AVI BioPharma, Inc. (NASDAQ: AVII), a developer of RNA-based drugs,
today announced initial efficacy data from the ongoing Phase 1b/2
clinical trial of AVI-4658 for the systemic treatment of patients
with Duchenne muscular dystrophy (DMD), a genetic muscle wasting
disease caused by failure to produce dystrophin. Patients in the
first four (of six) cohorts completing 12 weeks of treatment with
different doses of AVI-4658 (0.5, 1.0, 2.0 or 4.0 mg/kg) have had
their muscles biopsied. Analysis of the post treatment biopsies
found that patients in the 2 and 4 mg/kg drug-treatment cohorts (3
of 3 in total) showed correctly spliced mRNA for dystrophin. One of
these patients, in the 2mg/kg cohort, showed robust expression of
dystrophin protein by western blot and immunofluorescent analysis.
No RNA or protein expression signal was detected in patients from
the 0.5 mg/kg or 1.0 mg/kg cohorts after completing treatment.
Restoration of functional dystrophin expression is considered
critical for successful treatment of DMD.
Treatment with AVI-4658 in the three patients in the 2.0 and 4.0
mg/kg cohorts led to accurate skipping of exon 51, which is
believed to be necessary to restore the mRNA reading frame for
functional dystrophin expression in patients with this class of
mutations. Analysis of post-treatment biopsies by the reverse
transcription-polymerase chain reaction showed a new lower
molecular weight band of RNA resulting from the intended skipping,
or exclusion, of exon 51. The intensity of the higher molecular
weight band (which included exon 51) was correspondingly reduced.
In one of the patients at the 2.0 mg/kg dose, the appearance of
skipped mRNA was accompanied by a robust increase in expression of
dystrophin protein in the post treatment samples using both western
blot and immunofluorescent analysis. Western blot analysis detected
a fivefold increase in dystrophin expression, from 0.9% to 5.3% of
normal. Immunofluorescent analysis of the muscle biopsies from this
patient showed an increase in the percentage of dystrophin positive
muscle fibers from 1% pre-treatment to 21% in the post-treatment
biopsy. Quantitative intensity analysis of the amount of dystrophin
per fiber in patient samples before and after drug treatment showed
a sevenfold increase in dystrophin. When compared to the level of
dystrophin in normal muscle fibers, the dystrophin content per
patient fiber went from 5% pre-treatment to 37% in the
post-treatment biopsy.
"I am very encouraged by the evidence of accurate skipping of
exon 51 in three treated patients," stated Prof. Francesco Muntoni,
Professor of Pediatric Neurology and Head of the Dubowitz
Neuromuscular Centre at the UCL Institute of Child Health, London,
England and the trial's lead investigator. "These results suggest
that we are on the right path towards developing a drug that could
play a role in the treatment of DMD. The fact that one patient at
the 2 mg/kg dose showed significant expression of dystrophin
protein leads us to expect greater levels of dystrophin expression
following treatment with the higher doses of 10.0 mg/kg and 20.0
mg/kg of AVI-4658, which are currently underway in the trial."
Clinical Trial Design and Update
Study 28 is a Phase 1b/2 open label, dose-ranging clinical trial
assessing the safety, tolerability, pharmacokinetics and
exploratory efficacy of AVI-4658 in ambulatory DMD boys between the
ages of 5 and 15 years of age who have an error in the gene coding
for dystrophin that could be treated by skipping exon 51. Patients
are dosed once per week for 12 weeks by intravenous infusion.
Nineteen patients have been enrolled in total and assigned to one
of six dose cohorts: 0.5, 1.0, 2.0, 4.0, 10.0 or 20.0 mg/kg. After
completion of dosing, patients are followed for a further 14 weeks.
The primary objective of the trial is to assess the safety of
AVI-4658 at these doses over the 26-week duration of the trial.
To date, 9 of 10 patients in the first four cohorts (0.5 through
4.0 mg/kg) have completed dosing. A single patient (in the 4 mg/kg
cohort) withdrew from treatment due to DMD-related cardiomyopathy
(now stabilized and believed not to be drug related). An additional
patient was enrolled at 4 mg/kg but has not yet completed dosing.
All 8 patients in the fifth and sixth cohorts, receiving 10 or 20
mg/kg respectively, have initiated dosing.
Data from patients dosed to date demonstrate that AVI-4658
continues to be generally very well tolerated. Adverse events
reported to date are mostly mild, unrelated to drug treatment and
transient. In the patients who completed dosing, two serious
adverse events, both deemed unrelated to AVI-4658, were reported in
different patients after they completed their 12-week treatment
period and during the 14-week follow-up period.
Studies Towards US IND
AVI has completed a series of 12-week preclinical studies of
AVI-4658 under Good Laboratory Practice (GLP) conditions required
to open an Investigational New Drug (IND) application in the US.
The studies tested doses up to 960 mg/kg in both mdx and wild type
mice, and up to 320 mg/kg in non-human primates, both doses being
the maximum feasible single doses in these animals. In all cases
the PMO was well tolerated at doses equivalent to 80 mg/kg and 110
mg/kg in humans respectively (based on standard allometric
scaling), suggesting the potential for a wide therapeutic
index.
