1. Vaccination For Treatment of Cocaine Dependence Thomas A. Nguyen, M.D. University of Cincinnati, College of Medicine 1 © AMSP 2011

2. Substance Use Disorders (SUD) Cost $67 bill/yr in crime/↓ work Cost $67 bill/yr in crime/↓ work Rates past year: Rates past year: Alcohol (ETOH)- 8% Alcohol (ETOH)- 8% Cocaine~ 1% Cocaine~ 1% Opiates- 1% Opiates- 1% 2 © AMSP 2011

3. Cocaine Especially Problematic >2 million in U.S. cocaine dependent >2 million in U.S. cocaine dependent Serious consequences Serious consequences Medical: heart attack, stroke, seizure Medical: heart attack, stroke, seizure Psychological: psychosis, mood disturbance Psychological: psychosis, mood disturbance Legal: possession, trafficking, theft Legal: possession, trafficking, theft ER visits ↑ ~ 50% in past 10 yrs ER visits ↑ ~ 50% in past 10 yrs 3 © AMSP 2011

4. This Lecture Reviews Definitions Definitions Tx options & limitations Tx options & limitations Biology of cocaine use disorder (CUD) Biology of cocaine use disorder (CUD) How vaccines (vax) work & application to CUD How vaccines (vax) work & application to CUD 4 © AMSP 2011

5. Abuse & Dependence Abuse ≥1 of: Abuse ≥1 of: Failure in major obligations Failure in major obligations Hazardous situations use Hazardous situations use Legal problems Legal problems Social or interpersonal problems Social or interpersonal problems Dependence ≥3 of: Dependence ≥3 of: Tolerance Tolerance Withdrawal Withdrawal Unable ↓ use or quit Unable ↓ use or quit ↑ time find, use, & recover ↑ time find, use, & recover ↑ amount & time using ↑ amount & time using Stop important activities Stop important activities Use despite consequences Use despite consequences 5 © AMSP 2011

6. Clinical Vignette 38 yo, married, wm attorney in ER 38 yo, married, wm attorney in ER Suicidal thoughts (e.g.,withdrawal) Suicidal thoughts (e.g.,withdrawal) $30 crack cocaine/d $30 crack cocaine/d Binges $1000/weekend (e.g.,tolerance) Binges $1000/weekend (e.g.,tolerance) Paranoia after binge (e.g.,consequence) Paranoia after binge (e.g.,consequence) 6 © AMSP 2011

7. Clinical Vignette Diagnosis: cocaine dep Diagnosis: cocaine dep Tolerance Tolerance Withdrawal Withdrawal Psychological problems Psychological problems 7 © AMSP 2011

8. This Lecture Reviews Definitions √ Definitions √ Tx options & limitations Tx options & limitations Biology of CUD Biology of CUD How vax work & application to CUD How vax work & application to CUD 8 © AMSP 2011

9. Limited Medications for ETOH Disulfiram (Antabuse 250 mg/d) Disulfiram (Antabuse 250 mg/d) Inhibits aldehyde dehydrogenase Inhibits aldehyde dehydrogenase Causes physical symptoms Causes physical symptoms ↓ ETOH use in highly motivated patients ↓ ETOH use in highly motivated patients Many side effects Many side effects Placebo control studies rare Placebo control studies rare 9 © AMSP 2011

10. Limited Medications for ETOH Naltrexone (Revia 50mg/d) Naltrexone (Revia 50mg/d) Opioid receptor antagonist Opioid receptor antagonist Receptors key in reward Receptors key in reward May ↓ reward of drink May ↓ reward of drink ↓ heavy ETOH use ↓ heavy ETOH use 10 © AMSP 2011

11. Limited Medications for ETOH Acamprosate (Campral 1-2 g/d) Acamprosate (Campral 1-2 g/d) NMDA receptor antagonist NMDA receptor antagonist Receptors ↑ activity after abstinent Receptors ↑ activity after abstinent NMDA ↑ anxiety & insomnia NMDA ↑ anxiety & insomnia ↓ start drink & ↓ quantity of ETOH ↓ start drink & ↓ quantity of ETOH Overall, ↑ outcome 15% Overall, ↑ outcome 15% 11 © AMSP 2011

