FDA Approves AXS-05 as New Treatment for Alzheimer Disease Agitation

According to a new announcement, the FDA has approved Axsome Therapeutics’ AXS-05, an investigational, orally administered combination of dextromethorphan HBr and bupropion HCI, as a treatment for agitation in patients with dementia due to Alzheimer disease (AD). Marketed as Auvelity, the drug is the second FDA-approved treatment specific to treat agitation symptoms patients with AD.¹

AXS-05 is an oral N-methyl-D-aspartate receptor antagonist, sigma-1 receptor agonist and aminoketone CYP2D6 inhibitor that was previously approved in 2022 under the same brand name as a treatment for major depressive disorder in adults.²

“Agitation is highly prevalent in patients with Alzheimer’s disease and among the most burdensome aspects of the disease for patients and families. Alzheimer’s disease agitation is associated with accelerated cognitive decline, placement in assisted living and long-term care facilities, and increased mortality risk,” Jeffrey Cummings, MD, ScD, Chambers-Grundy Professor of Brain Sciences, UNLV Kirk Kerkorian School of Medicine, said in a statement.¹ “Treatment for agitation associated with Alzheimer disease dementia has been a critical unmet medical need. The approval of Auvelity for this condition has the potential to play an important role in patient care for this challenging and impactful symptom of Alzheimer disease.”

AXS-05 exerts its effects through dual activity on the NMDA receptor and sigma-1 receptor via its dextromethorphan component, while bupropion functions as a CYP2D6 inhibitor to increase dextromethorphan exposure; however, its exact mechanism in treating agitation associated with dementia because of AD remains unclear. To support patient access, the Auvelity OnMySide™ program will be available at launch, offering services such as a savings card for eligible commercially insured patients, medication samples, prior authorization assistance, and additional support resources.

Prior to AXS-05, the only FDA-approved therapy for AD agitation was brexpiprazole (Rexulti), a serotonin-dopamine activity modulator. Brexpiprazole, an antipsychotic, gained FDA greenlight in 2023 based on several trials in patients with AD agitation. To date, it carries a boxed warning for increased mortality in elderly patients with dementia-related psychosis.

“Agitation in patients with dementia due to Alzheimer disease is distressful, consequential, and challenging for patients, their caregivers and healthcare providers. Auvelity is the only FDA-approved product to result in a statistically significantly longer time to relapse of agitation symptoms, compared to placebo, in a long-term study,” George Grossberg, MD, professor and director of the division of Geriatric Psychiatry at the Saint Louis University School of Medicine, said in a statement.¹ “Importantly, Auvelity showed a compelling safety and tolerability profile, with rates of discontinuation due to adverse events that were low and matched those of placebo. The approval of Auvelity is a significant advancement that provides patients and their caregivers with a much-needed treatment option for this debilitating condition.”

AXS-05 should be taken exactly as prescribed by a health care provider, with dosing gradually increased over time depending on the indication and patient tolerability. For agitation associated with AD, patients start with 30 mg/105 mg once daily for 7 days, increase to twice daily on Day 8, and may reach the maximum dose of 45 mg/105 mg twice daily by Day 15 based on tolerability. Tablets should be swallowed whole and not crushed or split, missed doses should not be doubled, and patients should not adjust or discontinue therapy without consulting their healthcare provider.

The supplemental new drug application (sNDA) for AXS-05 was supported by 4 randomized, double-blind trials: ADVANCE-1 (NCT03226522), ADVANCE-2 (NCT05557409), ACCORD-1 (NCT04797715), and ACCORD-2 (NCT04947553). ACCORD-2 and ADVANCE-2, the most notable of the studies, included 167 and 408 patients, respectively, testing the efficacy and safety of AXS-05 in AD agitation.³

