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 key secondary endpoints in
the STRIDE-1 trial by rapidly and statistically significantly
improving symptoms of depression on the Montgomery-Åsberg
Depression Rating Scale (MADRS), as early as Week 1 and for the
overall 6-week treatment period, as compared to the active
comparator bupropion in patients with treatment resistant
depression (TRD). The STRIDE-1 trial did not reach statistical
significance on the Week 6 primary endpoint on MADRS. STRIDE-1 was
a randomized, double-blind, active-controlled, multi-center, U.S.
trial, in which 312 adult patients with confirmed TRD, who had
failed two or three prior treatments, were randomized to treatment
with either AXS-05 (45 mg dextromethorphan/105 mg bupropion) or 150
mg bupropion, twice daily for 6 weeks.
AXS-05 rapidly and significantly improved
symptoms in patients with TRD as measured by MADRS averaged over
the entire 6-week treatment period, a key secondary endpoint, with
mean reductions of 8.6 for AXS-05 versus 6.7 for bupropion
(p=0.031). The rapid onset of action with AXS-05 treatment was
demonstrated with statistically significant mean MADRS reductions
at Week 1, the earliest time point measured, of 5.2 versus 3.6
respectively for AXS-05 and bupropion (p=0.02), and at Week 2 of
8.0 versus 6.1 respectively for AXS-05 and bupropion (p=0.035),
both time points being key secondary endpoints. At Week 6, the
primary endpoint, AXS-05 demonstrated a numerically greater
improvement in MADRS, with mean reductions of 11.6 for AXS-05
versus 9.4 for bupropion (p=0.117).
AXS-05 rapidly and significantly improved
depressive symptoms in patients with TRD as measured by the Quick
Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR-16)
averaged over the entire 6-week treatment period, with mean
reductions of 3.3 for AXS-05 versus 2.3 for bupropion (p=0.013).
Rates of remission from depression (defined as QIDS-SR-16 ≤5) were
statistically significantly greater for AXS-05 compared to
bupropion at Week 1 (p=0.001) and at every time point thereafter,
being achieved by 18.2% of AXS-05 patients compared to 8.2% of
bupropion patients at Week 6 (p=0.012).
AXS-05 significantly improved cognitive function
in patients with TRD as compared to bupropion, assessed using the
Cognitive subscale of the Massachusetts General Hospital Cognitive
and Physical Functioning Questionnaire (CPFQ) (p=0.011). Cognitive
dysfunction is well documented in the different phases of major
depression, and plays an important role in functional recovery from
major depression. The improvement in cognitive function with AXS-05
was rapid as compared to bupropion, reaching statistical
significance as early as Week 2 (p=0.01) and at every time point
thereafter. The Cognitive subscale of the CPFQ assesses
sharpness/mental acuity, and the ability to focus/maintain
attention, to remember/recall information, and to find words.
Statistical significance for the superiority of AXS-05 versus
bupropion was also achieved for the entire CPFQ (p=0.014), which
assesses physical in addition to cognitive functioning.
AXS-05 rapidly and significantly reduced anxiety
symptoms in patients with TRD as compared to bupropion, assessed
using the Hamilton Anxiety Scale (HAM-A) (p=0.009). AXS-05
demonstrated numerical improvement versus the active comparator
bupropion for all other efficacy variables assessed.
“In patients with depression that is resistant
to current treatments, AXS-05 demonstrated a rapid and clinically
meaningful improvement in depressive symptoms and in cognitive
function. The results with AXS-05 in this trial are especially
notable in light of the well-known low level of response in
treatment resistant depression, the use of an active comparator
administered at a higher dose, and the administration of the active
comparator for twice the duration of AXS-05 administration,” 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.
“The results of the STRIDE-1 trial add to the growing body of
evidence for the anti-depressant effects of AXS-05, an NMDA
receptor antagonist with multimodal activity. These data suggest
that AXS-05 may represent a novel approach both for the frontline
treatment of major depressive disorder, and for treatment resistant
depression.”
The positive findings with AXS-05 in patients
with TRD build upon the rapid and statistically significant
improvements in depressive symptoms in patients with MDD previously
demonstrated in two pivotal trials, the ASCEND active-controlled
trial and the GEMINI placebo-controlled trial. 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 and ASCEND trials are
sufficient to support submission of a New Drug Application (NDA)
for AXS-05 for the treatment of MDD, as previously disclosed.
