Cytisinicline confirmed to be efficacious, well-tolerated in smokers set to quit

Cytisinicline’s efficacy and tolerability for smoking cessation has been validated in another large phase III trial conducted in the US, with both the 6- and 12-week treatments yielding positive benefits persisting through 24 weeks.

Results of the ORCA-3 trial showed that relative to placebo, the odds of achieving the primary outcome of biochemically verified continuous smoking abstinence during the last 4 weeks of treatment increased by about threefold with 6-week cytisinicline treatment (weeks 3–6: 14.8 percent vs 6.0 percent; odds ratio [OR], 2.9, 95 percent confidence interval [CI], 1.5–5.6; p<0.001) and by fourfold with 12-week cytisinicline treatment (weeks 9–12: 30.3 percent vs 9.4 percent; OR, 4.4, 95 percent CI, 2.6–7.3; p<0.001). [JAMA Intern Med 2025;doi:10.1001/jamainternmed.2025.0628]

Likewise, the odds of achieving the secondary outcome of continuous abstinence through week 24 were roughly sixfold higher with the 6-week (weeks 3–24: 6.8 percent vs 1.1 percent; OR, 6.3, 95 percent CI, 1.8–34.6; p<0.001) and the 12-week cytisinicline treatment (weeks 9–24: 20.5 percent vs 4.2 percent; OR, 5.8, 95 percent CI, 2.9–12.4; p<0.001) than with placebo.

These data confirm the results of ORCA-2, “which shared a similar study design but was conducted at different sites,” according to the investigators. [JAMA 2023;330:152-160]

Consistent across both ORCA-3 and ORCA-2 trials, the point-prevalence abstinence rates continued to increase in the 12-week cytisinicline arm throughout the active treatment period, they noted. This suggests that new quitting events consistently occurred beyond week 6, leading to higher tobacco abstinence rates during weeks 9–12.

“Taken together, these results suggest that those who do not quit by weeks 3–6 may benefit from continuing cytisinicline for 12 weeks,” the investigators said.

Craving suppressed

From baseline to week 6, mean craving scores, assessed using the Brief Questionnaire of Smoking Urges, decreased significantly more in the combined cytisinicline arms than in the placebo arm (–15.2 vs −12.0; p<0.001).

“Notably, craving levels were also significantly lower among all randomized participants, including those who continued to smoke while taking cytisinicline, indicating that cytisinicline effectively mitigates cravings even in those who do not quit,” the investigators pointed out.

“Furthermore, cotinine levels corroborated these findings, showing significantly lower cotinine levels among cytisinicline-treated participants who did not quit smoking at 6 or 12 weeks. These reductions suggest that among participants who did not quit, those receiving cytisinicline significantly decreased their smoking,” they added.

The investigators emphasized that cytisinicline has the potential not only to reduce cravings but also to reduce combustible tobacco intake, making it a viable treatment option for people aiming to reduce their intake and, ultimately, quit.

Well tolerated

The percentage of participants who experienced treatment-emergent adverse events (TEAEs) were comparable across the 6- and 12-week cytisinicline and placebo arms. The most common TEAEs were insomnia (11.0 percent, 11.9 percent, 7.6 percent), abnormal dreams (9.1 percent, 7.7 percent, 5.7 percent), nausea (9.5 percent, 6.9 percent, 7.3 percent), and headache (7.6 percent, 8.5 percent, 6.1 percent).

TEAEs led to drug discontinuation in 1.7 percent of participants in the combined cytisinicline arms and in 1.1 percent of those in the placebo arm. Serious TEAEs occurred in 3.1 percent of participants who received cytisinicline and in 3.1 percent of those who received placebo, with none being related to treatment.

“Cytisinicline was well tolerated in both [ORCA-3 and ORCA-2] trials… Adherence to the 6- and 12-week cytisinicline regimes was also high in both trials, with most participants randomized to cytisinicline retained (6-week cytisinicline, 74.0 percent for ORCA-2 and 78.7 percent for ORCA-3; 12-week cytisinicline, 83.3 percent and 80.3 percent, respectively),” the investigators said.

ORCA-3

“Cytisinicline is a plant-based alkaloid that binds selectively to α4β2 neuronal nicotinic acetylcholine receptors, which mediate nicotine dependence… [This drug] holds substantial promise, offering efficacy similar to varenicline but a more favourable adverse effect profile and addressing the limitations of treatments, such as nicotine replacement therapy and bupropion, which have lower efficacy or greater tolerability concerns,” according to the investigators.

ORCA-3 was conducted to confirm the results of ORCA-2, the first large cytisinicline randomized clinical trial conducted in the US, as well as support the cytisinicline application for FDA licensure.

Conducted at 20 clinical trial sites across the US, ORCA-3 included 792 adults (mean age 52 years, 55.4 percent female) who smoked at least 10 cigarettes per day, had expired air carbon monoxide of at least 10 ppm, and were ready to set a date to quit smoking. Exclusion criteria included prior use of cytisinicline; and use of bupropion, varenicline, nortriptyline, or any nicotine replacement product within 4 weeks of randomization or plans to use these medications during the study.

The participants were randomly allocated to the following treatment arms: (1) 3-mg cytisinicline three times daily for 12 weeks, (2) 3-mg cytisinicline three times daily for 6 weeks, followed by 6 weeks of placebo, and (3) placebo for 12 weeks. All participants received 10-min sessions of behavioural support with trained counsellors, starting before randomization and continuing through week 12, followed by shorter sessions at weeks 16, 20, and 24. In total, 79.3 percent of participants completed the trial.