Avanir Pharmaceuticals Announces Presentation of AVP-923 Phase II Results in Agitation in Patients with Alzheimer's Disease at the American Neurological Association Meeting

--Study Demonstrated Clinically Meaningful and Statistically Significant Improvement of Agitation in Patients with Alzheimer's Disease--

ALISO VIEJO, Calif., Oct. 13, 2014 -- Avanir Pharmaceuticals, Inc. (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
• 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

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
• 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.

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