ALISO VIEJO, Calif.,
Oct. 13, 2014 /PRNewswire/
-- Avanir Pharmaceuticals, Inc. (NASDAQ: AVNR)
today announced that results from the Phase II study evaluating
AVP-923 for the treatment of agitation in patients with Alzheimer's
disease were presented at the 2014 American Neurological
Association Meeting.
In this study utilizing the two-stage, sequential parallel
comparison design (SPCD), AVP-923 showed a clinically meaningful
and statistically significant improvement in agitation on the
primary endpoint and a majority of the secondary endpoints. Key
highlights from the poster were:
- AVP-923 showed a statistically significant benefit on the
agitation/aggression domain of the Neuropsychiatric Inventory (NPI)
(primary endpoint; p=0.00008)
- The NPI agitation/aggression score was reduced by 3.3 points
from baseline in AVP-923 treated patients at week five (stage 1;
p=0.0002 v. placebo) and was reduced by 2.0 points in stage 2
(p=0.021)
- The change in the NPI agitation/aggression score corresponds to
a mean (SD) reduction from baseline of 47 percent (43.1 percent)
for AVP-923 vs. 22 percent (50.8 percent) for placebo in Stage 1,
and 26 percent (67.5 percent) for AVP-923 vs. 6.7 percent (77.9
percent) for placebo in Stage 2.
- Treatment benefit with AVP-923 was evident at week one and was
sustained for the duration of the 10-week study
- AVP-923 also demonstrated significant improvements versus
placebo on the following outcomes: NPI total score (p=0.014), NPI4A
(p=0.001), NPI4D (p<0.001), clinical global impression of
change-agitation (p=0.0003), patient global impression of change
(p=0.001) and measures of caregiver burden (p≤0.05)
- AVP-923 was generally safe and well-tolerated and associated
with a low rate of discontinuation from the study (11.8
percent)
- Treatment with AVP-923 was not associated with cognitive
decline or somnolence
"Agitation and aggression in Alzheimer's disease are among the
most disruptive of dementia-related neuropsychiatric symptoms and
leading causes of institutionalization," said Jeffrey Cummings, MD, director of the Cleveland
Clinic Lou Ruvo Center for Brain Health, chair of the study
steering committee and a paid member of Avanir Pharmaceuticals
Advisory Board, Inc. "These study results are encouraging for
Alzheimer's patients suffering from agitation and their
caregivers."
"We are highly encouraged by these data showing a nearly 50
percent reduction in agitation for patients treated with AVP-923.
In addition, clear improvements in global measures of agitation, as
assessed by both clinicians and patients/caregivers, indicate the
improvement was deemed clinically meaningful," said Joao Siffert, MD, chief medical officer for
Avanir. "We are committed to working with regulatory agencies in
the United States and the EU with
the goal to advance the program and make the treatment available as
early as possible, upon approval, for patients with Alzheimer's
disease who have agitation."
Primary Endpoint
The treatment effect of AVP-923 was measured using the
agitation/aggression domain of the NPI. The NPI is a well-accepted
tool and was developed to provide a means of assessing
neuropsychiatric symptoms and psychopathology of patients with
Alzheimer's disease and other neurodegenerative disorders. The NPI
has proven to be sensitive to change and has been employed to
capture treatment related behavioral changes in patients receiving
cholinesterase inhibitors, antipsychotic agents, melatonin and a
variety of other anti-dementia and psychotropic compounds. The NPI
is comprised of 12 domains. The score for each domain is the
product of frequency (on a four-point scale) x severity (on a
three-point scale). The maximum score on any single
sub-domain is therefore 12. A 30 percent reduction in the
agitation/aggression domain of the NPI is considered to be a
clinically meaningful improvement in symptoms. The NPI
caregiver distress score provides internal validity to the score of
each NPI domain and the overall NPI.
At the study baseline, the NPI agitation/aggression domain was
7.0 and 7.1 for patients in the AVP-923 and placebo groups,
respectively. At the end of stage 1, scores for the AVP-923 treated
patients had reduced by 3.3 (SD=2.98), vs. 1.7 (SD=3.10) for
placebo (p<0.001), amounting to a 47 percent reduction and a
Standard Effect Size (SES)=0.505. In stage 2, where only placebo
non-responders were included in the primary analysis, a reduction
of 2.0 (SD=3.19) was observed in patients treated with AVP-923 vs.
0.8 for patients on placebo (p=0.021), corresponding to a 26
percent reduction for AVP-923 vs. a 6.7 reduction for placebo and a
SES=0.340.
Secondary Endpoints and Safety Measures
Clinical benefits were observed across a number of secondary
endpoints providing additional insight into the overall treatment
effect. Improvements were observed in the following measures
(SPCD analysis):
- Total NPI: p=0.014
- Two NPI domain clusters encompassing commonly observed symptoms
of agitation:
- NPI4A (agitation/aggression: irritability/lability; aberrant
motor behavior; and anxiety): p=0.001
- NPI4D (agitation/aggression; irritability/lability; aberrant
motor behavior; and disinhibition): p<0.001
- Clinical Global Impression of Change-agitation: p=0.0003
- Clinical Global Impression of Change-overall: p=0.005
- Patient Global Impression of Change: p=0.001
- Measures of caregiver distress/strain:
- Caregiver Distress – NPI agitation/aggression: p=0.01
- Caregiver Distress NPI total: p=0.014
- Caregiver Strain Index (CSI): p=0.05
- Cornell Scale for Depression in
Dementia (CSDD): p=0.02
Additionally, there was no evidence of cognitive decline for
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).
