FDA Issues CRL for Cytisinicline for Smoking Cessation in Adults

The US Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) for cytisinicline for smoking cessation in adults.¹ The CRL identified manufacturing concerns, with no deficiency in clinical safety or efficacy of the drug.

The CRL response cited outstanding manufacturing-related issues from an inspection of a third-party manufacturing facility, as well as final product labeling that was not completed by the FDA action date. Achieve Life Sciences, developers of the drug, noted that the manufacturing practice issues are not specific to cytisinicline and are related to general manufacturing at the facility. The company intends to resubmit the NDA with updated manufacturing information.

Information originally submitted in the NDA included positive phase 3 trials ORCA-2 and ORCA-3, which showed cytisinicline resulted in significantly higher rates of smoking abstinence compared with placebo.² Trials included over 2000 participants across phase 3 studies, as well as safety data from over 400 participants who received at least 6 months of cumulative cytisinicline exposure, and over 200 participants who received at least 1 year of cumulative exposure. Phase 3 trials used 6 and 12 week courses of 3 mg cytisinicline, along with standard behavioral support, which showed greater rates of abstinence compared with placebo at the end of treatment and at 24 weeks.³ Participant abstinence from smoking was biochemically verified, along with participants completing the Questionnaire of Smoking Urges.

In the ORCA-2 trial, continuous abstinence rates for the 6-week course were 25.3% during weeks 3 to 6 and 8.9% during weeks 3 to 24. For the 12-week course, continuous abstinence rates were 32.6% for weeks 9 to 12 and 21.1% during weeks 9 to 24. ORCA-3 similarly demonstrated Continuous abstinence rates for the 6-week treatment at 6.8% from weeks 3 to 24 and 20.5% for the 12-week treatment in weeks 9 to 24.³ Reduction in craving at week 6 was greater for cytisinicline than placebo. Notably, tolerability was favorable across both trials; the most commonly reported adverse effects were nausea, abnormal dreams, and headache, consistent with the profile observed in earlier studies. No significant neuropsychiatric safety signals were identified, an important consideration given prior concerns with other smoking cessation pharmacotherapies.

“The FDA’s feedback provides a clear and actionable path forward,” said Andrew D Goldberg, MD, chief executive officer of Achieve.¹ “Our clinical data stands on its own: 2 successful phase 3 trials and a robust open-label safety study. As we work with the FDA to resolve these remaining requirements, we are simultaneously advancing our commercial readiness for launch. We remain fully committed to bringing this treatment to the patients who need it.”

In July 2024, cytisinicline was designated a Breakthrough Therapy by the FDA. Achieve Life Sciences then submitted a New Drug Application for cytisinicline in June 2025, which was subsequently approved in September 2025.⁴

Cytisinicline is a plant-derived alkaloid with a high binding affinity to the nicotinic acetylcholine receptor.³ Because of its affinity for this receptor, it is believed to reduce reward and satisfaction associated with nicotine products. As a partial agonist at this receptor, cytisinicline both stimulates low-level dopaminergic activity to reduce withdrawal symptoms and competitively blocks nicotine binding, attenuating the reward reinforcement effects of continued tobacco use. This dual mechanism distinguishes it from nicotine replacement therapies, which supply exogenous nicotine, and from bupropion, which acts primarily through dopaminergic and noradrenergic pathways.

In the smoking cessation prescription space, the most recently approved medication for smoking cessation was varenicline (Chantix) in 2006, making cytisinicline a long-awaited addition.⁵ Prior to varenicline, no medications had been approved for smoking cessation for almost 10 years, since bupropion was approved as Zyban in 1997.⁶ Varenicline's market withdrawal in 2021 due to nitrosamine impurity concerns, and the subsequent reduced availability of generic formulations, left a notable gap in nonnicotine pharmacotherapy options for clinicians.

Developers of cytisinicline shared they have completed transferring production technology to a new commercial manufacturing partner, where a batch of the drug has been successfully manufactured and tested. The company intends to resubmit the NDA in the end of 2026 with updates on primary manufacturing included. A potential FDA decision with these changes could be scheduled for the first half of 2027.

References

1. Achieve Life Sciences receives Complete Response Letter from FDA for cytisinicline NDA. Press release. June 22, 2026. Accessed June 22, 2026. https://ir.achievelifesciences.com/news-events/press-releases/detail/264/achieve-life-sciences-receives-complete-response-letter-from-fda-for-cytisinicline-nda

2. Rigotti NA, Benowitz NL, Prochaska JJ, et al. Cytisinicline for smoking cessation: the ORCA phase 3 replication randomized clinical trial. JAMA Int Med. 2025;185(6):648-655.

3. Rigotti NA, Benowitz NL, Prochaska J, et al. Cytisinicline for smoking cessation: a randomized clinical trial. JAMA. 2023;330(2):152-160.

4. Achieve Life Sciences announces FDA acceptance of cytisinicline New Drug Application for treatment of nicotine dependence for smoking cessation. Press release. September 3, 2025. Accessed June 8, 2026. https://ir.achievelifesciences.com/news-events/press-releases/detail/238/achieve-life-sciences-announces-fda-acceptance-of-cytisinicline-new-drug-application-for-treatment-of-nicotine-dependence-for-smoking-cessation

5. Smoking cessation medicine varenicline receives FDA approval. Oncology. 2006;20(7).

6. Huecker MR, Smiley A, Saadabadi A. Bupropion. National Center for Biotechnology Information. 2024. Accessed June 8, 2026. https://www.ncbi.nlm.nih.gov/books/NBK470212/