ALISO VIEJO, Calif.,
Sept. 22, 2015 /PRNewswire/ --
Avanir Pharmaceuticals, Inc. today announced that results
from a phase II study evaluating the efficacy and safety of AVP-923
for the treatment of agitation in patients with Alzheimer's disease
were published today in the Journal of the American Medical
Association (JAMA). The study showed that patients with
moderate to severe agitation secondary to Alzheimer's disease who
were treated with AVP-923 (a combination of dextromethorphan and
quinidine) had a clinically meaningful and statistically
significant improvement measured by the agitation/aggression domain
of the Neuropsychiatric Inventory (NPI), compared with patients
treated with placebo (p<0.001; primary endpoint). The treatment
effect with AVP-923 was evident by week one (p=0.04) and remained
significant at the end of the 10-week study. Additionally,
statistically significant clinical effects were observed with
AVP-923 across the majority of secondary endpoints, including the
NPI total score, clinical global impression of change-agitation,
patient global impression of change and measures of caregiver
burden. AVP-923 was shown to be generally well tolerated in this
elderly population that also received multiple concomitant
medications during the study period. Treatment-emergent adverse
events were consistent with the known safety profile of AVP-923.
The most common adverse events were falls, diarrhea, and urinary
tract infection occurring in less than 10% of patients.
"Agitation, which can include such behaviors as shouting,
cursing, hitting, kicking and pacing, is a common and distressing
symptom in people with Alzheimer's disease and is a major reason
they are transitioned from home to residential care," said
Jeffrey Cummings, M.D., director of
the Cleveland Clinic Lou Ruvo Center for Brain Health, lead author
of the paper, chair of the study steering committee, and a member
of Avanir Pharmaceuticals' Scientific Advisory Board. "In some
studies, agitation in Alzheimer's disease has been shown to be
associated with increased cognitive compromise and mortality. Safe
and effective therapies for Alzheimer's disease-related agitation
are needed."
"The results from this phase II agitation study are very
encouraging, especially given the magnitude and consistency of the
effects observed across endpoints assessed by investigators and
caregivers," said Joao Siffert,
M.D., executive vice president, R&D, and chief medical officer
at Avanir. "Based on meeting the efficacy and safety endpoints of
this study, Avanir expects to begin a phase III program called
TRIAD™ later this year."
Phase II Study Design
The 10-week randomized,
double-blind, placebo-controlled, multicenter phase II study
evaluated efficacy, safety and tolerability of AVP-923 for the
treatment of agitation in Alzheimer's patients. The study utilized
a two-stage, sequential parallel comparison design (SPCD), which
was intended to reduce placebo response rates. The design consisted
of two consecutive double-blind treatment stages, each of 5-week
duration. A total of 220 Alzheimer's patients, aged 50 to 90 years,
were enrolled at 42 sites in the U.S. In stage 1, eligible patients
were randomized in a 3:4 ratio to receive either AVP-923 (dose
escalated from dextromethorphan 20 mg/quinidine 10 mg once per day
to dextromethorphan 30 mg/quinidine 10 mg twice per day) or
placebo. At the end of week 5, patients who initially received
placebo were stratified according to their response to treatment
and subsequently re-randomized in a 1:1 ratio to receive either
AVP-923 or placebo for the remainder of the study (an additional 5
weeks of treatment). Patients who initially received AVP-923
continued to receive the drug at a dose of dextromethorphan 30
mg/quinidine 10 mg twice per day for the remainder of the
study.
The primary efficacy endpoint was change from baseline in the
agitation/aggression domain of the NPI, a well-accepted scale
developed to assess neuropsychiatric symptoms and psychopathology
of patients with Alzheimer's disease and other neurodegenerative
disorders. The primary endpoint followed a standard analysis of
SPCD by combining the change on the NPI agitation/aggression domain
from baseline to week 5 (stage 1: full analysis population) and
change from week 5 to week 10 (stage 2: patients who were
re-randomized after being considered "non-responders" to placebo
during the initial 5 weeks).
Secondary efficacy endpoints included global assessments of
disease severity, other neuropsychiatric symptoms, cognition,
activities of daily living, quality of life and caregiver distress
and strain. Standard safety assessments were also conducted.
Phase II Study Results
For the primary endpoint,
AVP-923 significantly improved the NPI agitation/aggression score
compared with placebo in the primary SPCD analysis (p<0.001).
Treatment effect was evident in both stages of the trial, even when
placebo responders were included in the stage 2 comparison.
- In stage 1, mean NPI agitation/aggression scores were reduced
by 3.3 points with AVP-923 (from 7.1 at baseline to 3.8 at week 5)
and by 1.7 points with placebo (from 7.0 at baseline to 5.3)
(p=0.0002 versus placebo).
- In stage 2, in which only placebo non-responders were included
in the primary analysis, mean NPI agitation/aggression scores were
reduced by 2.0 points with AVP-923 (from 5.8 to 3.8) and by 0.9
points with placebo (from 6.7 to 5.8) (p=0.02 versus placebo).
