Treatment with cytisinicline was associated with a greater likelihood of smoking abstinence when compared with placebo, according to topline phase 3 trial results.

Cytisinicline is a plant-based alkaloid that is believed to act as a partial agonist, preventing nicotine from binding to nicotinic acetylcholine receptors and releasing dopamine. Interaction with these receptors is expected to reduce withdrawal symptoms and satisfaction associated with smoking.

The placebo-controlled ORCA-2 study ( Identifier: NCT04576949) evaluated the safety and efficacy of cytisinicline as a treatment for smoking cessation in 810 adult smokers. Patients were randomly assigned (1:1:1) to receive cytisinicline 3mg taken 3 times daily for a period of either 6 or 12 weeks, or placebo. They were then monitored for smoking abstinence for 24 weeks post randomization; behavioral support was provided through the duration of the trial.

The average age of the study participants was 54 years. At baseline, patients smoked on average 20 cigarettes per day. Median smoking history was reported to be 38 years with 4 prior quit attempts.

The primary endpoint of the study was biochemically verified continuous abstinence measured during the last 4 weeks of the treatment period (weeks 3 to 6 or weeks 9 to 12). Smoking abstinence was verified by weekly expired carbon monoxide measurements 10 or less parts per million.

Results showed that both treatment regimens demonstrated significantly better quit rates than placebo. Patients who received 6 weeks of cytisinicline were 8 times more likely to have quit smoking during the last 4 weeks compared with placebo (P <.0001); the abstinence rate during weeks 3 through 6 was 25.3% for cytisinicline and 4.4% for placebo.

Those who received 12 weeks of cytisinicline were 6.3 times more likely to quit smoking during the last 4 weeks of treatment compared with placebo (P <.0001); the abstinence rate during weeks 9 through 12 was 32.6% for cytisinicline and 7.0% for placebo.

“These data confirm that cytisinicline, if approved by the FDA, has the potential to become the first new agent approved in nearly 2 decades and an important treatment option for smoking cessation, which is much needed given the limitations, particularly the significant side effects associated with existing agents,” said John Bencich, CEO of Achieve Life Sciences.

Insomnia, abnormal dreams, headaches, and nausea were the most commonly reported adverse events during the trial.

Cytisinicline is also being evaluated in the phase 3 ORCA-3 trial ( Identifier: NCT05206370), which will include 750 adult smokers.


Achieve Life Sciences announces successful, statistically significant smoking cessation results in phase 3 ORCA-2 clinical trial of cytisinicline in adult smokers. News release. April 27, 2022.