An additional GLP study of AVI-4225 PMO, to skip exon 23, in the
mdx mouse has also been completed, with similar encouraging reports
of good tolerability. The histopathology is currently being
reviewed but initial reports suggest that the muscles of treated
mice show improvement over the 12 weeks of study.
"AVI-4658 continues to demonstrate the good safety profile
associated with PMO-based drug candidates. Data from the recently
completed series of preclinical studies required to open an IND in
the US suggest that this good tolerability is likely to continue at
higher doses," stated Stephen B. Shrewsbury, M.D., Senior Vice
President and Chief Medical Officer, AVI BioPharma, Inc. "This is
critically important given that any DMD drug based on exon skipping
is expected to be administered regularly over the entire course of
a patient's life."
The clinical trial of AVI-4658 is being conducted in London, UK
at the UCL Institute of Child Health / Great Ormond Street Hospital
NHS Trust facilities by members of the MDEX Consortium led by
Professor Muntoni and by Professor Kate Bushby at the Royal
Victoria Infirmary, Newcastle-Upon-Tyne, UK, which is the
coordinating center for the European Treat Neuromuscular Diseases
(Treat-NMD) initiative. The clinical costs for the trial are
provided, in part, by the UK Medical Research Council.
About Duchenne Muscular Dystrophy
Duchenne Muscular Dystrophy (DMD) is one of the most common
fatal genetic disorders to affect children around the world.
Approximately one in every 3,500 boys worldwide is afflicted with
DMD with 20,000 new cases reported each year. It is a devastating
and incurable muscle-wasting disease associated with specific
inborn errors in the gene that codes for dystrophin, a protein that
plays a key structural role in muscle fiber function. Symptoms
usually appear in male children by age three. Progressive muscle
weakness of the legs and pelvis eventually spreads to the arms,
neck, and other areas. By age 10, braces may be required for
walking, and most patients are confined to a wheelchair by age 12.
Eventually, this progresses to complete paralysis and increasing
difficulty in breathing requiring ventilatory support. The
condition is terminal and death usually occurs before the age of
30. The outpatient cost of care for a non-ambulatory DMD boy is
among the highest of any disease. There is currently no cure for
DMD, but for the first time ever, there are promising therapies in
or moving into development.
Conference Call
AVI management will hold a conference call to review the initial
data from the ongoing Phase 1b/2 clinical trial on Tuesday,
December 22, 2009, at 8:30 AM Eastern time (5:30 AM Pacific
Time).
Individuals interested in listening to the live conference call
may do so by dialing 877-879-6209 toll free within the United
States and Canada, or 719-325-4794 for international callers. A
replay of the call will be available by dialing 888-203-1112 toll
free within the United States and Canada, or 719-457-0820 for
international callers. The passcode for the replay is 1823048. In
addition, a recording of the call will be available within
approximately 24 hours at www.avibio.com.
About AVI BioPharma
AVI BioPharma is focused on the discovery and development of
RNA-based drugs utilizing proprietary derivatives of its antisense
chemistry (morpholino-modified phosphorodiamidate oligomers or
PMOs) that can be applied to a wide range of diseases and genetic
disorders through several distinct mechanisms of action. Unlike
other RNA therapeutic approaches, AVI's antisense technology has
been used to directly target both messenger RNA (mRNA) and its
precursor (pre-mRNA), allowing for both up- and down-regulation of
targeted genes and proteins. AVI's RNA-based drug programs are
being evaluated for the treatment of Duchenne muscular dystrophy,
including an ongoing systemic Phase 1b/2 clinical trial of exon
skipping with AVI-4658. AVI's antiviral programs have demonstrated
promising outcomes in Ebola Zaire and Marburg Musoke virus
infections and may prove applicable to other viral targets such as
Junín, influenza, HCV or Dengue viruses. For more information,
visit www.avibio.com.
About the MDEX Consortium
The MDEX consortium led by Professor Francesco Muntoni, is a
multidisciplinary enterprise to promote translational research into
muscular dystrophies, and is formed by the clinical groups of
Professor Francesco Muntoni (UCL Institute of Child Health) and
Professor Kate Bushby and Professor Volker Straub (Newcastle
University), and scientists from Imperial College London (Professor
Dominic Wells), UCL Institute of Child Health (Dr. Jennifer
Morgan), Royal Holloway University of London (Professor George
Dickson), Oxford University (Dr. Matthew Wood) and University of
Western Australia (Professor Steve Wilton). In addition, the
charities Muscular Dystrophy Campaign (MDC), Action Duchenne and
Duchenne Family Support Group also participate in the Consortium.
For more information, visit www.mdex.org.uk.
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Reform Act of 1995: The statements that are not historical facts
contained in this release are forward-looking statements that
involve risks and uncertainties, including, but not limited to, the
results of research and development efforts, the results of
preclinical and clinical testing, the effect of regulation by the
FDA and other agencies, the impact of competitive products, product
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