AVANIR Pharmaceuticals (AVNR) Presents Detailed Zenvia Confirmatory Phase III Results

Oct. 13, 2009 (Business Wire) — AVANIR Pharmaceuticals, Inc. (NASDAQ: AVNR) today announced detailed results from the confirmatory double-blind Phase III STAR trial evaluating two doses of the investigational drug Zenvia™ (dextromethorphan/quinidine) compared to placebo in the treatment of pseudobulbar affect (PBA) in patients with underlying multiple sclerosis (MS) or amyotrophic lateral sclerosis (ALS). Over the course of the 12-week study, Zenvia 30/10 mg and 20/10 mg met the primary efficacy endpoint by reducing PBA episode rates by an incremental 47.2% and 47.8% respectively, beyond placebo (p<0.0001). These results were presented today during a late-breaker poster session at the 134th Annual Meeting of the American Neurological Association in Baltimore, MD (Poster Number: WIP-24).

EFFICACY HIGHLIGHTS

• Both the Zenvia 30/10 mg and 20/10 mg groups met the primary efficacy endpoint by demonstrating a significant reduction in daily PBA episode rates relative to the placebo group
• The proportion of patients with complete remission of PBA episodes was significantly greater in both Zenvia treatment groups versus placebo
• The percent of days that were episode-free was significantly higher in the Zenvia groups versus placebo
• Zenvia 30/10 mg demonstrated statistical superiority in time to onset of clinically meaningful effect
• Both Zenvia groups demonstrated a greater proportion of patients versus placebo that achieved response thresholds of 50%, 75% and 90% improvement
• Mean reduction from baseline in CNS-LS score was significantly greater for both Zenvia treatment groups than in the placebo group
• Zenvia 30/10 mg demonstrated significantly greater mean improvement in SF-36 Mental Health Summary scores compared to placebo
• Zenvia 30/10 mg demonstrated significantly greater mean improvement in Beck Depression Inventory scores compared to placebo

In an additional analysis of the primary endpoint pre-specified in the protocol, the percentage of patients that achieved and maintained complete episode remission during the last 14 days of the study was 76% in the Zenvia 30/10 mg group, 80% in the 20/10 mg group and 61% in the placebo group (p=0.0024 and p=0.0001).

Proportion of Patients with No PBA Episodes in Previous 14 Days at Each Study Visit
Study Visit				Zenvia 30/10 mgN = 110				Zenvia 20/10 mgN = 107				PlaceboN = 109				p-values 30/10mg vs. placebo 20/10mg vs. placebo
Day 15				59%				54%				47%				p=0.0123 p=0.1528
Day 29				68%				70%				55%				p=0.0094p=0.0015
Day 57				74%				77%				60%				p=0.0071 p=0.0021
Day 84				76%				80%				61%				p=0.0024 p=0.0001

Responder Analysis of Reduction in Daily PBA Episode Rates (ITT Population)a
Responder Analysis – Proportion of Patients				Zenvia 30/10 mgN = 110				Zenvia 20/10 mgN = 107				PlaceboN = 109
Decrease in PBA Episodes ≥ 50%				78.84%				76.29%				61.38%
Decrease in PBA Episodes ≥ 75%				67.30%				62.88%				41.58%
Decrease in PBA Episodes ≥ 90%				50.96%				51.54%				32.67%

p<0.0001 for overall treatment effect throughout the entire study. ^aITT = intent-to-treat population, refers to all patients randomized.

A 30% decrease from baseline in number of PBA episodes was considered to indicate the onset of a clinically meaningful effect. At day 15, the earliest time point assessed, 72% of patients in the Zenvia 30/10 mg group had experienced an onset of meaningful effect compared to 59% in the placebo group (p<0.0358). The difference between the Zenvia 20/10 mg and placebo groups showed a trend for a higher proportion in the 20/10 mg group.

“Frequent, unrelenting and unpredictable emotional outbursts may occur in progressive neurological conditions, such as ALS, MS, and dementia, or strokes and traumatic brain injuries. The results of the STAR trial indicate that the new low dose formulations of Zenvia can dramatically reduce the debilitating episodes of PBA and may one day help improve the lives of these patients,” said Benjamin Rix Brooks, MD, Director of Carolinas Neuromuscular/ALS-MDA Center and Steering Committee Member for the STAR trial.

“We were thrilled with the Zenvia clinical profile that emerged in the STAR trial,” said Randall Kaye, MD, AVANIR’s Chief Medical Officer. “The data demonstrated a profound treatment effect across multiple efficacy measures in PBA combined with an improved safety and tolerability profile relative to the previous formulation. With the STAR trial data in hand, our team is now working to expeditiously assemble and submit our full response to the FDA approvable letter with the objective of securing approval in the second half of 2010.”

