Axsome Therapeutics AXS-05 Meets Primary Endpoint in Phase 2 Trial for Major Depressive Disorder Treatment

Axsome Therapeutics Inc, a clinical-stage biopharmaceutical company developing novel therapies for the management of central nervous system (CNS) disorders, earlier this month that its novel, oral, investigational NMDA receptor antagonist with multimodal activity known as AXS-05 met its primary endpoints in the ASCEND Phase 2 trial in major depressive disorder.

AXS-05 was found to improve symptoms of depression in the ASCEND study, which was a randomized, double-blind, active controlled, multi-center, U.S. trial. The trial participants were 80 adult patients with confirmed major depressive disorder, moderate to severe, and were treated with AXS-05 (45 mg dextromethorphan/105 mg bupropion), or the active comparator bupropion (105mg), twice a day for 6 weeks.

Over the course of the 6-week trial AXS-05 demonstrated a statistically significant reduction in the Montgomery-Åsberg Depression Rating Scale (MADRS) compared to bupropion (p<0.001). At the end of the 6 weeks AXS-05 showed a 17.2-point reduction in the MADRS total score compared to bupropion’s 12.1-point reduction (p=0.013). In its first week AXS-05 rapidly reduced depressive symptoms and on the Clinical Global Impression-Improvement scale (CGI-I) demonstrated a statistically significant improvement over bupropion at week 1 (p=0.045). Numerical superiority on the MADRS scale was achieved in week 1 as well, and statistical significance over bupropion achieved, and maintained thereafter, in week 2.

According to Professor Maurizio Fava, MD, Executive Vice Chair, Department of Psychiatry, Massachusetts General Hospital (MGH) and Associate Dean for Clinical & Translational Research, Harvard Medical School, “The clinically meaningful improvements in depressive symptoms seen with AXS-05 in this study were achieved versus an active comparator that is a well-established antidepressant, as early as only one week after initiation of treatment.” AXS-05 was found to be superior to bupropion on multiple prespecified secondary endpoints, such as MADRS-6 (p=0.007 at Week 6); percentage of responders on MADRS-6 (response defined as ≥ 50% reduction from baseline) (p=0.014 at Week 6); CGI-I (p=0.045 at Week 1, and 0.051 at Week 6); Clinical Global Impression-Severity scale (CGI-S) (p=0.028 at Week 6); percentage of patients achieving remission on MADRS (remission defined as MADRS ≤10) (p=0.004 at Week 6).

Rates of adverse effects were similar between AXS-05 and bupropion, and retention of patients in the study was favorable and higher in the AXS-05 treatment arm. “The demonstration of a significant and rapid antidepressant effect with AXS-05, coupled with favorable safety, point to a differentiated clinical profile,” said Herriot Tabuteau, MD, Chief Executive Officer of Axsome. “This data also suggests that AXS-05 has important biological activity and support the continued development of this novel multimodal agent in MDD as well as in other neuropsychiatric indications. These results build on the positive interim futility analyses for the Phase 3 trial of AXS-05 in treatment resistant depression and the Phase 2/3 trial of AXS-05 in Alzheimer’s disease agitation. The topline results of the ongoing Phase 3 trial of AXS-05 in treatment resistant depression, anticipated later this quarter, should add to the body of clinical data with AXS-05 in mood disorders.”

AXS-05 is considered a glutamate receptor modulator, which is a new mechanism of action believed to help enhance brain levels of serotonin, noradrenaline, and dopamine, which are key to the regulation of mood. 51% of the patients in the trial had experienced three, or more, major depressive episodes before the study and 23% of the participants received first line treatment from a current major depressive episode prior to treatment with AXS-05. Previously, AXS-05 was granted Fast track designation by the FDA for the treatment of TRD. After the results of the ASCEND trial, Axsome intends to meet with the FDA again to define a potential path of regulation for AXS-05 in the treatment of the larger Major Depressive Disorder population.