12. Limited Medications for Opioids Methadone (Methadone ≥ 80mg/d) Methadone (Methadone ≥ 80mg/d) Long acting opioid receptor agonist Long acting opioid receptor agonist Daily dosing → no withdrawal Daily dosing → no withdrawal Blunts euphoria if take opioids Blunts euphoria if take opioids ↑ abstinence, ↑ employment, ↓ crime ↑ abstinence, ↑ employment, ↓ crime ↓ relapse ↓ relapse 12 © AMSP 2011

13. Limited Medications for Opioids Buprenorphine (Subutex 16- 20mg/d) Buprenorphine (Subutex 16- 20mg/d) Long acting opioid partial agonist Long acting opioid partial agonist ↑ abstinence & ↓ relapse ↑ abstinence & ↓ relapse 13 © AMSP 2011

14. Limited Medications for Opioids Naltrexone (Revia 50-100mg/d) Naltrexone (Revia 50-100mg/d) Opioid receptor antagonist Opioid receptor antagonist Blocks opioid high Blocks opioid high ↑ abstinence & ↓ relapse ↑ abstinence & ↓ relapse All need motivation to take All need motivation to take ↑ modest outcome ↑ modest outcome 14 © AMSP 2011

15. Limited Medications for Nicotine Nicotine replacement (gum, patch, spray, etc) Nicotine replacement (gum, patch, spray, etc) 2X quit rate 2X quit rate Buproprion SR (Zyban 150mg BID) Buproprion SR (Zyban 150mg BID) Inhibits DA & NE reuptake Inhibits DA & NE reuptake 2X quit rate 2X quit rate Varenicline (Chantix 1mg/BID) Varenicline (Chantix 1mg/BID) Selective nicotine receptor partial agonist Selective nicotine receptor partial agonist 3X quit rate 3X quit rate 15 © AMSP 2011

16. Limited Tx Options for CUD No effective meds for CUD No effective meds for CUD High noncompliance & relapse High noncompliance & relapse Drop out~ 50% from tx Drop out~ 50% from tx Relapse- 52% 1 yr after tx Relapse- 52% 1 yr after tx 16 © AMSP 2011

17. Behavioral Interventions Cognitive behavioral therapy (CBT) Cognitive behavioral therapy (CBT) Emphasizes skills training Emphasizes skills training Helps recognize consequences Helps recognize consequences Legal Legal Medical Medical Occupational Occupational 17 © AMSP 2011

18. CBT (cont’d) Recognize dysfunctional thinking Recognize dysfunctional thinking Substitute w/ rational thoughts Substitute w/ rational thoughts Develop coping skills Develop coping skills Anticipate triggers Anticipate triggers Incorporate strategies to cope w/ triggers Incorporate strategies to cope w/ triggers Abstinence @ 17wks: CBT (40%) vs. tx as usual (TAU) (23%) Abstinence @ 17wks: CBT (40%) vs. tx as usual (TAU) (23%) 18 © AMSP 2011

19. Contingency Management (CM) Reinforced behaviors more likely repeated Reinforced behaviors more likely repeated Received vouchers for goods w/ ↓ cocaine use Received vouchers for goods w/ ↓ cocaine use ↑ compliance: CM (50%) vs. no tx (5%) ↑ compliance: CM (50%) vs. no tx (5%) ↓ continued use: CM (52%) vs. TAU (27%) ↓ continued use: CM (52%) vs. TAU (27%) 19 © AMSP 2011

20. Behavioral Interventions Combination tx- abstinence @ 3 wks: CBT (35%); CM (60%); Combo (70%) Combination tx- abstinence @ 3 wks: CBT (35%); CM (60%); Combo (70%) Novel tx approaches needed Novel tx approaches needed Understanding CUD impact on CNS Understanding CUD impact on CNS Technological advances → new approaches (e.g., vax) Technological advances → new approaches (e.g., vax) 20 © AMSP 2011

21. This Lecture Reviews Definitions √ Definitions √ Tx options & limitations √ Tx options & limitations √ Biology of CUD Biology of CUD How vax work & application to CUD How vax work & application to CUD 21 © AMSP 2011

