Date: 25-Mar-2020

Axsome Speed Up Completion Of ADVANCE-1 Phase 2/3 Trial Of AXS-05 In Alzheimers Disease Agitation

Axsome Therapeutics, a clinical-stage biopharmaceutical company developing novel therapies for the management of central nervous system (CNS) disorders, announced that it is accelerating the completion of the ADVANCE-1 phase 2/3 trial of AXS-05 in patients with Alzheimer’s disease (AD) agitation to ensure the safety of this vulnerable patient population during the COVID-19 pandemic, while maintaining the integrity of the clinical trial. AXS-05 (dextromethorphan/bupropion modulated delivery tablet) is a novel, oral, investigational NMDA receptor antagonist with multimodal activity. Randomizations into the study have concluded and patient participation is concluding. With the acceleration of trial completion, topline results from ADVANCE-1 are now expected in early second quarter of 2020, versus previous guidance of the third quarter of 2020.

The decision to accelerate the completion of this trial was made in light of the newly issued US Food and Drug Administration (FDA) Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic, which discusses the potential impact of the pandemic on the conduct of clinical trials and on the resulting need to ensure the safety of trial participants. The ADVANCE-1 trial is enrolling only patients 65 years of age or older, the demographic at highest risk for COVID-19 related fatalities. The conclusion of patient randomization and participation in the ADVANCE-1 trial enables patient compliance with recent and evolving COVID-19 related national, state and local government directives and executive orders that persons 65 years and older isolate at home.

In the original design of the trial, approximately 435 patients were to be randomized in a 1:1:1 ratio to receive AXS-05, bupropion, or placebo for 5 weeks (approximately 145 patients per treatment arm). The AXS-05 and placebo arms are fully enrolled and more than 90% of patients in these arms are estimated to have completed the study. In December 2018, an independent data monitoring committee (IDMC) performed an unblinded, pre-specified interim analysis for futility on the first approximately 30% of the targeted number of patients. The IDMC recommended continuation of the AXS-05 and placebo treatment arms and no further randomization of patients to the bupropion treatment arm. Subsequently, patients were randomized in a 1:1 ratio to receive AXS-05 or placebo.

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).

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that manifests initially as forgetfulness advancing to severe cognitive impairment and memory loss. It afflicts an estimated 5 million individuals in the United States, a number that is anticipated to increase to approximately 14 million by 2050. In addition to cognitive decline, individuals diagnosed with AD frequently experience behavioral and psychological symptoms including agitation which is reported in approximately 45% of patients. Agitation is characterized by emotional distress, aggressive behaviors, disruptive irritability, and disinhibition. Agitation in patients with AD has been associated with increased caregiver burden, decreased functioning, earlier nursing home placement, and increased mortality. There are currently no therapies approved by the FDA for the treatment of agitation in patients with AD.

AXS-05 is a novel, oral, patent-protected, investigational NMDA receptor antagonist with multimodal activity under development for the treatment of major depressive disorder and other central nervous system (CNS) disorders. AXS-05 consists of a proprietary formulation and dose of dextromethorphan and bupropion and utilizes Axsome’s metabolic inhibition technology. The dextromethorphan component of AXS-05 is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, also known as a glutamate receptor modulator, which is a novel mechanism of action, meaning it works differently than currently approved therapies for major depressive disorder. The dextromethorphan component of AXS-05 is also a sigma-1 receptor agonist, nicotinic acetylcholine receptor antagonist, and inhibitor of the serotonin and norepinephrine transporters. The bupropion component of AXS-05 serves to increase the bioavailability of dextromethorphan, and is a norepinephrine and dopamine reuptake inhibitor, and a nicotinic acetylcholine receptor antagonist. AXS-05 is covered by more than 40 issued US and international patents which provide protection out to 2034. AXS-05 has been granted FDA Breakthrough Therapy designation for the treatment of MDD as well as Fast Track designations for the treatment of treatment resistant depression and for the treatment of Alzheimer’s disease agitation. AXS-05 is not approved by the FDA.