Small Molecule · AXS-05

AXS-05 (dextromethorphan-bupropion)

Phase 2Axsome Therapeutics, Inc. (AXSM)

Oral, fixed-dose combination of dextromethorphan (45 mg) and bupropion (105 mg). Dextromethorphan is the active CNS moiety — an uncompetitive NMDA receptor antagonist and sigma-1 receptor agonist (with serotonin/norepinephrine transporter inhibition); bupropion (an aminoketone NDRI) acts as a CYP2D6 inhibitor that slows dextromethorphan first-pass metabolism, raising and sustaining its plasma exposure. Marketed as AUVELITY. First approved for major depressive disorder (2022); FDA-approved 30 Apr 2026 for agitation associated with dementia due to Alzheimer's disease — the first non-antipsychotic approved for this indication.

Also known as: AXS-05, Auvelity, dextromethorphan-bupropion, dextromethorphan hydrobromide / bupropion hydrochloride

Data current as of

Key facts

Modality
Small molecule
Chemical class
morphinan, Aminoketone
DEA schedule
Unscheduled
Mechanism
NMDA receptor antagonist
Highest phase
Approved
Lead indication
Tobacco use disorder
Developer
Axsome Therapeutics, Inc. (AXSM)
Designations
Breakthrough Therapy, Priority Review
Trials
5 tracked · 244 sites

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.

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

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

Development timeline#

2020202220242026TodayPhase 214 Aug 2026 — readout (met) — Pivotal Phase 3 smoking-cessation trial of AXS-05 (NCT07766655) registered and recruiting14 Aug 2026 — Trial registered — Pivotal Phase 3 smoking-cessation trial of AXS-05 registered (NCT07766655) and recruiting23 Feb 2026 — phase change — 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).15 Apr 2019 — readout (met) — AXS-05 meets primary endpoint in Phase 2 smoking-cessation trial: 25% greater reduction in cigarettes/day vs bupropion (P=.0016)31 Mar 2019 — phase change — Phase 2 investigator-initiated smoking-behavior trial (NCT03471767; Duke University, PI James Davis; Axsome collaborator) completed (primary completion 31 Mar 2019).Phase 2/317 Apr 2020 — phase change — Phase 2/3 ADVANCE-1 (NCT03226522) completed; AXS-05 met primary CMAI endpoint vs placebo.Phase 38 Apr 2025 — readout (met) — Phase 3 AXS-05 AD-agitation program complete: ACCORD-2 relapse-prevention positive (HR 0.276, P=.001); ADVANCE-2 supportive but missed primary endpoint26 Jun 2020 — phase change — FDA granted Breakthrough Therapy designation for AXS-05 in Alzheimer's disease agitation, based on ADVANCE-1.Filed (NDA)30 Dec 2025 — phase change — FDA accepted the sNDA for AXS-05 in AD agitation and granted Priority Review with a 30 April 2026 PDUFA date.Approved30 Apr 2026 — readout (met) — FDA approves AUVELITY (AXS-05) for agitation associated with dementia due to Alzheimer's disease — first non-antipsychotic approved30 Apr 2026 — FDA approval — FDA approves AUVELITY (AXS-05) for agitation associated with dementia due to Alzheimer's disease
Phase change Readout Event UpcomingHover a marker for details.
Phase 2Mar 2019 – Aug 2026
  1. metPivotal Phase 3 smoking-cessation trial of AXS-05 (NCT07766655) registered and recruitingTobacco use disorder
  2. Trial registeredPivotal Phase 3 smoking-cessation trial of AXS-05 registered (NCT07766655) and recruitingTobacco use disorder
  3. 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).Tobacco use disorder↗
  4. metAXS-05 meets primary endpoint in Phase 2 smoking-cessation trial: 25% greater reduction in cigarettes/day vs bupropion (P=.0016)Tobacco use disorder↗
  5. Phase 2 investigator-initiated smoking-behavior trial (NCT03471767; Duke University, PI James Davis; Axsome collaborator) completed (primary completion 31 Mar 2019).Tobacco use disorder
ApprovedApr 2026
  1. metFDA approves AUVELITY (AXS-05) for agitation associated with dementia due to Alzheimer's disease — first non-antipsychotic approvedAgitation in Alzheimer's disease↗
  2. FDA approvalFDA approves AUVELITY (AXS-05) for agitation associated with dementia due to Alzheimer's diseaseAgitation in Alzheimer's disease↗
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.Agitation in Alzheimer's disease↗
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 endpointAgitation in Alzheimer's disease↗
  2. FDA granted Breakthrough Therapy designation for AXS-05 in Alzheimer's disease agitation, based on ADVANCE-1.Agitation in Alzheimer's disease↗
Phase 2/3Apr 2020
  1. Phase 2/3 ADVANCE-1 (NCT03226522) completed; AXS-05 met primary CMAI endpoint vs placebo.Agitation in Alzheimer's disease

