Axsome Therapeutics, a biopharmaceutical company developing novel therapies for the management of central nervous system (CNS) disorders, today announced positive results from the open-label Phase 2 COMET-SI trial of AXS-05 in patients with major depressive disorder (MDD) who have suicidal ideation (SI). Patients treated with AXS-05 experienced a rapid reduction of suicidal ideation, rapid functional improvement, and rapid, substantial, and durable improvements in overall depressive symptoms.

The COMET-SI trial evaluated 37 patients with suicidal ideation, defined as a score of ≥3 on the Suicidality Item of the Montgomery-Åsberg Depression Rating Scale (MADRS-SI), at baseline. Patients were treated with AXS-05 (45 mg dextromethorphan-105 mg bupropion modulated delivery tablet) twice daily for up to 12 months. AXS-05 is a novel, oral, investigational NMDA receptor antagonist with multimodal activity.

A rapid reduction in suicidal ideation was observed with AXS-05 treatment, as demonstrated by reductions in the MADRS-SI score of 67.6% by Week 1, the earliest time point measured, 73.5% by Week 2, and 82.4% by Week 4. Resolution of suicidal ideation with AXS-05 treatment was achieved by 60.0% of patients by Week 1, 68.8% by Week 2, and 77.8% of patients by Week 4. The resolution was defined as a MADRS-SI score of 0 or 1 on a 0 to 6 scale.

The effect of AXS-05 on suicidal ideation in the open-label COMET-SI trial is consistent with new controlled data from the previously completed placebo-controlled GEMINI and active-controlled ASCEND trials of AXS-05 in the treatment of MDD. Integrated analysis from these trials demonstrated a rapid reduction in MADRS-SI scores with AXS-05 compared to placebo or active control, which was statistically significant at Week 1, the earliest time point assessed (p=0.001 versus control).

The improvement in suicidal ideation with AXS-05 treatment in the COMET-SI trial was accompanied by rapid, substantial, and durable improvement in functional impairment, as measured by the Sheehan Disability Scale (SDS). The SDS is a patient-rated scale designed to assess function in work, social life, and family life, and is among the most commonly used function scales in depression clinical trials. Functional response on the SDS (defined as a total score of ≤12) was achieved after treatment with AXS-05 by 51.4% of patients at Week 1, 62.5% of patients at Week 2, and 76.9% of patients at Week 6.

Clinicians reported rapid, substantial, and durable global improvement in depression, measured by the Clinical Global Impression of Improvement (CGI-I) scale, in patients treated with AXS-05 in the COMET-SI trial. Marked or moderate improvement in depressive symptoms was achieved after treatment with AXS-05 by 40.0% of patients at Week 1, 59.4% of patients at Week 2, and 69.2% of patients at Week 6.

AXS-05 treatment in the COMET-SI trial also resulted in rapid, substantial, and durable improvement in depressive symptoms as measured by the MADRS total score. Patients experienced a mean reduction from baseline in the MADRS total score of 12.9 points at Week 1, 17.8 points at Week 2, and 22.8 points at Week 6. Clinical response on the MADRS (defined as ≥50% reduction in total score from baseline) was achieved after treatment with AXS-05 by 25.7% of patients at Week 1, 46.9% of patients at Week 2, and 69.2% of patients at Week 6. Remission from depression (defined as MADRS ≤10) was achieved after treatment with AXS-05 by 11.4% of patients at Week 1, 28.1% of patients at Week 2, and 50.0% of patients at Week 6.

“These early data are the first for AXS-05 in major depressive disorder patients with suicidal ideation, and highlight the rapid onset of action of AXS-05, observed by the first week, on clinically important measures in this serious condition,” said Herriot Tabuteau, MD, Chief Executive Officer of Axsome. “The results of the COMET-SI trial suggest that AXS-05, as an oral NMDA receptor antagonist, may provide unique benefits to patients by potentially rapidly and durably improving not only suicidal thoughts but also functional impairment associated with depression. These positive effects expand on and are consistent with the differentiated clinical profile of AXS-05 observed in our completed controlled trials in patients with major depressive disorder.”

AXS-05 was well tolerated in the COMET trial. The safety profile observed was consistent with what was previously reported in controlled trials of AXS-05 in MDD, with the most commonly reported adverse events being dizziness, nausea, headache, dry mouth, and decreased appetite.

