First Patient Dosed in Phase 3 SUMMIT Trial of AXS-05 for Smoking Cessation

Axsome Therapeutics today announced that the first patient has been dosed in the SUMMIT phase 3 trial of AXS-05 (dextromethorphan-bupropion) for smoking cessation.¹ AXS-05 is a novel, oral, investigational N-methyl-D-aspartate (NMDA) receptor antagonist, sigma-1 agonist, and aminoketone CYP2D6 inhibitor.

In the SUMMIT (Studying NMDA and Sigma-1 in Smoking Cessation Treatment) randomized, double-blind, active- and placebo-controlled, multicenter trial, investigators will assess the efficacy and safety of AXS-05 as a smoking cessation treatment in adults. Active smokers will be randomly assigned in a 1:1:1 ratio to receive AXS-05, bupropion, or placebo for approximately 12 weeks. The primary endpoint will be smoking abstinence at the end of the 12-week treatment period. Additional trial sites are expected to begin enrollment following the first dosing.

This move to investigate AXS-05 for smoking cessation comes as the field has seen mixed regulatory news this year. Cytisinicline, another nicotinic agent in development for smoking cessation, received a Complete Response Letter from the US Food and Drug Administration (FDA) in June 2026 over manufacturing rather than efficacy concerns, showing that clinical benefit alone does not guarantee approval in this indication.² AXS-05's dual NMDA/sigma-1 mechanism differs from nicotinic-receptor-targeted approaches like cytisinicline and varenicline, positioning it as a mechanistically distinct entrant if SUMMIT data prove supportive.

Smoking in the US

In the US, there are approximately 34 million adults who smoke cigarettes and more than 50% of those individuals have a smoking-related disease.³ Smoking is the single largest cause of preventable disease in the US, accounting for 1 in 5 deaths.⁴ The overall cost of smoking exceeds $300 billion annually in the US making it a significant health-economic need. Nearly 70% of adult smokers say they want to quit but only 3% to 5% who attempt to quit without assistance are successful for 6 to 12 months.⁵

Other Uses of AXS-05

AXS-05 (Auvelity) is already currently approved by the FDA for the treatment of major depressive disorder in adults and agitation associated with dementia due to Alzheimer disease.⁶ AXS-05 is not yet approved by the FDA as a smoking cessation treatment. AXS-05 is covered by a robust patent estate extending out to at least 2043.

References

1. Axsome Therapeutics initiates SUMMIT phase 3 trial of AXS-05 in smoking cessation. News release. August 31, 2026. Accessed August 31, 2026. https://www.globenewswire.com/news-release/2026/08/31/3353172/33090/en/axsome-therapeutics-initiates-summit-phase-3-trial-of-axs-05-in-smoking-cessation.html

2. Walters J. FDA issues CRL for cytisinicline for smoking cessation in adults. Psychiatric Times. June 22, 2026. https://www.psychiatrictimes.com/view/fda-issues-crl-for-cytisinicline-for-smoking-cessation-in-adults

3. Smoking Cessation: A Report of the Surgeon General. CDC. May 15, 2024. Accessed August 31, 2026. https://www.cdc.gov/tobacco-surgeon-general-reports/reports/2020-smoking-cessation/index.html

4. Tobacco-related mortality. CDC. Accessed August 31, 2026. https://archive.cdc.gov/www_cdc_gov/tobacco/data_statistics/fact_sheets/health_effects/tobacco_related_mortality/index.htm

5. Hughes JR, Keely J, Naud S. Shape of the relapse curve and long-term abstinence among untreated smokers. Addiction. 2003;99(1):29-38.

6. Kuntz L. FDA approves Auvelity for treatment of agitation in Alzheimer disease. Psychiatric Times. April 30, 2026. https://www.psychiatrictimes.com/view/fda-approves-auvelity-for-treatment-of-agitation-in-alzheimer-disease