22. Biology of CUD Coke ↑ DA in CNS Coke ↑ DA in CNS Blocks DA reuptake transporter Blocks DA reuptake transporter ↑ DA → reinforcing effects ↑ DA → reinforcing effects Coke- small molecule crosses blood brain barrier (BBB) Coke- small molecule crosses blood brain barrier (BBB) 22 © AMSP 2011

23. Biology of CUD Route of administration = onset of CNS effects Route of administration = onset of CNS effects Smoking- 6-8 secs in modest amts Smoking- 6-8 secs in modest amts IV-15 secs in large amts IV-15 secs in large amts Intranasal- minutes in lower amts Intranasal- minutes in lower amts More delay & ↓ amts → ↓ reinforce More delay & ↓ amts → ↓ reinforce 23 © AMSP 2011

24. This Lecture Reviews Definitions √ Definitions √ Tx options & limitations √ Tx options & limitations √ Biology of CUD √ Biology of CUD √ How vax work & application to CUD How vax work & application to CUD 24 © AMSP 2010

25. How vax work Definitions Definitions Antigens (Ags): substances → immune response Antigens (Ags): substances → immune response Antibodies (Abs): proteins made in antigen response Antibodies (Abs): proteins made in antigen response 25 © AMSP 2011

26. Active Immunity Active Immunity (AI) → specific Ab Active Immunity (AI) → specific Ab Confers longer immunity (memory) Confers longer immunity (memory) ↓ cost vs. monoclonal Abs (mAbs) ↓ cost vs. monoclonal Abs (mAbs) Requires time for Ab production Requires time for Ab production Inter-individual variability Inter-individual variability 26 © AMSP 2011

27. Passive Immunity Passive immunity (PI) Passive immunity (PI) Immediate onset Immediate onset ↑ expensive than AI ↑ expensive than AI Shorter immunity than AI Shorter immunity than AI ↓ inter-individual variability ↓ inter-individual variability Both types of immunotherapy must: Both types of immunotherapy must: Elicit immune response Elicit immune response Produce Abs specific to coke Produce Abs specific to coke 27 © AMSP 2011

28. Vax Strategies Goal: prevent coke entering CNS Goal: prevent coke entering CNS ↑ immune response → Abs production ↑ immune response → Abs production Abs bind to coke Abs bind to coke Ab-coke complex large: Ab-coke complex large: Cannot cross BBB Cannot cross BBB Cannot cross placenta Cannot cross placenta 28 © AMSP 2011

29. Tetanus (1µg/mL) vs. coke (40µg/mL) Tetanus (1µg/mL) vs. coke (40µg/mL) ↑ Abs = ↑ coke binding → ↓ coke in CNS ↑ Abs = ↑ coke binding → ↓ coke in CNS Efficacy = 80% binding Efficacy = 80% binding Blunted response = 50% binding Blunted response = 50% binding Not interfere w/ coke metabolism Not interfere w/ coke metabolism ↓ metabolism = ↑ coke fx in periphery ↓ metabolism = ↑ coke fx in periphery 29 © AMSP 2011 Development of AI

30. Types of Clinical Trials Preclinical Preclinical In vivo or vitro In vivo or vitro Mechanism of action, toxicity Mechanism of action, toxicity Phase 0 Phase 0 Not efficacy = use low dose Not efficacy = use low dose Absorption & metabolism Absorption & metabolism 30 © AMSP 2011

31. Types of Clinical Trials Phase I (human tolerability) Phase I (human tolerability) Multiple ascending doses Multiple ascending doses Observe reaction Observe reaction Phase II (↑ subjects) Phase II (↑ subjects) Selected or randomized w/ control Selected or randomized w/ control Phase IIa- assess dosing Phase IIa- assess dosing Phase IIb- assess efficacy Phase IIb- assess efficacy 31 © AMSP 2011

32. Types of Clinical Trials Phase III (large randomized controlled multicenter trials) Phase III (large randomized controlled multicenter trials) Phase IIIa (effectiveness) Phase IIIa (effectiveness) Vs. placebo Vs. placebo Vs. “gold standard” tx Vs. “gold standard” tx Phase IIIb ( effectiveness beyond original approval ) Phase IIIb ( effectiveness beyond original approval ) 32 © AMSP 2011

