FDA Issues CRL to Cytisinicline for Smoking Cessation

Achieve Life Sciences received a Complete Response Letter (CRL) from the US Food and Drug Administration (FDA) for its New Drug Application (NDA) for cytisinicline, a plant-derived nicotinic acetylcholine receptor partial agonist under review for smoking cessation in adults.¹ The Agency identified no deficiencies in clinical efficacy or safety; the CRL cites outstanding current Good Manufacturing Practice (cGMP) observations at a third-party manufacturing facility and incomplete final product labeling.¹

The CRL does not reflect new questions about cytisinicline's clinical evidence package, which includes a pair of successful phase 3 trials and a long-term open-label safety study. Smoking cessation remains one of the highest-yield interventions in primary care, yet available pharmacotherapy options have seen limited expansion in nearly 2 decades; varenicline (Chantix) and bupropion have remained the dominant prescription options since the mid-2000s.²

“The FDA’s feedback provides a clear and actionable path forward,” Andrew Goldberg, MD, Chief Executive Officer of Achieve, said in a statement. “Our clinical data stands on its own: two 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.”

Cytisinicline Efficacy in ORCA-2 and ORCA-3

The NDA rests on data from the ORCA-2 and ORCA-3 trials, both double-blind, randomized, placebo-controlled phase 3 studies conducted across multiple US sites. Participants received cytisinicline 3 mg three times daily for either 6 or 12 weeks alongside behavioral support, or placebo for 12 weeks.

In the trials, cytisinicline administered for either 6 or 12 weeks, alongside standard behavioral support, demonstrated significantly greater smoking abstinence rates by the end of treatment and in long-term abstinence through week 24 compared to placebo. This long-term safety data was previously reported and presented at the American Thoracic Society (ATS) International Conference in May 2026.

Cytisinicline Safety Profile and ICER Comparative Assessment

Safety data supporting the NDA include more than 1500 participants with cytisinicline exposure across the clinical program, with more than 400 participants receiving at least 6 months of cumulative exposure and over 200 receiving at least one year.¹ No treatment-related serious adverse events were reported in the pivotal trials. The most commonly reported adverse effects across both cytisinicline arms and placebo were insomnia, abnormal dreams, headache, and nausea.³

The tolerability profile has drawn attention in the context of comparisons with varenicline. A December 2025 analysis from the Institute for Clinical and Economic Review (ICER) found cytisinicline to have similar efficacy to varenicline with significantly fewer gastrointestinal side effects, rating cytisinicline as at least as good and possibly somewhat better than varenicline on net health benefit.

For primary care physicians managing patients who previously discontinued varenicline due to GI tolerability concerns, this differentiation may carry clinical relevance once cytisinicline reaches the market. A Cochrane network meta-analysis of more than 300 trials identified cytisine (the parent compound of cytisinicline) alongside varenicline as among the most effective options for long-term smoking abstinence.

The CRL pertains specifically to observations at Achieve's prior third-party manufacturing partner, which received an Official Action Indicated classification for general cGMP matters unrelated to cytisinicline.¹ Achieve has partnered with Adare Pharma Solutions, a US-based contract manufacturer, as its new primary commercial manufacturer, completing analytical method technology transfer, a first engineering batch, and full qualification of testing procedures.¹

The company intends to resubmit the NDA in Q4 2026, with a potential approval window in the first half of 2027.¹ Cytisinicline also holds FDA Breakthrough Therapy designation for nicotine e-cigarette cessation, an indication for which no approved pharmacotherapy currently exists.¹

References

1. Achieve Life Sciences, Inc. Achieve Life Sciences receives Complete Response Letter from FDA for cytisinicline NDA. Published June 22, 2026. Accessed June 22, 2026. https://www.globenewswire.com/news-release/2026/06/22/3315277/0/en/achieve-life-sciences-receives-complete-response-letter-from-fda-for-cytisinicline-nda.html

2. Institute for Clinical and Economic Review. Cytisinicline is effective for smoking cessation. Published December 11, 2025. Accessed June 22, 2026. https://icer.org/news-insights/press-releases/institute-for-clinical-and-economic-review-publishes-evidence-report-on-medication-for-smoking-cessation/

3. Rigotti NA, et al. Cytisinicline for smoking cessation: ORCA-2. JAMA. 2023. doi:10.1001/jama.2023.11450

4. Rigotti NA, et al. Cytisinicline for smoking cessation in adults: the ORCA-3 randomized clinical trial. JAMA Intern Med. 2025. doi:10.1001/jamainternmed.2025.0546