ADDITIONAL EFFICACY RESULTS

An important efficacy secondary endpoint analysis was based on the change from baseline to end of study using the Center for Neurologic Studies Lability Scale (CNS-LS). The CNS-LS is a validated instrument measuring the frequency and severity of PBA, where a higher score indicates more severe PBA. Additional secondary endpoints included the Neuropsychiatric Inventory Questionnaire (NPI-Q) and the Beck Depression Inventory (BDI-II). No worsening of NPI-Q scores was demonstrated relative to placebo. Data from these secondary efficacy endpoints are summarized in the following table:

Change in Mean Scores on Secondary Outcomes From Baseline to End of Study (ITT Population)a
Secondary Endpoint				Zenvia 30/10 mgN = 110				Zenvia 20/10 mgN = 107				PlaceboN = 109				p-values 30/10mg vs. placebo 20/10mg vs. placebo
CNS – Lability Scale Score				-8.17				-8.24				-5.7				p=0.0002 p=0.0113
Neuropsychiatric Inventory Questionnaire – Frequency Score				-1.62				-2.56				-1.33				p=n/sb p=n/s
Neuropsychiatric Inventory Questionnaire – Severity Score				-0.74				-1.59				-0.98				p=n/s p=n/s
Beck Depression Inventory				-1.59				-1.03				+0.03				p=0.0336 p=n/s

^aITT = intent-to-treat population, refers to all patients randomized. ^bn/s = non-statistically significant.

An additional secondary endpoint was the SF-36 Health Status Survey, a validated scale used to assess mental and physical health where a 3-point increase is considered a clinically meaningful improvement. Quality of life was improved for Zenvia 30/10 mg treated patients as indicated by improvements over placebo in the SF-36 Mental Summary Score, Social Functioning, Mental Health and Bodily Pain sub-domain scores. SF-36 data are summarized below:

Change From Baseline to End of Study in SF-36 Health Status Scores (ITT Population)a

SF-36 Domain

Zenvia 30/10 mgN = 110

Zenvia 20/10 mgN = 107

PlaceboN = 109

P-Values 30/10mg vs. placebo 20/10mg vs. placebo

SF-36 Mental Summary

+4.51

+1.77

+0.28

p = 0.0193 p = n/sb

Vitality Scale

-0.90

-5.30

-4.05

p = n/s p = n/s

Social Functioning

+9.34

+1.42

-3.09

p = 0.0033 p = n/s

Role Emotional

+11.55

-1.81

+2.36

p = n/s p = n/s

Mental Health Scale

+5.53

+3.09

-0.28

p = 0.0028 p = n/s

SF-36 Physical Summary

-0.76

-1.03

-1.35

p = n/s p = n/s

Physical Functioning

-0.90

-5.30

-4.05

p = n/s p = n/s

Role Physical

+3.47

-4.26

-1.75

p = n/s p = n/s

Bodily Pain

+4.09

+5.84

-1.13

p = 0.0740 p = 0.0678

General Health

-1.47

-2.95

-1.40

p = n/s p = n/s

^aITT = intent-to-treat population, refers to all patients randomized. ^bn/s = non-statistically significant.

SAFETY AND TOLERABILITY RESULTS

Overall, Zenvia was generally safe and well tolerated in this study. In the STAR trial, 91.8%, 82.2% and 86.2% of patients completed the 12-week double blind phase of the study in the Zenvia 30/10 mg, Zenvia 20/10 mg and placebo groups, respectively. The most common reason for early withdrawals was due to adverse events (AEs) with 3.6%, 7.5% and 1.8% for the Zenvia 30/10 mg, Zenvia 20/10 mg and placebo groups discontinuing due to AEs, respectively. Reported AEs were generally mild to moderate in nature and the most commonly reported adverse events reported more frequently for Zenvia than placebo were dizziness (18.7%, 10.8%, 5.7%), nausea (13.1%, 7.8%, 9.4%) and diarrhea (10.3%, 13.7%, 6.6%) for Zenvia 30/10 mg, Zenvia 20/10 mg and placebo, respectively. While commonly reported, falls, headache, somnolence and fatigue were no different than placebo. The proportion of patients reporting at least one serious adverse event (SAE) was 7.3% in the Zenvia 30/10 mg group, 8.4% in the Zenvia 20/10 mg group and 9.2% in the placebo group. During the course of the study there were no clinically meaningful changes in QT interval, no reported pro-arrhythmic events, no reports of any cardiovascular SAEs and no new cardiovascular safety signals were observed. Seven deaths were reported and all occurred in patients with ALS (3 in each of the Zenvia groups and 1 in the placebo group). All deaths were associated with respiratory depression, respiratory failure, and/or progression of ALS.

