Background

AXS-05 is a fixed-dose combination of two approved drugs being developed for the treatment of agitation in people with Alzheimer’s disease. One component, dextromethorphan, is the active ingredient in several brands of cough syrup. Dextromethorphan is a weak antagonist of NMDA receptors, an agonist of sigma 1 receptors—molecular chaperones located in membranes of the endoplasmic reticulum—and inhibits serotonin and norepinephrine transporters, nicotinic acetylcholine receptors, and microglial activation. The other component is bupropion, a drug prescribed to treat depression and to help people stop smoking. Bupropion slows the metabolism of dextromethorphan and increases its plasma concentration. This approach is similar to that taken for AVP-923 and AVP-786, which combined dextromethorphan with quinidine. Bupropion also acts as a norepinephrine and dopamine reuptake inhibitor and a nicotinic acetylcholine receptor antagonist.

Findings

Trial registries or the peer-reviewed literature contain no information on Phase 1 trials.

In July 2017, Axsome began ADVANCE, a Phase 2/3 multisite study to compare the efficacy and safety of a five-week course of AXS-05, bupropion, or placebo in 366 people with a diagnosis of probable AD and agitation. AXS-05 was titrated to a final dose of 45 mg dextromethorphan and 105 mg bupropion twice daily. The primary outcome was change from baseline in the Cohen-Mansfield Agitation Inventory. In April 2020, the company released topline results, claiming a statistically significant 15.4-point reduction in CMAI with treatment, compared to a decrease of 11.5 points with placebo or 10.0 points with bupropion only. Seventy percent of patients had a clinical response, defined as 30 percent or greater improvement on the CMAI. The drug reportedly improved scores on a clinical global assessment of change for agitation. Most common side effects were sleepiness, dizziness, and diarrhea; no serious adverse events were observed related to the drug. AXS-05 caused no cognitive decline as measured by the MMSE, or sedation (see press release, slides). 

On June 26, 2020, the U.S. Food and Drug Administration granted AXS-05 breakthrough therapy designation for agitation in Alzheimer’s disease; the drug combination already holds breakthrough therapy as well as fast-track status for depression. 

In December 2020, a Phase 3 trial called ACCORD began testing twice-daily AXS-05 for agitation in 178 patients with AD. After nine weeks of open-label treatment, responders were randomized to drug or placebo for up to 26 weeks. The primary outcome was time from randomization to relapse of agitation. The trial ran at 63 sites in the U.S. and Canada, with an open-label extension of up to 24 weeks offered to completers. In November 2022, Axsome announced positive top-line results. According to its press release, treatment delayed time to relapse, resulting in a 3.6-fold lower risk of relapse. AXS-05 also improved key secondary outcomes, including reducing relapse rate from 25.9 percent in the placebo group to 7.5 percent among treated participants. In the open-label period, patients improved on the CMAI, clinician and caregiver impressions of agitation, caregiver burden, patient quality of life, and depressive symptoms. No sedation or cognitive decline, extra adverse events, or excess trial dropouts were reported on treatment, compared to placebo.

Subsequently, the open-label extension was expanded to one year, and modified to include a 24-week, randomized withdrawal study. Participants who completed ACCORD or ADVANCE could enroll in this trial. All received one year of treatment, and then clinical responders were randomized to AXS-05 or placebo for up to six months. The primary outcomes are safety and time to relapse after the double-blind randomization. The trial will also assess change in the CMAI. The study enrolled 295 people at 45 locations in the U.S., Canada, and Puerto Rico. In company publications, it is referred to as ACCORD-2.

AXS-05 has completed trials in major depressive disorder, treatment-resistant depression, and smoking cessation. In 2020, the company filed for marketing approval for major depression, and in August 2022, the FDA approved AXS-05 to treat major depressive disorder. Marketed as Auvelity, it was the first oral NMDA receptor agonist approved for this condition (press release; Iosifescu et al., 2022; Tabuteau et al., 2022, McIntyre & Jain, 2024). 

In September 2022, Axsome began ADVANCE-2, a parallel-group Phase 3 trial for Alzheimer’s disease agitation. It was to enroll 350 people for up to five weeks treatment with twice-daily AXS-05 or placebo, with an optional six-month open-label extension. The primary outcome is change in the CMAI after five weeks. The company said it plans to apply for approval after this trial and its open-label extension are complete, in hopes of satisfying prior FDA feedback calling for long-term safety data from at least 300 patients treated for six months and 100 patients for one year (press release).

In November 2024, the company began another 25-week open-label safety extension for participants who complete ACCORD-2 and ADVANCE-2.

On December 30, 2024, Axsome announced top-line results for ADVANCE-2 and ACCORD-2 (press release). The ADVANCE-2 parallel group trial missed its primary endpoint of significant reduction in CMAI score compared to placebo. In the 408-person study, AXS-05 reduced the CMAI by 13.8 points, versus 12.6 points for placebo. The company noted that results for most secondary endpoints numerically favored AXS-05 over placebo; none reached significance. Safety was consistent with earlier trials.

In contrast, the ACCORD-2 withdrawal trial met its primary endpoint, delaying time to relapse. Patients on continuous AXS-05 had a 3.6-fold lower risk of relapse compared to those switched to placebo, with 8.4 percent of AXS-05 patients relapsing versus 28.6 percent of placebo patients. AXS-05 significantly reduced the number of patients who worsened on measures of agitation and on the Clinical Global Impression of Severity for Alzheimer’s disease. The trial enrolled 295 patients in the one-year open-label phase. Most of them improved on the CMAI or other measures of agitation, and 167 were randomized to AXS-05 or placebo in the double-blind withdrawal phase.

The company disclosed results of long-term safety studies requested by the FDA. In a total of 456 patients treated for up to 12 months, AXS-05 was well tolerated and no new safety signals identified. AXS-05 did not increase the risk of falls, or cause cognitive decline, or sedation. The most common adverse event was headache in 5.5 percent of participants. There were no deaths. Axsome plans to submit for FDA approval in the second half of 2025.

For details on AXS-05 trials, see clinicaltrials.gov.