Updated results from ORCA-3 phase III trial evaluating cytisinicline for smoking cessation.- Achieve Life Sciences, Inc

Achieve Life Sciences, Inc. , a late-stage specialty pharmaceutical company focused on the global development and commercialization of cytisinicline as a treatment of  nicotine dependence for smoking cessation, announced that complete trial results from its ORCA-3 were published in the Journal of the American Medical Association (JAMA) Internal Medicine. ORCA-3 was the second randomized, placebo-controlled Phase III clinical trial evaluating cytisinicline for smoking cessation in 792 U.S. adults. The authors concluded that ORCA-3 reaffirms cytisinicline’s efficacy and tolerability for smoking cessation in adult smokers at both 6- and 12-week treatment durations, including reduction in nicotine cravings and extended cessation benefits through 24 weeks.

In addition to previously reported topline results announced in May 2023, the published completed trial results provided further evidence of cytisinicline’s highly targeted effect on treating nicotine dependence by binding to specific nicotine receptors. These consistent results, now published from two large, randomized PhaseIII trials, demonstrated that cytisinicline significantly reduced nicotine cravings and increased the likelihood of quitting smoking. In clinical trials, cytisinicline was well tolerated, which is thought to be due to limited other off-target binding effects that can result in side effects known to be associated with currently available treatments. Similar to the first Phase III trial, ORCA-3 participants had an average age of 53 years, smoked a median of 20 cigarettes per day at baseline, and had a median smoking history of 36 years with four prior quit attempts.

“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,” said Cindy Jacobs, MD, PhD, President and Chief Medical Officer of Achieve Life Sciences. “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.”

Results from the ORCA-3 study show that cytisinicline significantly increased the odds of smoking cessation compared to placebo. Cytisinicline also reduced nicotine craving which led to decreased nicotine intake, even among those who continued smoking, as evidenced by both lower craving scores and reduced cotinine levels, a well-known metabolite of nicotine.

“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,” said Nancy Rigotti, MD, Professor of Medicine at Harvard Medical School, Director of Tobacco Research and Treatment Center, Massachusetts General Hospital, and ORCA Program Investigator. “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 plans to submit the cytisinicline New Drug Application (NDA) to the FDA in June 2025.

About ORCA-3
The Phase III ORCA-3 trial evaluated 792 adults who smoked cigarettes daily and was conducted at 20 clinical trial locations in the U.S. The trial was initiated in January 2022 and completed enrollment in September 2022, with topline results reported in May 2023. ORCA-3 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 four weeks of treatment. Secondary outcome measures assessed continued abstinence rates through 6 months from the start of study treatment. The full manuscript is published in Journal of the American Medical Association (JAMA) Internal Medicine.

Citation : April 21, 2025- Cytisinicline for Smoking CessationThe ORCA Phase III Replication Randomized Clinical Trial; Nancy A. Rigotti, MD; Neal L. Benowitz, MD; Judith J. Prochaska, PhD, MPH; et alMark Rubinstein, MD; Anthony Clarke, PhD; Brent Blumenstein, PhD; Daniel F. Cain, BSc; Cindy Jacobs, PhD, MD. JAMA Intern Med. Published online April 21, 2025. doi:10.1001/jamainternmed.2025.0628.