AVANIR Pharmaceuticals Presents Zenvia Phase III Results in Multiple Sclerosis Patient Population at Controversies in Neurology Congress
ALISO VIEJO, Calif., October 9, 2009 - AVANIR Pharmaceuticals, Inc. (NASDAQ:AVNR) today announced additional detailed results from the confirmatory double-blind Phase III STAR trial evaluating two doses of the investigational drug ZenviaTM (dextromethorphan/quinidine) compared to placebo in the treatment of pseudobulbar affect (PBA) among patients with underlying multiple sclerosis (MS) or amyotrophic lateral sclerosis (ALS). Over the course of the 12-week study in the MS patient subset, Zenvia 30/10 mg met the primary efficacy endpoint by reducing PBA episode rates by an incremental 11.9% beyond placebo (p=0.0280). The lower dose Zenvia 20/10 mg group did not achieve a statistically significant reduction in PBA episode rates compared to placebo. These results were presented today during a late-breaker poster session at the 3rd World Congress on Controversies in Neurology in Prague, Czech Republic (Poster Number: 11).
Efficacy Highlights - MS Cohort:
Zenvia 30/10 mg dose met the primary endpoint in the subset of patients with underlying MS by significantly reducing PBA episode rates compared to placebo
Both Zenvia groups demonstrated a numerical reduction in mean CNS-LS scores but did not achieve statistical significance versus placebo in this small subset of MS patients
Zenvia 30/10 mg demonstrated relief of MS-related pain in the subset of MS patients with moderate-to-severe pain
"PBA represents an area of high unmet medical need with no FDA-approved treatments currently available. Although the involuntary emotional outbursts of PBA cause considerable impairment for millions of individuals in the United States, it is under recognized and commonly misdiagnosed," said poster presenter Daniel Wynn, MD, Director, Clinical Research, Co-Director, Consultants in Neurology Multiple Sclerosis Center and STAR Trial Steering Committee member. "If approved, Zenvia will be an important treatment option to ameliorate the profound distress caused by PBA among individuals afflicted with neurologic disease or injury and their caregivers."
"We were very pleased that Zenvia demonstrated significant improvement in PBA episodes in the MS sub-population as well as encouraging proof of concept data in MS-related pain," said Randall Kaye, MD, AVANIR's Chief Medical Officer. "This is especially exciting given that the STAR trial was not powered to detect an efficacy signal in such a small number of patients. These data provide additional insight into the clinical utility of Zenvia and help shape our plans for future drug development."
ADDITIONAL EFFICACY RESULTS
An important pre-specified secondary endpoint was the reduction of pain associated with MS using the 11-point Pain Rating Scale (PRS). All MS patients enrolled in the study assessed their daily pain regardless of baseline pain level or use of concomitant analgesics. Mean pain scores in MS patients (all patients regardless of baseline pain score) were decreased from baseline across time in the Zenvia 30/10 mg group. Mean scores at days 15 and 29 showed trends for superiority of Zenvia 30/10 mg over placebo (p=0.0512 and p=0.0859, respectively). In an additional preliminary analysis that included only MS patients with moderate-to-severe pain at baseline (PRS score =4), mean PRS scores in the Zenvia 30/10 mg group were significantly lower than those in the placebo group on days 29, 57, and 84. Data from this important secondary efficacy endpoint are summarized in the following table:
PRS Scores Across Time in MS Patients With Baseline Score =4 (ITT Population)a
Study Visit Zenvia 30/10 mg
n = 26
n = 22
Baseline 5.62 (1.53) 5.85 (1.75) 0.33
Day 15 2.74 (2.66) 2.99 (2.54) 0.24
Day 29 2.42 (2.63) 2.92 (2.67) 0.01
Day 57 2.02 (2.49) 2.68 (2.57) <0.0001
Day 84 2.01 (2.57) 2.84 (3.09) <0.0001
Zenvia 20/10 mg did not show a statistically significant p-value versus placebo. aITT = intent-to-treat population, refers to all patients randomized. bt-test comparing means. PRS scores computed as independent data.
