DPN pain is a common complication of diabetes that has significant impact on outcomes of concern to patients including sleep, activity and quality of life. In a multi-center, 3-month, double-blind Phase III trial, active treatment with Zenvia 45/30 mg dosed twice daily (DM/Q 45) and 30/30 mg DM/Q dosed twice daily (DM/Q 30) over a three month period, was compared to placebo. AVANIR previously announced in April 2007 that both doses of Zenvia had met the primary endpoint of statistically significant improvements versus placebo as recorded in daily patient diary entries using the Pain Rating Scale, as defined in the Special Protocol Assessment (SPA) with the U.S. Food and Drug Administration (FDA). In addition the DM/Q 45 met statistical significance for 4 out of 5 secondary endpoints reported.
Highlights of new Zenvia data presented at ICNP:
-- DM/Q 45 achieved 53%, 59% and 59% improvement versus baseline, DM/Q 30 achieved 43%, 48% and 48% improvement and placebo achieved 27%, 34% and 39% improvement at days 30, 60 and 90, respectively in the Pain Rating Scale.
-- 28% of patients in the DM/Q 45 arm and 27% in the DM/Q 30 arm obtained "a lot" of or "complete" pain relief at three months versus 17% in the placebo group (p=0.0008 and p=0.0017 respectively)
-- Active treatment with both Zenvia doses significantly reduced pain interference with daily activities (p less than 0.0001), and sleep (p less than 0.0001) compared with placebo.
-- The magnitude of the improvements in quality-of-life with Zenvia treatment was approximately 50% greater than that obtained with placebo (p=0.05 for DM/Q 45 and p=0.08 for DM/Q 30).
-- QTc interval mean change was 5 and 2 milliseconds in the DM/Q 45 and DM/Q 30 treatment groups, respectively compared to the screening visit, versus a mean change in QTc interval of -2 milliseconds for placebo at day 92.
-- There were no cases of Torsade de Pointes (a life-threatening condition) or sudden death reported.
"The Phase III trial data indicate that both doses of Zenvia demonstrated significantly superior reduction of pain compared with placebo in patients with DPN pain. Additionally, Zenvia was generally safe and well tolerated, and safety data were consistent with previous clinical studies with no new safety signals noted," said study investigator Aziz Shaibani, MD, FACP, Clinical Assistant Professor, Department of Medicine, Baylor College of Medicine, Houston, Texas.
"Based on the data from this study, we conclude that Zenvia provides significantly greater improvements compared with placebo in pain-related outcomes in patients with DPN pain, including pain relief, activity and sleep. These are important outcomes to patients suffering from daily pain as a complication of their diabetes," stated Randall Kaye, MD, Chief Medical Officer of AVANIR Pharmaceuticals.
Highlights of Posters
Poster: "EFFICACY AND SAFETY OF DEXTROMETHORPHAN/QUINIDINE IN TREATING PAINFUL DIABETIC PERIPHERAL NEUROPATHY: RESULTS OF A PHASE III, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED TRIAL," includes:
-- Treatment with Zenvia resulted in a more rapid and marked reduction in pain scores relative to placebo, with a trend toward greater pain reduction at the higher dose.
-- Both active treatment groups had lower pain ratings than placebo patient s (p less than 0.0001 for both comparisons), demonstrating significantly greater reductions in pain compared with placebo. Pain score averaged over the study periods were significantly lower than placebo in the DM/Q 45 arm for comparisons at days 30, 60 and 90 (p less than 0.0001 for each comparison) and in the DM/Q 30 arm (p less than 0.0001 at days 30 and 60, p=0.0071 at day 90). The consistency in the magnitude of response suggests that the pain reduction obtained with active treatment relative to placebo were maintained over the entire study duration.
-- Improvements from baseline with active treatment appeared to be dose dependent, with the higher dose resulting in improvements that were almost twice as great as placebo.
-- Both doses demonstrated significantly better improvements in pain from baseline that were maintained over the duration of the study.
-- The incidence of AEs was higher in the DM/Q 45 group (91%), compared with placebo (80%) and DM/Q 30 (79%), with the proportion of patients discontinuing due to an AE higher in both active treatments compared with placebo.
-- The most common AEs were dizziness, nausea, diarrhea, fatigue and somnolence and were generally mild to moderate in severity.
-- There were no statistically significant differences in serious adverse event rates reported in the DM/Q 45, DM/Q 30 and placebo groups, and no deaths occurred during the study.
Poster: "IMPROVED PATIENT-CENTERED OUTCOMES WITH DEXTROMETHORPHAN/ QUINIDINE VS PLACEBO IN A PHASE III, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED TRIAL INVESTIGATING PAINFUL DIABETIC PERIPHERAL NEUROPATHY," reports on the secondary efficacy endpoints in the Phase III study on outcomes of importance to patients, including pain relief, sleep and quality-of-life. Highlights include:
-- Both Zenvia doses were significantly superior to placebo in relieving pain. The pattern reported in the Pain Relief Scale complemented that shown by the Pai n Rating Scale scores over the same time period as reported in the primary efficacy analysis.
