AXS-05 · program
AXS-05 (dextromethorphan-bupropion) for Tobacco use disorder
Indications for AXS-05: Tobacco use disorder · Phase 2 Agitation in Alzheimer's disease · Approved
AXS-05 (dextromethorphan-bupropion) is in development for smoking cessation / tobacco use disorder, positioned as a novel NMDA-receptor-antagonist (glutamatergic) mechanism for nicotine dependence. A completed, positive Phase 2 investigator-initiated trial (NCT03471767), run with Duke University (PI James Davis) and Axsome as collaborator, met its primary endpoint: over a 3-week assessment AXS-05 reduced cigarettes per day by 8.49 vs 6.79 for bupropion (a 25% greater reduction; P=.0016), announced 15 Apr 2019. This is not the lead indication — AXS-05 was first approved for major depressive disorder (2022) and for Alzheimer's disease agitation (Apr 2026). Axsome plans to initiate a pivotal Phase 2/3 trial of AXS-05 in smoking cessation in Q2 2026 (per the Q4/full-year 2025 business update, 23 Feb 2026); that pivotal study is not yet initiated or registered.
Development timeline
- UpcomingAxsome plans to initiate a pivotal Phase 2/3 trial of AXS-05 in smoking cessation in Q2 2026↗
- Per the Q4/full-year 2025 business update, Axsome plans to initiate a pivotal Phase 2/3 trial of AXS-05 in smoking cessation in Q2 2026 (not yet initiated).↗
- metAXS-05 meets primary endpoint in Phase 2 smoking-cessation trial: 25% greater reduction in cigarettes/day vs bupropion (P=.0016)↗
- Phase 2 investigator-initiated smoking-behavior trial (NCT03471767; Duke University, PI James Davis; Axsome collaborator) completed (primary completion 31 Mar 2019).
Readouts
- Pivotal Phase 2/3 initiation Q2 2026AnticipatedRegistry results
Axsome plans to initiate a pivotal Phase 2/3 trial of AXS-05 in smoking cessation in Q2 2026 ↗
- 2019-04-15ReportedTopline datametNCT03471767
AXS-05 meets primary endpoint in Phase 2 smoking-cessation trial: 25% greater reduction in cigarettes/day vs bupropion (P=.0016) ↗
Clinical trials in Tobacco use disorder
NCT03471767Phase 2Completedn=58
A Randomized, Double-Blind 4-Week Study to Evaluate the Impact of AXS-05 on Smoking Behavior
mixedsecondaryPercentage of participants with >50% reduction in expired carbon monoxide (CO) — 52.0% (AXS-05) vs 30.4% (bupropion) (0.15)
Secondary biochemical endpoint numerically favored AXS-05 (52.0% vs 30.4% achieving >50% expired-CO reduction) but did not reach statistical significance (P=.15).
metprimaryChange in smoking intensity (cigarettes per day) from baseline to Week 3, AXS-05 vs bupropion — AXS-05 -8.49 cigarettes/day vs bupropion -6.79 cigarettes/day (25% greater reduction) (0.0016)
Primary endpoint met: AXS-05 (45 mg dextromethorphan/105 mg bupropion BID, n=31) produced a 25% greater reduction in cigarettes smoked per day vs bupropion SR (105 mg BID, n=27) over the 3-week assessment (P=.0016). Announced 15 Apr 2019.
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| Auvelity extended-release tablet (dextromethorphan HBr / bupropion HCl)multilayer extended-release tablet; bupropion (CYP2D6 inhibitor) boosts oral bioavailability of dextromethorphan Two strengths: dextromethorphan HBr 45 mg / bupropion HCl 105 mg and dextromethorphan HBr 30 mg / bupropion HCl 105 mg. Start one 45/105 mg tablet once daily in the morning; after 3 days increase to one tablet twice daily, at least 8 hours apart (max recommended dosage). | Oral | Twice daily | t½ 22 h · Tmax 3 h |
Mechanism of action
Dextromethorphan, the active CNS moiety, is an uncompetitive NMDA receptor antagonist and sigma-1 receptor agonist that also inhibits the serotonin and norepinephrine transporters; bupropion is a norepinephrine-dopamine reuptake inhibitor (NDRI) that, as a CYP2D6 inhibitor, slows dextromethorphan metabolism to raise and sustain its exposure. The exact mechanism for the treatment of Alzheimer's disease agitation is not fully established.
| Target | Action | Affinity |
|---|---|---|
| NMDA receptorprimaryGRIN1 | Antagonist | —ⓘ |
| Norepinephrine transporter (NET)SLC6A2 | Reuptake inhibitor | —ⓘ |
| Serotonin transporter (SERT)SLC6A4 | Reuptake inhibitor | —ⓘ |
| Sigma-1 receptorSIGMAR1 | Agonist | —ⓘ |
← Full AXS-05 compound page (identity, identifiers, all indications)
Sources
- A Randomized, Double-Blind 4-Week Study to Evaluate the Impact of AXS-05 on Smoking Behavior (NCT03471767) — ClinicalTrials.gov
- AUVELITY (dextromethorphan hydrobromide, bupropion hydrochloride) extended-release tablets — FDA label — DailyMed / NLM
- Axsome announces FDA approval of AUVELITY for agitation associated with dementia due to Alzheimer's disease — Axsome Therapeutics / GlobeNewswire
- Axsome Therapeutics Announces AXS-05 Achieves Primary Endpoint in Phase 2 Trial in Smoking Cessation — Axsome Therapeutics / GlobeNewswire
- Axsome Therapeutics Reports Fourth Quarter and Full Year 2025 Financial Results and Provides Business Update (smoking-cessation pivotal Phase 2/3 planned Q2 2026) — Axsome Therapeutics (GlobeNewswire)
- Clinical Profile of AXS-05 in Treating Alzheimer's Disease Agitation: Results from the Phase 2/3 Development Program — Alzheimer's & Dementia (Cummings et al., 2024) / PMC
- Compositions and methods for increasing the metabolic lifetime of dextromethorphan (mechanism: NMDA antagonist, sigma-1 agonist, 5-HTT inhibition) — USPTO