1. Frank Vocci, Ph.D. Director, DPMCDA June 7, 2006
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Stratus-US Study ( unpublished)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
Most new cases of drug dependence develop during adolescence. Perhaps there is something special (“sensitive”) about adolescence for developing addiction.
0.2
0.0 5 10 15 20 25 30 35 40 45 50 55 60 65 75
Age
Age at tobacco, at alcohol and at cannabis dependence, 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 , June 1, 2003.

15. This is a slide showing the brain activation patterns, as seen with functional MRI, of a teenager on the left, and an adult, on the right, when shown faces with different emotions. The teens, when making a judgment as the what kind of emotion is represented on the face activated the amygdala, perhaps more along the lines of a gut reaction, while the adults used an area of the prefrontal cortex, the area more involved in reasoning and reflection.

16. Using Brain Imaging Technology
…to better communicate with adolescents
fMRI used to determine Coke vs. Pepsi preference
McClure et al., 2004
In their study, the researchers first determined the Coke versus Pepsi preference of 67 volunteer subjects, both by asking them and by subjecting them to blind taste tests. They then gave the subjects sips of one drink or the other as they scanned the subjects' brains using functional magnetic resonance imaging (fMRI). In this widely used imaging technique, harmless magnetic fields and radio signals are used to measure blood flow in regions of the brain, with such flow indicating brain activity levels. In the experiments, the sips were preceded by either "anonymous" cues of flashes of light or pictures of a Coke or Pepsi can.
The experimental design enabled the researchers to discover the specific brain regions activated when the subjects used only taste information versus when they also had brand identification. While the researchers found no influence of brand knowledge for Pepsi, they found a dramatic effect of the Coke label on behavioral preference. The brand knowledge of Coke both influenced their preference and activated brain areas including the "dorsolateral prefrontal cortex" and the hippocampus. Both of these areas are implicated in modifying behavior based on emotion and affect. In particular, wrote the researchers, their findings suggest "that the hippocampus may participate in recalling cultural information that biases preference judgments."
The researchers concluded that their findings indicate that two separate brain systems--one involving taste and one recalling cultural influence--in the prefrontal cortex interact to determine preferences.

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
Drug
12 Week
Quit Rate %
52 Week
placebo 18 10
Bupropion 30 16
Varenicline 44 22

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