FDA Issues CRL for Cytisinicline NDA for Smoking Cessation

Achieve Life Sciences received a Complete Response Letter (CRL) from the United States (US) Food and Drug Administration (FDA) for its New Drug Application (NDA) for cytisinicline as a treatment for nicotine dependence, the company announced June 22, 2026. The CRL cited manufacturing-related observations from an FDA current good manufacturing practice inspection of a third-party facility and incomplete final product labeling by the action date, with no clinical efficacy or safety deficiencies identified by the agency, according to Achieve.¹

“The FDA’s feedback provides a clear and actionable path forward,” said Andrew D. Goldberg, MD, chief executive officer of Achieve. The company said it plans to resubmit the NDA in the fourth quarter of 2026 with a new primary commercial manufacturing partner.

The CRL concerns Achieve’s prior third-party manufacturing facility, which received an Official Action Indicated classification from the FDA for general cGMP matters at the facility, according to the company. Achieve stated these observations were not specific to cytisinicline. The NDA’s Prescription Drug User Fee Act action date was June 20, 2026, and Achieve previously disclosed on April 15, 2026, it expected a CRL before or by this date.¹

Achieve said it had already partnered with US-based Adare Pharma Solutions as its new primary commercial manufacturing partner. The company reported completion of analytical method technology transfer to Adare’s facility, manufacture of a first cytisinicline engineering batch, and qualification of testing procedures at the site. If the resubmission occurs as planned in the fourth quarter of 2026, Achieve said potential FDA approval could occur in the first half of 2027, followed by US commercial launch.¹

The regulatory update leaves the NDA unresolved pending manufacturing and labeling matters. The company’s statement does not include additional FDA correspondence, inspection details, labeling issues, or a firm review timeline after resubmission.

ORCA Phase 3 Data

The cytisinicline NDA is supported by a clinical development program with more than 1500 clinical trial participants exposed to the investigational therapy, according to Achieve. The pivotal phase 3 ORCA-2 and ORCA-3 trials evaluated cytisinicline administered for either 6 or 12 weeks with standard behavioral support compared with placebo. The company reported significantly greater smoking abstinence rates by end of treatment and greater long-term abstinence through week 24 with cytisinicline vs placebo.¹

The press release did not provide abstinence rate estimates, confidence intervals, P values, or subgroup findings from either ORCA trial. Safety data cited by Achieve included more than 400 participants with at least 6 months of cumulative cytisinicline exposure and more than 200 participants with at least 1 year of cumulative exposure. These long-term safety data were previously reported and presented at the American Thoracic Society International Conference in May 2026.¹

From an evidence interpretation standpoint, the CRL as described by Achieve does not appear to challenge the clinical data package, but the NDA remains unapproved while the cited manufacturing and labeling issues are pending. Clinicians will need published trial data and eventual FDA labeling, if approved, to assess dose, duration, contraindications, warnings, and comparative safety in practice.

Cytisinicline Mechanism and Nicotine Dependence Context

Cytisinicline is described by Achieve as a plant-based alkaloid with high binding affinity to nicotinic acetylcholine receptors. The company stated the drug is intended to aid smoking and e-cigarette cessation through interaction with nicotine receptors in the brain, with potential effects on nicotine craving and reward.¹

The immediate regulatory filing is for smoking cessation in adults. Achieve also reported completion of a phase 2 study of cytisinicline in nicotine e-cigarette cessation, an end-of-phase 2 meeting with the FDA, and Breakthrough Therapy designation for the vaping cessation indication. The company noted no FDA-approved treatments are specifically indicated as aids for nicotine e-cigarette cessation.¹

Nicotine dependence remains a major public health burden. A recent report cited by Achieve estimated approximately 25 million US adults smoke combustible cigarettes and nearly 18 million US adults use e-cigarettes.² Among adolescents, 2024 National Youth Tobacco Survey data cited in the press release found approximately 1.6 million US middle and high school students reported current e-cigarette use.³

References

1. Achieve Life Sciences. Achieve Life Sciences receives Complete Response Letter from FDA for cytisinicline NDA. GlobeNewswire. 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. Agaku I. Tobacco product use among US adults, 2023-2024. NEJM Evidence. doi:10.1056/EVIDpha2500339

3. Jamal A, Park-Lee E, Birdsey J, et al. Tobacco product use among middle and high school students—National Youth Tobacco Survey, United States, 2024. MMWR Morb Mortal Wkly Rep. 2024;73:917-924.