The Science behind Champix: From Idea to Tablet

1. The Science behind Champix: From Idea to Tablet Jotham W. Coe and Ivan Efremov , PhDs Department of NeurosciencePfizer Global Research and DevelopmentGroton, CT jwcoe@pfizer.com

2. C. Everett Koop

3. Smoking is the Leading Cause of Preventable Death Preventable Causes of Death in the United States Tobacco Use: (435,000 deaths of which 399,000 were related to smoking; the remainder to secondhand smoke and smokeless tobacco) 37.5% Diet/Activity(400,000) Illicit Use of Drugs (17,000) Motor Vehicles (43,000) Sexual Behavior (20,000) Firearms (29,000) Toxic Agents (55,000) Microbial Agents(75,000) Alcohol (85,000) Adapted from Mokdad AH et al. JAMA. 2004;291:1238-1245. CDC. MMWR. 2008;57:1226-1228. 3

4. Smoking is a Risk Factor Across an Array of Diseases Cardiovascular • Ischemic Heart Disease • Stroke – Vascular Dementia • Peripheral Vascular Disease • Abdominal Aortic Aneurysm Respiratory Cancer • COPD • Community-acquired Pneumonia • Poor Asthma Control • Lung • Oral Cavity/Pharynx • Laryngeal • Esophageal • Stomach • Pancreatic • Kidney • Bladder • Cervical • Leukemia Active Smoking Reproductive • Erectile Dysfunction • Reduced Fertility • Pregnancy Complications • Low Birthweight • SIDS Other • Adverse Surgical Outcomes/Wound Healing • Hip Fractures • Low Bone Density • Cataract and Macular Degeneration • Peptic Ulcer Disease • Metabolic Syndrome Adapted from CDC Surgeon General’s Report 2004 Adapted from CDC. Surgeon General’s Report. 2004. Weitzman M et al. Circulation. 2005;112:862-869. 4

5. b2 b2 a4 a4 b2 4b2 Nicotinic Receptor Nicotine Addiction: Reinforcing Behavior • Nicotine binds predominantly to nicotinic acetylcholine (nACh) receptors in the CNS; the primary is the 42 nicotinic receptor in the Ventral Tegmental Area (VTA) • Binding of nicotine to the 42 nicotinic receptor in the VTA results in a release of dopamine in the Nucleus Accumbuns (nAcc) which is believed to be linked to reward

6. b2 b2 a4 a4 b2 4b2 Nicotinic Receptor Mechanism of Action of Nicotine in the Central Nervous System • Roller coaster of dopamine signals, self-regulated by the smoker

7. Smokers make multiple quit attempts,but failure is the norm: Nicotine is addictive! Total Smokers – 51 M Want to Quit – 36 M 70% Try to Quit - 23 M 45% 4% of those who try Actually quit ~ 1 Million (2%) Sources: WHO http://www1.worldbank.org/tobacco/index.htm; US National Health Interview Survey,1995

8. Withdrawal Symptoms from Stopping Smoking Incidence 70% Increased appetite 60% Restlessness 60% Depression 50% Irritability/aggression Craving for nicotine 70% 60% Poor concentration Sleep disturbance 25% Lightheadedness 10% Duration (weeks) or more Jarvis MJ.BMJ 2004;328:277-279.

9. 18 Cigarette (nicotine delivery, 1-2 mg) Gum (nicotine delivery, 4 mg) Nasal spray (nicotine delivery, 1 mg) Transdermal patch (nicotine delivery, 15-21 mg) 16 14 12 Plasma Nicotine Concentration (μg/L) 10 8 6 4 2 0 -10 0 10 20 30 40 50 60 70 80 90 100 110 120 Time Post-administration (minutes) Nicotine Delivery by Cigarettes and Nicotine Replacement Therapy (NRT) • NRT has rates of delivery which are all less than that of cigarette smoking • NRT acts as an agonist alone, mimicking nicotine in its mechanism of action • Peak levels achieved by NRT are about 30-50% of those achieved by smoking Adapted from 1. Benowitz NL et al. Clin Pharmacol Ther. 1988;44:23-28; 2. Schneider NG et al. Clin Pharmacokinet.1996;31:65-80; 3. Benowitz NL. Drugs. 1993;45:157-170.

