Avanir Pharmaceuticals Announces JAMA Publication of Phase II Study Results Showing AVP-923 Significantly Reduced Agitation in Patients with Alzheimer's Disease

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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