Avanir Pharmaceuticals Announces Zenvia Safety and Efficacy Data from Star Trial Open Label Extension
ALISO VIEJO, Calif., November 10, 2009 - AVANIR Pharmaceuticals, Inc. (NASDAQ: AVNR) today announced efficacy, safety and tolerability results from the 12-week open-label extension phase of the confirmatory Phase III STAR trial evaluating the investigational drug ZenviaTM (dextromethorphan/quinidine) in the treatment of patients with pseudobulbar affect (PBA).
- Patients maintained on Zenvia 30/10 mg demonstrated statistically significant incremental improvement in their CNS-LS scores over the additional 12-week treatment period of the open-label study (p<0.0001)
- Patients that titrated from Zenvia 20/10 mg to Zenvia 30/10 mg demonstrated statistically significant incremental improvement in their CNS-LS scores (p<0.0001)
- Patients originally on placebo that initiated Zenvia 30/10 mg demonstrated statistically significant improvement in their CNS- LS scores (p<0.0001)
- Zenvia 30/10 mg was generally safe and well tolerated with 92.9% of patients completing the 12-week treatment period of the open-label study
- Reported rates of adverse events (AEs) were low overall, mild to moderate in nature and consistent with the reported AEs in the double-blind phase
- The overall mortality rate observed in patients with amyotrophic lateral sclerosis, or ALS, (a terminal condition) was consistent with historic norms
- "These long term STAR data suggest that the new low dose formulation of Zenvia provides sustained efficacy by reducing the frequency and severity of PBA episodes over a 6 month treatment period," said Randall Kaye, MD, AVANIR's Chief Medical Officer. "This is the first time the efficacy of Zenvia has been studied beyond 12 weeks and we are very pleased to see the durability of response over a 24-week period. Furthermore, the new low dose Zenvia formulation demonstrated a favorable long term safety and tolerability profile with a low overall rate of reported adverse events."
"These open-label data from the extension phase of the STAR trial are the final data elements necessary to submit a complete response to the FDA approvable letter," said Keith Katkin, AVANIR's President and CEO. "Our team is working to file a complete response early in the second calendar quarter of 2010, with an FDA approval decision expected approximately six months later. If approved by the FDA, we hope to make Zenvia available as quickly as possible to the significant number of patients in the U.S. currently suffering from the debilitating episodes of PBA."
PATIENT DISPOSITION AND EFFICACY RESULTS
Of the 283 patients who completed the 12-week double-blind phase, a total of 253 patients (or 89.4%) elected to enroll in the open-label extension; 94 who originally recevied Zenvia 30/10 mg, 76 who originally received Zenvia 20/10 mg and 83 who originally received placebo. All patients enrolled in the open-label extension received the Zenvia 30/10 mg dose twice daily in order to collect additional safety data at the highest tested dose. A total of 235 (or 92.9%) completed the 12-week treatment period of the open-label study.
In the open-label study, the efficacy 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 and intensity of PBA. In this efficacy endpoint analysis, patients originally receiving Zenvia 30/10 mg in the double-blind phase reported a statistically significant treatment response over the course of their second 12 weeks of treatment compared to open-label baseline (p<0.0001). In addition, patients that switched to Zenvia 30/10 mg from either Zenvia 20/10 mg or placebo achieved a statistically significant incremental improvement in their CNS-LS scores compared to baseline which was maintained over the 12-week treatment period (p<0.0001 for both groups). The efficacy results of the open-label study are summarized in the table below:
Mean CNS-LS Scores Over Time
Original Treatment Cohort
Study Visit Total Open-Label Group (30/10 mg)
N = 253
Zenvia 30/10 mg
N = 94
Zenvia 20/10 mg
N = 76
N = 83
Open-Label Baseline 13.8 13.4 13.7 14.4
Visit 2 (day 15) 11.1 10.8 11.9 10.6
Visit 3 (day 42) 11.1 10.7 11.9 10.9
Visit 4 (day 84) 11.2 10.8 11.3 11.5
p-value (day 84 versus baseline) p <0.0001 p <0.0001 p <0.0001 p <0.0001
ITT Population - All patients received Zenvia 30/10 mg in the open label study; lower scores indicate better response; open-label baseline scores differ from the end of the double-blind as some patients stopped receiving therapy between the final double-blind visit and the open-label baseline visit
SAFETY AND TOLERABILITY RESULTS
Overall, Zenvia was generally safe and well tolerated in this open-label study. A total of 235 (or 92.9%) of patients completed the 12 weeks of treatment in the open-label study. The most common reason for early withdrawals was due to adverse events (AEs). Early withdrawal due to AEs occurred in 4.0% of patients and the reported AEs were generally mild to moderate in nature. The most commonly reported AEs are summarized in the table below:
Most Common Adverse Events
Open-Label Phase Double-Blind Phase*
Zenvia 30/10 mg
N = 253
Zenvia 30/10 mg
N = 108
Zenvia 20/10 mg
N = 102
N = 108
Falls 40 (15.8%) 22 (20.4%) 14 (13.7%) 22 (20.4%)
Fatigue 30 (11.9%) 9 (8.3%) 11 (10.8%) 9 (8.3%)
Headache 27 (10.7%) 15 (13.9%) 15 (14.7%) 16 (14.8%)
Urinary Tract Infection 19 (7.5%) 8 (7.4%) 4 (3.9%) 3 (2.8%)
Constipation 17 (6.7%) 7 (6.5%) 7 (6.9%) 9 (8.3%)
Dizziness 17 (6.7%) 20 (18.5%) 11 (10.8%) 6 (5.6%)
Muscular Weakness 17 (6.7%) 6 (5.6%) 5 (4.9%) 4 (3.7%)
Back Pain 16 (6.3%) 5 (4.6%) 5 (4.9%) 4 (3.7%)
Somnolence 16 (6.3%) 11 (10.2%) 9 (8.8%) 10 (9.3%)
Nausea 15 (5.9%) 14 (13.0%) 8 (7.8%) 10 (9.3%)
Nasopharyngitis 14 (5.5%) 9 (8.3%) 6 (5.9%) 8 (7.4%)
Pain in Extremity 14 (5.5%) 5 (4.6%) 2 (2.0%) 8 (7.4%)
* Data from the double-blind portion of the STAR trial previously reported; for comparative purposes only, not a head-to-head safety comparison
The percent of patients reporting at least one serious adverse event (SAE) was 5.5%. A total of 14 patients experienced SAEs over the course of the study. None of the SAEs were deemed by the investigators to be possibly or probably treatment related. No cardiovascular SAEs were reported.
