Cytisinicline Significantly Helped People Who Smoke Remain Abstinent

Participants receiving cytisinicline for smoking cessation were able to remain continually abstinent with fewer nicotine cravings than those receiving placebo.1

“More deaths each year in the U.S. are attributed to cigarette smoking than to any other preventable cause, and our current smoking cessation treatment options are limited,” investigator Nancy Rigotti, MD, Professor of Medicine at Harvard Medical School, Director of Tobacco Research and Treatment Center, Massachusetts General Hospital, said in a statement.2 “The study findings published today suggest that cytisinicline, if approved by the FDA, could help many smokers to quit and reduce the smoking-related risks to their health.”

Achieve Life Sciences announced results from the 3-group double-blind, placebo-controlled, replication randomized, phase 3 ORCA-3 clinical trial. The trial was conducted at 20 clinical trial sites in the US from January 2022 to March 2023, with data analyses performed from May 3, 2023, to March 20, 2024, and compared a novel cytisinicline regimen at 6 and 12 weeks to placebo among adults who smoked 10 or more cigarettes daily and sought to quit. Participants were randomized 1:1:1 to 3-mg cytisinicline 3 times daily for 12 weeks; 3-mg cytisinicline 3 times daily for 6 weeks followed by placebo for 6 weeks; or placebo 3 times daily for 12 weeks. The investigators followed up participants for 24 weeks and all groups received behavioral support.

The trial randomized 792 participants with a mean age of 52.0 years (standard deviation [SD], 11.8), 429 (55.4%) of which were female, and who smoked a mean of 20.4 cigarettes per day (SD, 7.5). Overall, 628 (79.3%) completed the trial.1

The investigators found that smoking abstinence and smoking urges were significantly improved in the intervention groups. For 6-week treatment, 39 (14.8%) in the cytisinicline group (14.8%) were abstinent during weeks 3 to 6 as compared with 16 (6.0%) in the placebo group (odds ratio [OR], 2.9 [95% CI, 1.5-5.6]; P <.001). For 12-week treatment, 80 (30.3%) in the cytisinicline group were abstinent during weeks 9 to 12 (OR, 4.4; 95% CI, 2.6-7.3; P < .001) as compared with 25 (9.4%) in the placebo group.1

Continuous abstinence rates for the 6-week treatment were 6.8% in the cytisinicline group compared with 1.1% in the placebo group from weeks 3 to 24; furthermore, continuous abstinence rates for the 12-week treatment were 20.5% in the cytisinicline group compared with 4.2% in the placebo group for weeks 9 to 24.1

Looking at reduction in craving, a secondary outcome, Rigotti and colleagues found that the cytisinicline group had a greater reduction (−15.2 points [95% CI, −16.4 to −14.0]) than the placebo group (−12.0 points [95% CI, −13.5 to −10.5]; P <.001).1

“Most people who smoke want to quit and it often takes multiple attempts to do so successfully. Our trial participants were no exception and had multiple previous quit attempts, although less than half had previously tried varenicline, possibly due to its well-known adverse event profile,” Cindy Jacobs, MD, PhD, President and Chief Medical Officer of Achieve Life Sciences added to the statement.2 “Cytisinicline is very selective in targeting only nicotine receptors and has shown limited binding to other off-target receptors that can cause side effects, like nausea and gastrointestinal disturbances. We believe this leads to a highly tolerable treatment with cytisinicline, as demonstrated in our clinical trial program.”

Achieve plans to submit a New Drug Application (NDA) for cytisinicline to the FDA in June 2025.

REFERENCES

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

Achieve Life Sciences Announces Cytisinicline Phase 3 ORCA-3 Trial Publication on Smoking Cessation in JAMA Internal Medicine. News release. Achieve Life Sciences. April 21, 2025. https://www.globenewswire.com/news-release/2025/04/21/3064783/0/en/Achieve-Life-Sciences-Announces-Cytisinicline-Phase-3-ORCA-3-Trial-Publication-on-Smoking-Cessation-in-JAMA-Internal-Medicine.html