Axsome remains on track to submit the NDA in the fourth quarter of
2020.
AXS-05 was well tolerated in the trial. The most
commonly reported adverse events in the AXS-05 arm were dizziness
and nausea. The rates of discontinuation due to adverse events were
low in both treatment groups (2.6% for AXS-05 and 1.9% for
bupropion). There were 3 serious adverse events in the AXS-05 arm,
consisting of migraine; overdose; and suicidal ideation, which
occurred more than one week after the cessation of treatment.
Treatment with AXS-05 was not associated with psychotomimetic
effects, weight gain, or sexual dysfunction.
“These STRIDE-1 results provide the first
evidence of clinical activity of AXS-05 in patients with treatment
depression, an area of high unmet medical need. Although the
primary endpoint at week 6 did not reach statistical significance,
we are encouraged by the overall results as they continue to
demonstrate a rapid, statistically significant onset of action for
AXS-05 which, in this study, has translated through to even the
most difficult-to-treat population,” said Herriot Tabuteau, MD,
Chief Executive Officer of Axsome. “The differentiated profile of
AXS-05 demonstrated in the STRIDE-1 trial, including rapid
induction of remission, and positive effects on cognition and
anxiety, support the continued development of AXS-05 in treatment
resistant depression, and initiation of a second Phase 3 trial in
this indication is anticipated in the third quarter. Separately, we
remain on track to file an NDA in the fourth quarter for AXS-05 in
the treatment of major depressive disorder, based on the previously
completed positive GEMINI and ASCEND trials. We expect data
readouts from our INTERCEPT Phase 3 trial of AXS-07 in early
treatment of migraine imminently, and from our ADVANCE-1 Phase 2/3
trial of AXS-05 in Alzheimer’s disease agitation in early second
quarter.”
“STRIDE-1 is now the third efficacy trial in
which AXS-05 has demonstrated a rapid, statistically significant
onset of action in patients with depression and it is the second
trial against the active comparator bupropion in which AXS-05 has
demonstrated statistically significant improvement in depressive
symptoms,” said Cedric O’Gorman, MD, Senior Vice President of
Clinical Development and Medical Affairs of Axsome. “The novel NMDA
mechanism and multimodal action of AXS-05 may be especially
relevant to patients with TRD given the growing evidence for the
importance of glutamatergic modulation in depression. The observed
improvements in both cognition and anxiety with AXS-05 are also
noteworthy and expand AXS-05’s therapeutic profile in CNS
disorders.”
Based on the results of the STRIDE-1 trial,
Axsome intends to initiate a second Phase 3 trial of AXS-05 in
patients with treatment resistant depression in the third quarter
of 2020. 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
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
STRIDE-1 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 over the entire 6-week treatment period
(key secondary endpoint), with mean reductions of 8.6 for AXS-05
versus 6.7 for bupropion (p=0.031).
- AXS-05 was associated with a statistically significant mean
reduction from baseline in the Quick Inventory of Depressive
Symptomatology-Self-Rated (QIDS-SR-16) total score over the entire
6-week treatment period, with mean reductions of 3.3 for AXS-05
versus 2.3 for bupropion (p=0.013).
- Remission from depression (defined as QIDS-SR-16 ≤5) was
statistically significantly greater for AXS-05 compared to
bupropion, being achieved by 18.2% of AXS-05 patients compared to
8.2% of bupropion patients at Week 6 (p=0.012).
Time Course of Effect on Depressive Symptoms
- At Week 1 (key secondary endpoint), the earliest time point
assessed, AXS-05 demonstrated a statistically significant mean
reduction from baseline in the MADRS total score of 5.2 versus 3.6
for bupropion (p=0.02).
- At Week 2 (key secondary endpoint), AXS-05 demonstrated a
statistically significant mean reduction from baseline in the MADRS
total score of 8.0 versus 6.1 for bupropion (p=0.035).
- At Week 6 (primary endpoint), AXS-05 demonstrated a numerically
greater improvement in MADRS, with mean reductions of 11.6 for
AXS-05 versus 9.4 for bupropion (p=0.117).
- At Week 1, remission rates (defined as QIDS-SR-16 ≤5) were
statistically significantly greater with AXS-05 versus bupropion
(p=0.001), with statistical significance maintained at every time
point thereafter.
