A Review of Data on AXS-05 for Alzheimer Disease Agitation in Advance of Next Week's PDUFA Date

The US Food and Drug Administration has set a Prescription Drug User Fee Act (PDUFA) target action date of April 30, 2026, for Axsome Therapeutics' supplemental New Drug Application (sNDA) for dextromethorphan-bupropion (AXS-05) for the treatment of agitation associated with Alzheimer disease (AD). In advance of this decision date, let’s take a look at the data.¹

Breakthrough Therapy Designation

AXS-05 is Axsome’s novel, oral, investigational N-methyl-D-aspartate (NMDA) receptor antagonist, sigma-1 agonist, and aminoketone CYP2D6 inhibitor being developed for the treatment of Alzheimer disease agitation and smoking cessation. AXS-05 was granted FDA Breakthrough Therapy designation for AD agitation back in 2020, the second Breakthrough Therapy designation granted to Axsome for AXS-05 (the first being for major depressive disorder).²

The application was granted Priority Review, signaling a 6-month review period due to the potential for significant improvement over existing options. The Breakthrough Therapy designation for AXS-05 in AD agitation was supported by the positive results from from several phase 3 studies, including the pivotal phase 2/3 ADVANCE-1 study, a randomized, double-blind, controlled, multicenter US trial. Investigators treated 366 participants with AD with AXS-05, bupropion, or placebo. Treatment with AXS-05 resulted in a rapid, substantial, and statistically significant improvement in agitation as compared with placebo. On the primary endpoint, AXS-05 demonstrated a statistically significant mean reduction from baseline in the Cohen Mansfield Agitation Inventory (CMAI) total score compared to placebo at week 5, with mean reductions of 15.4 points for AXS-05 and 11.5 points for placebo (P=0.010). AXS-05 was also superior to bupropion on the CMAI total score (P <0.001), establishing component contribution.

As to safety profile, AXS-05 was also well tolerated and not associated with cognitive impairment or sedation. The most commonly reported adverse events in the AXS-05 arm were somnolence (8.2% for AXS-05 vs 4.1% for bupropion and 3.2% for placebo), dizziness (6.3%, 10.2%, 3.2%, respectively), and diarrhea (4.4%, 6.1%, 4.4%, respectively).²

Early Results

Back in 2022, Axsome announced positive data from ACCORD-1, the first of the phase 3 studies from Axsome. Results showed that AXS-05 met its primary end point of delay in time to relapse and preventing relapse of agitation. In the double-blind portion of the study, investigators noted a 3.6-fold lower risk of relapse of agitation symptoms when treated with AXS-05 relative to placebo (HR, 0.275; P = .014). The secondary end point, preventing relapse of AD agitation, was also met, as 7.5% of AXS-05-treated patients relapsed vs 25.9% of those who switched to placebo (P = .018).

Another trial, ACCORD-2, was a multicenter trial including 167 participants with AD agitation who completed an open-label treatment period followed by a 26-week, double-blind, placebo-controlled randomized withdrawal period. In the study, AXS-05 met its primary end point, with participants receiving AXS-05 demonstrating a statistically significant delay in the time to relapse of agitation relative to placebo, assessed by the Cohen-Mansfield Agitation Inventory (CMAI) total score (hazard ratio for time to relapse of 0.276; P = .001). The investigational agent also met its key secondary end point of AD agitation relapse, with 8.4% of treated patients relapsing vs 28.6% of those on placebo (P = .001).

Other Available Agents

In May 2023, brexpiprazole (Rexulti) became the first medication to receive supplemental approval from the FDA for the treatment of agitation associated with dementia due to AD. Its effectiveness for this indication was determined through two 12-week, randomized, double-blind, placebo-controlled, fixed-dose studies. Evidence from one of these studies indicated that brexpiprazole at fixed doses of 2 or 3 mg/day is more efficacious than placebo at reducing agitation associated with AD.^3,4

The mean difference in CMAI total scores at week 12 was –22.6 from baseline in the brexpiprazole groups, whereas the placebo group had a change of –17.3 from baseline (difference of −5.32; 95% CI, −8.77 to −1.87; P = .003; effect size = 0.35). All other secondary efficacy end point measures (CGI-S, CGI-I, CMAI subscale scores and response rates, and NPI-NH) also showed statistically significant greater improvement in the brexpiprazole group compared with placebo.

For the CGI-S score as related to agitation, there was a mean difference of –1.2 for the brexpiprazole group compared with a –0.9 mean difference in the placebo group (difference of –0.27; 95% CI, –0.47 to –0.07; P = .008; effect size = 0.31).

However, when looking at the brexpiprazole subgroups, only the 3-mg group showed statistically significant improvement in the CGI-S score. The CGI-I mean score for the brexpiprazole group at the end of 12 weeks was 2.7, whereas the placebo group had a mean score of 3.0 (difference of –0.33; 95% CI, –0.57 to –0.09; P = .007). The NPI-NH total score in the brexpiprazole group showed a mean difference of –17.3 from baseline compared with –12.7 for placebo (difference of –4.60; 95% CI, –7.33 to –1.88; P = .01; effect size = 0.39).

Stay Tuned for Updates

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References

1. Kuntz L. sNDA submitted for AXS-05 for the treatment of Alzheimer disease agitation. Psychiatric Times. November 4, 2025. https://www.psychiatrictimes.com/view/snda-submitted-for-axs-05-for-the-treatment-of-alzheimer-disease-agitation

2. Axsome Therapeutics receives FDA breakthrough therapy designation for AXS-05 for the treatment of Alzheimer’s disease agitation. News release. June 26, 2020. Accessed November 4, 2025. https://axsometherapeuticsinc.gcs-web.com/news-releases/news-release-details/axsome-therapeutics-receives-fda-breakthrough-therapy-0?field_nir_news_date_value%5Bmin%5D=

3. Lee D, Slomkowski M, Hefting N, et al. Brexpiprazole for the treatment of agitation in Alzheimer dementia: a randomized clinical trial. JAMA Neurol. Published online November 6, 2023.

4. Allen J, Dickan A, Woo J, et al. Exploring the role of brexpiprazole in Alzheimer dementia agitation. Psychiatric Times. 2024;41(1).