10. Hypothetical Effects on Mesolimbic DA Release of Smoking and Smoking with Nicotine Replacement Therapy (NRT) or Partial Agonist Response to nicotine NRT + smoking Partial agonist + smoking Smoking Time

11. Nicotine Nicotine Part Ag Part ag Partial Agonist Antagonist 50% 50% Potential to block reinforcing effectswhen smoking Potential to relieve craving and withdrawal when quitting Rationale for 42 nAChR Partial Agonists SmokingNo Partial Ag No SmokingPartial Ag Smoking+ Partial Ag 42 nAChR Agonist Response 100% Dual action of a partial agonist

12. 1994

13. Lupinus spp., Lupine Laburnum anagyroides Golden chain tree

14. Bromo-Cytisine R Decreased Binding Me, Bn, Allyl, SO2CF3, etc. Y Decreased Binding E+, Me, Bn, Allyl, Aryl, etc. $1700/g!! plant sources genetic synthetic . . . X Br, Cl, Me, Ac, Aryl, OR etc Potent ha4b2 Binding (0.2 nm) Selective (>100x) Partial Agonist, in vitro 56% PA, DATO (0.05 mg/kg, p.o.) Self Admin and Discrimination

16. Cytisine Total Synthesis Intramolecular Heck Route Org. Lett.2000, 2, 4205 also 4201

17. Synthesis: Clues from Nature Tobacco plant Golden Chain Opium poppy Morphine Nicotine Cytisine

18. Minor side product CP-526,555 Varenicline Chantix Champix a4b2 nAChR antagonist a4b2 nAChR partial agonist

19. Varenicline

20. Nicotinic Receptor Binding Affinities (nM) a4b2 a3b4 a7 a1bgd • 0.1 • 285 • 870 • 2600 hn N H diffraction N N

21. Dopamine Turnover in Rat Nucleus Accumbens 100 DOPAC+HVA/DA, % Nicotine 80 vehicle w/ Nicotine 1 mg/kg,s.c. 60 ++ 40 ++ p ,.01 vs nicotine 20 0 vehicle nicotine Varenicline 5.6 mg/kg,s.c. 34% agonist 66% antagonist

22. Varenicline 1 mg/kg po + Nicotine 0.32 mg/kg sc Nicotine 0.32 mg/kg sc Varenicline 1 mg/kg po Varenicline 1 mg/kg po Nicotine 0.32 mg/kg Partial Agonist Effect on Dopamine Releasein Rat Nucleus Accumbens 200 175 150 Dopamine Release in N. Accumbens % of Basal ± SEM 125 100 75 -180 -120 -60 0 60 120 180 240 300 360 Time (minutes)

23. Varenicline 1 mg/kg po + Nicotine 0.32 mg/kg sc Nicotine 0.32 mg/kg sc Varenicline 1 mg/kg po Nicotine 0.32 mg/kg Antagonist Effect on Dopamine Releasein Rat Nucleus Accumbens 200 175 150 Dopamine Release in N. Accumbens % of Basal ± SEM 125 100 75 -180 -120 -60 0 60 120 180 240 300 360 Time (minutes)

24. ADME properties in human Drug Metabolism and Disposition2006, 34, 121-30 • Absorption • Small (MW=211), very water soluble • Good membrane penetration (passive diffusion), highly absorbed • 99% of recovered 14Cmaterial excreted in urine • Not a substrate for the P-glycoprotein efflux transporter • Distribution • Low protein binding (fu 0.8) • Moderate volume of distribution (1.9 L/kg) • Metabolism • Excreted >90% as unchanged drug in the urine • Minor hydroxy- and N-carbamoylglucuronide metabolites • Parent drug represents 90% of circulating drug-related material • Does not inhibit cytochrome P450 enzymes • Excretion • Renal clearance (mainly passive diffusion): 2.4 mL/min/kg • Long half life: T1/2 ~24 hr (accumulated data from multiple clinical studies)

26. Varenicline: Most Common Adverse EventsFrom 12-week Fixed-Dose, Placebo-Controlled Studies * Includes Preferred Terms: Insomnia/Initial insomnia/Middle insomnia/Early morning awakening Adverse events listed occurred in >5% and twice the rate seen in placebo-treated patients Prescribing Information. Pfizer Inc, New York, NY. (May 2006)

27. Withdrawal Symptoms from Stopping Smoking Incidence 70% Increased appetite 60% Restlessness 60% Depression 50% Irritability/aggression Craving for nicotine 70% 60% Poor concentration Sleep disturbance 25% Lightheadedness 10% Duration (weeks) or more Jarvis MJ.BMJ 2004;328:277-279.