AXS-05 · program

AXS-05 (dextromethorphan-bupropion) for Agitation in Alzheimer's disease

ApprovedApprovedAxsome Therapeutics, Inc. (AXSM)
  • Breakthrough Therapy
  • Priority Review

Indications for AXS-05: Tobacco use disorder · Phase 2 Agitation in Alzheimer's disease · Approved

FDA approved AUVELITY (AXS-05) on 30 April 2026 for the treatment of agitation associated with dementia due to Alzheimer's disease — the first non-antipsychotic medicine approved for this indication. Developed under FDA Breakthrough Therapy designation (granted 26 Jun 2020) and reviewed under Priority Review. Approval supported by the Phase 2/3 ADVANCE-1 trial (positive, primary CMAI endpoint, P=.010) and the Phase 3 ACCORD-2 relapse-prevention study (statistically significantly longer time to relapse), within a program that also included the Phase 3 ADVANCE-2 (numerically favorable, missed significance) and ACCORD-1 trials and a long-term safety experience of 456 patients. AD agitation is not the lead indication: AXS-05 was first approved for major depressive disorder in 2022. Commercial launch in AD agitation on track for June 2026.

Data current as of

Development timeline

ApprovedApr 2026
  1. metFDA approves AUVELITY (AXS-05) for agitation associated with dementia due to Alzheimer's disease — first non-antipsychotic approved↗
Filed (NDA)Dec 2025
  1. FDA accepted the sNDA for AXS-05 in AD agitation and granted Priority Review with a 30 April 2026 PDUFA date.↗
Phase 3Jun 2020 – Apr 2025
  1. metPhase 3 AXS-05 AD-agitation program complete: ACCORD-2 relapse-prevention positive (HR 0.276, P=.001); ADVANCE-2 supportive but missed primary endpoint↗
  2. FDA granted Breakthrough Therapy designation for AXS-05 in Alzheimer's disease agitation, based on ADVANCE-1.↗
Phase 2/3Apr 2020
  1. Phase 2/3 ADVANCE-1 (NCT03226522) completed; AXS-05 met primary CMAI endpoint vs placebo.

Readouts

  • 2026-04-30ReportedRegulatorymet

    FDA approves AUVELITY (AXS-05) for agitation associated with dementia due to Alzheimer's disease — first non-antipsychotic approved ↗

  • 2025-04-08ReportedTopline datametNCT04947553

    Phase 3 AXS-05 AD-agitation program complete: ACCORD-2 relapse-prevention positive (HR 0.276, P=.001); ADVANCE-2 supportive but missed primary endpoint ↗

Clinical trials in Agitation in Alzheimer's disease

NCT05557409ADVANCE-2Phase 3Completedn=408

ADVANCE-2: A Randomized, Double-blind, Placebo-controlled Trial to Assess the Efficacy and Safety of AXS-05 for the Treatment of Alzheimer's Disease Agitation

Started Sept 2022· Primary completion Nov 2024· 📍 55 sites across 2 countries (United States, Puerto Rico)

missedprimaryCMAI total score change from baseline to Week 5 (AXS-05 vs placebo) — -13.8 points (AXS-05) vs -12.6 (placebo)

Numerically favored AXS-05 but did not reach statistical significance for the primary CMAI endpoint; safety was consistent with prior studies. Reported 8 Apr 2025.

NCT04947553ACCORD-2Phase 3Completedn=456

ACCORD-2: An Open-Label and Double-Blind, Randomized Withdrawal Study to Assess the Long-term Safety and Efficacy of AXS-05 in Subjects With Dementia of the Alzheimer's Type

Started Jun 2021· Primary completion Dec 2024· 📍 47 sites across 3 countries (United States, Canada, Puerto Rico)

metprimaryTime to relapse of agitation (open-label then randomized withdrawal; 26-week double-blind) — Hazard ratio 0.276 (3.6-fold lower relapse risk); 8.4% relapsed on AXS-05 vs 28.6% on placebo (0.001)

Pivotal Phase 3 relapse-prevention study supporting approval: continued AXS-05 produced a statistically significantly longer time to relapse of agitation vs placebo (HR 0.276; P=.001). Reported 8 Apr 2025.

metsecondaryWorsening of overall Alzheimer's severity (CGI-S) — 13.3% worsened on AXS-05 vs 39.3% on placebo (<0.001)

Fewer AXS-05 patients showed worsening of overall Alzheimer's disease severity vs placebo during the randomized-withdrawal period (P<.001).

metexploratoryLong-term safety (up to 12 months, n=456) — AEs 39.9%; falls 3.1% (0.2% drug-related); SAEs 2.6%; no deaths

In 456 patients treated for up to 12 months AXS-05 was well tolerated with no new safety signals; not associated with increased falls, cognitive decline, or sedation.