AXS-05 (dextromethorphan-bupropion) for Tobacco use disorder#

Phase 2ActiveTobacco use disorder indication →

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.

Readouts

  • 2026-08-14ReportedRegistry resultsmet

    Pivotal Phase 3 smoking-cessation trial of AXS-05 (NCT07766655) registered and recruiting

  • 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) ↗

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

ApprovedApprovedAgitation in Alzheimer's disease indication →

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.

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#

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 StatesPuerto 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 StatesCanadaPuerto 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.

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.

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).

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 StatesCanada

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).

NCT03471767Phase 2Completedn=58

A Randomized, Double-Blind 4-Week Study to Evaluate the Impact of AXS-05 on Smoking Behavior

Started Mar 2018· Primary completion Mar 2019· 1 site across 1 country

United States

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.

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).

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 StatesAustralia

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.

Conference coverage#

AXS-05 appears in 5 CNS Pulse conference abstracts:

Sources#

  1. A Randomized, Double-Blind 4-Week Study to Evaluate the Impact of AXS-05 on Smoking Behavior (NCT03471767) — ClinicalTrials.gov
  2. A Randomized, Double-Blind, Placebo and Active-Controlled Trial to Evaluate the Efficacy and Safety of AXS-05 for Smoking Cessation in Adults — ClinicalTrials.gov
  3. ACCORD-2: long-term safety/efficacy of AXS-05 in dementia of the Alzheimer's type (NCT04947553) — ClinicalTrials.gov
  4. ACCORD: randomized-withdrawal trial of AXS-05 for AD agitation (NCT04797715) — ClinicalTrials.gov
  5. ADVANCE-1: AXS-05 for agitation in dementia of the Alzheimer's type (NCT03226522) — ClinicalTrials.gov
  6. ADVANCE-2: AXS-05 for Alzheimer's disease agitation (NCT05557409) — ClinicalTrials.gov
  7. Auvelity (AXS-05) therapeutics profile — AD agitation program, Breakthrough Therapy (26 Jun 2020), trial designs — ALZFORUM
  8. AUVELITY (dextromethorphan hydrobromide, bupropion hydrochloride) extended-release tablets — FDA label — DailyMed / NLM
  9. Axsome announces FDA approval of AUVELITY for agitation associated with dementia due to Alzheimer's disease — Axsome Therapeutics / GlobeNewswire
  10. Axsome announces successful completion and results of the Phase 3 AXS-05 AD-agitation program (ADVANCE-2, ACCORD-2) — Axsome Therapeutics / BioSpace
Show all 16 sources
  1. Axsome Therapeutics Announces AXS-05 Achieves Primary Endpoint in Phase 2 Trial in Smoking Cessation — Axsome Therapeutics / GlobeNewswire
  2. Axsome Therapeutics Announces FDA Approval of AUVELITY for the Treatment of Agitation Associated with Dementia due to Alzheimer's Disease (8-K Ex-99.1) — Axsome Therapeutics
  3. 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)
  4. 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
  5. Compositions and methods for increasing the metabolic lifetime of dextromethorphan (mechanism: NMDA antagonist, sigma-1 agonist, 5-HTT inhibition) — USPTO
  6. FDA grants Priority Review to AXS-05 for AD agitation, sets 30 Apr 2026 PDUFA date — Patient Care Online