Agitation caused by Alzheimer’s disease currently has one FDA-approved therapy, but that drug brings serious safety risks. An Axsome Therapeutics drug has mixed results from its latest slate of clinical tests in this indication, but company executives say the balance weighs in favor of the therapy and they’re planning to take the data to the FDA.
The Axsome drug, Auvelity, is already approved as a treatment for major depressive disorder. The preliminary results announced Monday are from two tests of the pill as a treatment for Alzheimer’s agitation. In one of the studies, the drug met the main goal by showing a statistically significant delay in the time to relapse. This study also met a key secondary goal of preventing relapse of Alzheimer’s agitation.
The data are less clear for the second Phase 3 test that posted preliminary data Monday. While the drug showed numerical improvement on the trial’s main goal, Axsome said these results were not enough to be statistically significant. Nevertheless, the company points to statistical significance achieved in two previous Phase 3 tests in Alzheimer’s agitation. With three pivotal clinical trials achieving statistically significant results and one showing numerical improvement, the company said it is readying a new drug application it expects to file with the FDA in the second half of 2025.
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Auvelity initially won FDA approval in 2023 as a treatment for depression, specifically major depressive disorder. This drug is a combination of two older medications, the depression drug buproprion and dextromethorphan, a medication that crosses the blood-brain barrier to target NMDA receptors. Dextromethorphan is commonly used in cough drugs; its targeting and blocking of NMDA receptors suppresses activity in the brain that causes coughing. NMDA receptors are found throughout the central nervous system and play key roles in functions such as learning and memory. Axsome has been testing whether blocking these receptors can also treat the agitation caused by Alzheimer’s.
The first drug specifically approved for treating Alzheimer’s agitation was Rexulti, from partners Lundbeck and Otsuka Pharmaceutical. Rexulti, which is thought to work by affecting serotonin receptors, was initially approved in 2015 as a treatment for both major depressive disorder and schizophrenia. The following year, Rexulti was approved as a maintenance treatment for schizophrenia. The drug’s label was expanded to Alzheimer’s agitation in 2023.
Rexulti, across all of its approved indications, generated 3.8 billion Danish krone (about $530 million) in revenue in the first nine months of 2024, a 15% increase compared to the same period in the prior year. In its financial reports, Lundbeck attributes the revenue growth to prescriptions for Alzheimer’s agitation. The drug has also received approvals in this indication in Australia, Israel, Malaysia, Singapore, and Switzerland.
In depression, Axsome’s Auvelity competes in a crowded market of branded and generic medications. The drug accounted for $198.7 million in revenue for the first nine months of 2024, according to the company’s most recent financial report. Alzheimer’s agitation represents a large market where Rexulti would be Auvelity’s only competitor. But the Axsome drug has the opportunity to offer a safety edge.
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Rexulti’s label carries a black box warning for higher risks of suicidal thoughts and behaviors, which is consistent with other atypical antipsychotics. Across Auvelity’s Phase 3 studies, Axsome says its drug was safe and well tolerated in the elderly study participants. Furthermore, Auvelity was not associated with increased risk of falls, cognitive decline, or sedation and there were no deaths reported in patients who received the study drug.
The black box warning for Rexulti is a significant limiting factor for use of the drug in elderly patients, William Blair analyst Myles Minter wrote in a note sent to investors on Monday. Axsome’s Auvelity could differentiate itself with a different mechanism of action that does not introduce the same dangerous safety risks as Rexulti.
“We remain bullish on approval prospects and believe Axsome maintaining breakthrough therapy designation despite Rexulti’s approval highlights that the FDA recognizes there remains a high unmet need here despite approved therapy, which should bode well for Axsome from a regulatory perspective,” Minter said.
The outstanding question is whether the clinical data are sufficient. Given the clinical trial that fell short of statistical significance, Minter said the FDA will need to show regulatory flexibility toward the Axsome drug. There’s precedent for neuropsychiatry drugs overcoming the failure of a pivotal study to win FDA approval based on the totality of data. One example noted by Minter is Rexulti, whose development program in Alzheimer’s agitation resulted in two positive studies and one negative study.
To Leerink Partners analyst Marc Goodman, the results posted Monday create the most confusion for Auvelity’s prospects in Alzheimer’s agitation. Of the four Phase 3 tests of Auvelity in this indication, two were randomized, placebo-controlled studies and two were withdrawal studies. In withdrawal studies, all patients receive the study drug at first. But after a period of time, patients who show response to treatment are randomly assigned to either continue receiving the study drug or complete the trial on a placebo. Of the two clinical trials posting data Monday, the withdrawal study is the one that met its goal.
Goodman said it’s unclear how the FDA will view the Auvelity withdrawal studies. He added that Leerink expects an FDA advisory committee will be convened to discuss the balance of the drug’s efficacy and safety, and the positive safety data may sway the vote.
Public domain image by Flickr user SciTechTrend