NCT04797715ACCORD-1Phase 3Completedn=178

ACCORD (Assessing Clinical Outcomes in Alzheimer's Disease Agitation): A Double-blind, Placebo-controlled, Randomized Withdrawal Trial of AXS-05 for Agitation in Dementia of the Alzheimer's Type

Started Dec 2020· Primary completion Nov 2022· 📍 63 sites across 2 countries (United States, Canada)

metprimaryTime to relapse of agitation (randomized-withdrawal design) (0.014)

First (Phase 3) relapse-prevention study with a randomized-withdrawal design; AXS-05 met the primary endpoint of delaying time to agitation relapse vs placebo (P=.014).

NCT03226522ADVANCE-1Phase 2/3Completedn=366

ADVANCE-1: A Randomized, Double-blind, Placebo-controlled Trial of AXS-05 for the Treatment of Agitation in Dementia of the Alzheimer's Type

Started Jul 2017· Primary completion Apr 2020· 📍 78 sites across 2 countries (United States, Australia)

metprimaryCMAI total score change from baseline to Week 5 (AXS-05 vs placebo) — -15.4 points (AXS-05) vs -11.5 (placebo); -10.0 (bupropion arm) (0.010)

AXS-05 produced a statistically significant reduction in CMAI total score vs placebo at Week 5 (~15.4 vs ~11.5 points; P=.010). Pivotal positive trial supporting approval.

Formulations

FormulationRouteRegimenPharmacokinetics
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).
OralTwice dailyt½ 22 h · Tmax 3 h

Mechanism of action (compound-wide)

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.

TargetActionAffinity
NMDA receptorprimaryGRIN1Antagonist—ⓘ
Norepinephrine transporter (NET)SLC6A2Reuptake inhibitor—ⓘ
Serotonin transporter (SERT)SLC6A4Reuptake inhibitor—ⓘ
Sigma-1 receptorSIGMAR1Agonist—ⓘ

← Full AXS-05 compound page (identity, identifiers, all indications)

Sources

  1. ACCORD-2: long-term safety/efficacy of AXS-05 in dementia of the Alzheimer's type (NCT04947553) — ClinicalTrials.gov
  2. ACCORD: randomized-withdrawal trial of AXS-05 for AD agitation (NCT04797715) — ClinicalTrials.gov
  3. ADVANCE-1: AXS-05 for agitation in dementia of the Alzheimer's type (NCT03226522) — ClinicalTrials.gov
  4. ADVANCE-2: AXS-05 for Alzheimer's disease agitation (NCT05557409) — ClinicalTrials.gov
  5. Auvelity (AXS-05) therapeutics profile — AD agitation program, Breakthrough Therapy (26 Jun 2020), trial designs — ALZFORUM
  6. AUVELITY (dextromethorphan hydrobromide, bupropion hydrochloride) extended-release tablets — FDA label — DailyMed / NLM
  7. Axsome announces FDA approval of AUVELITY for agitation associated with dementia due to Alzheimer's disease — Axsome Therapeutics / GlobeNewswire
  8. Axsome announces successful completion and results of the Phase 3 AXS-05 AD-agitation program (ADVANCE-2, ACCORD-2) — Axsome Therapeutics / BioSpace
  9. 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
  10. Compositions and methods for increasing the metabolic lifetime of dextromethorphan (mechanism: NMDA antagonist, sigma-1 agonist, 5-HTT inhibition) — USPTO
  11. FDA grants Priority Review to AXS-05 for AD agitation, sets 30 Apr 2026 PDUFA date — Patient Care Online