BOTHELL, WA, Jun 02 (MARKET WIRE) —
AVI BioPharma, Inc. (NASDAQ: AVII), a developer of RNA-based drugs, today
announced topline biopsy data from Study 28, the ongoing Phase 1b/2
clinical trial of AVI-4658, AVI’s lead drug candidate being developed as
a systemically administered treatment for a substantial subgroup of
patients with Duchenne muscular dystrophy (DMD), a genetic muscle wasting
disease caused by failure to produce dystrophin. Topline biopsy data from
the study demonstrated the first ever reported generation of new
dystrophin-positive muscle fibers of more than 50% of normal in a patient
with DMD following systemic administration of a drug. All patients in the
two highest dose cohorts of the study demonstrated generation of new
dystrophin-positive muscle fibers, although treatment responses varied
across and within treatment groups. Generation of functional dystrophin
is considered critical for successful treatment of DMD, and AVI intends
further clinical evaluation of AVI-4658 to help optimize a dosing regimen
to achieve more consistent improvements among patients.
Patients completing 12 weeks of treatment with six different doses of
AVI-4658 (0.5, 1.0, 2.0, 4.0, 10 or 20 mg/kg) had their muscles biopsied
before and after treatment, and analysis of the post treatment biopsy
findings include:
– Data reported today for the patients in the 10 and 20 mg/kg
drug-treatment cohorts completing the 12 weekly doses (8 of 8
patients) showed consistent skipping of exon 51 in the dystrophin
mRNA, providing evidence of systemic biologic activity of AVI-4658.
– Three patients, one each in the 2.0, 10 and 20 mg/kg cohorts,
demonstrated substantial generation of new dystrophin-positive muscle
fibers, including the first ever reported generation of
dystrophin-positive muscle fibers of more than 50% of normal in a
patient following systemic administration of a drug.
– All 8 patients in the 10 and 20 mg/kg cohorts demonstrated generation
of new dystrophin-positive muscle fibers.
– The three patients, one each in the 2.0, 10 and 20 mg/kg cohorts,
demonstrating substantial generation of new dystrophin-positive muscle
fibers had multiple fold increases in dystrophin protein expression
measured by Western blot over baseline, with patients in the 20 mg/kg
cohort demonstrating the highest increases. These three patients also
had noted increases in dystrophin per fiber.
“These results are very encouraging. The muscle cells of the
patients at the higher levels had clear qualitative and quantitative
changes in their dystrophin expression and this was not associated with
any sign of inflammation or immune response against dystrophin-positive
fibers. To look at the muscle biopsies of these treated patients under
the microscope, and appreciate the new production of dystrophin compared
to the pre-treated muscles, reveals a very different picture from that
typically observed in DMD 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. “This trial demonstrates the potential of a
systemically administered drug to induce a substantial novel dystrophin
protein expression in multiple patients with DMD at levels that may
produce a clinically meaningful effect on the course of the disease.
Based on these results and on how the patients tolerated the study drug,
I believe that AVI-4658 has the potential to become a disease modifying
drug in the treatment of DMD.”
Study Details
AVI-4658 was generally well tolerated in all Study 28 patients, and there
has been no evidence of anti-dystrophin antibodies or T and B cell
infiltration. In the patients completing dosing, two serious adverse
events (one instance each of post operative nausea and vomiting, and an
ankle fracture), 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 of the trial.
Treatment with AVI-4658 in all patients in the 10 and 20 mg/kg cohorts
showed consistent skipping of exon 51, which is believed necessary to
restore the mRNA reading frame and dystrophin expression in a substantial
subgroup of patients with specific mutations. Analysis of post-treatment
biopsies by reverse transcription-polymerase chain reaction (RT-PCR)
confirmed the new mRNA resulting from the intended skipping, or
exclusion, of exon 51.
All 8 patients in the 10 and 20 mg/kg cohorts treated with AVI-4658
demonstrated generation of new dystrophin-positive muscle fibers as
measured by immunofluorescent analysis of their muscle biopsies.
