A NEW Phase III trial has strengthened the evidence supporting cytisinicline as an effective and well-tolerated medication for smoking cessation, offering renewed hope for clinicians seeking pharmacological tools to combat nicotine addiction.
Conducted between January 2022–March 2023 across 20 USA sites, the ORCA-3 trial randomised 792 adult daily smokers (≥10 cigarettes/day) into three groups. Participants received either 3 mg cytisinicline three times daily for 12 weeks, the same regimen for 6 weeks followed by placebo, or placebo throughout. All groups also received behavioural support. The trial was double-blind and placebo-controlled, with outcomes assessed up to 24 weeks following treatment. Data analysis was completed in March 2024.
Results showed significantly higher continuous smoking abstinence rates for both cytisinicline groups compared to placebo. During the treatment periods, 14.8% of those on the 6-week cytisinicline regimen remained abstinent versus 6.0% on placebo (odds ratio [OR]: 2.9; 95% CI: 1.5–5.6; P<0.001). For the 12-week regimen, abstinence rose to 30.3% versus 9.4% for placebo (OR: 4.4; 95% CI: 2.6–7.3; P<0.001). From treatment end to 24 weeks, continuous abstinence was also sustained: 6.8% in the 6-week group vs 1.1% for placebo, and 20.5% vs 4.2% respectively. Cytisinicline significantly reduced nicotine cravings as measured by the Questionnaire of Smoking Urges, with a mean reduction of −15.2 points compared to −12.0 points for placebo (P<0.001). Importantly, no treatment-related serious adverse events were reported.
The ORCA-3 findings reaffirm cytisinicline’s efficacy in achieving sustained smoking cessation and reducing nicotine craving. With strong tolerability and statistically robust outcomes, cytisinicline offers a promising new pharmacotherapy option for clinicians managing tobacco dependence.
Reference
Rigotti NA et al. Cytisinicline for smoking cessation: the ORCA phase 3 replication randomized clinical trial. JAMA Intern Med. 2025; DOI:10.1001/jamainternmed.2025.0628.
