Axsome Therapeutics Announces AXS-05 Achieves Primary Endpoint in Phase 2 Trial in Major Depressive Disorder
Demonstrated statistically significant improvement in MADRS scores compared to active comparator (p<0.001 on primary endpoint)
Rapid improvement in depressive symptoms demonstrating statistically significant superiority over active comparator within the first week (p=0.045 on CGI-I)
Improvement with AXS-05 versus active comparator seen on multiple secondary endpoints, including remission in 47% of AXS-05 patients versus 16% of active comparator patients (p=0.004)
Data support ongoing development of AXS-05 in treatment resistant depression and further development in MDD
Potentially first-in-class, oral NMDA receptor antagonist with multimodal activity for the treatment of depression
Company to host conference call at
AXS-05 met the prespecified primary endpoint by demonstrating a highly statistically significant reduction in the
AXS-05 was superior to bupropion on multiple prespecified secondary endpoints, with statistically significant effects demonstrated on most, including the following: 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). Additionally, the treatment effect observed with bupropion in the study was consistent with that observed in prior published trials.
“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,” said Professor
Fifty-one percent (51%) of patients in the trial had experienced three or more major depressive episodes prior to enrollment. Twenty-three percent (23%) of study participants had received first line treatment in their current major depressive episode prior to treatment with study medication.
AXS-05 was safe and well tolerated with no serious adverse events. The most commonly reported adverse events in the AXS-05 arm were nausea, dizziness, dry mouth, decreased appetite, and anxiety. Overall, rates of adverse events were similar between AXS-05 and bupropion. Retention of patients in the study was favorable overall and higher in the AXS-05 treatment arm. There was no meaningful difference between the two treatment arms in discontinuations due to adverse events. Treatment with AXS-05 was not associated with psychotomimetic effects, weight gain, or sexual dysfunction.
“The demonstration of a significant and rapid antidepressant effect with AXS-05, coupled with favorable safety, point to a differentiated clinical profile,” said
AXS-05 is a novel, oral, non-competitive NMDA receptor antagonist, also known as a glutamate receptor modulator, a new mechanism of action which is thought to help enhance synaptic connections and improve the communication between brain cells in people with major depressive disorder. In addition, AXS-05 enhances brain levels of serotonin, noradrenaline, and dopamine, which are key neurotransmitters involved in the regulation of mood; and displays anti-inflammatory properties, which may be relevant to treating MDD. The multimodal actions of AXS-05 may be complementary and synergistic for the treatment of this biologically-based condition. AXS-05 is covered by more than 30 issued U.S. and international patents providing protection out to 2034, and Axsome maintains worldwide rights.
“AXS-05 is an example of Axsome’s commitment to address significant unmet needs in CNS disorders through innovation. There have been no new significant pharmacological approaches in the treatment of depression over the past 30 years despite its growing contribution to the overall global burden of disease,” said Cedric O’Gorman, MD, Senior Vice President of Clinical Development and Medical Affairs of Axsome. “If approved, AXS-05 would be the first orally administered NMDA receptor antagonist, or glutamate receptor modulator, for the treatment of depression. This novel mechanism of action and AXS-05’s multimodal actions are different from the profile of all currently marketed antidepressants. We look forward to the continued evaluation of the potential of AXS-05 through our ongoing late stage clinical trials in multiple large indications with limited treatment options.”
The detailed results of the ASCEND trial are expected to be presented at upcoming scientific meetings. AXS-05 is also being evaluated in the STRIDE-1 Phase 3 trial in patients with treatment resistant depression (TRD), defined as patients with MDD who have failed two or more antidepressant treatments. AXS-05 was granted Fast Track designation by the
Summary of Topline Results of the ASCEND Trial
Effect on Depressive Symptoms
- AXS-05 was associated with a statistically significant mean reduction from baseline in the
Montgomery-Åsberg Depression Rating Scale (MADRS) total score, calculated at each time point in the study and averaged, of 13.7 points for AXS-05 compared to 8.8 for bupropion (p<0.001).
- At Week 6, AXS-05 was associated with a statistically significant mean reduction from baseline in the MADRS total score of 17.2 points compared to a reduction of 12.1 points for bupropion (p=0.013).
- Remission, an absence of clinically significant symptoms of depression, prospectively defined as a MADRS total score of ≤ 10, was seen at Week 6 in 47% of patients who received AXS-05, compared to 16% of patients who received bupropion (p=0.004).
- Multiple other secondary endpoints improved in favor of AXS-05 with most achieving statistical significance (e.g. MADRS-6, CGI-I, CGI-S, etc.).
Time Course of Effect on Depressive Symptoms
- AXS-05 demonstrated a statistically significant reduction in total MADRS scores from baseline during the first two weeks of treatment as compared to bupropion (p=0.01).
- Numerical superiority of AXS-05 over bupropion for the reduction from baseline in the total MADRS score was seen at Week 1, with statistical significance achieved at Week 2 and at all time points thereafter. The effect was sustained as evidenced by a reduction, at Week 6, of 17.2 points for AXS-05 compared to a reduction of 12.1 points for bupropion (p=0.013).
- Remission rates were statistically significantly superior for AXS-05 as compared to bupropion starting at Week 2 (p=0.004) and at every time point thereafter including Week 6 (p=0.004).
- Improvement on the Clinical Global Impression-Improvement (CGI-I) scale was statistically significantly greater for AXS-05 as compared to bupropion at Week 1 (p=0.045); improvement with AXS-05 compared to bupropion on the CGI-I was also seen at Week 6 (p=0.051), with 59% of AXS-05 patients “Very Much Improved” compared to 27% of bupropion patients.
Safety and Tolerability
- AXS-05 was safe and well tolerated in the trial with similar rates of adverse events in the AXS-05 and bupropion arms.
- There were no serious adverse events, and there was no meaningful difference between the two treatment arms in discontinuations due to adverse events.
- The most commonly reported adverse events in the AXS-05 arm were nausea, dizziness, dry mouth, decreased appetite, and anxiety.
- Treatment with AXS-05 was not associated with psychotomimetic effects, weight gain, or increased sexual dysfunction.
Conference Call Information
Axsome will host a conference call and webcast with slides today at
About the ASCEND Trial
ASCEND (Assessing Clinical Episodes in Depression) is a Phase 2, randomized, double-blind, active-controlled, multicenter trial of AXS-05 in patients with major depressive disorder (MDD) conducted in
About Major Depressive Disorder (MDD)
Major depressive disorder (MDD) is a debilitating, chronic, biologically-based disorder characterized by low mood, inability to feel pleasure, feelings of guilt and worthlessness, low energy, and other emotional and physical symptoms, and which impairs social, occupational, educational, or other important functioning. In severe cases, MDD can result in suicide. According to the
AXS-05 is a novel, oral, investigational medicine under development for the treatment of major depressive disorder and other central nervous system (CNS) disorders. AXS-05 consists 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 available therapies for depression. 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 30 issued U.S. and international patents which provide protection out to 2034. AXS-05 is not approved by the
3. Rush AJ, et al. (2007) Am J. Psychiatry 163:11, pp. 1905-1917 (STAR*D Study).
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Source: Axsome Therapeutics, Inc.