Axsome Therapeutics Announces AXS-05 Achieves Primary Endpoint in GEMINI Phase 3 Trial in Major Depressive Disorder
Demonstrated rapid, durable, and statistically significant improvement in depressive symptoms as measured by MADRS total score compared to placebo (p=0.002 on primary endpoint)
Statistically significant improvement at week 1 in MADRS total score compared to placebo (key secondary endpoint, p=0.007)
Statistically significant improvement versus placebo on all secondary endpoints at week 6, including remission (p<0.001), disease severity (p=0.002), functional impairment (p=0.002), and quality of life (p=0.011)
Positive results support NDA filing of AXS-05 for MDD, anticipated in 2H 2020
Potentially first-and-only, oral NMDA receptor antagonist with multimodal activity for the treatment of depression
Company to host conference call today at
AXS-05 met the primary endpoint by demonstrating a highly statistically significant reduction in the
AXS-05 demonstrated rapid onset of action with statistically significant improvement as compared to placebo on numerous endpoints at Week 1, or only 4 days after the start of twice daily dosing. Statistically significant improvements at Week 1 were observed for MADRS total score (key secondary endpoint, p=0.007); Patient Global Impression-Improvement (PGI-I) (p=0.008); Clinical Global Impression-Severity (CGI-S) (p=0.013); Clinical Global Impression-Improvement (CGI-I) (p=0.035); Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR-16) (p=0.016); Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) (p=0.031); and other endpoints.
On all secondary endpoints including the following, AXS-05 demonstrated statistically significant improvement at Week 6 compared to placebo, reflecting increasing treatment effects over time: clinical response on the MADRS total score (defined as ≥50%) (p<0.001); PGI-I (p=0.007); CGI-S (p=0.002); CGI-I (p=0.016); QIDS-SR-16 (p=0.001); Sheehan Disability Scale (SDS) (p=0.002); and Q-LES-Q-SF (p=0.011).
"AXS-05 demonstrated a rapid and very clinically meaningful improvement in depressive symptoms, observed after only one week, in this large and well-controlled Phase 3 trial in major depressive disorder. Given the known challenges of conducting trials in psychiatry, it is very encouraging to see replication of Phase 2 findings in such a robust way,” said Professor
AXS-05 was well tolerated in the trial. The most commonly reported adverse events in the AXS-05 arm were dizziness, nausea, headache, diarrhea, somnolence, and dry mouth. There was one serious adverse event in the AXS-05 arm which was deemed by the investigator not to be study-drug related. The rates of discontinuation due to adverse events were low in both treatment groups (6.2% for AXS-05 and 0.6% for placebo). Treatment with AXS-05 was not associated with psychotomimetic effects or weight gain.
“We are very pleased with the compelling results of the GEMINI trial which demonstrate the potential for AXS-05 to provide significant benefits to patients living with depression, based on observed rapid and sustained antidepressant effects, resulting from its potentially first-in-class, oral NMDA receptor antagonist and multimodal mechanism of action,” said
AXS-05 was granted Breakthrough Therapy designation by the
“Depression is a major public health concern with most patients failing to adequately respond to currently approved antidepressants,” said Cedric O’Gorman, MD, Senior Vice President of Clinical Development and Medical Affairs of Axsome. “The potentially fatal consequences of depression highlight the need to rapidly and effectively control depressive symptoms. The positive results of the GEMINI study are significant and exciting because they bring us closer to our goal of addressing this public health need with a potentially first-in-class, rapid-acting, effective, oral, antidepressant which can be safely administered at home. With its modulation of glutamate neurotransmission, if approved, AXS-05 would represent the first mechanistically novel oral pharmacotherapy for depression in over 30 years.”
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 is 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 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 41 issued U.S. and international patents providing protection out to 2034, and Axsome maintains worldwide rights.
Detailed study results, including additional secondary endpoints, will be submitted for presentation at upcoming medical meetings and for publication. 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, and in the ADVANCE-1 trial in patients with Alzheimer’s disease agitation. AXS-05 was granted Fast Track designations by the
Summary of Topline Results of the GEMINI 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 of 16.6 points for AXS-05 compared to 11.9 for placebo at Week 6 (p=0.002).
- Remission, an absence of clinically significant symptoms of depression, prospectively defined as a MADRS total score of ≤10, was seen at Week 6 in 39.5% of patients who received AXS-05, compared to 17.3% of patients who received placebo (p<0.001).
- Response, defined as a ≥50% improvement in the MADRS total score, was seen at Week 6 in 54.0% of patients who received AXS-05, compared to 34.0% of patients who received placebo (p<0.001).
- All secondary endpoints improved in favor of AXS-05 and achieved statistical significance at Week 6 (e.g. PGI-I, CGI-S, CGI-I, QIDS-SR-16, MADRS-6, etc.).
Time Course of Effect on Depressive Symptoms
- AXS-05 demonstrated a statistically significant mean reduction from baseline in the MADRS total score of 7.3 points for AXS-05 compared to 4.9 points for placebo at Week 1 (p=0.007), with statistical significance for this measure maintained at all time points thereafter.
- Statistically significant improvements at Week 1 were also observed for the PGI-I (p=0.008), CGI-S (p=0.013), CGI-I (p=0.035), QIDS-SR-16 (p=0.016), MADRS-6 (p=0.019), and other endpoints. Statistically significant effects on these measures were generally maintained at all time points thereafter.
- Remission rates were statistically significantly greater for AXS-05 as compared to placebo at Week 2 (p=0.013) and at every time point thereafter.
Quality of Life and Functional Impairment
- AXS-05 was associated with a statistically significant improvement in quality of life, as measured by the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF), compared to placebo at Week 1 (p=0.031), and at every time point thereafter (p=0.011, at Week 6).
- AXS-05 was associated with a statistically significant reduction in functional impairment, as measured by the Sheehan Disability Scale (SDS), compared to placebo at Week 2 (p=0.003), and at every time point thereafter (p=0.002, at Week 6).
Safety and Tolerability
- AXS-05 was well tolerated in the trial.
- The most commonly reported adverse events in the AXS-05 arm were dizziness, nausea, headache, diarrhea, somnolence, and dry mouth. There was one serious adverse event in the AXS-05 arm which was deemed by the investigator not to be study-drug related.
- The rates of discontinuation due to adverse events were low in both treatment groups (6.2% for AXS-05 and 0.6% for placebo).
- Treatment with AXS-05 was not associated with psychotomimetic effects or weight gain.
Conference Call Information
Axsome will host a conference call and webcast with slides today at
About the GEMINI Trial
GEMINI (Glutamatergic and Monoaminergic Modulation in Depression) was a Phase 3, randomized, double-blind, multicenter, placebo-controlled trial of AXS-05 in patients with major depressive disorder (MDD) conducted in the U.S. A total of 327 patients with a confirmed diagnosis of moderate to severe MDD were randomized in a 1:1 ratio to receive AXS-05 (45 mg dextromethorphan/105 mg bupropion) (n=163), or placebo (n=164), twice daily for 6 weeks. The mean
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, 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 41 issued U.S. and international patents which provide protection out to 2034. AXS-05 has been granted
National Institute of Mental Health. (2017). Major Depression. Retrieved from https://www.nimh.nih.gov/health/statistics/major-depression.shtml. World Health Organization. Fact Sheets: Depression, accessed October 9, 2018, http://www.who.int/en/news-room/fact-sheets/detail/depression.
- Rush AJ, et al. (2007) Am J. Psychiatry 163:11, pp. 1905-1917 (STAR*D Study).
Forward Looking Statements
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Source: Axsome Therapeutics, Inc.