COMET-SI Results Summary

A total of 37 patients with major depressive disorder (MDD) who had suicidal ideation at baseline were treated with AXS-05 (45 mg dextromethorphan-105 mg bupropion modulated delivery tablet) twice daily for up to 12 months. Suicidal ideation was defined as a score of ≥3 on the Suicidality Item of the Montgomery- Åsberg Depression Rating Scale (MADRS-SI) on a 0 to 6 scale. Topline results are summarized below:

• The mean MADRS-SI score was 3.4 at baseline. The mean MADRS total score was 36.8 at baseline. The mean Sheehan Disability Scale score was 21.2 at baseline.
• Treatment with AXS-05 was associated with reductions from baseline in the MADRS-SI score of 67.6% by Week 1, the earliest time point assessed, 73.5% by Week 2, and 82.4% by Week 4 (mean point reductions of 2.3, 2.5, 2.8, respectively).
• Resolution of suicidal ideation, defined as a MADRS-SI score of 0 or 1, after treatment with AXS-05 was achieved by 60.0% of patients by Week 1, 68.8% of patients by Week 2, and 77.8% of patients by Week 4.
• Functional response on the Sheehan Disability Scale (defined as a total score of ≤12) after treatment with AXS-05, was achieved by 51.4% of patients at Week 1, 62.5% of patients at Week 2, and 76.9% of patients at Week 6.
• Marked or moderate improvement in depressive symptoms after treatment with AXS-05, assessed by the Clinical Global Impression of Improvement scale, was achieved by 40.0% of patients at Week 1, 59.4% of patients at Week 2, and 69.2% of patients at Week 6.
• Treatment with AXS-05 was associated with a mean reduction from baseline in the MADRS total score of 12.9 points at Week 1, 17.8 points at Week 2, and 22.8 points at Week 6.
• Clinical response on the MADRS (defined as ≥50% reduction from baseline) after treatment with AXS-05 was achieved by 25.7% of patients at Week 1, 46.9% of patients at Week 2, and 69.2% of patients at Week 6.
• Remission from depression (defined as MADRS ≤10) after treatment with AXS-05 was achieved by 11.4% of patients at Week 1, 28.1% of patients at Week 2, and 50.0% of patients at Week 6.

AXS-05 is a novel, oral, uncompetitive NMDA receptor antagonist, also known as a glutamate receptor modulator, a new mechanism of action that is thought to help enhance synaptic connections and improve the communication between brain cells in people with depression. AXS-05 is also a sigma-1 receptor agonist; 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 depression. AXS-05 is covered by more than 93 issued U.S. and international patents providing protection out to 2040, and Axsome maintains worldwide rights. AXS-05 was granted Breakthrough Therapy designation by the U.S. Food and Drug Administration (FDA) for the treatment of MDD in March 2019.

About the COMET-SI Trial

The COMET-SI trial was a Phase 2, open-label study evaluating the efficacy and safety of AXS-05 in patients with major depressive disorder (MDD) who had suicidal ideation (SI), defined as a score of ≥3 on the Suicidality Item of the Montgomery-Åsberg Depression Rating Scale (MADRS-SI). Enrolled patients were treated with AXS-05 (45 mg dextromethorphan-105 mg bupropion modulated delivery tablet) twice daily for up to 12 months. Efficacy measures included the MADRS-SI score, the MADRS total score, Clinical Global Impression of Improvement (CGI-I), and the Sheehan Disability Scale (SDS).

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 Department of Health and Human Services, an estimated 7.8% of U.S. adults, or approximately 19.4 million, experience MDD each year. According to the World Health Organization (WHO), depression is the leading cause of disability worldwide and is a major contributor to the overall global burden of disease. Nearly two-thirds of diagnosed and treated patients do not experience adequate treatment response with currently available first-line therapy, highlighting the need for additional therapies with new mechanisms of action. The majority of initial failures also fail second-line treatment. Patients diagnosed with MDD are defined as having treatment-resistant depression (TRD) if they have failed to respond to two or more antidepressant therapies.

About AXS-05

AXS-05 (dextromethorphan-bupropion modulated delivery tablet) is a novel, oral, patent-protected, investigational NMDA receptor antagonist with multimodal activity under development for the treatment of major depressive disorder and another central nervous system (CNS) disorders. AXS-05 utilizes a proprietary formulation and dose of dextromethorphan and bupropion, and Axsome’s metabolic inhibition technology, to modulate the delivery of the components.

The dextromethorphan component of AXS-05 is an uncompetitive 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 an 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 93 issued U.S. and international patents which provide protection out to 2040. AXS-05 has been granted the U.S. Food and Drug Administration (FDA) Breakthrough Therapy designation for the treatment of MDD. AXS-05 is not approved by the FDA.

About Axsome Therapeutics, Inc.

Axsome Therapeutics, Inc. is a biopharmaceutical company developing novel therapies for the management of central nervous system (CNS) disorders for which there are limited treatment options. For the many people facing unsatisfactory treatments for CNS disorders, Axsome accelerates the invention and adoption of life-changing medicines. Axsome’s core CNS product candidate portfolio includes five clinical-stage candidates, AXS-05, AXS-07, AXS-09, AXS-12, and AXS-14. AXS-05 is being developed for major depressive disorder (MDD), Alzheimer’s disease (AD) agitation, and as a treatment for smoking cessation. AXS-07 is being developed for the acute treatment of migraine. AXS-12 is being developed for the treatment of narcolepsy. AXS-14 is being developed for fibromyalgia. AXS-05, AXS-07, AXS-09, AXS-12, and AXS-14 are investigational drug products not approved by the FDA.