Axsome to ask FDA to approve AXS-05 for Alzheimer’s agitation
Company recently released results of ACCORD-2, ADVANCE-2 studies
Axsome Therapeutics plans this year to ask the U.S. Food and Drug Administration (FDA) to approve its oral therapy AXS-05 as a treatment for agitation related to Alzheimer’s disease.
The company recently announced results from two Phase 3 trials testing AXS-05. One study, ACCORD-2, hit its main goal while the other, ADVANCE-2, didn’t. Axsome said it will use data from these trials along with two earlier studies that both hit their main goals as a basis for a new drug application (NDA) toward approving AXS-05, which is designed to ease agitation by modulating certain brain signaling molecules.
“We are very pleased with the successful completion of the planned Phase 3 clinical trial program of AXS-05 in the treatment of Alzheimer’s disease agitation,” Herriot Tabuteau, MD, Axsome’s CEO, said in a company press release. “With the strong results of the ACCORD-2 trial, AXS-05 has now demonstrated substantial and statistically significant improvements in Alzheimer’s disease agitation across three pivotal, Phase 3, placebo-controlled trials, underscoring its potential to provide meaningful benefit to patients living with this condition and their families.”
In the Phase 3 ACCORD-2 study (NCT04947553), all 295 patients were initially treated with AXS-05 for up to one year. The patients who saw a reduction in agitation symptoms while on the therapy were then randomly assigned to either keep taking it or switch to a placebo. The study’s main goal was to see if patients given AXS-05 would be less likely to have a recurrence of agitation, which was assessed using a standardized measure called the Cohen-Mansfield Agitation Inventory (CMAI). A reduction in CMAI score of at least 30% was considered a clinical response.
Positive results from ACCORD-2
In the study’s first part where all were given AXS-05, more than two-thirds (69%) had a clinical response within the first six weeks of therapy. At the same time, more than 70% saw improvements in clinician- and caregiver- rated measures of agitation.
Of the 295 participants, 167 entered into the placebo-controlled part of the trial. The study met its main goal, showing that patients who continued on AXS-05 were more than three times less likely to have a recurrence of agitation than those who switched to a placebo. Fewer than 1 in 10 (8.4%) of patients on AXS-05 relapsed, but more than 1 in 4 (28.6%) patients taking a placebo did.
In clinician-rated measures, significantly fewer patients given AXS-05 than a placebo had a worsening of agitation (20.5% vs. 41.7%) or a worsening of overall Alzheimer’s severity (13.3% vs. 39.3%).
The results from ACCORD-2 are largely consistent with an earlier study called ACCORD (NCT04797715) that also showed AXS-05 was better than a placebo at preventing agitation relapse in Alzheimer’s patients.
“Agitation is one of the most troubling and consequential aspects of Alzheimer’s disease, poses significant challenges to both the patient and their family, and represents a high unmet need,” said Jeffrey Cummings, MD, a researcher at the University of Nevada Las Vegas. “The robust, clinically meaningful efficacy results of the ACCORD-2 trial are consistent with the statistically significant results of the previously completed ADVANCE-1 and ACCORD-1 Phase 3 trials of AXS-05.”
ADVANCE-2 fails to meet main goal
ADVANCE-2 (NCT05557409) enrolled 408 people with Alzheimer’s-related agitation and the participants were randomly assigned to take AXS-05 or a placebo for five weeks. ADVANCE-1 (NCT03226522), a smaller Phase 3 study, had shown that AXS-05 was better than a placebo at reducing the CMAI score in a similar timeframe.
ADVANCE-2 was intended to also show that AXS-05 was significantly better than a placebo at reducing the CMAI score. It failed to meet this goal, however. The score reduction was slightly more with AXS-05 than with a placebo, but the difference wasn’t statistically significant, meaning it’s mathematically plausible the difference could be random chance. Axsome pointed out, nevertheless, that the main finding, as well as most secondary findings, tended to favor AXS-05 over a placebo even if the difference wasn’t statistically meaningful.
“The improvements in the AXS-05 arm relative to placebo in ADVANCE-2 did not reach statistical significance. However, we are pleased with the very positive controlled safety data from this trial which will be an essential part of our planned NDA submission of AXS-05 in Alzheimer’s disease agitation, which is targeted for the second half of 2025,” Tabuteau said.
The participants who completed ACCORD-2 or ADVANCE-2 were able to enroll in an extension study (NCT06736509) that’s tracking the long-term safety of AXS-05. Results so far have shown AXS-05 is generally tolerated well, the most common side effect being headache. No serious side effects related to the therapy were reported and AXS-05 treatment wasn’t associated with sedation or worsened cognitive problems.
“Importantly, short and long-term treatment with AXS-05 was well tolerated and not associated with increased mortality, risk of falls, sedation, or cognitive decline,” Cummings said. “Taken together, results from this comprehensive Phase 3 program encompassing distinct clinical trial designs strongly support the potential for AXS-05 to become an important treatment for patients living with Alzheimer’s disease agitation.”
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