Two secondary endpoints, the Alzheimer's Disease Cooperative
Study-Activities of Daily Living (ADCS-ADL) Inventory and Quality
of Life-AD (QoL-AD) Measure (patient and caregiver) showed no
difference between treatment groups (p=NS).
In the study, AVP-923 was shown to be generally well tolerated
with treatment emergent adverse events consistent with the known
safety profile of AVP-923. The most common adverse events (with an
incidence greater than 3 percent and greater than placebo) were
falls (8.6 percent versus 3.9 percent), diarrhea (5.9 percent
versus 3.1 percent) and urinary tract infection (5.3 percent versus
3.9 percent) for AVP-923 versus placebo, respectively. In addition,
no new cardiovascular safety signals and no clinically significant
changes in QTc were observed in the study. Serious adverse
events were reported in 7.9 percent of patients receiving AVP-923
versus 4.7 percent receiving placebo. The overall patient
discontinuation rate was low (11.8 percent); 5.3 percent of
patients discontinued the study due to an adverse event in the
AVP-923 group versus 3.1 percent in the placebo group.
Phase II Study Design
The 10-week randomized, double-blind, placebo-controlled,
multicenter Phase II study evaluated the efficacy, safety and
tolerability of AVP-923 for the treatment of agitation in
Alzheimer's patients. The study utilized a sequential parallel
comparison design (SPCD) intended to reduce placebo response rates,
and consisted of two consecutive double-blind treatment stages,
each of 5-week duration. A total of 220 Alzheimer's patients in
the United States were enrolled.
Eligible patients were initially randomized in a 3:4 ratio to
receive either AVP-923 (dose escalated from DM 20mg/Q 10mg to DM
30mg/Q 10mg) 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 AVP-923 DM 30mg/Q 10mg for
the remainder of the study.
The main efficacy measure was the agitation/aggression domain of
the Neuropsychiatric Inventory (NPI). The primary endpoint followed
a standard analysis of SPCD by combining the change from baseline
to week 5 (stage 1: full analysis population) and change from week
5 to week 10 (stage 2) on the NPI agitation/aggression domain
(patients who were considered "non-responders" to placebo during
the initial 5 weeks). Secondary outcome measures included global
assessments of disease severity, other neuropsychiatric symptoms,
cognition, activities of daily living, quality of life and
caregiver strain. Standard safety assessments were also
conducted.
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 percent of community-dwelling dementia
patients and in more than 80 percent 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.
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 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 www.avanir.com.
AVANIR® is a trademark or registered trademark of
Avanir Pharmaceuticals, Inc. in the
United States and other countries.
©2014 Avanir Pharmaceuticals, Inc. All Rights
Reserved.
Forward Looking Statements
Except for the
historical information contained herein, the matters set forth in
this press release, including statements regarding Avanir's plans,
potential opportunities, financial or other expectations,
projections, goals objectives, milestones, strategies, market
growth, timelines, legal matters, product pipeline, clinical
studies, product development and the potential benefits of its
commercialized products and products under development are
forward-looking statements within the meaning of the "safe harbor"
provisions of the Private Securities Litigation Reform Act of 1995.
These forward-looking statements are subject to risks and
uncertainties that may cause actual results to differ materially,
including the risks and uncertainties associated with delays in the
release of study results, risks related to the outcome of further
analysis of the data from the study, whether preclinical and
clinical results for AVP-923 or other dextromethorphan drug
products will be predictive of future clinical study results,
whether regulatory agencies domestically and internationally will
discuss advancement of one or more programs into pivotal studies,
whether study data will be accepted for presentation and/or
publication and whether a drug candidate can ultimately be
successfully developed for commercialization, whether future
clinical trials will be completed on time or at all, potential
changes in cost, formulation, scope and duration of the clinical
studies, obtaining additional indications for commercially marketed
products domestically and internationally, obtaining and
maintaining regulatory approvals domestically and internationally,
whether new drugs can be successfully commercialized, and other
risks detailed from time to time in the Company's most recent
Annual Report on Form 10-K and other documents subsequently filed
with or furnished to the Securities and Exchange Commission. These
forward-looking statements are based on current information that
may change and you are cautioned not to place undue reliance on
these forward-looking statements, which speak only as of the date
of this press release. All forward-looking statements are qualified
in their entirety by this cautionary statement, and the Company
undertakes no obligation to revise or update any forward-looking
statement to reflect events or circumstances after the issuance of
this press release.
Avanir Investor & Media Contact
Ian Clements, Ph.D.
ir@avanir.com
+1 (949) 389-6700
BrewLife Media Contact
Kelly
France, Ph.D.
kfrance@brewlife.com
+1 (415) 946-1076
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SOURCE Avanir Pharmaceuticals, Inc.