- AVP-923 demonstrated significant improvements versus placebo on
a number of pre-specified secondary endpoints in the SPCD analysis,
including the NPI total score, multiple caregiver distress ratings,
physician and patient global impression of change and the
Cornell scale for depression in
dementia.
There was no evidence of cognitive decline in patients treated
with AVP-923 as shown by the Mini-Mental State Examination (MMSE),
a widely utilized measure of general cognitive function (SPCD
analysis p=0.053; trend in favor of AVP-923) and the Alzheimer's
Disease Assessment Scale-Cognition (ADAS-Cog) (p=NS). Additionally,
treatment with AVP-923 was not associated with sedation.
Post hoc analyses showed similar improvement in NPI
agitation/aggression scores with AVP-923 in patients taking
concomitant acetylcholinesterase inhibitors, memantine,
antidepressants or antipsychotics compared with those not receiving
these agents.
AVP-923 was generally safe and well tolerated. The most commonly
occurring treatment-emergent adverse events (greater than 3%) were
falls (8.6% versus 3.9%), diarrhea (5.9% versus 3.1%), urinary
tract infection (5.3% versus 3.9%), and dizziness (4.6% versus
2.4%) for AVP-923 versus placebo, respectively. While falls were
more common among patients receiving AVP-923, an imbalance in
pre-randomization risk for falls and an approximately 25% greater
patient-day exposure to AVP-923 versus placebo may have contributed
to the higher rate of falls compared to placebo. Serious adverse
events were reported in 7.9% of patients receiving AVP-923 versus
4.7% receiving placebo. No new cardiovascular safety signals and no
clinically significant changes in QTc were observed in the study.
AVP-923 was associated with a low rate of discontinuation from the
study, with 5.3% of patients discontinuing the study due to an
adverse event in the AVP-923 group versus 3.1% in the placebo
group.
About Agitation in Alzheimer's Disease
An estimated 6
million Americans have Alzheimer's disease, a number that has
doubled since 1980 and is expected to be as high as 16 million by
2050. Alzheimer's disease is generally characterized by cognitive
decline, impaired performance of daily activities, and behavioral
disturbances. Behavioral and psychiatric symptoms develop in as
many as 60% of community-dwelling dementia patients and in more
than 80% of patients with dementia living in nursing homes.
Dementia-related behavioral symptoms, including agitation, can be
extremely distressing to the individual, the family and caregivers.
These behavioral disturbances have been associated with more rapid
cognitive decline, institutionalization and increased caregiver
burden. There are currently no approved treatments for agitation in
patients with dementia related to Alzheimer's disease.
About AVP-923
AVP-923 is a combination of two
well-characterized compounds, the active CNS ingredient
dextromethorphan hydrobromide (an uncompetitive NMDA receptor
antagonist, sigma-1 receptor agonist and inhibitor of the serotonin
transporter [SERT] and norepinephrine transporter [NET]) plus
low-dose quinidine sulfate (a CYP2D6 enzyme inhibitor), which
serves to increase the bioavailability of dextromethorphan. AVP-923
is known to have certain cardiovascular risks and drug-drug
interactions. Patients with a history of certain cardiovascular
risks and on certain drugs were excluded from the study. AVP-923 is
an investigational drug not approved by the FDA for the treatment
of agitation in Alzheimer's disease.
About Avanir Pharmaceuticals, Inc.
Avanir
Pharmaceuticals, Inc. is a biopharmaceutical company focused on
bringing innovative medicines to patients with central nervous
system disorders of high unmet medical need. As part of our
commitment, we have extensively invested in our pipeline and are
dedicated to advancing medicines that can substantially improve the
lives of patients and their loved ones. For more information about
Avanir, please visit http://www.avanir.com.
Avanir is a subsidiary of Otsuka
America, Inc. (OAI), a holding company established in the
U.S. in 1989. OAI is wholly owned by Otsuka Pharmaceutical Co.,
Ltd., a global healthcare company with the corporate philosophy:
'Otsuka-people creating new products for better health
worldwide.'
Otsuka Pharmaceutical is a leading firm in the challenging area
of mental health and also has products and research programs for
several under-addressed diseases including tuberculosis, a
significant global public health issue. These commitments
illustrate more powerfully than words how Otsuka is a "big venture"
company at heart, applying a youthful spirit of creativity in
everything it does.
Otsuka Pharmaceutical and its affiliates employ approximately
30,000 people globally, and the company welcomes you to visit its
global website at: http://www.otsuka.co.jp/en/index.php
Avanir® and TRIAD™ are trademarks or registered trademarks of
Avanir Pharmaceuticals, Inc. in the
United States and other countries.
©2015 Avanir Pharmaceuticals, Inc. All Rights Reserved.
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SOURCE Avanir Pharmaceuticals, Inc.