1. 1 Varenicline for smoking cessation Robert West University College London Logroño, October 2006 www.rjwest.co.uk

2. 2 Outline Mechanism of action Clinical findings Comparison with other medications

3. 3 Mechanism of action It is proposed that: –Chronic nicotine ingestion from cigarettes sets up an acquired drive resulting from chronically reduced activity in the mesolimbic dopamine pathway experienced as a ‘need’ to smoke analogous to need for food etc. –Nicotine stimulates activity in the mesolimbic dopamine pathway, relieving the drive state and also providing positive reward Varenicline attaches to the nicotine receptors concerned and activates them to a limited degree, reducing the drive state and blocking nicotine from attaching to the receptors

4. 4 Motivation to smoke Smoking Impulse to smoke Desire to smoke Need to smoke Positive evaluations of smoking Anticipated enjoyment Anticipated benefit Nicotine ‘hunger’ Unpleasant mood and physical symptoms Smoker ‘identity’ Beliefs about benefits of smoking Cues/triggers Reminders www.primetheory.com

5. 5 Action on the nicotinic receptor Varenicline is a ‘partial agonist’ binding with high affinity to the α4β2 nicotinic acetylcholine receptor believed to be important in the development and maintenance of nicotine dependence This type of receptor is found in the ventral tegmental area (VTA) in the midbrain – the location of the cell bodies of the mesolimbic dopamine pathway http://biology.ridley.on.ca/human_genome_project/hgi99/nicotineaddiction.htm http://www.cnsforum.com/content/pictures/imagebank/hirespng/rcpt_sys_nic_ag1.png binding site

6. 6 The effect on the reward pathway Stimulating the VTA nicotinic receptors results in dopamine release in the nucleus accumbens, but chronic stimulation by nicotine leads to reduced activity in the pathway in the absence of nicotine Varenicline is thought to have enough activity reduce this deficiency without having sufficient activity to be rewarding itself At the same time it blocks the receptor so that nicotine cannot get access to it, thus reducing the rewarding effects of nicotine

7. 7 Varenicline as a partial agonist Blocks reward Craving; Withdrawal relief Dose, exposure Effect 0% 100% 50% Maximum effect Full agonist Partial agonist 1. EMEA Package Insert. Annex I Summary of Product Characteristics. Pfizer Inc, New York, NY. 2006.

8. 8 Clinical findings A 12-week course of varenicline 1mg bid. has been found to be safe and effective in large scale clinical trials It appears to be more effective than the standard course of bupropion Giving those who are abstinent at the end of the course a further 12 weeks of medication enhances long-term abstinence still further on average

9. 9 Comparative studies: design *Titrated during Week 1. BL=baseline; W=week; C=clinic visit; T=telephone contact. Treatment PhaseNon-treatment Phase Varenicline 1 mg bid* Bupropion 150 mg bid* Placebo Screening Visit Baseline Randomization Week 12Week 52 CTTCTTCTCTCCTTCTTCTCTCCCCCCCCCCCCCCCCCCCCCCCCCCC WWWWWWWWWWW 1316202428323640444852 BW WWWWWWWWWWW L123456789101112 Nontreatment Follow-upTreatment Period Randomization Target Quit Date 1. Jorenby DE, et al. JAMA. 2006;296:56-63. 2. Gonzales D, et al. JAMA. 2006;296:47-55.

10. 10 Comparative studies: abstinence data Gonzales DH, Rennard SI, Billing CB, et al. A pooled analysis of varenicline: an α4β2 nicotinic receptor partial agonist vs. bupropion for smoking cessation. SRNT Paper sessions PA9-2, PA9-3, 2006. 0 5 10 15 20 25 30 35 40 45 50 Responders (%) Week 1216202428323640444852 0 10 20 30 40 Odds Ratio (95% CI) V vs P2.82(2.06, 3.86; P <0.0001) V vs B1.56(1.19, 2.06; P <0.0013) B vs P1.80(1.29, 2.51; P <0.0004) Varenicline 1 mg bid (n=692) 22.5% Bupropion 150 mg bid (n=669) 15.7% Placebo (n=684) 9.4% CA rate (%) Varenicline Bupropion Placebo

11. 11 Comparative studies: recruitment to abstinence Some evidence that in the first 4 weeks, smokers on varenicline are being ‘recruited into abstinence’ – i.e. had smoked after the quit date but then became abstinence 1. Jorenby DE, et al. JAMA. 2006;296:56-63. 2. Gonzales D, et al. JAMA. 2006;296:47-55. 1 2

12. 12 Comparative studies: PROs Analysis of the PROs (Patient-Reported Outcomes) indicates that varenicline: –reduced patient ratings of urges to smoke compared with placebo and bupropion –reduced ratings of mood disturbance compared with placebo –reduced patient ratings of satisfaction and reward from their cigarette in those who smoked a cigarette after the quit date, compared with placebo and bupropion Manuscript in preparation

13. 13 Extended use study: design BL= baseline; W=week; C=clinic visit; T=telephone contact. Open-label Phase Non-treatment Follow-up Phase Varenicline 1 mg bid Placebo Week 24 Week 52 CTCTCTCTCCTCTCTCTC WWWWWWWWW 252628323640444852 Non-treatment Follow-up (Double-blind) CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCC WWWWW 1314162024 BW WWWWWWWWW L123456781012 Double-blind Treatment Open-label Treatment RandomizationTarget Quit Date Week 12 Varenicline 1 mg bid (titrated) Double-blind Phase Baseline 1. Tonstad S, et al. JAMA. 2006;296:64-71.

14. 14 Week % of Patients Varenicline: 43.6% Placebo: 36.9% P =0.02 OR 1.34 Extended use study: findings Tonstad S, et al. JAMA. 2006;296:64-71.

15. 15 Summary of safety data –During clinical trials, approximately 4000 individuals have been exposed to varenicline –In placebo-controlled studies, discontinuations due to adverse events were 11.4% Varenicline 1 mg 9.7% placebo –The most frequent (>10%) AEs associated with varenicline 1 mg vs placebo were Nausea (28.6%) Abnormal Dreams Insomnia Headache EMEA Package Insert. Annex I Summary of Product Characteristics. Pfizer Inc, New York, NY. 2006.

16. 16 Comparison with other medications Direct comparison with bupropion has indicated an advantage for varenicline No published studies comparing varenicline with nicotine replacement therapy but one study has been completed Serious adverse event profile is favourable compared with bupropion but experience is much more limited

17. 17 Summary 1.Studies conducted to date have found varenicline to be safe and effective at helping smokers to stop. 2.The size of effect on abstinence appears to be greater than is found with a standard course of bupropion. 3.No serious adverse effects have been found but nausea is a relatively common side effect. 4.Adding a further 12 weeks to the initial course of 12 weeks of varenicline has been found in one study to improve abstinence rates 6 months after the end of treatment 5.Varenicline appears to work through two mechanisms: 1) reducing the need to smoke and 2) reducing the rewarding effect of the cigarette if the patient lapses in the first few weeks after the quit date, thus reducing the risk of that lapse turning into a full relapse 6.Varenicline was designed specifically to achieve this mechanism of action by being a partial agonist binding with high affinity to the alpha4beta2 nicotinic acetylcholine receptor which is believed to be central to the addictive properties of nicotine.