New Pharmacotherapies for Assisting Smokers in Their Cessation Efforts-

Update

Frank Vocci, Ph.D.Director, DPMCDA

June 7, 2006

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• CB1 inverse agonist/ antagonist• Stratus-US Study ( unpublished)• Quit rates in the 20 mg group were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

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

Nicotine Vaccine

• Being produced by three companies

• Potential indications:– Aid to cessation– Prevention of relapse– And prevention of smoking

Nicotine Vaccine

Nicotine Vaccine

Nicotine Vaccine Blocks Nicotine Self-

Administration

NicVAX

Hedonic Value and the Possible Role of a Vaccine

Nicotine Vaccine Update

• Nabi trial will be complete in September 2007

And now for the question: Can Someone Smoke Enough to Overcome the Vaccine

Titer ?

NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003.NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003.

AgeAge

Age at tobacco, at alcohol and at cannabis dependence, as per DSM IV

0.00.0

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

1.21.2

1.41.4

1.61.6

1.81.8

55 1010 1515 2020 2525 3030 3535 4040 4545 5050 5555 65656060

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THCTHCALCOHOLALCOHOL

TOBACCOTOBACCO

Addiction Is a Developmental Disease starts in adolescence and childhood

Addiction Is a Developmental Disease starts in adolescence and childhood

7575

Source: Adriana, W. et al., J of Neurosci, 23(11), pp. 4712-4716, June 1, 2003.Source: Adriana, W. et al., J of Neurosci, 23(11), pp. 4712-4716, June 1, 2003.

During A Between Session Progressive Ratio Schedule for

Nicotine Self Administration

During A Between Session Progressive Ratio Schedule for

Nicotine Self Administration

Animals Pre-Exposed to Nicotine During Peri- and Post-Adolescence Differed

Animals Pre-Exposed to Nicotine During Peri- and Post-Adolescence Differed

For Transcript Levels of DifferentSubunits of the nAChRs in

the Ventral Midbrain

For Transcript Levels of DifferentSubunits of the nAChRs in

the Ventral Midbrain

When reading emotion, teens (left) rely more on the amygdala, while adults (right) rely more on the frontal cortex.

Deborah Yurgelon-Todd, 2000

Emotions

Using Brain Imaging TechnologyUsing Brain Imaging Technology

• fMRI used to determine Coke vs. Pepsi preference • fMRI used to determine Coke vs. Pepsi preference

…to better communicate with adolescents…to better communicate with adolescents

McClure et al., 2004McClure et al., 2004

Branding Bias & Neural Activation

Using Brain Imaging TechnologyUsing Brain Imaging Technology

• fMRI used to determine preference for Super Bowl commercials

• fMRI used to determine preference for Super Bowl commercials

…to better communicate with adolescents…to better communicate with adolescents

Iacoboni et al., 2006

Iacoboni et al., 2006

NFL Disney AdNFL Disney Ad

FedEx Caveman AdFedEx Caveman Ad

Super Bowl Ad- Activity in R IFG- Empathy

Brain Activation and Acceptance or Rejection of

an Offer

Immediate versus Delayed Reward Systems- Sanfey et

al 2006

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

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

Varenicline

Varenicline Phase II Trials- Tonstad study

Drug 12 WeekQuit Rate %

52 WeekQuit Rate %

placebo 18 10

Bupropion 30 16

Varenicline 44 22

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