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AVANIR Pharmaceuticals (AMEX:AVN) announced that the company has submitted the final modules of a "rolling" submission of the new drug application (NDA) for Neurodex(TM), an investigational new drug, to the U.S. Food and Drug Administration (FDA) as an electronic common technical document (eCTD). AVANIR is seeking approval to market Neurodex as a treatment for pseudobulbar affect (PBA), also known as pathological laughing and crying, emotional lability, and emotional incontinence. Pseudobulbar affect is a neurological condition characterized by the disinhibition or loss of control of the motor expression of emotion. Symptoms of PBA include uncontrollable crying or laughing that is out of context with the social setting. It can be severe, unremitting, and persistent. PBA occurs secondary to neurological disease or injuries including amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease, multiple sclerosis (MS), stroke, traumatic brain injury, and dementias such as Alzheimer's disease. If approved, Neurodex would be the first drug indicated to treat PBA. "Completing this NDA submission marks a key milestone in AVANIR's commitment to develop treatments for chronic conditions such as PBA," said James E. Berg, Vice President of Clinical and Regulatory Affairs at AVANIR. "The Neurodex NDA submission is supported by a data package that, as previously reported, shows the consistency with which Neurodex helps patients address PBA symptoms." The NDA for Neurodex contains data from two controlled, multicenter Phase III clinical trials: one conducted in ALS patients and the other in MS patients. Data was also submitted from its open-label clinical study evaluating the safety of long-term exposure to Neurodex(TM) in patients with PBA associated with a variety of neurological disorders. Following the NDA submission, AVANIR will submit additional safety data from the ongoing open-label clinical study, including a 120-day safety update required by FDA regulations. "Neurological disorders and brain injuries can affect patients' lives in devastating ways, but one consequence, PBA, is frequently overlooked or misdiagnosed," said Hillel Panitch, MD, Professor of Neurology at the University of Vermont College of Medicine and Director of the Multiple Sclerosis Center at Fletcher Allen Health Care in Burlington, Vermont. "Even though its hallmark characteristics -- uncontrollable laughing and crying -- were described by Charles Darwin more than 130 years ago, the mechanisms underlying PBA are still not clear. However, the debilitating effects of the condition have been well documented. PBA can be seriously disabling in social or occupational settings, adversely affecting the quality of life for patients." "With no drug currently approved for the treatment of PBA, this NDA submission represents an important step forward in the potential care and treatment of patients suffering from pseudobulbar affect as a result of devastating underlying neurological disease or injury," concluded Dr. Panitch. AVANIR Pharmaceuticals is a pharmaceutical company focused on developing and commercializing novel therapeutic products for the treatment of chronic diseases. AVANIR's product candidates address therapeutic markets that include central nervous system and cardiovascular disorders, inflammation, and infectious disease. AVANIR's preclinical research and development program for inflammatory disease is partnered with Novartis. 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. Editor's Note Under normal conditions, the frontal, temporal, and motor cortices of the brain send carefully modulated signals to the brainstem and cerebellum to coordinate appropriate, voluntary displays of emotion. It is hypothesized that neurological diseases and injuries, such as ALS, MS, Alzheimer's disease, stroke, and traumatic brain injury, impact the excitatory action of glutamate.(2) In these disease and injury states, excessive glutamate signaling occurs, leading to neurological damage.(3, 4) When this type of damage occurs along the corticobulbar pathways of the brain, the result may lead to involuntary displays of affect such as crying and/or laughing.(5-9) Originally discovered by Richard A. Smith, MD, of the Center for Neurologic Study, Neurodex is believed to be an anti-excitatory therapy that is comprised of dextromethorphan and an enzyme inhibitor that slows the otherwise rapid metabolism of dextromethorphan.(10) Dextromethorphan has activity both as a sigma-1 receptor agonist and as an NMDA receptor antagonist, and may work to control PBA by reducing excessive glutamate excitatory neurotransmission.(3, 11) Both of these receptor types are located in regions of the brain that are believed to be involved in controlling emotional expression. Neurodex is thought to act by binding to sigma-1 receptors inhibiting glutamate release, and by binding to post-synaptic NMDA receptors, inhibiting glutamate mediated responses. Because epidemiological data are not available, the precise number of patients with PBA in the United States is currently not known. Based on estimates of the number of patients with each primary disorder, the available clinical literature and primary market research, it is surmised that approximately one million individuals may suffer from PBA. The most recent double blind Phase III clinical study in MS patients with PBA was completed in June 2004, in which 150 patients at 22 clinical sites were randomized to receive either placebo or Neurodex on a 12-hour dosing schedule for 85 days. The Center for Neurological Study Lability Scale (CNS-LS), a validated instrument