Axsome Therapeutics, Inc. (NASDAQ: AXSM), a clinical-stage
biopharmaceutical company developing novel therapies for the
management of central nervous system (CNS) disorders, today
announced that AXS-05, a novel, oral, investigational NMDA receptor
antagonist with multimodal activity, met the primary endpoint and
rapidly and significantly improved symptoms of depression in the
GEMINI Phase 3 trial in major depressive disorder (MDD). The GEMINI
study was a randomized, double-blind, placebo-controlled,
multi-center, U.S. trial, in which 327 adult patients with
confirmed moderate to severe MDD were randomized to treatment with
either AXS-05 (dextromethorphan/bupropion modulated delivery
tablet) or placebo once daily for the first 3 days and twice daily
thereafter for a total of 6 weeks.
AXS-05 met the primary endpoint by demonstrating
a highly statistically significant reduction in the
Montgomery-Åsberg Depression Rating Scale (MADRS) total score
compared to placebo at Week 6, with mean reductions from baseline
of 16.6 points for AXS-05 and 11.9 points for placebo (p=0.002).
AXS-05 rapidly and durably improved depressive symptoms as compared
to placebo with statistical significance on the MADRS total score
demonstrated at Week 1, the earliest time point assessed, and at
all time points thereafter. Rates of remission from depression
(defined as MADRS ≤10) were statistically significantly greater for
AXS-05 compared to placebo at Week 2 (p=0.013) and at every time
point thereafter, being achieved by 39.5% of AXS-05 patients
compared to 17.3% of placebo patients at Week 6 (p<0.001).
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 Maurizio
Fava, MD, Psychiatrist-in-Chief at Massachusetts General Hospital
(MGH), Director of the Division of Clinical Research of the MGH
Research Institute, and Associate Dean for Clinical &
Translational Research at Harvard Medical School. “Clinical
depression is a potentially life-threatening condition. Currently
marketed antidepressants fail to provide adequate treatment
response in almost two thirds of treated patients, and may take up
to six to eight weeks to provide clinically meaningful response.
These data suggest that AXS-05, as an oral NMDA receptor antagonist
with multimodal activity, may represent a novel treatment for major
depressive disorder.”
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 Herriot
Tabuteau, MD, Chief Executive Officer of Axsome. “The progress of
the AXS-05 clinical program in mood disorders reflects Axsome’s
commitment to accelerating innovation to address serious CNS
disorders. With GEMINI and the previously completed ASCEND study,
the efficacy of AXS-05 in major depressive disorder has now been
demonstrated in two positive well-controlled trials, enabling the
filing of an NDA for AXS-05, which is anticipated in the coming
year.”
AXS-05 was granted Breakthrough Therapy
designation by the U.S. Food and Drug Administration (FDA) for the
treatment of MDD in March 2019. Based on the outcome of the FDA
Breakthrough Therapy meeting, Axsome believes the positive results
of the GEMINI trial, along with the previously completed ASCEND
trial of AXS-05 in MDD, are sufficient to support submission of a
New Drug Application (NDA) for AXS-05 for the treatment of MDD.
Axsome plans to file the NDA in the second half of 2020.
“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 FDA for the treatment of TRD
and for the treatment of Alzheimer’s disease agitation.
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 8:00 AM Eastern to discuss the topline results
of the GEMINI trial of AXS-05 in major depressive disorder. To
participate in the live conference call, please dial (844) 698-4029
(toll-free domestic) or (647) 253-8660 (international), and use the
passcode 1022339. The live webcast can be accessed on the “Webcasts
& Presentations” page of the “Investors” section of the
Company’s website at axsome.com. A replay of the webcast will be
available for approximately 30 days following the live event.
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 Montgomery-Åsberg Depression
Rating Scale (MADRS) total scores at baseline were 33.6 for the
AXS-05 group and 33.2 for the placebo group. The primary endpoint
of the study was the change from baseline in the MADRS total score
at Week 6. Secondary endpoints included MADRS change at Weeks 1 and
2, remission, response, Clinical Global Impression-Improvement
(CGI-I), Clinical Global Impression-Severity (CGI-S), Patient
Global Impression-Improvement (PGI-I), MADRS-6, Sheehan Disability
Scale (SDS), other quality of life measures, safety and
tolerability. P-values were calculated based on least square mean
estimates.
