstinent periods into consideration, and is a conservative measure to assess outcome %

20. Rates of Attendance Differential attrition between treatment groups Comment: drop-out rate in naturalistic trials could be an objective outcome measure of efficacy Days Attendance rate (%) * * **

21. Population Relative Benefit (95% CI) of treatment 3 months6 months12 months All trials (n= 17 ) 1.33 (1.20-1.47)1.47 (1.29-1.69)1.95 (1.58-2.42) 1 year trials (n= 5 ) 1.39 (1.20-1.54)1.50 (1.25-1.82)1.95 (1.54-2.40) Values at all time points p < 0.001 Campral’s Sustained Effect On Rate Of Abstinence (Morgan, 2003)

22. Campral Demonstrates A Significant Effect on Continuous Abstinence at 6 Months

23. Campral significantly increases the stable recovery duration (SRD) p= 0.021 Last relapse Days 64 days 48 days Ref.: ADISA-Study

24. Absolute abstinence after 6 months of treatment in two Belgian studies CAMPRAL +NO Psycho- social Follow-up CAMPRAL + Psychosocial Follow-up 14% 32% Absolute Abstinence ( % patients) CAPRISO StudyPelc et al. 1992 Absolute Abstinence ( % patients) 4% 24% PlaceboCAMPRAL

25. Rate of Complete Abstinence After Detoxification CAPRISO STUDY Randomized Placebo-controlled Study * Randomized Psycho-social follow-up Study ** N = 104 N = 100 **Acamprosate in the treatment of alcohol dependence: A 6-month post- detoxification study Professor I. Pelc and colleagues, 1992 * * Capriso Study Professor I. Pelc and colleagues, 2001 Placebo Acamprosate 4% 24% Acamprosate No FU FU 14% 32%

26. Comparison of different types of psychotherapies Unadjusted for differences in prognostic factors! ns ns CAD(%): Cumulative Abstinence Duration CAP(%): Complete Abstinence 1289 patients NEAT Observational, non randomized studies (Pelc et al. 2003)

27. Campral and Quality of Life (SF-36) PFPhysical Functioning RPRole limitations due to physical problems RERole limitations due to emotional problems SFSocial functioning MHMental health VTEnergy and vitality BPBodily pain GHGeneral health perception HTHealth transition over time Normative Reference Population (UK) Ref.: Pooled NEAT-Study

28. Adapted from E. Tempesta et al. Alcohol & Alcoholism Vol. 35, No. 2. Campral and relapse prevention in the treatment of alcohol dependence: a placebo-controlled study. 1 1.05 1.1 1.15 1.2 1.25 1.3 1.35 1.4 1.45 1.5 0306090120150180 Mean frequency score Treatment period (days) n = 330 * p < 0.05 Frequency-score:0 = no drinking 1 = up to twice / week 3 = every day of the week * * * * * Placebo CAMPRAL ® 2 = 3-6 times / week Frequency Of Alcohol Consumption In Patients Who Relapsed Ref.: TEMPESTA-Study

29. Number Of Drinks Per Drinking Day In Relapsers GROUP A: Campral + medical consulting (6 visits of 10 minutes each in weeks 2, 4, 10,16, 22, 28) GROUP B: Campral + minimal intervention 6 visits of 10 minutes each in weeks 2, 4, 10,16, 22, 28 plus 3 sessions of motivational interviewing of 20 minutes each by a physician in weeks 2, 3, 4 GROUP C: Campral + brief intervention 6 visits of 10 minutes each in weeks 2, 4, 10,16, 22, 28 plus 7 sessions of cognitive behavioural therapy of 60 minutes delivered by a social worker or a psychologist in weeks 2, 3, 4, 5, 6, 7, 8 Threshold of social drinking (3 drinks per day) Ref.: MICADO-Study

30. Results Of Pooled Safety Analysis Gastro-intestinal Dermatological Muscular Neurological/psychological Genito-urinary/sexual Cardio/pulmonary Tiredness 25.1% 9.1% 8.3% 37.5% 16.4% 7.6% 12.8% 18.4% 9.4% 6.5% 35.2% 11.2% 7.1% 10.8% 0.001 ns 0.003 ns Campral ® (n=839) Placebo (n=784) P Adverse effects during first month of treatment

31. Campral & At-Risk Patients Patients with Hepatic Dysfunction : Pharmacokinetic parameters of Campral are not affected Therefore no adjustment of dosage is required Patients with Renal Dysfunction : Linear correlation between creatinine clearance values and mean residence time for Campral Contraindication in patients with severe renal dysfunction (creatinine clearance ≤30 mL/min).

32. Modes Of Drinking: Alcoholism 1.SOCIAL: in a social setting 2.HABIT: from habit, for the taste 3.STRESS: to escape psychological difficulties 4.PHYSICAL DEPENDENCE: to avoid withdrawal symptoms 5.STIMULUS: as a stimulus for activity, for assertiveness Each mode is rated on a 4 level scale Validated for time and inter-Rater reliability: 0 = never 1 = seldom 2 = sometimes 3 = frequently

33. Comparison Between Performances On The Serial & The Alphabetical Recall Scores On The Alpha-Span Test Effect of group: F 1,58 =43.6, p<.001; Effect of condition: F 1,58 =90.9, p<.001 Interaction between group and condition: F 1,58 =54.6, p<.001 * Post-hoc analysis indicated that ALC performed lower only in alphabetic recall (p<.01) ScoreScore

34. Average Number Of Errors Made By Alcoholics & Controls On The Hayling Test Note. *** p<.001 PointsofpenaltyPointsofpenalty

35. Alcoholism Strategies of treatment (I) EnvironmentPatient 1. Listening 2. Understanding : 3. Caring : 2. Help and support Motivational interview Type of consumption (occasional, excessive, dependence) Situations of consumption Co-morbidity, psychosocial difficulties Inform Weaning Follow-up

36. Alcoholism Strategies of treatment (II) Withdrawal Follow-up Removing pharmacodependence - Valium (Diazepam) or Tiapridal (Tiapride) for substitution - Vitamins B - Hydration (sweetened fruit juices) - Acamprosate (4 to 6 per day from the 3th day) - Control of abstinence (controlled drinking ?) - Learning of alternative abilities to drinking - Specific Psychotherapies - Acamprosate during 1 year, including during relapses at home or hospital Medico-Psycho-Social

37. Alcoholism Strategies of treatment (III) Clinical case Drinking : Initially in occasional social contact, then more regularly and finally excessive drinking. Since 1999 (38 years) : withdrawal symptoms, psychological dependence +, physical dependence ++, loss of control. 1 st request for treatment (en 2000, she’s 39) : medical assessment : N, except γGT 85 (N<36) psychological : major relational disorders with her husband, girl : anorexia nervosa, suicide attempt. social : N Withdrawal (hospital) effective, Acamprosate during 1 year (333 mg 6 times per day). Ambulatory follow-up, individual psychotherapy (assertiveness) and systemic familial therapy. Stabilization during 6 years. Relapse (in 2006, she’s 45) : in relation to the crisis with her husband. Withdrawal (at home) : effective, again Acamprosate 1 year. Follow up : dysthymic disorders, antidepressants, decision of marital separation. Stabilization (2007… 46 years) Mrs D. born in 1961, higher education, married, 3 children (2 boys, 1 girl), regular work.