AVANIR Announces Positive Phase III Study Results for Zenvia
Zenvia Met Primary Efficacy Endpoint in Confirmatory Trial
Zenvia Demonstrated Improved Safety and Tolerability Profile
August 11, 2009
ALISO VIEJO, Calif., - AVANIR Pharmaceuticals, Inc.
(NASDAQ:AVNR) today announced that the investigational drug Zenvia™(dextromethorphan/quinidine)
met its primary efficacy endpoint in the treatment of pseudobulbar
affect (PBA) in the confirmatory Phase III STAR trial. Both Zenvia 30/10
mg and 20/10 mg provided a statistically significant reduction in
episode rates over the course of the study when compared to placebo
(p<0.0001). In an additional analysis of the primary endpoint, at week
twelve (end of study), patients in the Zenvia 30/10 mg group reported a
statistically significant mean reduction of 88% from baseline in PBA
episode rates (p=0.01). Also in this study, Zenvia was generally safe
and well tolerated. AVANIR management will conduct a conference call to
discuss this announcement today at 5:00 AM PDT (8:00 AM EDT).
"Frequent, unpredictable and often intense emotional outbursts may take
a devastating toll on patients with PBA and their loved ones. The
results of the STAR trial indicate that the new low dose formulation of
Zenvia can substantially reduce the number of PBA episodes that these
patients experience," said Jeffrey Cummings, MD, Augustus Rose Professor
of Neurology at the David Geffen School of Medicine at UCLA and Steering
Committee Chairman for the STAR trial. "With no FDA approved treatments
currently available, there is a real unmet medical need for the
estimated 2 million patients in the U.S. living with the burden of PBA."
"The STAR data indicate that the new low dose Zenvia formulations offer
an improved safety and tolerability profile while continuing to deliver
statistically significant and clinically meaningful efficacy in the
treatment of PBA," said Keith Katkin, AVANIR's President and CEO. "We
are very encouraged by the top-line results and we believe that the STAR
data should be sufficient to address the issues outlined in the FDA
approvable letter. We hope to have a full presentation of the STAR trial
results at a scientific meeting later this year and plan to submit our
complete response to the FDA in the first half of 2010."
EFFICACY RESULTS
The primary efficacy analysis was based on the changes from baseline in
crying/laughing episode rates recorded in the patient diary. Episode
counts were reported and analyzed as a rate expressed as episodes per
day. The primary outcome was the additional reduction in episode rates
experienced with Zenvia 30/10 mg compared to placebo. In the STAR trial,
Zenvia 30/10 mg provided a 47.2% incremental reduction in 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 also
provided a statistically significant incremental reduction of episode
rates compared to placebo (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 frequency and severity of PBA. In this secondary endpoint analysis,
patients receiving Zenvia 30/10 mg reported a significantly greater
reduction in mean CNS-LS score compared to patients who received placebo
(p=0.0002).
Additional secondary endpoints were included to help expand the
Company's understanding of the potential clinical utility of Zenvia.
These additional endpoints include: 1) SF-36 Health Survey, 2)
Neuropsychiatric Inventory Questionnaire (NPI-Q), 3) Beck Depression
Inventory (BDI-II), and 4) Pain Rating Scale score (MS patients only).
Data from these secondary efficacy endpoints, as well as additional
exploratory analyses, are expected to be reported at an upcoming
scientific meeting later this year.
SAFETY AND TOLERABILITY RESULTS
Overall, Zenvia was generally safe and well tolerated in this study. In
the STAR trial, 90.9%, 82.2% and 86.2% of 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 most common reason for early
withdrawals was due to adverse events (AEs). Early withdrawal due to AEs
occurred in 3.7%, 7.8% and 1.9% for the Zenvia 30/10 mg, Zenvia 20/10 mg
and placebo groups, respectively. The proportion of patients reporting
at least one AE was 83.2% in the Zenvia 30/10 mg group, 80.4% in the
Zenvia 20/10 mg group and 81.1% in the placebo group. Reported AEs were
generally mild to moderate in nature. The most commonly reported adverse
events that appeared to be more frequent than placebo were dizziness,
nausea and diarrhea. While commonly reported, falls, headache,
somnolence and fatigue were no different than placebo. The most commonly
reported AEs (>5% of patients) in the Zenvia treatments groups are
summarized in the table below.
Most Common Adverse Events (>5% of patients)
Zenvia 30/10 mg Zenvia 20/10 mg Placebo
N = 107 N = 102 N = 106
Falls 22 (20.6) 14 (13.7) 21 (19.8)
Dizziness 20 (18.7) 11 (10.8) 6 (5.7)
Headache 15 (14.0) 15 (14.7) 16 (15.1)
Nausea 14 (13.1) 8 (7.8) 10 (9.4)
Diarrhea 11 (10.3) 14 (13.7) 7 (6.6)
Somnolence 11 (10.3) 9 (8.8) 10 (9.4)
Fatigue 9 (8.4) 11 (10.8) 9 (8.5)
Nasopharyngitis 9 (8.4) 6 (5.9) 8 (7.5)
Constipation 7 (6.5) 7 (6.9) 9 (8.5)
Muscle Spasms 7 (6.5) 8 (2.0) 10 (9.4)
The proportion of patients reporting at least one serious adverse event
(SAE) was 6.5% in the Zenvia 30/10 mg group, 8.8% in the Zenvia 20/10 mg
group and 10.4% in the placebo group. A total of 38 SAEs occurred in 27
patients over the course of the study. Of the 38 SAEs reported in the
study, only two were deemed by the investigators to be possibly or
probably treatment-related; zero in the Zenvia 30/10 mg group, two in
the Zenvia 20/10 mg group and zero in the placebo group. In addition,
there was a numerical difference in respiratory SAEs with five patients
(4.7%) in the Zenvia 30/10 mg group, three patients (2.9%) in the Zenvia
20/10 mg group and two patients (1.9%) in the placebo group experiencing
respiratory SAEs.
