Avanir Pharmaceuticals Announces Positive Top-line Results from Stroke and TBI Cohorts of PRISM II Study

-- Results Show NUEDEXTA Provides Meaningful Reduction of PBA Episodes and is Generally Well Tolerated in PBA Patients Who Had an Underlying Stroke or Traumatic Brain Injury --

ALISO VIEJO, Calif. , June 30, 2015 /PRNewswire/ --  Avanir Pharmaceuticals, Inc. today announced top-line data from the PRISM II study showing that treatment with NUEDEXTA® was associated with a statistically significant reduction in symptoms of pseudobulbar affect (PBA) in patients with traumatic brain injury (TBI) or stroke. PBA is a distressing condition characterized by sudden and uncontrollable outbursts of laughing and/or crying resulting from certain neurologic diseases or brain injury. PRISM II is a phase IV study evaluating the safety and effectiveness of NUEDEXTA in treating PBA in patients with dementia/Alzheimer's disease, stroke and TBI. Data from patients with PBA secondary to TBI were presented Monday, June 29th at the 33rd Annual Symposium of the National Neurotrauma Society in Santa Fe, New Mexico . Data from patients with PBA secondary to dementia/Alzheimer's disease were presented at last year's American Neurological Association Meeting, and full results from the stroke cohort will be presented at a future date.

"The improvement in PBA symptoms that we saw in the TBI and stroke cohorts of this study are consistent with what we saw in the pivotal phase III study of PBA in patients with multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS), as well as that seen for PBA patients with dementia also enrolled in PRISM II. The data show that physicians, patients and caregivers see treatment benefit, providing further evidence that NUEDEXTA can offer relief from the disruptive and debilitating effects of PBA," said Joao Siffert, M.D., executive vice president, R&D, and chief medical officer at Avanir. "We have now studied NUEDEXTA in over 1,000 patients of different ages, including many above 70 years of age, who had PBA resulting from a wide variety of neurological disorders. In all groups, we have seen consistent levels of effectiveness and safety."

Enrollment in PRISM II is complete with 134 patients with PBA in the dementia/Alzheimer's disease cohort, 120 patients with PBA in the TBI cohort, and 113 patients with PBA in the stroke cohort. The average age of patients in this study was 72 for dementia/Alzheimer's disease, 61 for stroke and 46 for TBI. The effectiveness endpoints included a PBA symptom rating scale called the Center for Neurologic Study-Lability Scale (CNS-LS; scored from 7 = no symptoms to 35 = maximum symptoms), the number of weekly PBA episodes, the degree to which PBA symptoms affected overall quality of life (QOL; 0 = "Not at all" and 10 = "Significantly"), and Clinician and Patient Global Impression of Change with respect to PBA (CGI-C; PGI-C). Standard safety measures were recorded throughout the study.

TBI Cohort Top-Line Results

  • At baseline, patients had a mean CNS-LS score of 20.5 and were suffering from a median of 10 PBA episodes per week.
  • At the end of the study period, mean CNS-LS improved to 11.9 (P<0.001 compared with baseline) and the median number of PBA episodes decreased to one per week, with an overall 78.5% reduction in episode count compared to baseline (P<0.001).
  • Consistent improvement was observed in other effectiveness endpoints.
    • 73.0% of patients or caregivers rated themselves/the patient as being much/very improved on the PGI-C (P<0.001).
    • Clinicians rated 78.0% of the patients to be much/very much improved on the CGI-C (P<0.001).
  • Adverse events (AE) were reported by 43 patients (35.8%) with 23 (19.2%) having an AE deemed to be treatment-related. The most commonly reported AE was diarrhea (8.3%). A total of four patients had serious AEs (none of which were deemed to be treatment-related), and 14 patients discontinued the study due to AEs. The AE profile was generally consistent with that observed in other trials of NUEDEXTA.

Stroke Cohort Top-Line Results

  • At baseline, patients had a mean CNS-LS score of 20.8 and were suffering from a median of 10 PBA episodes per week.
  • At the end of the study period, mean CNS-LS improved to 13.1 (P<0.001 compared with baseline) and the median number of PBA episodes decreased to two per week with an overall 75.5% reduction in episode count compared to baseline (P<0.001).
  • Consistent improvement was observed in other effectiveness endpoints.
    • 68.0% of patients or caregivers rated themselves/the patient as being much/very improved on the PGI-C (P<0.001).
    • Clinicians rated 75.0% of patients to be much/very much improved on the CGI-C (P<0.001).
  • AEs were reported by 40 patients (35.4%) with 16 (14.2%) having an AE deemed to be treatment-related. The most commonly reported AEs were diarrhea (4.4%), headache (3.5%) and constipation (2.7%). A total of seven patients had serious AEs (none of which were deemed to be treatment-related), and six patients discontinued the study due to AEs. This AE profile was generally consistent with that observed in other trials of NUEDEXTA.

About PRISM II
The objectives of the study were to evaluate the safety, tolerability and effectiveness of NUEDEXTA capsules containing 20 mg dextromethorphan hydrobromide (DM) and 10 mg quinidine sulfate (Q) for treatment of PBA in patients with Alzheimer's disease and other dementias, stroke and traumatic brain injury.

