Achieve Life Sciences, Inc. announced the publication in JAMA of the results from the Phase 3 ORCA-2 randomized placebo-controlled clinical trial of cytisinicline as a treatment for smoking cessation, the first large trial of this medication conducted in the United States. The study authors concluded that cytisinicline demonstrated “smoking cessation efficacy and excellent tolerability” in adult smokers. ORCA-2 was the first of two Phase 3 clinical trials to report positive outcomes for cytisinicline in smoking cessation.

As reported, the ORCA-2 trial demonstrated that biochemically confirmed continuous smoking abstinence during the last 4 weeks of treatment, the primary outcome measure, was significantly higher for cytisinicline compared with placebo for both the 6- and 12-week treatment durations. For 6-week cytisinicline treatment vs placebo, 25.3% vs 4.4% of participants were abstinent during weeks 3 to 6, and participants receiving cytisinicline treatment had 8 times higher odds, or likelihood, to have quit smoking (odds ratio (OR) 8.0 [95% CI, 3.9-16.3]; P<.001). For 12-week cytisinicline treatment vs placebo, 32.6% vs 7.0% of participants were abstinent during weeks 9 to 12, and participants receiving cytisinicline treatment had 6 times higher odds, or likelihood, to have quit smoking (OR 6.3 [95% CI, 3.7-11.6]; P<.001).

Participants taking cytisinicline also had a rapid and sustained decline in cravings and smoking urges compared with placebo during the first 6 weeks of treatment. Continuous abstinence rates were also statistically significant through 6 months, the secondary outcome measure, for both treatment durations. For 6-week cytisinicline treatment vs placebo, 8.9% vs 2.6% of participants were abstinent during weeks 3 to 24, and participants had 4 times higher odds, or likelihood to have quit smoking (OR 3.7 [95% CI, 1.5-10.2]; P=0.002).

For 12-week cytisinicline treatment vs placebo, 21.1% vs 4.8% of participants were abstinent during weeks 9 to 24, and participants had 5 times higher odds, or likelihood to have quit smoking (OR 5.3 [95% CI, 2.8-11.1]; P<.001). Participants taking cytisinicline during the entire 12 weeks of study treatment showed successful quitting beyond 6 weeks of treatment. The probability of abstinence continued to increase after week 6 in participants who received 12 weeks of cytisinicline treatment, suggesting that continued new quitting attempts occurred and were successful among participants who had not achieved complete abstinence by week 6. These findings indicate that prolonged 12-week treatment for some people who smoke may be required to achieve successful abstinence.

Rates of abnormal dreams and insomnia occurred in less than 10% of each group, and rates of headache and nausea for cytisinicline were similar to placebo rates. Only 2.9% of subjects discontinued cytisinicline due to an adverse event and no drug-related serious adverse events occurred. ORCA-2 was the first of two Phase 3 clinical trials to report positive outcomes for cytisinicline efficacy and safety.

The Phase 3 ORCA-3 trial, for which results were reported in May 2023, also demonstrated statistically significant cessation rates for both 6- and 12-week cytisinicline and demonstrated that cytisinicline was very well-tolerated. Based on these data, Achieve expects to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for cytisinicline as an aid in treating nicotine dependence for smoking cessation in adults trying to quit cigarette smoking in the first half of 2024. If approved, cytisinicline would be the first FDA-approved, prescription treatment for smoking cessation available in the United States in nearly two decades.

The Phase 3 ORCA-2 trial evaluated 810 adults who smoked cigarettes on a daily basis at 17 clinical trial locations in the United States. The trial was initiated in October 2020 and completed enrollment in June 2021, with topline results reported in April 2022. ORCA-2 participants received 3mg cytisinicline dosed 3 times daily for either 6 or 12 weeks and were monitored through 24 weeks post randomization.

The trial was blinded, placebo-controlled, and all subjects received behavioral support for the duration of the trial. The primary endpoint was biochemically verified continuous abstinence during the last 4 weeks of treatment. Secondary outcome measures assessed continued abstinence rates through 6 months from the start of study treatment.