FDA Rejects Cytisinicline NDA for Now, Requests Manufacturing Resolution

Achieve Life Sciences has received a Complete Response Letter (CRL) from the U.S. Food and Drug Administration (FDA) for its New Drug Application (NDA) seeking approval of cytisinicline, an investigational treatment for nicotine dependence.

The FDA’s decision was not related to the clinical performance of cytisinicline. Instead, the agency cited unresolved manufacturing observations identified during a current Good Manufacturing Practice (cGMP) inspection of a former third-party manufacturing facility. The FDA also noted that final product labeling discussions were not completed before the agency’s action date.

The FDA identified no deficiencies concerning the efficacy or safety of cytisinicline, preserving confidence in the drug’s clinical profile and regulatory pathway.

Addressing Nicotine Dependence Gap

Cytisinicline is a plant-derived alkaloid that binds with high affinity to nicotinic acetylcholine receptors in the brain. By partially activating these receptors, the therapy helps reduce nicotine cravings and withdrawal symptoms while lowering the rewarding effects associated with smoking and vaping.

Nicotine addiction remains a significant public health challenge. Approximately 25 million adults in the United States continue to smoke combustible cigarettes, while nearly 18 million adults use e-cigarettes. Tobacco use remains the leading preventable cause of death worldwide, contributing to more than eight million deaths annually.

Currently, no FDA-approved therapies are specifically indicated for e-cigarette cessation, highlighting a growing treatment gap as vaping use continues among both adults and adolescents.

 Phase 3 Program Demonstrated Significant Smoking Abstinence Benefits

The cytisinicline NDA is supported by a comprehensive clinical development program involving more than 1,500 participants.

In the pivotal Phase 3 ORCA-2 (NCT04576949) and ORCA-3 (NCT05206370) studies, participants received either six or twelve weeks of cytisinicline alongside standard behavioral support. The treatment demonstrated significantly higher smoking abstinence rates than placebo at the end of treatment and maintained superior abstinence outcomes through Week 24.

Long-term safety findings further strengthened the application. More than 400 participants accumulated at least six months of cytisinicline exposure, while over 200 participants received at least one year of cumulative treatment. These safety results were presented at the American Thoracic Society International Conference in May 2026 and supported a favorable tolerability profile.

Company Advances New Manufacturing Strategy

The manufacturing observations cited in the CRL relate to Achieve’s previous contract manufacturing partner, which received an Official Action Indicated (OAI) classification for broader cGMP issues unrelated to cytisinicline itself.

To address the issue, Achieve previously selected U.S.-based Adare Pharma Solutions as its primary commercial manufacturing partner. The company has completed analytical method transfer activities, qualified testing procedures, and successfully produced its first cytisinicline engineering batch at the new facility.

Chief Executive Officer Andrew Goldberg, MD, said the FDA’s feedback provides a clear path toward approval and emphasized that the strength of the clinical package remains unchanged.

Path Forward

Achieve plans to resubmit the cytisinicline NDA during the fourth quarter of 2026, naming Adare Pharma Solutions as its primary manufacturing site. If the review proceeds as expected, FDA approval could occur during the first half of 2027, potentially paving the way for the first U.S. commercial launch of cytisinicline for nicotine dependence treatment.

Reference

Achieve Life Sciences Receives Complete Response Letter from FDA for Cytisinicline NDA:: Achieve Life Sciences, Inc. (ACHV)