Cognitive Function
- AXS-05 was associated with a statistically significant
improvement in cognitive function in patients as compared to
bupropion, assessed using the Cognitive subscale of the
Massachusetts General Hospital Cognitive and Physical Functioning
Questionnaire (CPFQ) (p=0.011).
- The improvement in cognitive function with AXS-05 was rapid as
compared to the active comparator bupropion, reaching statistical
significance as early as Week 2 (p=0.01) and at every time point
thereafter.
Anxiety Symptoms
- AXS-05 rapidly and significantly reduced anxiety symptoms as
compared to bupropion, assessed using the Hamilton Anxiety Scale
(HAM-A) (p=0.009).
Safety and Tolerability
- AXS-05 was well tolerated in the trial.
- The most commonly reported adverse events in the AXS-05 arm
were dizziness and nausea. There were 3 serious adverse events in
the AXS-05 arm, consisting of migraine; overdose; and suicidal
ideation, which occurred more than one week after the cessation of
treatment.
- The rates of discontinuation due to adverse events were low in
both treatment groups (2.6% for AXS-05 and 1.9% for
bupropion).
- Treatment with AXS-05 was not associated with psychotomimetic
effects, weight gain, or sexual dysfunction.
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 STRIDE-1 trial of AXS-05 in treatment resistant depression.
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
will join the call and will be available to answer questions. To
participate in the live conference call, please dial (844) 698-4029
(toll-free domestic) or (647) 253-8660 (international), and use the
passcode 4166236. 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 STRIDE-1 Trial
STRIDE-1 (Symptom Treatment in Resistant
Depression 1) was a Phase 3, randomized, double-blind, active
controlled trial to assess the efficacy and safety of AXS-05 in the
treatment of treatment resistant depression (TRD). Patients with
major depressive disorder (MDD) who had previously failed one or
two antidepressant treatments were treated in an open-label fashion
with 150 mg bupropion twice daily (300 mg total daily dose) (n=799)
during a 6-week lead-in period. Patients who failed to respond to
bupropion during this lead-in period were randomized in a 1:1 ratio
to treatment with bupropion at this same total daily dose (n=156),
or to treatment with AXS-05 (45 mg dextromethorphan/105 mg
bupropion) twice daily (90 mg dextromethorphan/210 mg bupropion
total daily dose) (n=156), for 6 weeks. The change in depressive
symptoms over time was measured using the Montgomery-Åsberg
Depression Rating Scale (MADRS) and the Quick Inventory of
Depressive Symptomatology-Self-Rated (QIDS-SR-16). The primary
endpoint was the change from baseline in the MADRS after 6 weeks of
treatment. The key secondary endpoints were the change from
baseline in the MADRS after 1 week of treatment, after 2 weeks of
treatment, the average change over entire 6-week double-blind
treatment period, and the Sheehan Disability Scale (SDS). Other
pre-specified secondary efficacy variables included the Cognitive
subscale of the Massachusetts General Hospital Cognitive and
Physical Functioning Questionnaire (CPFQ), and the Hamilton Anxiety
Scale (HAM-A).
About Treatment Resistant Depression
(TRD)
Patients diagnosed with major depressive
disorder (MDD) are defined as having TRD if they have failed two or
more antidepressant therapies. MDD is a serious condition
characterized by depressed mood or a loss of interest or pleasure
in daily activities consistently for at least a two-week period,
and which impairs social, occupational, educational, or other
important functioning. According to the National Institute of
Health, an estimated 7.1% of U.S. adults experience MDD each year.
Nearly two-thirds of diagnosed and treated patients do not
experience adequate treatment response with first-line therapy, and
the majority of these initial failures also fail second-line
treatment.
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
40 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 as well as Fast Track designations for the
treatment of treatment resistant depression and for the treatment
of Alzheimer’s disease agitation. 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 being developed for
major depressive disorder (MDD), treatment resistant depression
(TRD), Alzheimer’s disease (AD) agitation, and for smoking
cessation treatment. 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 the treatment of
fibromyalgia. AXS-05, AXS-07, AXS-09, AXS-12, and AXS-14 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.
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 MOMENTUM clinical trial to
provide a basis for approval of AXS-07 for the acute treatment of
migraine in adults with or without aura, pursuant to our special
protocol assessment; 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; unforeseen
circumstances or other disruptions to normal business operations
arising from or related to COVID-19; 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.
Axsome Contact: Mark Jacobson Chief Operating
Officer 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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