With varenicline currently unavailable, it is possible that cytisine might serve as an alternative pharmacotherapy to help patients to stop smoking. Here, clinical writer Rod Tucker investigates.
Tobacco smoking is a major cause of premature death and it is estimated that current smokers will die an average of 10 years earlier than non-smokers. But, despite the widespread acknowledgement of the dangers associated with smoking, millions of people across the world continue to smoke. In its most recent assessment, the World Health Organization suggests that tobacco kills more than eight million people each year – a figure that includes 1.3 million non-smokers who are exposed to secondhand smoke.
Although smoking is linked to a range of adverse health effects, much attention has been directed at the links with lung cancer. In fact, estimates suggest that 90% of lung cancer deaths are due to smoking. Fortunately, there is a large body of robust evidence supporting the effectiveness of pharmacotherapies for smoking cessation. In fact, even if smoking cessation is started at the time of a lung cancer diagnosis, there is still an improvement in overall survival.
The benefits of smoking cessation treatment were highlighted in a 2021 systematic review, which suggested that there was strong evidence for a range of pharmacologic and behavioural interventions at increasing smoking cessation. One such treatment is varenicline, which, according to the systematic review, was associated with a more than two-fold increase in the smoking cessation success rate.
However, varenicline is currently unavailable in the UK and Europe. It was withdrawn by the manufacturer, Pfizer in 2021 due to the presence of high levels of N-nitroso-varenicline – a probable human carcinogen.
Attention then turns to the most suitable alternatives to varenicline. One potential treatment cytisine but, despite being available for over 50 years, the drug is still not licensed in many countries beyond Eastern Europe. So, how effective is cytisine as an aid to smoking cessation, and why is it not widely available?
Cytisine under the microscope
Cytisine, or, more correctly, cytisinicline, is an alkaloid that is a partial nicotinic acetylcholine receptor agonist. Derived from the plant Cytisus laburnum, it was discovered in 1865, but it was not until 1912, that its pharmacological actions were described as almost indistinguishable from that of nicotine.
The drug was brought to market in 1964 under the brand name Tabex by the Bulgarian company Sopharma, which described it as a plant-based drug used for smoking secession. Today, cytisine is marketed in 18 countries, but is not authorised in the UK, European or US markets, nor any country where the regulatory approval processes of these countries are followed, such as New Zealand.
Much of the early research on cytisine was undertaken during the 1960s in Eastern Europe. However, due to a combination of language and Iron-Curtain barriers, many clinicians in westernised countries were largely unfamiliar with the drug.
Nevertheless, the early research had not gone completely unnoticed. The development of varenicline for instance, which has an identical mode of action to cytisine, was influenced by the recognition that partial nicotinic acetylcholine receptor agonists were implicated in regulating the mesolimbic dopaminergic pathway, which mediates many aspects of tobacco dependence.
The first systematic review of the clinical data on cytisine was undertaken in 2006. The review included data from 10 studies published between 1967 and 2005 in Bulgaria, Germany, Poland and Russia, three of which, were placebo-controlled trials. Although the authors of the review concluded that cytisine appeared to be effective, they also noted how most trials were of poor quality.
Since that first review, several more rigorous randomised trials have been conducted. One such trial in 2011, observed a significantly higher rate of sustained 12-month abstinence of 8.4% for cytisine compared to 2.4% with placebo (p = 0.001). The following year, a double-blind, randomised, placebo-controlled trial, also showed that cytisine was associated with a significantly greater abstinence rate compared to placebo (p = 0.01).
But, the true value of a drug‘s efficacy is really only established in trials using an active comparator. To date, several such trials have been undertaken with either varenicline or nicotine replacement therapy (NRT).
One such trial from 2014 compared cytisine for 25 days to eight weeks of NRT. In terms of continuous abstinence, cytisine was superior to NRT after one week, two months and six months.
When it comes to comparing varenicline, a trial in 2021 concluded that cytisine treatment for 25 days, compared with varenicline for 84 days, failed to demonstrate non-inferiority regarding smoking cessation. A second 2021 trial also concluded that cytisine and varenicline were not significantly different.
In contrast, however, a comparative study published in 2023, found that the standard 12-week varenicline treatment was more effective than the standard 4-week cytisine treatment. The study, which was undertaken in primary care practices in Croatia and Slovenia, showed that the smoking cessation rate after 24 weeks was 32.5% for varenicline but only 23.1% for cytisine. Despite this lower efficacy, the authors did conclude that adherence was higher, and the rate of adverse events lower, among participants assigned to cytisine.
The most recent trial, published in July 2023, compared a 3 mg dose of cytisine taken three times daily for 12 weeks, to the same dose for only six weeks followed by six weeks of placebo, or a placebo for 12 weeks. In both active regimens, cytisine significantly improved smoking cessation rates more than placebo.
Why is cytisine not licensed more widely?
While cost is always an important consideration for any treatment, cytisine has been shown in many analyses to be a cost-effective treatment option. For instance, one 2014 cost-effectiveness analysis concluded that cytisine is estimated to be both more clinically effective and cost-effective than varenicline. This was reaffirmed in a 2018 analysis, which concluded that the current provision of smoking cessation services in the Netherlands and England could benefit economically from the inclusion of cytisine.
With little doubt over its efficacy, other factors serve as a barrier to wider approval. Perhaps most pertinent is the concern that regulatory authorities in the UK, Europe and the US may require further placebo-controlled trials of cytisine in western European and/or North American populations. The current manufacturers, Sopharma in Bulgaria and Aflofarm in Poland, have little incentive to conduct such trials, especially as cytisine is now a generic product.
But, the current situation is more than likely to change in the near future. One US company, Achieve Life Sciences, has made great strides in evaluating cytisine through a series of randomised controlled trials. In fact, the company describes itself as ‘committed to advancing cytisinicline (cytisine) as a widely available treatment option to help people battling nicotine addiction.‘
Achieve Life Sciences established the Ongoing Research of Cytisinicline for Addiction (ORCA) program of clinical trials to advance the development and commercial availability of cytisine. Recently, the company reported findings from the ORCA-V1 Phase 2 trial in which a 3 mg dose of cytisine three times a day demonstrated a significantly significant better quit rate than placebo among adult users of nicotine e-cigarettes or vapes.
In the absence of a marketing authorisation, it is unlikely that cytisine will serve as an alternative to varenicline, at least in the short term. But, armed with a dossier of positive data, it is possible that cytisine will gain FDA approval in the next year or so. This is likely to lead to regulators in the UK and Europe also approving the drug, finally allowing many more millions of patients access to an effective smoking cessation aid.