STAR TRIAL DESIGN

The STAR (Safety, Tolerability and Efficacy Results of AVP-923 in PBA) trial is a confirmatory Phase III trial of Zenvia in patients with pseudobulbar affect (PBA). The randomized, multi-center, international STAR trial compares active treatment with Zenvia 30/10 mg BID and Zenvia 20/10 mg BID to placebo during a 12-week, double-blinded phase, followed by a 12-week, open-label safety extension study. At the conclusion of enrollment, AVANIR had enrolled a total of 326 patients (197 with underlying ALS and 129 with underlying MS) who exhibited signs and symptoms of PBA across 62 sites in the U.S. and Latin America. A total of 110, 107 and 109 patients were randomized to the Zenvia 30/10 mg group, the Zenvia 20/10 mg group and the placebo group, respectively. The primary efficacy analysis is based on the changes in crying/laughing episode rates recorded in patient diaries. Secondary endpoints for this clinical trial include: 1) Center for Neurologic Study-Lability Scale (CNS-LS) score; 2) Neuropsychiatric Inventory Questionnaire (NPI-Q); 3) SF-36 Health Survey; 4) Beck Depression Inventory (BDI-II); and 5) Pain Rating Scale score (MS patients only). Safety and tolerability of Zenvia are determined by reporting adverse events, physical exam, vital signs, electrocardiogram, respiratory function tests and clinical assessment of clinical laboratory variables. The STAR trial is being conducted under a Special Protocol Assessment (SPA) from the U.S. Food and Drug Administration (FDA). For more information visit www.pbatrial.com.

ABOUT PBA

Pseudobulbar affect (PBA), also known as emotional lability, is a neurologic disorder that occurs secondary to neurologic disease or brain injury causing sudden and unpredictable episodes of crying, laughing, or other emotional displays. PBA is estimated to impact approximately 2 million people in the United States with underlying neurologic conditions such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson’s disease, dementias including Alzheimer’s disease, stroke, and traumatic brain injury. PBA episodes may occur when disease or injury damages the area of the brain that controls normal expression of emotion. This damage can disrupt brain signaling causing a “short circuit” and triggering involuntary PBA episodes. PBA has been shown to impair the lives of patients in both social and occupational settings. There are currently no FDA approved treatments for PBA.

ABOUT ZENVIA

Zenvia™ (dextromethorphan/quinidine) is a combination of two well-characterized compounds: the therapeutically active ingredient dextromethorphan and the enzyme inhibitor quinidine, which serves to increase the bioavailability of dextromethorphan. This first-in-class drug candidate is believed to help regulate excitatory neurotransmission in two ways: through pre-synaptic inhibition of glutamate release via sigma-1 receptor agonist activity and through postsynaptic glutamate response modulation via uncompetitive, low-affinity NMDA antagonist activity. Zenvia is being developed for the treatment of pseudobulbar affect (PBA) and has successfully completed a Phase III trial for diabetic peripheral neuropathic (DPN) pain. In October 2006, the Company received an approvable letter for Zenvia in the treatment of PBA. The Company conducted the STAR trial under a Special Protocol Assessment (SPA) agreement with the FDA with the goal of addressing safety concerns raised in the Agency’s approvable letter for Zenvia in the treatment of PBA. For more information about this trial visit http://www.pbatrial.com, and for more information about the Agency’s SPA process, see http://www.fda.gov/cder/guidance/3764fnl.htm. In addition, AVANIR has conducted a Phase III study of Zenvia in DPN pain where the primary endpoints were successfully met. Subsequently the Company released top-line results of a formal PK study that identified alternative lower-dose quinidine formulations of Zenvia for DPN pain intended to deliver similar efficacy and improved safety/tolerability versus the formulations previously tested for this indication. AVANIR is now engaged in discussions with the FDA under the SPA process regarding the design of the next Phase III study in DPN pain and overall program requirements.

ABOUT AVANIR

AVANIR Pharmaceuticals, Inc. is a biopharmaceutical company focused on acquiring, developing, and commercializing novel therapeutic products for the treatment of central nervous system disorders. AVANIR’s lead product candidate, Zenvia, is being developed for the treatment of pseudobulbar affect (PBA) and has successfully completed a Phase III trial for diabetic peripheral neuropathic (DPN) pain. AVANIR has licensed its MIF inhibitor program to Novartis International Pharmaceuticals Ltd. and has sold its anthrax monoclonal antibody program to Emergent BioSolutions. The Company’s first commercialized product, Abreva^® (docosanol), is marketed in North America by GlaxoSmithKline Consumer Healthcare and is the leading over-the-counter product for the treatment of cold sores. Further information about AVANIR can be found at www.avanir.com and further information about pseudobulbar affect can be found at www.PBAinfo.org.

FORWARD LOOKING STATEMENTS

Statements in this press release that are not historical facts, including statements that are preceded by, followed by, or that include such words as “estimate,” “intend,” “anticipate,” “believe,” “plan,” “goal,” “expect,” “project,” or similar statements, are forward-looking statements that are subject to certain risks and uncertainties that could cause actual results to differ materially from the future results expressed or implied by such statements. For example, there can be no assurance that the U.S. Food and Drug Administration (FDA) will approve Zenvia for any indication, or that the Company will meet projected timelines. Risks and uncertainties affecting the Company’s financial condition and operations also include the risks set forth in AVANIR’s most recent Annual Report on Form 10-K and subsequent Quarterly Reports on Form 10-Q, and from time-to-time in other publicly available information regarding the Company. Copies of this information are available from AVANIR upon request. AVANIR disclaims any intent to update these forward-looking statements.

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