Varenicline for smoking cessation

1
Varenicline for smoking cessation

• Robert West
• University College London
• Logroño, October 2006
• www.rjwest.co.uk

2
Outline

• Mechanism of action
• Clinical findings
• Comparison with other medications

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
Motivation to smoke
www.primetheory.com
5
Action on the nicotinic receptor

• Varenicline is a partial agonist binding with
  high affinity to the a4ß2 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

binding site
http//biology.ridley.on.ca/human_genome_project/h
gi99/nicotineaddiction.htm
http//www.cnsforum.com/content/pictures/imagebank
/hirespng/rcpt_sys_nic_ag1.png
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
Varenicline as a partial agonist
1. EMEA Package Insert. Annex I Summary of
Product Characteristics. Pfizer Inc, New York,
NY. 2006.
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
Comparative studies design
Treatment Phase
Non-treatment Phase
Varenicline 1 mg bid
Bupropion 150 mg bid
Placebo
ScreeningVisit
BaselineRandomization
Week 12
Week 52
Randomization
Target Quit Date
Titrated during Week 1. BLbaseline Wweek
Cclinic visit Ttelephone contact.
1. Jorenby DE, et al. JAMA. 200629656-63. 2.
Gonzales D, et al. JAMA. 200629647-55.
10
Comparative studies abstinence data
40
30
22.5
Responders ()
20
CA rate ()
15.7
9.4
10
0
Varenicline 1 mg bid(n692)
Bupropion150 mg bid(n669)
Placebo(n684)
12
16
20
24
28
32
36
40
44
48
52
Week
Gonzales DH, Rennard SI, Billing CB, et al. A
pooled analysis of varenicline an a4ß2 nicotinic
receptor partial agonist vs. bupropion for
smoking cessation. SRNT Paper sessions PA9-2,
PA9-3, 2006.
11
Comparative studies recruitment to abstinence
1

• 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

2
1. Jorenby DE, et al. JAMA. 200629656-63. 2.
Gonzales D, et al. JAMA. 200629647-55.
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
Extended use study design
Open-labelPhase
Non-treatmentFollow-up Phase
Double-blindPhase
Varenicline 1 mg bid
Varenicline 1 mg bid(titrated)
Placebo
Week 24
Week 12
Baseline
Week 52
Randomization
Target Quit Date
BL baseline Wweek Cclinic visit Ttelephone
contact.
1. Tonstad S, et al. JAMA. 200629664-71.
14
Extended use study findings
Varenicline 43.6 Placebo 36.9 P0.02 OR 1.34
of Patients
Week
Tonstad S, et al. JAMA. 200629664-71.
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 (gt10) 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
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
Summary

• Studies conducted to date have found varenicline
  to be safe and effective at helping smokers to
  stop.
• The size of effect on abstinence appears to be
  greater than is found with a standard course of
  bupropion.
• No serious adverse effects have been found but
  nausea is a relatively common side effect.
• 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
• 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
• 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.