Introduction

"...the novel mechanism of action of varenicline may be responsible for the 'relatively high quit rates compared with placebo and the relative increase in quit rates over the medication treatment period,' a pattern not seen with other smoking cessation drugs."

The latest data available on the newest drug marketed to aid smoking cessation, varenicline, show that the drug is safe and effective, in both the short and long term for smokers trying to quit, according to the results of two phase 2 studies. The studies, by the US Varenicline Study Group in cooperation with researchers from the pharmaceutical company that developed and markets varenicline, Pfizer, are published in the August 14/28 issue of the Archives of Internal Medicine.^[1,2]

Varenicline (varenicline tartrate) is a partial agonist that selectively and specifically targets the nicotinic alpha-4/beta-2 receptor and acts by simultaneously blocking these nicotine receptors and stimulating dopamine. Oral varenicline has an agonist effect on dopamine release that amounts to about 30% to 60% of that with nicotine, which would appear to be enough to block craving and withdrawal without producing dependence or creating a competitive antagonist effect on nicotine.

In addition to the phase 2 data, the results of phase 3 randomized clinical trials by the same team of researchers were published simultaneously in JAMA in July.^[3-5] They showed that 12 weeks of treatment with varenicline was significantly more efficacious than placebo for smoking cessation at all time points and significantly more efficacious than bupropion at the end of treatment and at 24 weeks^[3] and 52 weeks.^[4] In smokers who had stopped smoking for 7 days at the end of varenicline treatment, a further 12 weeks of varenicline significantly reduced relapse compared with placebo for up to 1 year thereafter.^[5] An accompanying editorial said that although the studies demonstrated the efficacy of varenicline, there were concerns about the adverse-effect profile of the drug, particularly nausea, which occurred in almost 30% of the participants.^[6]

Clinical Trial Results

The first of these phase 2 studies was a randomized, placebo-controlled trial of the efficacy, tolerability, and safety of 3 doses of varenicline administered over 6 weeks. Bupropion, the primary non-nicotine-based treatment currently prescribed for smoking cessation in the United States, was selected as the active control.^[1] The study, conducted at 7 US sites between 2000 and 2003, was part of a phase 2 program developed to select the optimum dose for larger-scale, phase 3 trials.

Healthy subjects aged 18-65 years who smoked 10 or more cigarettes per day for 1 year or longer were randomly assigned to 1 of 5 treatment groups:

All subjects took their study medication 1 week before attempting to quit smoking on day 8 of the trial. All subjects received counseling for 10 minute or less per week, and everyone had the option of relapse prevention counseling during the 45-week follow-up period.

The investigators, led by Mitchell Nides, PhD, of Los Angeles Clinical Trials, report that both varenicline and bupropion were significantly more effective than placebo for short- and long-term smoking cessation. Continuous quit rate (CQR), defined as abstinence for any consecutive 28-day period during the treatment phase, was significantly higher for the 2 highest doses of varenicline and for bupropion vs placebo ( Table 1 ).

CQRs were confirmed by exhaled carbon monoxide monitoring and showed similar results. These showed that efficacy improved as the dose increased, with varenicline tartrate, 1 mg twice daily, providing the highest rates of continuous abstinence across all treatment groups, including bupropion. Long-term confirmed CQRs from week 4 to weeks 12, 24, and 52 were significantly higher than with placebo for each time point. By contrast, for bupropion, only the difference at week 12 was significant.

"In this study, varenicline tartrate, 1 mg twice daily, effectively helped subjects quit smoking, with response rates 3 times higher than those for placebo while demonstrating a good tolerability profile in this population of smokers who, on average, had smoked approximately 20 cigarettes per day for approximately 24 years," Dr Nides and his colleagues say. "Efficacy was maintained in the nondrug treatment phase through week 52."

Confirming Study

In a confirming study,^[2] also phase 2, varenicline taken over 12 weeks was shown to be effective in helping smokers quit, while being generally well tolerated. Cheryl Oncken, MD (University of Connecticut Health Center, Farmington), and colleagues studied 647 smokers to evaluate the efficacy, safety, and tolerability of 4 varenicline dosing regimens -- 2 with progressive dosing over the first week and 2 with a fixed-dose schedule. Healthy smokers aged 18-65 years were randomly assigned to 1 of 5 treatment groups:

Subjects received a smoking-cessation book and brief counseling at the start of treatment and just before the target quit date, which was 7 days after their first dose of varenicline. After 12 weeks, subjects were encouraged to participate in a 40-week assessment without the study drug.