Of note, three patients, one patient in each of the 2.0, 10 and 20 mg/kg
cohorts, demonstrated substantial generation of new dystrophin-positive
muscle fibers, which increased from 1% to 21%, 1% to 15%, and 3% to 55%
of normal, respectively, when comparing pre treatment to post treatment
samples. These three patients demonstrated a noted increase in dystrophin
per fiber as determined by immunofluorescent analysis as well as multiple
fold increases in dystrophin protein expression measured by Western blot
over baseline. Patients in the 20 mg/kg cohort demonstrated the greatest
fold increases when compared to the other cohorts measured by Western
blot.
Overall, patients in the 10 and 20 mg/kg cohorts, both quantitatively and
qualitatively, had more uniform and widespread dystrophin-positive fiber
distribution than patients receiving lower doses. Additionally, responses
of patients in the 20 mg/kg cohort appeared better than the patients in
the 10 mg/kg cohort.
“Having supported exon-skipping technology for more than a decade and
from its earliest stages, we’re delighted that AVI BioPharma has
demonstrated that systemic administration of an exon-skipping drug can
bring a substantial increase in dystrophin-positive muscle fibers in
patients with Duchenne muscular dystrophy,” says Valerie Cwik M.D.,
Muscular Dystrophy Association Executive Vice President, Research and
Medical Director. “Many questions remain, including optimal dosing, and
treatment applicability for specific mutations, but this is clearly an
important advance.”
Clinical Trial Design and Update
AVI-4658 is an RNA-based therapeutic employing AVI’s novel
phosphorodiamidate morpholino oligomer (PMO) based chemistry which can
work by exon skipping. It is being developed as a systemic treatment for
patients with DMD. 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 patients with DMD between
the ages of 5 and 15 years of age who have an error in the gene coding
for dystrophin that can be treated by skipping exon 51. Patients were
dosed once per week for 12 weeks by intravenous infusion. Nineteen
patients were 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. All patients completed dosing. Some
patients in the highest dose cohort remain in the 14 week follow-up
period.
“The topline results reported today are very promising and suggest an
overall very favorable profile, which is important considering that any
DMD therapy will likely be chronic, administered to children and
potentially life-long. Of particular importance was that AVI-4658 was
generally well tolerated as a systemic treatment in all Study 28
patients, which is consistent with our data demonstrating that AVI-4658
was well tolerated in preclinical studies up to an equivalent human dose
of approximately 100 mg/kg,” stated Stephen B. Shrewsbury, M.D., Senior
Vice President and Chief Medical Officer, AVI BioPharma, Inc. “Moving
forward, we will complete our data analysis and we intend to review the
clinical data with key opinion leaders and work with regulatory
authorities to finalize our plans for additional clinical development,
including optimizing a dosing regimen to provide a more consistent result
across potentially treatable patients.”
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 Network of Excellence TREAT-NMD. 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 affected
with DMD. Girls are rarely affected by the disorder. DMD 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
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 require full-time use of a
wheelchair by age 12. Eventually, this progresses to complete paralysis
and increasing difficulty in breathing due to respiratory muscle
dysfunction requiring ventilatory support, and cardiac muscle dysfunction
leading to heart failure. The condition is terminal and death usually
occurs before the age of 30. The outpatient cost of care for a
non-ambulatory DMD patient is very high. 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
topline biopsy data from the ongoing Phase 1b/2 clinical trial on June 2,
2010, at 8:30 AM Eastern time (5:30 AM Pacific Time).
The conference call may be accessed by dialing 866.202.0886 for domestic
callers and 617.213.8841 for international callers. The passcode for the
call is 97738469 and please specify to the operator that you would like
to join the “AVI BioPharma conference call.” The conference call will be
webcast live under the events section of AVI’s website at www.avibio.com,
and will be archived there following the call. Please connect to AVI’s
website several minutes prior to the start of the broadcast to ensure
adequate time for any software download that may be necessary.
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.
About AVI BioPharma
AVI BioPharma is focused on the discovery and
development of RNA-based drugs utilizing proprietary derivatives of its
antisense chemistry (phosphorodiamidate morpholino 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
Junin, influenza, HCV or Dengue viruses. For more information, visit
www.avibio.com.
“Safe Harbor” Statement under the Private Securities Litigation 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 development, commercialization and
technological difficulties, and other risks detailed in the company’s
Securities and Exchange Commission filings.
AVI Press and Investor Contact:
David A. Walsey
Senior Director, Investor Relations & Corporate Communications
425.354.5140
Investorrelations@avibio.com
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