In the open-label lead-in phase of ACCORD-2, 295 patients received AXS-05 for up to 12 months prior to randomization. By week 6, treatment was associated with a mean reduction of 20.4 points in Cohen Mansfield Agitation Inventory (CMAI) total score, representing a 46% decrease from baseline, with 69% of patients achieving a clinical response defined as at least a 30% reduction. Improvements in agitation were reported by 78% of participants on the modified Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change scale, while between 71% and 78% reported improvement on the Patient Global Impression of Change scale from weeks 4 through 8. Among those treated for at least 8 weeks, 70% achieved sustained clinical responses and subsequently advanced to the double-blind phase.⁴

Following this period, ACCORD-2 transitioned into a 26-week, double-blind, placebo-controlled randomized withdrawal phase. In this portion of the study, AXS-05 met its primary end point, demonstrating a statistically significant delay in time to relapse of agitation compared with placebo, as assessed by CMAI total score (HR, 0.276; P = .001). The therapy also achieved its key secondary end point, with relapse observed in 8.4% of patients receiving AXS-05 compared with 28.6% of those switched to placebo (P = .001).

Additional findings from ACCORD-2 showed that worsening on the Clinical Global Impression-Severity scale for agitation occurred in 20.5% of patients treated with AXS-05 compared with 41.7% of those receiving placebo (P = .004). Similarly, worsening in the CGI-S AD overall clinical status domain was reported in 13.3% of patients on AXS-05 versus 39.3% of those on placebo (P <.001).

In the phase 3 ADVANCE-2 trial, a total of 408 patients were randomly assigned to receive either AXS-05 or placebo over a 5-week treatment period. The study did not meet statistical significance for its primary end point, defined as change in CMAI total score, with a mean reduction of 13.8 points observed in the AXS-05 group compared with 12.6 points in the placebo group. Despite this, numerical improvements across both primary and secondary measures favored AXS-05. Among the 4 pivotal trials evaluating AXS-05, including ADVANCE-1 (NCT05557409), ADVANCE-2, ACCORD-1 (NCT04797715), and ACCORD-2, ADVANCE-2 was the only study that did not achieve statistical significance on its primary outcome.

Per the drug’s safety labeling, AXS-05 may cause serious adverse effects that require prompt medical attention. These include seizures, increased blood pressure, and neuropsychiatric effects such as manic episodes or unusual thoughts and behaviors. Patients may also be at risk for serotonin syndrome, a potentially life-threatening condition, as well as hyponatremia, particularly in older adults. Additional concerns include angle-closure glaucoma and dizziness, which may increase fall risk.

REFERENCES
1. Axsome Therapeutics Announces FDA Approval of AUVELITY® (dextromethorphan HBr and bupropion HCl) for the Treatment of Agitation Associated with Dementia due to Alzheimer’s Disease. News release. Axsome Therapeutics. April 30, 2026. Accessed April 30, 2026. https://www.globenewswire.com/news-release/2026/04/30/3285345/33090/en/axsome-therapeutics-announces-fda-approval-of-auvelity-dextromethorphan-hbr-and-bupropion-hcl-for-the-treatment-of-agitation-associated-with-dementia-due-to-alzheimer-s-disease.html
2. Axsome Therapeutics Announces FDA Approval of AUVELITY™, the First and Only Oral NMDA Receptor Antagonist for the Treatment of Major Depressive Disorder in Adults. News release. Axsome Therapeutics. August 19, 2022. Accessed April 30, 2026. https://axsometherapeuticsinc.gcs-web.com/node/10466/pdf
3. Axsome Therapeutics Reports Third Quarter 2025 Financial Results and Provides Business Update. News release. Axsome Therapeutics. November 3, 2025. Accessed April 30, 2026. https://www.manilatimes.net/2025/11/03/tmt-newswire/globenewswire/axsome-therapeutics-reports-third-quarter-2025-financial-results-and-provides-business-update/2214234
4. Axsome Therapeutics Announces Successful Completion and Results of Phase 3 Clinical Program of AXS-05 in Alzheimer’s Disease Agitation. News release. Axsome Therapeutics. December 30, 2024. Accessed April 30, 2026. https://www.biospace.com/press-releases/axsome-therapeutics-announces-successful-completion-and-results-of-phase-3-clinical-program-of-axs-05-in-alzheimers-disease-agitation