PRISM II is a nationwide, open-label, multicenter, study that enrolled 367 patients at approximately 100 study centers. Eligible patients were age ≥18 years with a clinical diagnosis of PBA and baseline score ≥13 on the CNS-LS. Patients with TBI due to a penetrating head injury were excluded. Patients were treated with NUEDEXTA twice daily for 12 weeks. The primary endpoint was change from baseline in PBA symptoms as measured by the CNS-LS, an instrument originally validated as a measure of PBA episode frequency and severity in patients with ALS and MS. Determination of effectiveness was based on a comparison of CNS-LS change in PRISM II with that seen for NUEDEXTA and placebo in a previous pivotal phase III study. Additional outcomes measures included number of weekly PBA episodes (laughing and/or crying); Mini-Mental State Examination; PBA impact on quality of life; CGIC; PGIC; patients' satisfaction with treatment; Patient Health Questionnaire (PHQ-9) (to evaluate mood symptoms), and a functional measure consisting of the Neurobehavioral Functioning Inventory for patients with TBI and Stroke Impact Scale for patients with stroke. Safety measures included monitoring of adverse events, concomitant medication usage, and vital signs.

The CNS-LS has been validated in ALS and MS patients.

Poster Presentation Details:
Title: Safety, Tolerability, and Effectiveness of Dextromethorphan/Quinidine for Pseudobulbar Affect in Traumatic Brain Injury: PRISM II
Poster Number: A2-01
Poster Session: A2 Poster Session I – Group A: Secondary Injury
Presentation Time: Monday, June 29th at 7:00 a.m. MDT

About PBA
PBA is a neurologic condition characterized by uncontrollable, disruptive laughing and/or crying outbursts that are often contrary or exaggerated to the patient's inner mood state. As a result, many of those afflicted with PBA show significant impairment on standard measures of health status, and impairments in occupational and social function, often leading to social isolation. PBA occurs secondary to a variety of neurologic conditions such as traumatic brain injury (TBI), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson's disease, stroke and Alzheimer's disease. When these disorders damage areas of the brain that regulate normal emotional expression, they can lead to uncontrollable, disruptive episodes of crying or laughing. For more information about PBA, please visit www.PBAFacts.com.

About NUEDEXTA
NUEDEXTA is an innovative combination of two well-characterized components, dextromethorphan hydrobromide, the ingredient active in the central nervous system, and quinidine sulfate, a metabolic inhibitor enabling therapeutic dextromethorphan concentrations. Dextromethorphan 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.

NUEDEXTA Important Safety Information
NUEDEXTA is indicated for the treatment of pseudobulbar affect (PBA). PBA occurs secondary to a variety of otherwise unrelated neurologic 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 underlying emotional state. PBA is a specific condition, distinct from other types of emotional lability that may occur in patients with neurological disease or injury.

NUEDEXTA (dextromethorphan hydrobromide and quinidine sulfate) 20mg/10mg capsules can interact with other medications causing significant changes in blood levels of those medications and/or NUEDEXTA which may lead to serious side effects. Adjust dose or use alternate treatment of the other medication when clinically indicated.

NUEDEXTA is contraindicated in patients concomitantly taking: QT-prolonging drugs metabolized by CYP2D6 (e.g., thioridazine and pimozide); monoamine oxidase inhibitors (MAOIs) within the preceding or following 14 days; other drugs containing quinidine, quinine, or mefloquine and in patients with a known hypersensitivity to these drugs or any of NUEDEXTA's components.

Discontinue use of NUEDEXTA if hepatitis, thrombocytopenia, serotonin syndrome or a hypersensitivity reaction occurs.

NUEDEXTA is contraindicated in patients with certain risk factors for arrhythmia: Prolonged QT interval; congenital long QT syndrome, history suggestive of torsades de pointes; heart failure; complete atrioventricular (AV) block or risk of AV block without an implanted pacemaker.

NUEDEXTA causes dose-dependent QTc prolongation. When initiating NUEDEXTA in patients at risk for QT prolongation and torsades de pointes, electrocardiographic (ECG) evaluation should be conducted at baseline and 3-4 hours after the first dose. Risk factors include left ventricular hypertrophy or dystrophy or concomitant use of drugs that prolong QT interval or certain CYP3A4 inhibitors.

The most common adverse reactions are diarrhea, dizziness, cough, vomiting, asthenia, peripheral edema, urinary tract infection, influenza, increased gamma-glutamyltransferase, and flatulence. NUEDEXTA may cause dizziness. Precautions to reduce the risk of falls should be taken, particularly for patients with motor impairment affecting gait or a history of falls.

These are not all the risks from use of NUEDEXTA. Please refer to the accompanying full Prescribing Information or visit www.NUEDEXTA.com.

About Avanir Pharmaceuticals, Inc.
Avanir Pharmaceuticals, Inc. is a biopharmaceutical company focused on bringing innovative medicines to patients with central nervous system disorders of high unmet medical need. As part of our commitment, we have extensively invested in our pipeline and are dedicated to advancing medicines that can substantially improve the lives of patients and their loved ones. For more information about Avanir, please visit http://www.avanir.com.

Avanir is a subsidiary of Otsuka America, Inc. (OAI), a holding company established in the U.S. in 1989. OAI is wholly owned by Otsuka Pharmaceutical Co., Ltd. , a global healthcare company with the corporate philosophy: 'Otsuka-people creating new products for better health worldwide.'

Otsuka Pharmaceutical is a leading firm in the challenging area of mental health and also has products and research programs for several under-addressed diseases including tuberculosis, a significant global public health issue. These commitments illustrate more powerfully than words how Otsuka is a "big venture" company at heart, applying a youthful spirit of creativity in everything it does.

Otsuka Pharmaceutical and its affiliates employ approximately 30,000 people globally, and the company welcomes you to visit its global website at: http://www.otsuka.co.jp/en/index.php

Avanir® is a trademark or registered trademark of Avanir Pharmaceuticals, Inc. in the United States and other countries.

©2015 Avanir Pharmaceuticals, Inc. All Rights Reserved.

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SOURCE Avanir Pharmaceuticals, Inc.