AVANIR Pharmaceuticals Presents Zenvia Phase III Results in Amyotrophic Lateral Sclerosis Patient Cohort at the International Symposium on ALS / MND

ALISO VIEJO, Calif.--(BUSINESS WIRE)--Dec 9, 2009 - AVANIR Pharmaceuticals, Inc. (NASDAQ: AVNR) today announced additional data from the subset of patients with amyotrophic lateral sclerosis (ALS) enrolled in the confirmatory Phase III STAR trial. This double-blind study evaluated two doses of the investigational drug Zenvia™ (dextromethorphan/quinidine) compared to placebo in the treatment of patients with pseudobulbar affect (PBA) secondary to ALS or multiple sclerosis (MS). In the ALS patient subset, both Zenvia 30/10 mg and Zenvia 20/10 mg met the primary efficacy endpoint by significantly reducing daily PBA episode rates compared to placebo (p<0.0001 for both treatment groups). These results were presented today during a podium presentation at the 20th International Symposium on ALS/MND in Berlin, Germany.

Highlights – ALS Patient Cohort:

  • Both Zenvia groups met the primary endpoint in the subset of patients with underlying ALS by significantly reducing daily PBA episode rates compared to placebo (p<0.0001 for both treatment groups)
     
  • Both Zenvia groups met the secondary endpoint in the subset of patients with underlying ALS by significantly reducing mean CNS-LS scores compared to placebo (p=0.0023 and 0.0004)
     
  • Zenvia was generally safe and well-tolerated in the ALS patient subset
     
  • Reported that 90.8%, 77.9% and 85.9% of ALS patients completed the 12-week double-blind phase of the study in the Zenvia 30/10 mg, Zenvia 20/10 mg and placebo groups, respectively
     


 

“The ALS patient population is especially impacted by the emotional outbursts of PBA with up to 50% of ALS patients affected by this socially disabling disorder. The new lower dose formulations of Zenvia demonstrated the ability to vastly reduce the number of PBA episodes and was well-tolerated in this vulnerable population,” said presenter Benjamin Rix Brooks, MD, Director of Carolinas Neuromuscular/ALS-MDA Center and Steering Committee Member for the STAR trial. “PBA is a condition with no effective treatments and an FDA-approved therapy could improve the lives of these patients and their caregivers.”


 

“We were very pleased that Zenvia demonstrated significant efficacy in the ALS sub-population,” said Randall Kaye, MD, AVANIR's Chief Medical Officer. “The Avanir team is now working expeditiously to file our complete response with the FDA early in the second quarter of 2010 so that, if approved, we can make Zenvia available to patients suffering from PBA.”


 

EFFICACY RESULTS


 

The primary efficacy analysis was based on the changes from baseline in crying/laughing episodes (PBA episodes) recorded in the patient diary. PBA episode counts were reported and analyzed as a rate expressed as episodes per day. The primary outcome was the additional reduction in PBA episode rates experienced with Zenvia 30/10 mg compared to placebo. In the ALS subset, Zenvia 30/10 mg provided a 62.9% incremental reduction in PBA episode rates compared to placebo over the course of the study (p<0.0001). In a secondary analysis of the primary endpoint, Zenvia 20/10 mg provided a 63.4% incremental reduction in PBA episode rates compared to placebo over the course of the study (p<0.0001).


 

An important 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 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 – ALS Patients (mean, standard deviation)

 


 
    Zenvia 30/10 mg n = 65

 


 
    Zenvia 20/10 mg n = 68

 


 
    Placebo n = 64

 


 
Baseline     19.3 (4.7)     21.1 (5.3)     19.8 (4.6)
Day 15     12.8 (4.4)     14.1 (5.1)     15.6 (4.6)
Mean Change     -6.6 (4.9)     -6.8 (5.3)     -4.2 (4.8)
Percent Change     -33.6%     -33.3%     -21.1%
p-value     0.0051     0.0468      
Day 84     11.8 (4.5)     12.7 (4.7)     15.0 (4.8)
Mean Change     -7.8 (5.6)     -8.4 (6.3)     -5.0 (4.4)
Percent Change     -38.8%     -39.8%     -24.5%
p-value     0.0023     0.0004      
                       

SAFETY AND TOLERABILITY RESULTS


 

Overall, Zenvia was generally safe and well-tolerated in the ALS population. In the ALS subset, the percent of patients completing the study was 90.8% for Zenvia 30/10 mg, 77.9% for Zenvia 20/10 mg, and 85.9% for placebo. The most common adverse events among ALS patients that were more frequent in the Zenvia groups than for placebo were dizziness, fatigue, nausea and diarrhea.


 

Most Common (‰¥5% of Total Population) Adverse Events (Safety Population)


 


Event, n (%)     ALS Patients Only
      Zenvia 30/10 mg (n = 65)

 


 
    Zenvia 20/10 mg (n = 68)

 


 
    Placebo (n = 64)

 


 
Fall     18 (27.7)

 


 
    10 (14.7)

 


 
    18 (28.1)

 


 
Dizziness     12 (18.5)

 


 
    8 (11.8)

 


 
    5 (7.8)

 


 
Headache     10 (15.4)

 


 
    7 (10.3)

 


 
    11 (17.2)

 


 
Nausea     8 (12.3)

 


 
    8 (11.8)

 


 
    7 (10.9)

 


 
Diarrhea     6 (9.2)

 


 
    12 (17.6)

 


 
    6 (9.4)

 


 
Somnolence     7 (10.8)

 


 
    5 (7.4)

 


 
    7 (10.9)

 


 
Fatigue     9 (13.8)

 


 
    7 (10.3)

 


 
    5 (7.8)

 


 
Nasopharyngitis     4 (6.2)

 


 
    5 (7.4)

 


 
    6 (9.4)

 


 
Constipation     6 (9.2)

 


 
    7 (10.3)

 


 
    9 (14.1)

 


 
Muscle spasms     6 (9.2)

 


 
    3 (4.4)

 


 
    9 (14.1)

 


 

In the ALS subset, seven patients in the Zenvia 30/10 mg group, nine patients in the Zenvia 20/10 mg group and eight patients in the placebo group reported serious adverse events (SAEs). Overall, there were seven deaths in patients with underlying ALS. In total, three deaths occurred in the Zenvia 30/10 mg arm, three in the 20/10 mg arm and one in the placebo arm. All deaths were respiratory related and appeared to be consistent with ALS disease progression.


 

CONCLUSIONS


 

 


 


  • In this trial, PBA episodes were frequent and severe at baseline in patients with underlying ALS. Both the Zenvia 30/10 mg dose and the Zenvia 20/10 mg dose were significantly superior to placebo for decreasing PBA episode rates.
     
  • Overall, Zenvia 30/10 mg and 20/10 mg were effective, safe, and well-tolerated for the treatment of PBA in patients with underlying ALS. The new formulation of Zenvia appeared to demonstrate equivalent efficacy with a potentially improved safety and tolerability profile, compared with formulations of higher doses.
     


 

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.


 

ABOUT PBA


 

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.


 

ABOUT ZENVIA


 

Zenvia™ (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.


 

ABOUT AVANIR


 

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 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.


 

To be included on AVANIR's e-mail alert list; click on the link below or visit AVANIR's website: http://www.b2i.us/irpass.asp?BzID=958&to=ea&s=0


 

 


 

Contact: AVANIR Investor Contacts

Eric Benevich

Brenna Mullen

949-389-6700

ir@avanir.com


 

 


 

 

Posted: December 2009

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