Additional data from ALS patients enrolled in confirmatory Phase III STAR trial announced

Dec 9 2009

AVANIR Pharmaceuticals, Inc. (NASDAQ: AVNR) today announced additional data from the subset of patients with amyotrophic lateral sclerosis (ALS) enrolled in the confirmatory Phase III STAR trial. This double-blind study evaluated two doses of the investigational drug Zenvia™ (dextromethorphan/quinidine) compared to placebo in the treatment of patients with pseudobulbar affect (PBA) secondary to ALS or multiple sclerosis (MS). In the ALS patient subset, both Zenvia 30/10 mg and Zenvia 20/10 mg met the primary efficacy endpoint by significantly reducing daily PBA episode rates compared to placebo (p<0.0001 for both treatment groups). These results were presented today during a podium presentation at the 20^th International Symposium on ALS/MND in Berlin, Germany.

Highlights – ALS Patient Cohort:

• Both Zenvia groups met the primary endpoint in the subset of patients with underlying ALS by significantly reducing daily PBA episode rates compared to placebo (p<0.0001 for both treatment groups)
• Both Zenvia groups met the secondary endpoint in the subset of patients with underlying ALS by significantly reducing mean CNS-LS scores compared to placebo>
• Zenvia was generally safe and well-tolerated in the ALS patient subset
• Reported that 90.8%, 77.9% and 85.9% of ALS 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 ALS patient population is especially impacted by the emotional outbursts of PBA with up to 50% of ALS patients affected by this socially disabling disorder. The new lower dose formulations of Zenvia demonstrated the ability to vastly reduce the number of PBA episodes and was well-tolerated in this vulnerable population,” said presenter Benjamin Rix Brooks, MD, Director of Carolinas Neuromuscular/ALS-MDA Center and Steering Committee Member for the STAR trial. “PBA is a condition with no effective treatments and an FDA-approved therapy could improve the lives of these patients and their caregivers.”

“We were very pleased that Zenvia demonstrated significant efficacy in the ALS sub-population,” said Randall Kaye, MD, AVANIR’s Chief Medical Officer. “The Avanir team is now working expeditiously to file our complete response with the FDA early in the second quarter of 2010 so that, if approved, we can make Zenvia available to patients suffering from PBA.”

EFFICACY RESULTS

The primary efficacy analysis was based on the changes from baseline in crying/laughing episodes (PBA episodes) recorded in the patient diary. PBA episode counts were reported and analyzed as a rate expressed as episodes per day. The primary outcome was the additional reduction in PBA episode rates experienced with Zenvia 30/10 mg compared to placebo. In the ALS subset, Zenvia 30/10 mg provided a 62.9% incremental reduction in PBA episode rates compared to placebo over the course of the study (p<0.0001). In a secondary analysis of the primary endpoint, Zenvia 20/10 mg provided a 63.4% incremental reduction in PBA episode rates compared to placebo over the course of the study (p<0.0001).

An important 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 severity of PBA, where a higher score indicates more severe PBA. Results from this secondary endpoint are summarized in the following table:

SAFETY AND TOLERABILITY RESULTS

Overall, Zenvia was generally safe and well-tolerated in the ALS population. In the ALS subset, the percent of patients completing the study was 90.8% for Zenvia 30/10 mg, 77.9% for Zenvia 20/10 mg, and 85.9% for placebo. The most common adverse events among ALS patients that were more frequent in the Zenvia groups than for placebo were dizziness, fatigue, nausea and diarrhea.

Most Common (≥5% of Total Population) Adverse Events (Safety Population)

In the ALS subset, seven patients in the Zenvia 30/10 mg group, nine patients in the Zenvia 20/10 mg group and eight patients in the placebo group reported serious adverse events (SAEs). Overall, there were seven deaths in patients with underlying ALS. In total, three deaths occurred in the Zenvia 30/10 mg arm, three in the 20/10 mg arm and one in the placebo arm. All deaths were respiratory related and appeared to be consistent with ALS disease progression.

CONCLUSIONS

• In this trial, PBA episodes were frequent and severe at baseline in patients with underlying ALS. Both the Zenvia 30/10 mg dose and the Zenvia 20/10 mg dose were significantly superior to placebo for decreasing PBA episode rates.
• Overall, Zenvia 30/10 mg and 20/10 mg were effective, safe, and well-tolerated for the treatment of PBA in patients with underlying ALS. The new formulation of Zenvia appeared to demonstrate equivalent efficacy with a potentially improved safety and tolerability profile, compared with formulations of higher doses.

STAR TRIAL DESIGN

The STAR (Safety, Tolerability and Efficacy Results of AVP-923 in PBA) trial was a confirmatory Phase III trial of Zenvia in patients with pseudobulbar affect (PBA). The randomized, multi-center, international STAR trial compared 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 extension study. At the conclusion of enrollment of the double-blind phase, 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 52 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 was based on the changes in crying/laughing episode rates recorded in patient diaries. Secondary endpoints for this clinical trial included: 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 were determined by reporting adverse events, physical exam, vital signs, electrocardiogram, respiratory function tests and clinical assessment of clinical laboratory variables. A total of 283 patients completed the double-blind phase and 253 (or 89.4% of eligible patients) enrolled in the 12-week open label extension. All patients in the open-label extension received Zenvia 30/10 mg twice daily. Efficacy was assessed at baseline and during subsequent clinic visits using the CNS-LS score. Safety and tolerability assessments were the same as in the double-blind phase of the study. The STAR trial was conducted under a Special Protocol Assessment (SPA) from the U.S. Food and Drug Administration (FDA).