that assesses frequency and severity of PBA episodes,(1) was utilized as the primary efficacy endpoint. A minimum CNS-LS score was required for inclusion in the study. For the primary endpoint, patients receiving Neurodex benefited from a significantly greater reduction in CNS-LS score than those receiving placebo (p less than 0.0001). The four secondary endpoints evaluated in the trial also significantly favored Neurodex, namely reduction in number of PBA episodes (p=0.0002), improvement in assessed quality of life (p less than 0.0001), improvement in assessed quality of relationships (p=0.0001), and reduction in pain intensity (p=0.0271). Overall, Neurodex was well-tolerated in the MS patient population. The majority of reported side effects (adverse events) were mild or moderate. Of the adverse events reported in 5% or more of the patients, a statistically significant difference between Neurodex and placebo was observed only for dizziness. In the Neurodex group, 14% of patients withdrew from therapy due to adverse events, compared to 11% withdrawing in the placebo group. In 2002, AVANIR completed a Phase III clinical trial of Neurodex in the treatment of PBA in patients with ALS. One hundred forty patients with ALS who also suffered from PBA were enrolled at 17 academic study sites throughout the U.S. in the double blind, controlled Phase III study. The patients received capsules containing either Neurodex, dextromethorphan (DM) alone, or quinidine (Q) alone, twice daily for four weeks. The Neurodex arm showed statistically and clinically greater improvements than both the DM-only arm (p=0.0013) and the Q-only arm (p=0.0002) in the primary efficacy endpoint: change in the CNS-LS score. In the intent-to-treat population, the adjusted mean improvement in CNS-LS for patients treated with Neurodex was approximately twice the improvement in patients treated with either DM only or Q only. Neurodex patients also exhibited lower overall episode rates, (p less than 0.0001 for both arms) improved quality of life scores, (p=0.0009 for the DM-only arm and p=0.0041 for the Q-only arm), and improved quality of relationship scores (p less than 0.0001 for the DM-only arm and p=0.0007 for the Q-only arm). Neurodex's side effects reported in the Phase III clinical trial in ALS patients were anticipated, based on the pharmacology of DM and the patient population. Early withdrawal due to adverse events occurred in 24% of Neurodex patients, 6% of DM-only patients, and 8% of Q-only patients. Adverse events reported for Neurodex included nausea, dizziness, somnolence, and diarrhea. All of these adverse events resolved when therapy was discontinued. An open label study is being conducted to assess the safety of chronic exposure to Neurodex in patients with PBA associated with various neurological disorders including ALS, MS, stroke, Alzheimer's disease, Parkinson's disease, and traumatic brain injury. Results from this study reported in the NDA show a safety profile similar to that observed in the controlled efficacy studies of Neurodex. As in the ordinary course, additional results from this study will be reported to FDA during the review period. References: 1. Moore SR, Gresham LS, Bromberg MB, Kasarkis E. Smith RA. A self report measure of affective lability. Journal of Neurology, Neurosurgery, and Psychiatry. 1997; 63:89-93. 2. Greenamyre JT. The role of glutamate in neurotransmission and in neurologic disease. Arch Neurol. 1986; 43:1058-1063. 3. Mattson MP. Excitotoxic and excitoprotective mechanisms: abundant targets for the prevention and treatment of neurodegenerative disorders. Neuromolecular Med. 2003; 3:65-94. 4. Bittigau P, Ikonomidou C. Glutamate in neurologic diseases. J Child Neurol. 1997; 12:471-485. 5. Robinson RG. Neuropsychiatric consequences of stroke. Annu Rev Med. 1997; 48:217-229. 6. Poeck K. Pathophysiology of emotional disorders associated with brain damage. In: Vinken PJ, Bruyn GW, eds. Handbook of Clinical Neurology. Amsterdam: North-Holland Publishing Co; 1969:343-367. 7. Feinstein A, Feinstein K, Gray T, et al. Prevalence and neurobehavioral correlates of pathological laughing and crying in multiple sclerosis. Arch Neurol. 1997; 54:1116-1121. 8. Starkstein SE, Migliorelli R, Teson A, et al. Prevalence and clinical correlates of pathological affective display in Alzheimer's disease. J Neurol Neurosurg Psychiatry. 1995; 59:55-60. 9. Arciniegas DB, Topkoff J. The neuropsychiatry of pathologic affect: an approach to evaluation and treatment. Semin Clin Neuropsychiatry. 2000; 5:290-306. 10. Pope LE, Khalil MH, Berg JE, Stiles M, Yakatan GJ, Sellers EM. Pharmacokinetics of dextromethorphan after single or multiple dosing in combination with quinidine in extensive and poor metabolizers. J Clin Pharmacol. 2004; 10:1132-1142. 11. Maurice T, Lockhart BP. Neuroprotective and anti-amnesic potentials of sigma-receptor ligands. Prog Neuropsychopharmacol Biol Psychiatry. 1997; 21:69-102. 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," "anticipate," "believe," "plan," or "expect," 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. There can be no assurance that AVANIR's new drug application for Neurodex(TM) will be accepted for filing by the FDA, that Neurodex will receive regulatory approval, or that even if such regulatory approval is received, AVANIR will be able to market Neurodex successfully. Final review decisions made by the FDA and other regulatory agencies concerning clinical trial results are often unpredictable and outside the influence and/or control of the company. 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 or obligation to update these forward-looking statements.