Cytisinicline Shows Strong Promise for Smoking Cessation: Phase 3 Trial Confirms Efficacy and Tolerability

"The ORCA phase 3 trial confirmed that cytisinicline is both effective and well-tolerated for helping people quit smoking, whether taken for 6 or 12 weeks. Its positive effects lasted up to 24 weeks. The treatment works by reducing the urge to smoke," the researchers wrote in JAMA Internal Medicine.

There is a growing need for new and effective medications to help people quit smoking. Cytisinicline, a plant-based compound that partially activates α4β2 nicotinic acetylcholine receptors in the brain, has shown promise in one previous U.S. trial for aiding smoking cessation. However, more robust data was needed to confirm its benefits. Therefore, Nancy A. Rigotti, Massachusetts General Hospital, Harvard Medical School, Boston, and colleagues aimed to validate these earlier findings by comparing the effectiveness and tolerability of cytisinicline against a placebo, while also exploring its ability to reduce nicotine cravings, believed to be a key part of how it works.

For this purpose, the researchers conducted a three-arm, double-blind, placebo-controlled phase 3 trial (ORCA-3) at 20 U.S. sites between January 2022 and March 2023. Adults who smoked at least 10 cigarettes daily and wanted to quit were randomly assigned to receive cytisinicline 3 mg three times daily for either 12 weeks, 6 weeks followed by placebo, or placebo for 12 weeks, with all groups also receiving behavioral support. The trial followed participants for 24 weeks, focusing on continuous abstinence during the final four weeks of treatment and from treatment end to week 24, along with changes in craving and adverse events.

The key findings were as follows:

• A total of 792 participants were randomized, with a mean age of 52 years; 55.4% were female, and the average number of cigarettes smoked per day was 20.4. Six-hundred twenty-eight participants (79.3%) completed the trial.
• Both cytisinicline groups showed significantly better outcomes compared to placebo.
• In the 6-week cytisinicline group, 14.8% achieved abstinence during weeks 3 to 6, compared to 6.0% in the placebo group (OR 2.9).
• In the 12-week cytisinicline group, 30.3% were abstinent during weeks 9 to 12, versus 9.4% in the placebo group (OR 4.4).
• From weeks 3 to 24, 6.8% of participants on the 6-week cytisinicline regimen maintained continuous abstinence, compared to 1.1% on placebo.
• From weeks 9 to 24, 20.5% of those on the 12-week cytisinicline regimen remained abstinent, compared to 4.2% on placebo.
• Cytisinicline led to a greater reduction in nicotine cravings at week 6 compared to placebo (–15.2 points vs –12.0 points).
• The treatment was well tolerated, with no serious side effects linked to cytisinicline.

"The findings from the large, multisite phase 3 trial reaffirm cytisinicline’s strong efficacy and excellent tolerability for smoking cessation. Taken at 3 mg three times daily with behavioral support, cytisinicline significantly reduced nicotine cravings and sustained abstinence rates, confirming its role as a partial nicotine agonist," the authors wrote.

"Its favorable safety profile, comparable efficacy to varenicline, and advantages over current options like nicotine replacement therapy and bupropion position it as a promising and well-tolerated alternative. These results support the adoption of cytisinicline not only for quitting traditional cigarettes but also for addressing dependence on other nicotine delivery products," they concluded.

Reference:

Rigotti NA, Benowitz NL, Prochaska JJ, et al. Cytisinicline for Smoking Cessation: The ORCA Phase 3 Replication Randomized Clinical Trial. JAMA Intern Med. Published online April 21, 2025. doi:10.1001/jamainternmed.2025.0628