Smoking cessation drug led to almost a third of smokers quitting during phase III trial

A smoking cessation drug that could be the first newly approved treatment for nearly 20 years saw almost a third of users quit smoking at one point during a phase III trial.

The study, published in JAMA on 11 July 2023, tested cytisinicline among 810 adults who smoked cigarettes daily and wanted to quit. It is first of two phase III clinical trials to be conducted by Achieve Life Sciences, the drug’s manufacturer.

Cytisinicline is a naturally-occurring plant-based alkaloid that binds selectively to nicotinic receptors in the brain that regulate nicotine dependence, alleviating the urge to smoke and reducing the severity of nicotine withdrawal symptoms.

The researchers said that the drug works in a similar way to the smoking cessation product varenicline (Champix; Pfizer), which was recalled in the UK by Pfizer in October 2021 owing to the presence of a possible human carcinogen.

A recall notice from the Medicines and Healthcare products Regulatory Agency (MHRA), published at the time, said that patients could be offered buproprion instead; however, in April 2023, the government said that there were shortages of the drug, which is more commonly used to treat depression.

In the same month, the government said it was working with medicine suppliers to restore supply of varenicline in England.

Known as ORCA-2, the cytisinicline trial compared two durations of treatment — 6 and 12 weeks — versus a placebo, with a follow-up at 24 weeks. The primary outcome measure was biochemically confirmed continuous smoking abstinence for the last four weeks of treatment.

In the 12-week group, 33% of participants using cytisinicline versus 7% using placebo were abstinent during weeks 9 to 12. For the 6-week group, abstinence was 25% for the cytisinicline group versus 4% for placebo during weeks 3 to 6.

Over the longer term, ORCA-2 found a statistically significant increase in continuous abstinence through 6 months for both treatment durations. Abstinence from weeks 9 to 24 for the 12-week group was 21% for cytisinicline versus 5% for placebo. For the 6-week group, abstinence from weeks 3 to 24 was 9% for cytisinicline versus 3% for placebo.

The study reported that cytisinicline was also well tolerated by participants, with no serious drug-related adverse events reported and low rates of typical side effects, such as nausea and insomnia.

Nancy Rigotti, director of Massachusetts General Hospital’s Tobacco Research and Treatment Center and lead author of the study, said: “There is an urgent need for new medications to treat tobacco smoking because existing products don’t help all smokers to quit and can have unacceptable side effects, yet no new smoking cessation medication has been approved by the US Food and Drug Administration (FDA) for nearly two decades.

“If approved by regulators, cytisinicline could be a valuable new option to treat tobacco dependence.”

Darush Attah-Zadeh, clinical fellow respiratory pharmacist at the North West London Integrated Care Board, and co-chair of the Taskforce for Lung Health medicines optimisation working group, said the cytisinicline trial results could pave the way for approvals globally.

“There have been similar exciting headlines like this before and I am hoping that it will lead to FDA approval”, he said. “If it does, then I don’t think it will be long before the MHRA approves it here.

“These data confirm that cytisinicline, if approved by the FDA, then hopefully the MHRA, has the potential to become the first new agent approved in nearly two decades and an important treatment option for treating tobacco dependence, which is much needed given the limitations with existing agents.

“With the unavailability of other non-nicotine treatments we’re seeing with varenicline (Champix) and buproprion (Zyban), I would welcome this as another option.”