Axsome Asks FDA to Approve Questionable Alzheimer’s Agitation Drug

By Simon Spichak | January 20th, 2025

Axsome Therapeutics will file for FDA approval of a drug to treat agitation in people with Alzheimer’s later this year. Outside experts aren’t impressed.

Alzheimer’s disease is a lot more than memory loss. Many people with the disease develop psychiatric problems like agitation — which are hard to treat.  As many as half of people who develop Alzheimer’s develop agitation, which may cause pacing, restlessness, as well as verbal and physical aggression. However, most psychiatric drugs aren’t effective — or necessarily even safe — for people with dementia.

There are a few companies working to bring more options to the table — with mixed results. Last year, the FDA approved the first drug for treating Alzheimer’s agitation, Rexulti (generic name: brexpiprazole). The drawback: The drug increases patients’ risk of mortality. Drugmakers are still trying to develop drugs that are well-tolerated and come with fewer side effects. 

Axsome Therapeutics is betting its experimental drug AXS-05 will be a better option for patients. AXS-05 was approved in 2022 by the FDA for treating depression, under the brand name Auvelity.

In 2020, the company shared data showing that the drug reduced agitation in Alzheimer’s patients by 3.9 points more than placebo on a 203-point scale in its Phase 2/3 trial. The overall change in agitation scores, although statistically significant, is well below the threshold for what is considered “clinically meaningful” — or noticeable — by patients and their caregivers. 

Two years later, the company shared data from another Phase 3 trial showing people taking the drug were less likely to experience a relapse in symptoms.  

Now, after yet two more Phase 3 trials, the company thinks the drug is ready for Alzheimer’s patients as well. The company plans to submit their data for approval this year. But there’s a catch.

Dr. Jeffrey Cummings, vice chair of research at the UNLV Department of Brain Health, who has provided consultation services and has presented trial data on the company’s behalf, said in a press release that “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.”

The press release did not mention that Cummings was involved in the trials or a consultant for the company. 

Experts who weren’t involved in the trials told Being Patient a different story: The results presented in the press release suggest the drug doesn’t seem to work. 

“It’s difficult to summon up enthusiasm for a treatment for agitation in Alzheimer’s disease that is absolutely no better than placebo in reducing agitation symptoms,” Rob Howard, a professor of old age psychiatry at University College London Institute of Mental Health, who was not involved in the trials, told Being Patient. He is also concerned about the potential risk of increased agitation upon withdrawal of the drug.

According to Axsome’s website, the earlier Phase 2/3 and Phase 3 trials have not been published in peer-reviewed scientific journals — a process that enables transparency, allowing other scientists and clinicians to assess the results.

Eric Widera, a geriatrician and professor of medicine at UCSF who was not involved in the company’s trials, told Being Patient he isn’t convinced by the unpublished data. “They didn’t even have enough internal belief in the [2022] study design and outcomes to even publish it in the last two years, so it doesn’t really deserve a comment from me,” Widera said of the earlier trial results.  “Selective and delayed reporting of trial results distorts the perceived effectiveness of medications,” he said. “This type of selective publication and delayed reporting are not new and are significant sources of bias […], particularly in studies funded by pharmaceutical companies.”

As to the new studies, Widera agreed with Howard that the press release didn’t present a glowing picture of the drug’s efficacy: “The data from the press release argues that the drug didn’t work,” he told Being Patient.

The new data behind AXS-05

AXS-05 is a pill that targets many different proteins in the brain, affecting brain signalling in the hopes of alleviating some of the agitation that develops with dementia. 

Axsome Therapeutics shared data from two separate Phase 3 clinical trials — following 2020’s unpublished Phase 2/3 and 3 trials — that continued to investigate whether the drug is effective. 

The first of these two newer trials, called ACCORD-2, enrolled 295 people who had Alzheimer’s and agitation. They gave all the patients AXS-05 for a year, and found that roughly half, or 167, of the patients improved. Then, they switched half of those patients over to placebo to see if they’d experience a relapse in symptoms. Those who continued to receive AXS-05 were far less likely to relapse compared to the placebo group. There were no drug-related deaths among participants in this trial, and the drug did not lead to sedation or cognitive decline. 

Axsome’s second trial for AXS-05, called ADVANCE-2, was a randomized double-blind placebo-controlled trial that enrolled 408 participants with Alzheimer’s disease and agitation. 

Half of the participants were randomized to receive the drug and the other half received the placebo — neither researchers nor the patients knew who had actually received the drug. Over five weeks, the drug did not reduce agitation in the patients.

It’s deja vu for Axsome Therapeutics. The company filed for approval of a migraine drug on the basis of mixed results from two Phase 3 trials. And, they’re  currently involved in a shareholder lawsuit for allegedly making false and misleading statements over its migraine drug, which was rejected by the FDA in 2022. (They’ve since resubmitted the drug for approval.)

UPDATED 28 January 2025, 1:30 P.M. ET: This article was updated with additional context surrounding the unpublished 2022 Phase 2/3 and Phase 3 trials, to provide more clarity for readers. We also clarified the trials that Widera referred to in his quote about unpublished studies.

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2 thoughts on “Axsome Asks FDA to Approve Questionable Alzheimer’s Agitation Drug

  1. Actually the drug worked worked in 3 of 4 P3 Alz+ agitation trials. The only drug approved for that indication is Rexulti and it worked in 2 of 3 P3s with most of the improved patients in Eastern European pop not the USA. 05 unlike Rexulti had NO patient deaths associated with its drug.

    1. Hi Mike, thanks for your comment and your read! You’ve pointed out that we were unclear, so we went ahead and issued an update to this article, to clarify that the data we are discussing is from the new trials featured in Axsome’s Dev. 202 press release, and that this new data followed the two earlier, yet unpublished clinical trials (a Phase 2/3 and a Phase 3). We’re looking at endpoints here, sure, but we’re also looking at benchmarks for what’s understood to be clinically meaningful for patients — Our reporting team sent Axsome’s press release to two third-party experts who were not involved in the trials for outside comment, and both of their interpretations, upon evaluating the data presented in the new trials, were that the drug does not appear to be effective. Please don’t hesitate to reach out if you have any further questions.

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