Avanir Pharmaceuticals, Inc. announced that it has filed an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA) to begin a large phase II clinical trial of AVP-923, an investigational drug for the treatment of central neuropathic pain in patients with Multiple Sclerosis (MS). The FDA has acknowledged receipt of the submission and the company expects that the IND filing will be subject to standard 30-day review.

“Over half of MS patients suffer from chronic and debilitating pain, with a substantial negative impact on their quality of life. With no FDA-approved therapies to treat central neuropathic pain in MS patients, this represents an area of high unmet medical need,” said Randall Kaye, MD, chief medical officer of Avanir Pharmaceuticals. “The team at Avanir has done an exemplary job of designing and developing a program to explore the potential of AVP-923 in MS-related pain as well as other important endpoints including fatigue, sleep quality and cognition. We are excited about the potential of this compound, which may ultimately represent a new approach to treating central neuropathic pain in MS patients.”

“This marks the third IND for the NUEDEXTA/AVP-923 program and demonstrates our belief that the dual sigma-1 receptor agonist and NMDA receptor antagonist binding profile has significant potential beyond PBA,” said Keith A Katkin, president and CEO of Avanir Pharmaceuticals. “In addition, we intend to file another IND within the next year to begin studying the potential use of AVP-923 in other forms of emotional lability – specifically anger, irritability, and other behavioural symptoms of dementia.”

The objectives of the study are to evaluate the safety, tolerability, and efficacy of three dose levels of AVP-923 capsules for the treatment of central neuropathic pain in a population of patients with multiple sclerosis. AVP-923 is a combination of Dextromethorphan (DM) and Quinidine (Q). The trial is a multi-centre, randomized, double-blind, placebo-controlled, 4-arm parallel group study. Eligible patients will be randomized to receive one of the three dose levels of AVP-923 containing either 45mg DM/10 mg Q, 30mg DM/10mg Q, 20mg DM/10mg Q or placebo, daily for 12 weeks. The primary efficacy endpoint is the Pain Rating Scale obtained from daily patient diaries. Secondary endpoints include measures of fatigue, disability, impact of MS on daily life, sleep quality, cognition and depression. Safety will be assessed by monitoring adverse events, clinical laboratory tests, ECGs, physical examinations, and vital signs.

The filing of this IND represents the next step in Avanir's plan to broadly develop AVP-923 for conditions of the Central Nervous System (CNS). Avanir expects to enroll approximately 400 patients at 65 centres both in the US and internationally. The company anticipates enrolling the first patient into the trial before the end of 2011.

Multiple Sclerosis is an autoimmune demyelinating disease of the Central Nervous System (CNS) characterized by numerous disabling symptoms, including abnormal function of the motor, sensory and visual systems. Pain and fatigue are two of the most common symptoms related to disability in MS patients, often leading to social isolation and inability to work. The initial disease course often demonstrates multiple exacerbations and remissions, with the variety of symptoms determined by the location of the plaques in the brain and spinal cord. Among the many symptoms and types of disabilities associated with MS, chronic pain has an important impact on daily life of patients with this disease and may affect work retention in this population. Pain in MS patients may be induced by a variety of mechanisms including musculoskeletal disorders, spasms and trigeminal neuralgia, but central neuropathic pain due to the involvement of sensory pathways is the most frequent, estimated to affect over 55% of patients.

An important type of MS-related pain is central neuropathic pain. Central pain can be defined as pain in a neurologic distribution with altered sensation and no evidence of peripheral neuropathy. In one study, 55% of people with MS had “clinically significant pain” at some time. Almost half (48%) were troubled by chronic pain.

AVP-923 is a combination of two well-characterized compounds: the active ingredient dextromethorphan hydrobromide (an uncompetitive NMDA receptor antagonist and sigma-1 agonist) and the enzyme inhibitor quinidine sulfate (a CYP450 2D6 inhibitor), which serves to increase the bioavailability of dextromethorphan.

The dosage form of AVP-923 of 20 mg DM/10 mg Q (twice daily) is approved by the FDA under the brand name Nuedexta capsules which is indicated for the treatment of Pseudobulbar Affect (PBA).

Nuedexta is the first and only FDA-approved treatment for Pseudobulbar Affect (PBA). Nuedexta is an innovative combination of two well-characterized components; dextromethorphan hydrobromide (20 mg), the ingredient active in the central nervous system, and quinidine sulfate (10 mg), a metabolic inhibitor enabling therapeutic dextromethorphan concentrations. It acts on sigma-1 and NMDA receptors in the brain, although the mechanism by which Nuedexta exerts therapeutic effects in patients with PBA is unknown.

It is indicated for the treatment of Pseudobulbar Affect (PBA). PBA occurs secondary to a variety of otherwise unrelated neurological conditions, and is characterized by involuntary, sudden, and frequent episodes of laughing and/or crying. PBA episodes typically occur out of proportion or incongruent to the patient's underlying emotional state. Studies to support the effectiveness of Nuedexta were performed in patients with Amyotrophic Lateral Sclerosis (ALS) and Multiple Sclerosis (MS). It has not been shown to be safe and effective in other types of emotional lability that can commonly occur, for example, in Alzheimer's disease and other dementias. The primary outcome measure, laughing and crying episodes, was significantly lower in the Nuedexta arm compared to placebo. The secondary outcome measure, the Centre for Neurologic Studies Lability Scale (CNS-LS), demonstrated a significantly greater mean decrease in CNS-LS score from baseline for the Nuedexta arm compared to placebo.

Nuedexta can interact with other medications causing significant changes in blood levels of those medications and/or Nuedexta. It is contraindicated in patients receiving drugs that both prolong QT interval and are metabolized by CYP2D6 (e.g., thioridazine and pimozide) and should not be used concomitantly with other drugs containing quinidine, quinine, or mefloquine and also taking Monoamine Oxidase Inhibitors (MAOIs) or in patients who have taken MAOIs within the preceding 14 days. It is contraindicated in patients with a known hypersensitivity to its components.

Nuedexta may cause serious side effects, including possible changes in heart rhythm. It is contraindicated in patients with a prolonged QT interval, congenital long QT syndrome or a history suggestive of torsades de pointes, in patients with heart failure as well as patients with, or at risk of, complete Atrio-Ventricular (AV) block, unless the patient has an implanted pacemaker.

It causes dose-dependent QTc prolongation. When initiating in patients at risk of QT prolongation and torsades de pointes, electrocardiographic (ECG) evaluation of QT interval should be conducted at baseline and 3-4 hours after the first dose. The most common adverse reactions in patients taking Nuedexta are diarrhoea, dizziness, cough, vomiting, weakness, swelling of feet and ankles, urinary tract infection, flu, elevated liver enzymes, and flatulence. It may cause dizziness. For reducing the risk precautions should be taken.

Patients should take Nuedexta exactly as prescribed and not more than 2 capsules in a 24- hour period, make sure that there is an approximate 12-hour interval between doses, and not take a double dose after they miss a dose.

Avanir Pharmaceuticals, Inc. is a biopharmaceutical company focused on bringing innovative medicines to patients with central nervous system disorders of high unmet medical need.