Overall, there were seven deaths in the study, all 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. Of the seven
deaths that were reported, five of the deaths (four in the Zenvia
treatments arms and one in the placebo arm) occurred at least five days
after study drug had been discontinued. There was one reported death in
the Zenvia 20/10 mg group that was considered possibly
treatment-related, which occurred five days after study drug had been
discontinued.
During the study, there were no significant changes observed in
laboratory values from baseline to end of study in any treatment group.
In order to evaluate the potential for respiratory depression, nocturnal
oxygen saturation was measured. There was a decrease in mean nocturnal
oxygen saturation of 0.7% in the Zenvia 20/10 mg group (p=0.0472);
however, no difference was observed in the higher 30/10 mg dose group
relative to placebo.
CARDIOVASCULAR SAFETY
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.
Electrophysiological Measures Zenvia 30/10 mg Zenvia 20/10 mg Placebo
Analysis of Central Tendency
N = 107 N = 102 N = 106
Mean QTc – Baseline (QTcB/QTcF) 418.3 / 407.0 416.2 / 403.8 415.9 /
404.8
Mean QTc – Day 84 (QTcB/QTcF) 420.8 / 411.6 413.2 / 404.6 416.9 / 406.0
Mean ? in Baseline to Day 84 (QTcB/QTcF) 3.0 / 4.9 -1.9 / 1.2 1.5 / 1.1
Outlier Categorical Analysis (Visit 2 through Visit 5)*
Absolute > 450 msec (QTcB/QTcF) 6.3% / 1.9% 4.9% / 1.2% 6.1% / 2.4%
Absolute > 480 msec (QTcB/QTcF) 0.2% / 0.0% 0.0% / 0.0% 0.9% / 0.0%
Absolute > 500 msec (QTcB/QTcF) 0.0% / 0.0% 0.0% / 0.0% 0.2% / 0.0%
? 30 – 60 msec (QTcB/QTcF) 7.0% / 7.2% 3.9% / 2.9% 6.6% / 3.5%
? > 60 msec (QTcB/QTcF) 0.5% / 0.0% 0.2% / 0.0% 0.5% / 0.5%
? > 90 msec (QTcB/QTcF) 0.0% / 0.0% 0.0% / 0.0% 0.0% / 0.0%
* Percent of EKGs taken over the course of the study
"Overall, the STAR data would suggest that the new low dose formulation
of Zenvia provides an improved safety and tolerability profile relative
to the previous formulation," said Randall Kaye, MD, AVANIR's Chief
Medical Officer. "We look forward to receipt and analysis of the full
data set from the double blind phase of the STAR trial as well as
results from the open-label extension study to further evaluate the
safety and efficacy of the new dose formulations."
CONFERENCE CALL
AVANIR management will hold a conference call to discuss this
announcement today at 5:00 AM PDT (8:00 AM EDT). Domestic investors may
listen to the call by dialing (877) 558-3407, conference ID number
24703376, five to ten minutes before the start of the call.
International investors may listen to the call by dialing (706)
679-1941, conference ID number 24703376. A replay of the conference call
will be available within a few hours after the call ends. Investors may
listen to the replay by dialing (800) 642-1687, conference ID number
24703376. Today's conference call also will be webcast and can be
accessed at www.avanir.com. Investors interested in listening to the
live webcast should log on before the conference call begins to download
any software required. Both the audio replay and the archive of the
conference call webcast will remain available for several days.
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 threemonth, double-blinded phase,
followed by a three-month, open-label extension study. At the conclusion
of enrollment, 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 is 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
are determined by reporting adverse events, physical exam, vital signs,
electrocardiogram, respiratory function tests and clinical assessment of
clinical laboratory variables. The STAR trial is being 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. 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, lowaffinity 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 is conducting a confirmatory Phase III study under a Special
Protocol Assessment (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.
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 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 overthe- 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, that subsequent complete analysis of clinical
data will be consistent with the preliminary top-line data reported
herein, or that the Company will meet projected clinical or regulatory
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
AVANIR Investor Contacts
Eric Benevich or Brenna Mullen, 949-389-6700
ir @avanir.com
or
Media Contacts:
Porter Novelli
Holli Dickson, 619-849-5380
hdickson @pnlifesciences.com
or
Kara DePolo, 619-849-5382
kdepolo @pnlifesciences.com