CQRs for weeks 4 through 7 and 9 through 12, the primary efficacy measures, were all significantly higher in the varenicline treatment groups compared with placebo ( Table 2 ).

During weeks 9-52, abstinence rates were higher in the pooled varenicline 0.5-mg-twice-daily and the pooled 1-mg-twice-daily groups (18.5% and 22.4%, respectively) compared with the placebo group (3.9%) (both P < .001).

Side Effects

The most common varenicline-associated adverse event in both studies was nausea (between 17.5% and 52.0% in the first study and 26.3% to 41.9% in the second). The incidence of nausea was significantly higher in the higher-dose groups compared with placebo. However, in general the effect was deemed to be mild to moderate in severity and typically transitory, and in the end discontinuations due to nausea were < 5% in each trial. Furthermore, individualized titration appeared to reduce the overall incidence of nausea.

Other adverse events that occurred most frequently in the participants taking varenicline included insomnia, headache, abnormal dreams, and taste perversion. The incidence of all of these adverse events, except headache, increased with increasing dose.

Commentary

Both of these phase 2 studies reported significant reductions in the urge to smoke and in some of the rewarding effects of smoking compared with placebo. The investigators pointed that this may be especially important, as this may assist in promoting abstinence and preventing relapse. They also suggest that the novel mechanism of action of varenicline may be responsible for the "relatively high quit rates compared with placebo and the relative increase in quit rates over the medication treatment period," a pattern not seen with other smoking-cessation drugs.

The investigators concluded by saying, "Future studies are warranted to compare the efficacy of varenicline to other smoking cessation pharmacotherapies and to determine whether a longer duration of medication treatment improves smoking cessation rates."

In an accompanying editorial,^[7] Bankole A. Johnson, DSc, MD, PhD, chairman of the department of psychiatric medicine and professor in the department of neurology at the University of Virginia, Charlottesville, says that the 2 studies demonstrate "that varenicline is a novel medication to aid in smoking cessation...It was well tolerated and promises to be more effective in clinical practice than bupropion."

Dr. Johnson noted that other approaches to treating nicotine addiction are being developed. The most promising of these, he believes, are topiramate, a drug currently used as an anticonvulsant and for migraine prevention, and a nicotine conjugate vaccine that is in early clinical trials. "Pharmacological and immunological studies are opening up new vistas for safe, efficacious, and potent treatments for nicotine dependence," he writes. "Molecular genetic studies also are investigating how to identify those individuals vulnerable to becoming nicotine dependent and, once they are dependent, the treatments that might work best for them. All these advances will deliver real aid to curbing smoking. Now, a smoker who wants help to quit no longer has a legitimate excuse to delay seeking treatment."

Varenicline first became available, as Chantix, in the United States on August 1, 2006. In Europe, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Evaluation Agency issued a positive opinion recommending marketing authorization of varenicline in July. The CHMP's positive recommendation will be reviewed by the European Commission, which has authority to approve medicines for the European Union. A final decision from the Commission is expected "in the coming months." In Europe varenicline will be marketed as Champix.

	Varenicline			Bupropion	Placebo
	0.3 mg qd	1.0 mg qd	1.0 mg bid
CQR	28.6%	37.3%	48.0%	33.3%	17.1%
P value vs placebo	.03	< .001	< .001	.002

 

CQR	Varenicline				Placebo
	0.5 mg bid nontitrated	0.5 mg bid titrated	1.0 mg bid nontitrated	1.0 mg bid titrated
Weeks 4-7	37.2%	35.4%	38.8%	40.8%	10.9%
P value vs placebo	< .001	< .001	< .001	< .001
Weeks 9-12	47.3%	40.8%	44.2%	54.6%	11.6%
P value vs placebo	< 001	< .001	< .001	< .001

 

All of the studies reported above were supported by Pfizer.