Full Press Release Details
Therapeutics Announces AXS-05 Achieves Primary Endpoint in the ADVANCE-1 Pivotal Phase
2/3 Trial in Alzheimer's Disease Agitation
significant improvement in Alzheimer's disease agitation, as measured by the CMAI total score
compared to placebo (p=0.010, primary endpoint)
rapid and substantial improvement in Alzheimer's disease agitation starting at week 2 with
statistical significance at week 3 compared to placebo (p=0.007)
significant rates of clinical response (p=0.005) on the CMAI and improvement on the modified
Alzheimer's Disease Cooperative Study-CGIC scale for agitation (p=0.036) compared to placebo
and not associated with cognitive impairment or sedation
treatments are currently approved for Alzheimer's disease agitation
to host conference call today at 8:00 AM ET
YORK, April 27, 2020 (Globe Newswire) - 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 in the ADVANCE-1 Phase
2/3 trial and rapidly, substantially, and significantly improved agitation in patients with Alzheimer's disease as compared
to placebo. The ADVANCE-1 (Addressing Dementia via Agitation-Centered Evaluation) study was a randomized, double-blind, controlled,
multicenter, U.S. trial, in which 366 Alzheimer's disease patients were randomized to treatment with AXS-05 (dextromethorphan/bupropion
modulated delivery tablet, dose escalated to 45 mg/105 mg twice daily), bupropion (dose escalated to 105 mg twice daily), or matching
placebo, for 5 weeks.
are currently no FDA-approved treatments for Alzheimer's disease agitation. Alzheimer's disease is the most common
form of dementia and is characterized by cognitive decline, and behavioral and psychological symptoms including agitation. Agitation
is observed in up to 70% of patients with Alzheimer's disease and is associated with accelerated cognitive decline, earlier
nursing home placement, and increased mortality risk [1-3]. AXS-05 has been granted FDA Fast Track designation for the treatment
of Alzheimer's disease agitation.
met the primary endpoint by demonstrating a statistically significant mean reduction in the Cohen Mansfield Agitation Inventory
(CMAI) total score compared to placebo at Week 5, with mean reductions from baseline of 15.4 points for AXS-05 and 11.5 points
for placebo (p=0.010). These results represent a mean percentage reduction from baseline of 48% for AXS-05 versus 38% for placebo.
The CMAI is a 29-item caregiver-rated scale that assesses the frequency of agitation-related behaviors in patients with dementia,
including excessive motor activity such as pacing and restlessness, verbal aggression such as screaming and shouting, and physical
aggression such as grabbing, pushing, and hitting. AXS-05 was also superior to bupropion on the CMAI total score (p<0.001),
establishing component contribution.
rapidly improved agitation symptoms. Improvement on the CMAI total score with AXS-05 was numerically superior to placebo starting
at Week 2, achieving statistical significance at Week 3 (p=0.007) only one week after full dosing with AXS-05.
statistically significantly greater proportion of patients achieved a clinical response on the CMAI, defined as a 30% or greater
improvement from baseline, with AXS-05 as compared to placebo (73% versus 57%, p=0.005). These results were consistent with clinicians'
global assessments of change measured using the modified Alzheimer's Disease Cooperative Study-Clinical Global Impression
of Change for Agitation (mADCS-CGIC). AXS-05 demonstrated statistically significantly greater improvement in agitation as compared
to placebo on this measure (p=0.036).
am very pleased to see the promising results of the ADVANCE-1 trial, providing clear evidence of reduced agitation in Alzheimer's
disease by this investigational medicine," said Jeffrey Cummings, M.D., Sc.D., Director
of the Cleveland Clinic Lou Ruvo Center for Brain Health, and Chambers Professor of Brain Science at the University of Nevada
Las Vegas. "The clinically significant reductions in agitation were accompanied by a favorable safety and tolerability profile.
Agitation occurs in the majority of patients with Alzheimer's disease, is very distressing to patients and their families,
and is associated with greater risk of institutionalization and accelerated progression to severe dementia and death. Given the
lack of approved treatments for Alzheimer's disease agitation, and the safety concerns and modest or uncertain efficacy
of currently used off-label treatments, the AXS-05 study results represent a meaningful step forward toward urgently needed treatment
for this serious complication of Alzheimer's disease."
AXS-05 was well tolerated in the trial.
