FDA Issues Complete Response Letter for Cytisinicline NDA, Citing Manufacturing Deficiencies

The FDA has issued a complete response letter (CRL) for Achieve Life Sciences' new drug application (NDA) for cytisinicline for smoking cessation, citing deficiencies at a third-party manufacturing facility rather than concerns about the drug's efficacy or clinical safety.¹

Why Did the FDA Issue a CRL for Cytisinicline?

The CRL relates to outstanding manufacturing observations from a current Good Manufacturing Practice (cGMP) inspection of a prior third-party manufacturing partner, which received an Official Action Indicated classification for general cGMP matters at the facility not specific to cytisinicline. The FDA also cited incomplete final product labeling as of the agency's action date. No deficiencies in clinical efficacy or safety were identified.

What Is Achieve Life Sciences' Plan to Resubmit the Cytisinicline NDA?

The company had anticipated the CRL. In an April 15, 2026, disclosure, Achieve indicated it expected to receive the letter on or before its June 20, 2026, Prescription Drug User Fee Act date and had already transitioned to a new US-based contract manufacturer, Adare Pharma Solutions. Achieve has since completed analytical method technology transfer to Adare's facility, successfully manufactured its first cytisinicline engineering batch, and fully qualified all testing procedures at the site.

Achieve plans to resubmit its NDA in the fourth quarter of 2026, naming Adare as its primary manufacturing partner, with potential FDA approval targeted for the first half of 2027, to be followed by US commercial launch.

"The FDA's feedback provides a clear and actionable path forward," Andrew D. Goldberg, MD, CEO of Achieve, said in a statement. "Our clinical data stands on its own: 2 successful phase 3 trials and a robust open-label safety study."

What Clinical Evidence Supports Cytisinicline for Smoking Cessation?

The NDA rests on the ORCA-2 (NCT04576949) and ORCA-3 (NCT05206370) phase 3 trials, which enrolled more than 2000 adult smokers seeking to quit.² Participants received placebo or cytisinicline for 6 or 12 weeks with behavioral support; both durations significantly outperformed placebo on abstinence.

In ORCA-3, 14.8% of the 6-week group were abstinent during weeks 3 to 6 vs 6% on placebo, while 30.3% of the 12-week group were abstinent during weeks 9 to 12 vs 9.4% on placebo. Continuous abstinence through 24-week follow-up reached 6.8% and 20.5%, respectively, and cytisinicline significantly reduced nicotine cravings vs placebo.

The NDA's safety package leans heavily on ORCA-OL (NCT06435221), an open-label trial extending well beyond the pivotal trials' 6- and 12-week windows.³ Achieve presented the completed ORCA-OL dataset at the American Thoracic Society 2026 Annual Meeting, calling it the final piece of the NDA's evidence package.

ORCA-OL enrolled 475 adults who smoked, vaped, or both, dosing cytisinicline 3 mg 3 times daily for up to 52 weeks (median duration: 361 days), the first long-term cytisinicline safety study to include e-cigarette users.

Among participants, 66.3% had a treatment-emergent adverse event (AEs), although most were judged unrelated to the drug, and 94.8% were mild or moderate. Serious AEs occurred in 6.5% of participants, and only 5.7% discontinued due to a drug-related event. The most common AEs were abnormal dreams and insomnia (8.4% each) and upper respiratory infection (6.7%). Nausea, a frequent reason patients abandon other cessation drugs, occurred in just 2.5% of participants, consistent with phase 3 rates, and an independent safety committee found no new safety signals.

What Is Cytisinicline, and What Unmet Need Does It Address?

Cytisinicline is a plant-based alkaloid that binds to nicotinic acetylcholine receptors.¹ It is believed to aid smoking and e-cigarette cessation by reducing nicotine craving severity and diminishing the reward associated with nicotine use. The drug also holds an FDA breakthrough therapy designation for nicotine e-cigarette cessation, an indication for which no approved treatments currently exist. Approximately 25 million US adults smoke combustible cigarettes, and nearly 18 million use e-cigarettes, underscoring the unmet need the drug is intended to address.⁴

References

1. Achieve Life Sciences receives Complete Response Letter from FDA for cytisinicline NDA. News release. Achieve Life Sciences Inc. June 22, 2026. Accessed June 22, 2026. https://achievelifesciences.com/achieve-receives-complete-response-letter-from-fda-for-cytisinicline-nda/
2. Walters J. FDA accepts new drug application for cytisinicline for smoking cessation. Psychiatric Times^®. September 3, 2025. Accessed June 22, 2026. https://www.psychiatrictimes.com/view/fda-accepts-new-drug-application-for-cytisinicline-for-smoking-cessation
3. Achieve Life Sciences presents safety data from 52 weeks of continuous cytisinicline treatment. News release. Achieve Life Sciences Inc. May 19, 2026. Accessed June 22, 2026. https://www.globenewswire.com/news-release/2026/05/19/3297888/0/en/achieve-life-sciences-presents-safety-data-from-52-weeks-of-continuous-cytisinicline-treatment.html
4. Agaku I. Tobacco product use among U.S. adults, 2023-2024. NEJM Evid. 2026;5(4):EVIDpha2500339. doi:10.1056/EVIDpha2500339