An additional secondary 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 frequency and severity of PBA, where a higher score indicates more severe PBA. Results from this secondary endpoint are summarized in the following table:
CNS-LS Score - MS Patients
(mean, standard deviation)
Zenvia 30/10 mg
n = 45
Zenvia 20/10 mg
n = 39
n = 45
Baseline 20.58 (5.22) 20.85 (4.63) 20.04 (4.74)
Day 15 13.50 (5.17) 15.49 (5.67) 15.14 (4.28)
Mean Change -7.00 (5.78) -5.41 (5.94) -5.07 (5.25)
p-value 0.1318 0.2859
Day 84 11.86 (4.80) 12.82 (5.44) 13.39 (5.61)
Mean Change -8.79 (6.80) -8.00 (5.98) -6.68 (6.12)
p-value 0.2688 0.8154
SAFETY AND TOLERABILITY RESULTS
Overall, Zenvia was generally safe and well tolerated in the MS population. In the MS subset, the percent of patients completing the study was 93.3% for Zenvia 30/10 mg, 89.7% for Zenvia 20/10 mg, and 86.7% for placebo. Only 3 MS patients discontinued the study because of adverse events; all were in the Zenvia 20/10 mg group. One MS patient in the Zenvia 30/10 mg group and 2 MS patients in the placebo group reported non-fatal serious adverse events (SAEs). The most common adverse events among MS patients that were more frequent in the Zenvia groups than for placebo were dizziness, nausea, diarrhea, somnolence and nasopharyngitis.
Most Common (=5% of Total Population) Adverse Events (Safety Population)
Event, n (%) All Patients MS Patients Only
(n = 110)
(n = 107)
(n = 109)
(n = 45)
(n = 39)
(n = 45)
Fall 22 (20.6) 14 (13.7) 22 (20.4) 4 (8.9) 4 (10.3) 4 (8.9)
Dizziness 20 (18.7) 11 (10.8) 6 (5.7) 8 (17.8) 3 (7.7) 1 (2.2)
Headache 15 (14.0) 15 (14.7) 16 (15.1) 5 (11.1) 8 (20.5) 5 (11.1)
Nausea 14 (13.1) 8 (7.8) 10 (9.4) 6 (13.3) 0 (0) 3 (6.7)
Diarrhea 11 (10.3) 14 (13.7) 7 (6.6) 5 (11.1) 2 (5.1) 1 (2.2)
Somnolence 11 (10.3) 9 (8.8) 10 (9.4) 4 (8.9) 4 (10.3) 3 (6.7)
Fatigue 9 (8.4) 11 (10.8) 9 (8.5) 0 (0) 4 (10.3) 4 (8.9)
Nasopharyngitis 9 (8.4) 6 ( 5.9) 8 (7.5) 5 (11.1) 1 (2.6) 2 (4.4)
Constipation 7 (6.5) 7 (6.9) 9 (8.5) 1 (2.2) 0 (0) 0 (0)
Muscle spasms 7 (6.5) 8 (2.0) 10 (9.4) 1 (2.2) 1 (2.6) 1 (2.2)
Overall, Zenvia 30/10 mg and 20/10 mg were effective, safe, and well-tolerated for treatment of patients with PBA. The new formulation of Zenvia appeared to demonstrate comparable efficacy with a potentially improved safety and tolerability profile, compared with formulations of higher doses.
In this trial, PBA episodes were frequent and severe in patients with underlying MS. Zenvia was well-tolerated in this subset and Zenvia 30/10 mg was significantly superior to placebo for decreasing PBA episode rate, despite the small size of the subset.
Zenvia 30/10 mg demonstrated relief of MS-related pain in the subset of patients with moderate-to-severe pain.
STAR TRIAL DESIGN
The STAR (Safety, Tolerability and Efficacy Results of AVP-923 in PBA) trial is a confirmatory Phase III trial of Zenvia in patients with pseudobulbar affect (PBA). The randomized, multi-center, international STAR trial compares 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 safety extension study. At the conclusion of enrollment, AVANIR enrolled a total of 326 patients (197 with underlying ALS and 129 with underlying MS) who exhibited signs and symptoms of PBA across 62 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 include: 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. 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. 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 SPA agreement with the FDA utilizing a new lower quinidine dose formulation of Zenvia intended to address 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 is now engaged in discussions with the FDA under the SPA process regarding the design of the next Phase III study in DPN pain and overall program requirements.
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.