Comparative Effectiveness of Cytisinicline and Varenicline for Smoking Cessation: A Matching-Adjusted Indirect Comparison (MAIC)

Background: Pharmacologic options for supporting smoking cessation remain limited. Cytisinicline is a plant-based alkaloid that selectively binds to α4β2 nicotinic acetylcholine receptors, reducing nicotine craving and withdrawal symptoms, and has proven effective for smoking cessation in the phase III ORCA-2 and ORCA-3 trials, with a favorable safety profile. Using data from randomized clinical trials, we performed an indirect treatment comparison of varenicline, a guideline-recommended partial agonist of the nicotinic acetylcholine receptor used as first-line pharmacotherapy for tobacco cessation, vs cytisinicline for smoking cessation. Objectives: This analysis was designed to compare the efficacy and safety of cytisinicline vs varenicline using pooled data from the cytisinicline ORCA-2 and ORCA-3 trials, and the EAGLES trial of varenicline. Methods: ORCA-2 (conducted from October 2020 to December 2021), ORCA-3 (May 2023-March 2024), and EAGLES (November 2011-January 2015) enrolled adults who smoked at least 10 cigarettes daily and were motivated to quit. A matching-adjusted indirect treatment comparison was employed to adjust for patient population differences between the ORCA (cytisinicline) and EAGLES (varenicline) studies. Propensity score weighting was used to align patient characteristics, then efficacy outcomes, continuous smoking abstinence rate at Weeks 9-12 and Weeks 9-24, and safety outcomes, including treatment discontinuation due to adverse events, were assessed. Adjusted and unadjusted analyses (a standard Bucher and the Mantel-Haenszel approach) were performed. Results: There was no statistically significant difference in continuous abstinence between the cytisinicline and varenicline cohorts at the 9- to 12-week assessment (adjusted OR, 1.33; 95% CI, 0.86-2.05). Patients prescribed cytisinicline had higher odds of abstinence vs varenicline at the 9- to 24-week assessment (adjusted OR, 1.95; 95% CI, 1.13-3.34). Cytisinicline was associated with 82% lower odds of nausea vs varenicline (adjusted OR, 0.18; 95% CI, 0.10-0.31). Conclusion: Cytisinicline may be an effective and more tolerable alternative, especially for patients at risk of relapse or unable to tolerate varenicline.