Overall, there were three deaths in the open-label study, all in patients with underlying ALS. All three of the deaths were determined by investigators to be attributable to respiratory failure, which was consistent with ALS disease progression. No deaths were determined by the investigator to be possibly treatment related. The ALS mortality rate of 2.1% in the 12-week open-label study appeared to be consistent with historic norms of 4% to 6% mortality over 3 months reported in the epidemiologic literature.1, 2, 3, 4, 5
During the course of the study, no new cardiovascular safety signals were observed. There were no clinically meaningful changes in QT interval, no reported pro-arrhythmic events and no reports of any cardiovascular SAEs.
Analysis of Central Tendency Open-Label Phase
Zenvia 30/10 mg
N = 253
Double-Blind Phase Placebo*
N = 108
Mean QTc - Baseline (QTcB/QTcF) 418.1 / 406.7 415.5 / 404.3
Mean QTc - Day 84 (QTcB/QTcF) 419.9 / 410.0 416.8 / 405.8
Mean Ä in Baseline to Day 84 (QTcB/QTcF) 1.5 / 2.1 1.7 / 1.2
Outlier Categorical Analysis (Visit 2 through Visit 4)**
Absolute > 450 msec (QTcB/QTcF) 6.3% / 2.0 % 6.1% / 2.4%
Absolute > 480 msec (QTcB/QTcF) 0.4% / 0.1 % 0.9% / 0.0%
Absolute > 500 msec (QTcB/QTcF) 0.0% / 0.0 % 0.2% / 0.0%
Ä 30 - 60 msec (QTcB/QTcF) 3.8% / 3.4 % 6.6% / 3.5%
Ä > 60 msec (QTcB/QTcF) 0.0% / 0.1 % 0.5% / 0.5%
Ä > 90 msec (QTcB/QTcF) 0.0% / 0.0 % 0.0% / 0.0%
* Data from the placebo group in the double-blind portion of the STAR trial previously reported; for comparative purposes only, not a head-to-head comparison
** Percent of EKGs taken over the course of the study per protocol
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). For more information visit www.pbatrial.com.
Pseudobulbar affect (PBA), also known as emotional lability, is a neurologic disorder that occurs secondary to neurologic disease or brain injury causing sudden and unpredictable episodes of crying, laughing, or other emotional displays. Moderate to severe PBA is estimated to impact approximately 2 million people in the United States with underlying neurologic conditions such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson's disease, dementias including Alzheimer's disease, stroke, and traumatic brain injury. PBA episodes may occur when disease or injury damages the area of the brain that controls normal expression of emotion. This damage can disrupt brain signaling causing a "short circuit" and triggering involuntary PBA episodes. PBA has been shown to impair the lives of patients in both social and occupational settings. There are currently no FDA approved treatments for PBA.
ZenviaTM (dextromethorphan/quinidine) 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 being developed for the treatment of pseudobulbar affect (PBA) and has successfully completed a Phase III trial for diabetic peripheral neuropathic (DPN) pain. In October 2006, the Company received an approvable letter for Zenvia in the treatment of PBA. The Company conducted the STAR trial under a Special Protocol Assessment (SPA) agreement with the FDA with the goal of addressing safety concerns raised in the Agency's approvable letter for Zenvia in the treatment of PBA. For more information about this trial visit http://www.pbatrial.com, and for more information about the Agency's SPA process, see http://www.fda.gov/cder/guidance/3764fnl.htm. In addition, AVANIR has conducted a Phase III study of Zenvia in DPN pain where the primary endpoints were successfully met. Subsequently the Company released top-line results of a formal PK study that identified alternative lower-dose quinidine formulations of Zenvia for DPN pain intended to deliver similar efficacy and improved safety/tolerability versus the formulations previously tested for this indication.
AVANIR Pharmaceuticals, Inc. is a biopharmaceutical company focused on acquiring, developing, and commercializing novel therapeutic products for the treatment of central nervous system disorders. AVANIR's lead product candidate, Zenvia, is being developed for the treatment of pseudobulbar affect (PBA) and has successfully completed a Phase III trial for diabetic peripheral neuropathic (DPN) pain. AVANIR has licensed its MIF inhibitor program to Novartis International Pharmaceuticals Ltd. and has sold its anthrax monoclonal antibody program to Emergent BioSolutions. The Company's first commercialized product, Abreva® (docosanol), 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 and further information about pseudobulbar affect can be found at www.PBAinfo.org.
FORWARD LOOKING STATEMENTS
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," "project," 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. For example, there can be no assurance that the U.S. Food and Drug Administration (FDA) will approve Zenvia for any indication, or that the Company will meet projected timelines. Risks and uncertainties affecting the Company's financial condition and operations 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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