Pharmacokinetic data from phase 1 studies of AXS-05 showed it increases dextromethorphan concentrations into a potential therapeutic range. It was granted a Fast Track designation.
Herriot Tabuteau, MD
Positive outcomes have been reported in Axsome Therapeutic’s interim analysis of its phase 2/3 trial of AXS-05, the company’s investigational agent for agitation associated with Alzheimer disease.1
After an independent data monitoring committee (IDMC) conducted its unblinded, prespecified interim analysis for the futility of the ADVANCE-1 trial, it found that the therapy has shown enough to continue the exploration of its safety and efficacy (NCT03226522).
“The positive recommendation by the IDMC to continue the ADVANCE-1 trial is an important milestone for the Alzheimer’s disease agitation program and we look forward to the continued development of AXS-05 for this indication,” Herriot Tabuteau, MD, the chief executive officer of Axsome, said in a statement. “We are pleased that further enrollment to the bupropion single-agent arm is no longer deemed necessary. Inclusion of that arm was driven by the FDA’s guidelines to examine contribution of the individual components of product candidates like AXS-05 that contain two active agents.”
As well, the IDMC recommended no further randomization of subjects to the bupropion treatment arm of the study. The ADVANCE-1 trial randomized 435 patients in a 1:1:1 ratio to AXS-05, placebo, or bupropion, with a primary end point of the change in Cohen Mansfield Agitation Inventory (CMAI) for AXs-05 as compared to placebo.
The bupropion arm was included in order to assess the efficacy of AXS-05 in comparison with the bupropion, with a goal of displaying superiority, as required by the FDA’s combination product rule. AXS-05, a novel, oral, investigational drug product under development for the treatment of central nervous system disorders, consists of bupropion (to increase the bioavailability of dextromethorphan, as well as a norepinephrine and dopamine reuptake inhibitor and a nicotinic acetylcholine receptor antagonist) and dextromethorphan (an N-methyl-D-aspartate receptor antagonist, sigma-1 receptor agonist, nicotinic acetylcholine receptor antagonist, and an inhibitor of the serotonin and norepinephrine transporters) and utilizes metabolic inhibition technology developed by Axsome.
The pharmacokinetic data from phase 1 studies of the therapy suggested that AXS-05 increases dextromethorphan concentrations into a range that is potentially therapeutic. It has previously been granted FDA Fast Track designation status for Alzheimer disease agitation.
“Agitation is reported in up to 70% of Alzheimer’s disease patients, is highly distressing for patients and their caregivers, and is associated with significant negative outcomes, including earlier institutionalization and increased mortality,” said Cedric O’Gorman, MD, Senior Vice President of Clinical Development and Medical Affairs of Axsome. “There is currently no approved treatment for Alzheimer’s disease agitation. The significant clinical impact of this unmet medical need underscores the importance of the ADVANCE-1 trial in evaluating the potential of AXS-05 to treat this serious indication.”
This first interim analysis was performed on approximately 30% of the target number of subjects to assess futility. The second interim analysis is anticipated by Axsome to be performed on approximately 60% of the target number of subjects to assess efficacy.
“We anticipate that implementation of the IDMC’s recommendations may provide greater flexibility to our operating plans and timelines which we will evaluate in the coming weeks. We will continue to be rigorous with our oversight of the conduct of the study,” Tabuteau added.
1. Axsome Therapeutics Announces Positive Outcome of Interim Analysis of ADVANCE-1 Phase 2/3 Trial of AXS-05 in Alzheimer’s Disease Agitation [press release]. New York, New York: Axsome Therapeutics Inc; Published December 10, 2018. globenewswire.com/news-release/2018/12/10/1664251/0/en/Axsome-Therapeutics-Announces-Positive-Outcome-of-Interim-Analysis-of-ADVANCE-1-Phase-2-3-Trial-of-AXS-05-in-Alzheimer-s-Disease-Agitation.html. Accessed December 10, 2018.