The most commonly reported adverse events in the AXS-05 arm were somnolence (8.2% for AXS-05 versus 4.1% for bupropion and 3.2%
for placebo), dizziness (6.3%, 10.2%, 3.2%, respectively), and diarrhea (4.4%, 6.1%, 4.4%, respectively). The rates of discontinuation
due to adverse events were 1.3%, 2.0%, and 1.3% in the AXS-05, bupropion, and placebo arms, respectively. Serious adverse events
were reported in 3.1% of patients treated with AXS-05, compared to 8.2% of bupropion- and 5.7% of placebo-treated patients. No
serious adverse events were deemed to be related to study drug in any treatment arm. There was one death in the placebo arm, one
in the bupropion arm, and none in the AXS-05 arm. There was no evidence of cognitive decline for patients treated with AXS-05
as shown by the Mini-Mental State Examination (MMSE), a widely utilized measure of general cognitive function. Treatment with
AXS-05 was not associated with sedation.
are excited by the rapid and substantial effect of AXS-05 on agitation in patients with Alzheimer's disease observed in
this trial," said Herriot Tabuteau, MD, Chief Executive Officer of Axsome. "The positive ADVANCE-1 Phase 2/3 trial
represents a potentially important milestone for Alzheimer's disease patients, their caregivers, and physicians, particularly
given the lack of approved treatments for, and the serious and distressing nature of, Alzheimer's disease agitation. We
look forward to discussing these data with the FDA. These results underscore the potentially broad applicability of the pharmacology
of AXS-05, which has also resulted in positive pivotal trial results in major depressive disorder. We remain on track to submit
an NDA for AXS-05 for the treatment of major depressive disorder, as well as for our AXS-07 product candidate for the acute treatment
of migraine, both in the fourth quarter of this year."
the ADVANCE-1 trial, AXS-05 has now demonstrated efficacy in Alzheimer's disease agitation, depression, and smoking cessation
trials. Additionally, AXS-05 has shown a rapid onset of action in both Alzheimer's disease agitation and depression against
both active and placebo comparators," said Cedric O'Gorman, MD, Senior Vice President of Clinical Development and Medical
Affairs of Axsome. "Axsome is committed to accelerating the innovation of effective and safe medicines for the many people
underserved by currently available CNS therapies, as exemplified by our late-stage pipeline comprising five product candidates
in development for seven different indications."
is a novel, oral, non-competitive NMDA receptor antagonist with activity on other neurotransmitter systems (sigma-1, serotonin,
norepinephrine, dopamine) that have been implicated in the cognitive and behavioral abnormalities in Alzheimer's disease
[2,5,6]. AXS-05 may therefore enhance synaptic transmission and improve the functioning of cortical circuits in patients with
Alzheimer's disease and agitation. Microglial activation is believed to contribute to neuronal damage in neurodegenerative
diseases including Alzheimer's disease [7]. In vitro pharmacological actions of AXS-05 include inhibition of microglial
activation [8]. AXS-05 is covered by more than 42 issued U.S. and international patents providing protection out to 2034, and
Axsome maintains worldwide rights.
study results will be submitted for presentation at upcoming medical meetings and for publication.
of Topline Results of the ADVANCE-1 Trial
Course of Effect on Agitation
will host a conference call and webcast with slides today at 8:00 AM Eastern to discuss the topline results of the ADVANCE-1 trial
of AXS-05 in Alzheimer's disease agitation. To participate in the live conference call, please dial (844) 698-4029 (toll-free
domestic) or (647) 253-8660 (international), and use the passcode 9617816. 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.
(Addressing Dementia via Agitation-Centered Evaluation 1) was a Phase 2/3 randomized, double-blind, controlled, multicenter, U.S.
trial to evaluate the efficacy and safety of AXS-05 in patients with agitation associated with Alzheimer's disease. Patients
with a diagnosis of probable Alzheimer's disease and clinically meaningful agitation associated with their disease were
randomized, initially in a 1:1:1 ratio, to receive AXS-05 (dextromethorphan/bupropion, dose escalated from 30 mg/105 mg once daily
to 45 mg/105 mg twice daily), bupropion (dose escalated from 105 mg once daily to 105 mg twice daily), or matching placebo, for
5 weeks. An independent data monitoring committee performed an interim futility analysis and recommended no further randomization
to the bupropion arm. Subsequently, patients were randomized in a 1:1 ratio to receive AXS-05 or placebo. Total patients randomized
were 159, 49, and 158 to the AXS-05, bupropion, and placebo arms, respectively. The mean Cohen-Mansfield Agitation Inventory (CMAI)
total scores at baseline were 60.8, 66.1, and 59.3, respectively for the AXS-05, bupropion, and placebo groups. The minimum score
on the CMAI is 29, corresponding to the total absence of symptoms, with higher scores corresponding to greater agitation. The
of the study was the change from baseline in the CMAI total score at Week 5. P-values were calculated based on least square mean
Alzheimer's Disease (AD) Agitation
disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, and behavioral and psychological
symptoms including agitation. AD is the most common form of dementia and afflicts an estimated 6 million individuals in the United
States, a number that is anticipated to increase to approximately 14 million by 2050 [4]. Agitation is reported in up to 70% of