New Pharmacotherapies for Assisting Smokers in Their Cessation Efforts- Update

1. New Pharmacotherapies for Assisting Smokers in Their Cessation Efforts- Update Frank Vocci, Ph.D. Director, DPMCDA June 7, 2006

2. Rimonabant • CB1 inverse agonist/ antagonist • Stratus-US Study ( unpublished) • Quit rates in the 20 mg group were double that of placebo • Weight gain in the 20 mg group was 0.4 kg for 12 weeks versus 3.6 kg for placebo • FDA sent Sanofi a “non-approvable” letter… contents unknown

3. Rimonabant • May be sought after by smokers who want to quit but don’t want to gain weight • Could be tested with other therapies, especially NRT for additive effects • Has other metabolic effects which can independently reduce cardiovascular disease risk

4. Nicotine Vaccine • Being produced by three companies • Potential indications: • Aid to cessation • Prevention of relapse • And prevention of smoking

5. Nicotine Vaccine

6. Nicotine Vaccine

7. Nicotine Vaccine Blocks Nicotine Self-Administration

8. NicVAX

9. Hedonic Value and the Possible Role of a Vaccine

10. Nicotine Vaccine Update • Nabi trial will be complete in September 2007

11. And now for the question: Can Someone Smoke Enough to Overcome the Vaccine Titer ?

12. Addiction Is a Developmental Disease starts in adolescence and childhood 1.8 TOBACCO THC 1.6 ALCOHOL 1.4 1.2 1.0 % in each age group to develop first-time dependence 0.8 0.6 0.4 0.2 0.0 75 60 65 5 10 15 20 25 30 35 40 45 50 55 Age Age attobacco, atalcohol and at cannabisdependence, as per DSM IV NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003.

14. Animals Pre-Exposed to Nicotine During Peri- and Post-Adolescence Differed During A Between Session Progressive Ratio Schedule for Nicotine Self Administration For Transcript Levels of Different Subunits of the nAChRs in the Ventral Midbrain Source: Adriana, W. et al., J of Neurosci, 23(11), pp. 4712-4716, June 1, 2003.

16. McClure et al., 2004 Using Brain Imaging Technology …to better communicate with adolescents • fMRI used to determine Coke vs. Pepsi preference

17. Branding Bias & Neural Activation

18. Using Brain Imaging Technology …to better communicate with adolescents • fMRI used to determine preference for Super Bowl commercials NFL Disney Ad FedEx Caveman Ad Iacoboni et al., 2006

19. Super Bowl Ad- Activity in R IFG- Empathy

20. Brain Activation and Acceptance or Rejection of an Offer

21. Immediate versus Delayed Reward Systems- Sanfey et al 2006

22. Summary • Brain imaging can detect whether an intended effect is being produced • The effect may contradict what the individual actually verbalizes… people thought the FedEx ad was funny but the brain image showed a fear response • Multiple systems (Immediate reward, empathy, delayed reward, memory/bias, negative emotions) are involved in producing a response and emotional versus cognitive conflict resolution may ensue • Brain imaging could be used to determine whether an ad intended to increase consumer demand hit the mark or had the opposite effect • It may provide a more accurate, scientifically based assessment of consumer choice and decision-making

25. Varenicline • Partial agonist at the 4ß2 nicotine receptor • Partial agonists have some effects like nicotine but can also act like antagonists • A dual mechanism of action is proposed: • Partial nicotine-like effects • Nicotine blockade from cigarette smoking

26. Varenicline

27. Varenicline Phase II Trials- Tonstad study

28. New Therapies • Offer new prospects for smokers looking for an assist to quit smoking • Each may have distinct advantages • The vaccine may be useful for relapse prevention • Other medications are also being developed