Dr Cedric O'GormanCedric O'Gorman, MD
AXS-05, an investigational, oral N-methyl-D-aspartate (NMDA) receptor antagonist, is having its assessment in the phase 2/3 ADVANCE-1 clinical trial (NCT03226522) in the treatment of agitation in patients with Alzheimer disease accelerated to ensure patient safety during the coronavirus disease (COVID-19) pandemic, according to an Axsome Therapeutics announcement.1

This decision, the company noted, was made based on the newly issued guidance from the FDA, the Guidance on Conduct of Clinical Trials of Medical Products During COVID-19 Pandemic, which seeks to provide considerations in ensuring the safety of trial participants, maintaining compliance with good clinical practice guidelines, and minimizing the risks to trial integrity.2

In the study of Axsome’s dextromethorphan/bupropion modulated delivery tablet, randomization had been concluded to this point, and patient participation is concluding currently. The top-line results from ADVANCE-1—which randomized 435 patients in a 1:1:1 ratio to AXS-05, placebo, or bupropion—are now expected in the second quarter of 2020, a full quarter ahead of the prior schedule.

The trial’s primary end point is the change in Cohen Mansfield Agitation Inventory (CMAI) for AXS-05 as compared to placebo. The active treatment and placebo arms were fully enrolled, with upward of 90% of patients estimated to have completed the study to this point.
 
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In December 2018, an independent data monitoring committee (IDMC) performed an unblinded, pre-specified interim analysis for futility on roughly the first 30% of the targeted enrollment, recommending the continuation of the AXS-05 and placebo treatment arms and no further randomization of patients to the bupropion treatment arm. At that point, patients were randomized in a 1:1 ratio to receive AXS-05 or placebo. 

“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,” Cedric O’Gorman, MD, senior vice president, Clinical Development and Medical Affairs, Axsome, said at the time. “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.”

The bupropion arm was initially 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 consists of bupropion to increase the bioavailability of dextromethorphan, as well as a norepinephrine and dopamine reuptake inhibitor and a nicotinic acetylcholine receptor antagonist, as well as 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, according to 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.3

 AXS-05 (dextromethorphan/bupropion modulated delivery tablet) is a novel, oral, investigational NMDA receptor antagonist with multimodal activity. Randomizations in the study have concluded and patient participation is concluding. With the acceleration of trial completion, topline results from ADVANCE-1 are now expected in the early second quarter of 2020, versus previous guidance of the third quarter of 2020.

ADVANCE-1 (Addressing Dementia Via Agitation-Centered Evaluation 1) is a Phase 2/3 multicenter, randomized, double-blind, controlled trial to evaluate the efficacy and safety of AXS-05 in patients with agitation associated with Alzheimer’s disease. The primary efficacy measure is the Cohen-Mansfield Agitation Inventory (CMAI).
REFERENCES
1. Axsome Therapeutics Accelerates Completion of the ADVANCE-1 Phase 2/3 Trial of AXS-05 in Alzheimer’s Disease Agitation [press release]. New York, NY: Axsome Therapeutics; Published March 20, 2020. Accessed March 24, 2020. globenewswire.com/news-release/2020/03/20/2003954/0/en/Axsome-Therapeutics-Accelerates-Completion-of-the-ADVANCE-1-Phase-2-3-Trial-of-AXS-05-in-Alzheimer-s-Disease-Agitation.html
2. FDA. FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic: Guidance for Industry, Investigators, and Institutional Review Boards. FDA website. Published March 2020. Accessed March 24, 2020. fda.gov/media/136238/download
3. 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, NY: Axsome Therapeutics Inc; Published December 10, 2018. Accessed March 24, 2020. 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