33. Types of Clinical Trials Two successful Phase III trials for FDA approval Two successful Phase III trials for FDA approval Phase IV- post marketing surveillance Phase IV- post marketing surveillance 33 © AMSP 2011

34. Results of Vax Studies Phase I (human tolerability) Phase I (human tolerability) Significant Ab response to coke Significant Ab response to coke Well tolerated Well tolerated No serious adverse fx No serious adverse fx 34 © AMSP 2011

35. Results of Vax Studies Phase IIa (18 pts over 14 wks) (doses) Phase IIa (18 pts over 14 wks) (doses) 100µg x 4 injections 100µg x 4 injections 400µg x 5 injections 400µg x 5 injections Well tolerated Well tolerated No allergy No allergy Individual variability (30%-low Ab) Individual variability (30%-low Ab) Higher doses → ↑ clean & ↓ euphoria Higher doses → ↑ clean & ↓ euphoria 38 © AMSP 2011

36. Results of Vax Studies Phase IIb (115 pts over 24 wks) Phase IIb (115 pts over 24 wks) Randomized- five 360µg injections Randomized- five 360µg injections Controlled- five saline injections Controlled- five saline injections All pts received CBT All pts received CBT Ab levels ≥43µg/mL = ↓ euphoria Ab levels ≥43µg/mL = ↓ euphoria ↑ Ab levels = ↓ coke use ↑ Ab levels = ↓ coke use 53% (≥43µg/mL) vs. 23% (≤43µg/mL) abstinent @ wks 8-20 53% (≥43µg/mL) vs. 23% (≤43µg/mL) abstinent @ wks 8-20 36 © AMSP 2011

37. Results (cont’d) 37 © AMSP 2011

38. Limitations of Vax Variability in Abs response Variability in Abs response Abs diminish over time ~ 6 mos Abs diminish over time ~ 6 mos Able to override w/ ↑ cocaine use Able to override w/ ↑ cocaine use Able to use other stimulants Able to use other stimulants Vax not address cravings & withdrawal Vax not address cravings & withdrawal No long term data No long term data Vax available possibly by 2015 Vax available possibly by 2015 38 © AMSP 2010

39. Clinical Vignette Revisited 38 yo, married, wm attorney in ER 38 yo, married, wm attorney in ER Suicidal thoughts (e.g.,withdrawal) Suicidal thoughts (e.g.,withdrawal) Using $30 crack /d Using $30 crack /d Binges on $1000 crack/weekend (e.g., tolerance) Binges on $1000 crack/weekend (e.g., tolerance) Paranoia after binge (e.g.,consequence) Paranoia after binge (e.g.,consequence) 39 © AMSP 2011

40. Treatment w/ Vax First line tx = behavioral interventions First line tx = behavioral interventions Likely to relapse b/c of cravings Likely to relapse b/c of cravings Route of administration → rapid & intense euphoria Route of administration → rapid & intense euphoria Vax attenuates euphoria Vax attenuates euphoria ↓ euphoria = ↓ reinforcement ↓ euphoria = ↓ reinforcement ↓ reinforcement → prevents full relapse ↓ reinforcement → prevents full relapse ↑ vax effectiveness if pt well motivated ↑ vax effectiveness if pt well motivated Goal may be ↓ use rather than abstinence Goal may be ↓ use rather than abstinence 40 © AMSP 2011

41. Conclusions CUD costly to individuals & society CUD costly to individuals & society CUD no effective pharmacotherapy CUD no effective pharmacotherapy Coke’s properties appropriate for vax Coke’s properties appropriate for vax Vax blocks coke’s reinforcing fx Vax blocks coke’s reinforcing fx Early data support potential effectiveness of vax Early data support potential effectiveness of vax Vax has limitations Vax has limitations 41 © AMSP 2011

42. This Lecture Reviews Definitions √ Definitions √ Tx options & limitations √ Tx options & limitations √ Biology of CUD √ Biology of CUD √ How vax work & application to CUD √ How vax work & application to CUD √ 42 © AMSP 2011