-- Categorical analysis of the Pain Relief Rating Scale scores averaged at three months showed that almost twice as many patients in each of the Zenvia treatment groups obtained "a lot" of or "complete" pain relief as that in the placebo group.
-- Active treatment with both Zenvia doses significantly reduced pain interference with daily activities compared with placebo (p less than 0.0001).
-- Active treatment with both Zenvia doses significantly reduced pain interference with sleep compared with placebo (p less than 0.0001).
-- The consistency for reduced pain interference with both daily activities and reduced sleep interference across time periods during the study suggests that the benefits of Zenvia relative to placebo were maintained over the entire study period.
-- The magnitude of the improvements in quality-of-life with Zenvia was approximately 50% greater than that obtained with placebo (p=0.05 for DM/Q 45 and p=0.08 for DM/Q 30).
Cardiovascular findings were assessed by EKGs at screening, as well as clinical visits at day 1, 15 and 92. At day 15 the mean change in QTc interval compared to the screening visit was 1 millisecond in both treatment groups, versus a mean change in QTc interval of -2 milliseconds for placebo. At day 92 the mean change in QTc intervals was 5 and 2 milliseconds in the DM/Q 45 and DM/Q 30 treatment groups, respectively compared to the screening visit, versus a mean change in QTc interval of -2 milliseconds for placebo. These increases were consistent with what has been observed in previous studies. There were no cases of Torsade de Pointes or sudden death reported. The most commonly reported adverse events from this Phase III study were dizziness, nausea, diarrhea, fatigue and somnolence which were mild to moderate in nature. A higher number of patients in the DM/Q 45 and DM/Q 30 treatment groups (2 5.2% and 21.0%, respectively) discontinued due to an adverse event than compared to placebo (11.4%). There were no statistically significant differences in serious adverse event rates with 7.6%, 4.8% and 4.1% reported in the DM/Q 45, DM/Q 30 and placebo groups, respectively, and no deaths occurred during the study.
For more details, a PDF version of each poster can be found at the Company's website (www.avanir.com).
About Diabetic Neuropathic Pain
Diabetic neuropathic pain, one of the most debilitating forms of pain, is caused by nerve damage that can result from diabetes. It is often described as burning, tingling, stabbing, or pins and needles in the feet, legs, hands or arms. An estimated 3.5 million people in the United States experience diabetic neuropathic pain according to the American Diabetes Association.
Zenvia 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 currently in development for the treatment of Involuntary Emotional Expression Disorder (IEED) and DPN pain.
In October 2006, the Company received an approvable letter for the treatment of Zenvia in IEED. To address safety concerns raised in the FDA's approvable letter for Zenvia for the treatment of IEED, the company intends to initiate a confirmatory Phase III study with a new lower quinidine dose formulation of Zenvia. In April 2007 AVANIR completed a Phase III study in patients with diabetic peripheral neuropathic pain where all primary endpoints were successfully met. The Company is considering whether it would be necessary or advisable to study a similar lower dose of quinidine in a second Phase III trial being planned for DPN pain.
AVANIR Pharmaceuticals is focused on developing, acquiring and commercializing novel therapeutic products for the treatment of chronic diseases. AVANIR's products and product candidates address therapeutic markets that include the central nervous system, cardiovascular disorders, inflammation and infectious diseases. AVANIR currently markets FazaClo(R), the only orally-disintegrating formulation of clozapine for the management of severely ill schizophrenic patients who fail to respond adequately to standard drug treatments for schizophrenia. FazaClo is also indicated for reducing the risk of suicidal behavior in patients with schizophrenia or schizoaffective disorder. For full prescribing information and important safety information regarding FazaClo, please visit www.fazaclo.com. AVANIR's lead product candidate for the treatment of involuntary emotional expression disorder (IEED), Zenvia, is the subject of an approvable letter from the FDA. Additionally, AVANIR recently completed a Phase III clinical trial with Zenvia in patients with diabetic peripheral neuropathic (DPN) pain where all primary endpoints were met. AVANIR has an ongoing development program with Novartis International Pharmaceutical Ltd. for the treatment of inflammatory disease. The Company's first commercialized product, Abreva(R), 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.
Forward Looking Statement
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," or simila r 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. There can be no assurance that the Company will receive FDA regulatory approval for Zenvia for any indication or that the additional development work for Zenvia will be completed in the time periods that are anticipated. Final review decisions made by the FDA and other regulatory agencies concerning the Company's products and product candidates are often unpredictable and outside the influence and control of the Company, and it is possible that the FDA could disagree with the Company's interpretation of clinical trial results. Risks and uncertainties 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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