Kicking the habit

Worldwide, around 4.9 million people die from the effects of smoking every year. In the US alone, smoking-related illness costs the healthcare system around $167bn annually, is responsible for one in every five deaths and is the leading preventable cause of premature morbidity and mortality. It begs the question: why do so many people smoke?

The answer probably lies with nicotine, the alkaloid present in tobacco which is responsible for the addictive characteristics of smoking products.

Crossing the blood-brain barrier, nicotine activates nicotinic acetylcholine receptors (nAChRs) which release dopamine in the mesolimbic area of the brain, or the 'reward centre'. When you stop smoking, less dopamine is released, which elicits cravings and withdrawal symptoms.

Around 70 per cent of smokers say that they would like to give up smoking, but only about 5 per cent of those who try to overcome 'cold turkey' are successful. With the ever increasing personal and societal costs associated with smoking and related illness, the market for smoking cessation therapies is definitely on the rise.

New kid on the block
Recently, the US Food and Drug Administration (FDA) approved a novel pharmaceutical to help people give up smoking. Pfizer's varenicline (Chantix) is a derivative of the naturally occurring plant alkaloid cytisine and is a nAChR partial agonist selective for the 42 receptor subtype.

As a partial agonist, the product`s mechanism of action is two-fold: low-to-moderate activation of nAChRs to reduce cravings and withdrawal symptoms, and prevention of nicotine from binding due to receptor occupancy, which blocks the reinforcing effects.

Administered for 12 weeks, varenicline has demonstrated superior efficacy over GlaxoSmithKline's bupropion (Zyban), the only other marketed non-nicotine-based smoking cessation therapy, which was approved by America`s FDA almost 10 years ago.

In phase III trials, continuous abstinence rates in the last four weeks of treatment averaged 44 per cent, compared with around 30 per cent of bupropion and 18 per cent of placebo recipients, respectively; corresponding values after one year were approximately 22 per cent, 15 per cent and 9 per cent, respectively.

The launch of varenicline marked the sixth FDA-approved smoking cessation therapy to date; in addition to bupropion and varenicline, five nicotine replacement products are available, including gum, patch, nasal spray, inhaler and lozenge.

Analysts believe that varenicline has blockbuster potential, with peak sales of up to $1.3bn annually by 2014.

Another 42-specific nAChR partial agonist is also in the pipeline, with sanofi-aventis undertaking a phase III study of dianicline [SSR 591813] in up to 600 smokers. In a phase IIb study, treatment with dianicline met its primary endpoint of prolonged abstinence during the last four weeks of treatment, compared with placebo.

Vaccination route
It appears that vaccination could also be an option in modern day smoking cessation therapy, of which the most advanced are Nabi Biopharmaceuticals' NicVAX and Cytos Biotechnology's CYT002-NicQb. Both of these 'anti-smoking` vaccines are currently in phase II clinical development; NicVAX also has fast track designation from the FDA.

Both vaccines work in the same fashion. Nicotine itself is small enough to cross the blood-brain barrier, where it exerts its effects on the dopamine reward system and causes addiction. However, when complexed with an anti-nicotine antibody produced by immune stimulation with a vaccine, such as NicVAX or CYT002-NicQb, the molecule is no longer small enough to cross the blood-brain barrier and cannot bind to nAChRs.

NicVAX combines a nicotine derivative with recombinant exoprotein A from Pseudomonas aeruginosa, and CYT002-NicQb comprises nicotine chemically coupled to the virus-like particle Qb.

Cytos has completed a phase II study in 341 smokers which revealed that in subjects who experienced a high antibody response, 100?g of vaccine significantly increased rates of continuous abstinence, compared with placebo, at months six and 12 (54 per cent and 42 per cent, respectively).

Nabi is currently conducting a phase IIb proof-of-concept study in around 300 smokers. In an earlier phase II study, the highest dose of its vaccine produced a 33-40 per cent quit rate, compared with 9 per cent in placebo recipients.

An additional vaccine, TA-NIC, is being developed by Xenova Group, a subsidiary of Celtic Pharma.

Celtic launched a phase II trial of TA-NIC during the second quarter of 2006. Preliminary data from a phase I trial of the vaccine, which comprises a nicotine derivative conjugated to a recombinant cholera toxin B, indicated that self-reported quit rates were considerably greater in TA-NIC, compared with placebo, recipients. However, these claims will need to be solidified with the phase II programme.

Others have tried In the US and the EU, sanofi-aventis submitted marketing applications for its anti-obesity drug rimonabant to be used as a smoking cessation agent.

However, the selective cannabinoid CB1 receptor antagonist has been given the thumbs down for this indication in both territories. Its back-up molecule, surinabant, is now in phase I development for this indication.

Other compounds in development include GlaxoSmithKline's, GW 468816, which is in phase III.

The drug is designed to aid abstinence in people who have just quit smoking, delaying the time to relapse. The potential of the glycine receptor antagonist should become clear when data from the study is released.

ADX 10061 is a selective dopamine D₁ receptor antagonist in clinical development with Addex Pharmaceuticals for use in smoking cessation. The compound was previously investigated for alternative indications, such as schizophrenia and, as yet, its potential in smoking cessation remains to be seen.

Somaxon Pharmaceuticals is conducting phase II trials of nalmefene, an opioid receptor antagonist that is available for opioid abuse and is in phase II/III for pathological gambling and other impulse control disorders; positive efficacy has been reported.

The author
The author is Ben Richardson of Adis International, using information derived from Adis Clinical Trials Insight and R&D Insight.