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 National Institutes of Health, an
estimated 7.1% of U.S. adults, or approximately 17 million,
experience MDD each year1. 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 disease2. Nearly two thirds of diagnosed and treated patients do
not experience adequate treatment response with currently available
first-line therapy3, 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 the Montgomery-Åsberg Depression
Rating Scale (MADRS)
The Montgomery-Åsberg Depression Rating Scale
(MADRS) is a well-established, 10-item, validated rating scale used
to provide an assessment of depression, and as a guide to evaluate
recovery. This scale is an accepted regulatory endpoint for
depression. The scale is used in clinical research to rate the
severity of a patient’s depression by probing mood, feelings of
guilt, suicide ideation, insomnia, agitation, anxiety, weight loss,
and somatic symptoms.
About AXS-05
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 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 clinical-stage
biopharmaceutical company developing novel therapies for the
management of central nervous system (CNS) disorders for which
there are limited treatment options. Axsome’s core CNS product
candidate portfolio includes four clinical-stage candidates,
AXS-05, AXS-07, AXS-09, and AXS-12. AXS-05 is currently in a Phase
3 trial in treatment resistant depression (TRD), a Phase 3 trial in
major depressive disorder (MDD), and a Phase 2/3 trial in agitation
associated with Alzheimer’s disease (AD). AXS-05 is also being
developed for smoking cessation treatment. AXS-07 is currently in
two Phase 3 trials for the acute treatment of migraine. AXS-12 is
being developed for the treatment of narcolepsy. AXS-05, AXS-07,
AXS-09, and AXS-12 are investigational drug products not approved
by the FDA. For more information, please visit the Company’s
website at axsome.com. The Company may occasionally disseminate
material, nonpublic information on the company website.
References
- 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
Certain matters discussed in this press release
are “forward-looking statements”. We may, in some cases, use terms
such as “predicts,” “believes,” “potential,” “continue,”
“estimates,” “anticipates,” “expects,” “plans,” “intends,” “may,”
“could,” “might,” “will,” “should” or other words that convey
uncertainty of future events or outcomes to identify these
forward-looking statements. In particular, the Company’s statements
regarding trends and potential future results are examples of such
forward-looking statements. The forward-looking statements include
risks and uncertainties, including, but not limited to, the
success, timing and cost of our ongoing clinical trials and
anticipated clinical trials for our current product candidates,
including statements regarding the timing of initiation, pace of
enrollment and completion of the trials (including our ability to
fully fund our disclosed clinical trials, which assumes no material
changes to our currently projected expenses), futility analyses and
receipt of interim results, which are not necessarily indicative of
the final results of our ongoing clinical trials, and the number or
type of studies or nature of results necessary to support the
filing of a new drug application (“NDA”) for any of our current
product candidates; our ability to fund additional clinical trials
to continue the advancement of our product candidates; the timing
of and our ability to obtain and maintain U.S. Food and Drug
Administration (“FDA”) or other regulatory authority approval of,
or other action with respect to, our product candidates (including,
but not limited to, FDA’s agreement with the Company’s plan to
discontinue the bupropion treatment arm of the ADVANCE-1 study in
accordance with the independent data monitoring committee’s
recommendations); the potential for the ASCEND clinical trial,
combined with the GEMINI clinical trial results, to provide a basis
for approval of AXS-05 for the treatment of major depressive
disorder and accelerate its development timeline and commercial
path to patients; the Company’s ability to successfully defend its
intellectual property or obtain the necessary licenses at a cost
acceptable to the Company, if at all; the successful implementation
of the Company’s research and development programs and
collaborations; the success of the Company’s license agreements;
the acceptance by the market of the Company’s product candidates,
if approved; the Company’s anticipated capital requirements,
including the Company’s anticipated cash runway and the Company’s
current expectations regarding its plans for future equity
financings prior to the readout from its Phase 3 trials; and other
factors, including general economic conditions and regulatory
developments, not within the Company’s control. The factors
discussed herein could cause actual results and developments to be
materially different from those expressed in or implied by such
statements. The forward-looking statements are made only as of the
date of this press release and the Company undertakes no obligation
to publicly update such forward-looking statements to reflect
subsequent events or circumstance. The data disclosed in this press
release are considered topline data and subject to further
statistical review and the final results may vary.
Axsome Contact: Mark Jacobson Senior Vice
President, Operations Axsome Therapeutics, Inc. 200 Broadway, 3rd
Floor New York, NY 10038 Tel: 212-332-3243 Email:
mjacobson@axsome.com www.axsome.com
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