- AVI-4658 Well Tolerated in All Patients
- New, Dose Dependent, Dystrophin and Dystrophin Positive Fibers
Up to 55%
- Reduction in Key Inflammatory Markers; No Immune Response to
Newly Produced Dystrophin
- Restoration of the Dystrophin-Associated Glycoprotein Complex
in Muscle Cells
- General Stability in Exploratory Markers of Patient Clinical
Performance
- Results Support U.S. Phase 2 Trial Evaluating Higher Doses
Planned to Start This Year
AVI BioPharma, Inc. (NASDAQ: AVII), a developer of RNA-based
therapeutics, today announced that data from the recently completed
trial of AVI-4658, the Company's investigational drug candidate for
the treatment of Duchenne muscular dystrophy (DMD), demonstrated a
broadly favorable therapeutic profile with promising safety,
biological and exploratory clinical performance assessments that
supports rapid advancement of the program into the next phase of
clinical development. The data from AVI's Study 28, the completed
Phase 1b/2 clinical trial conducted in the U.K., were presented at
the 15th International Congress of the World Muscle Society.
Based on the Study 28 results presented today and other
supportive clinical and preclinical data, AVI plans to initiate a
randomized, double blind, placebo-controlled Phase 2 clinical trial
this year in the U.S evaluating higher doses of AVI-4658 in
patients with DMD. AVI-4658 is AVI's lead drug candidate in
development as a systemically administered treatment for a
substantial subgroup of patients with DMD, a genetic muscle wasting
disease caused by the absence of functional dystrophin in the
muscles.
"The data from this trial support the potential of AVI-4658 as a
promising disease modifying therapy for DMD and its planned
advancement into a Phase 2 study later this year," said Stephen B.
Shrewsbury, M.D., Senior Vice President and Chief Medical Officer
of AVI. "I'm encouraged by the broadly favorable profile seen to
date, particularly the safety and tolerability data, new dystrophin
expression, stable clinical performance, improvements in
inflammatory markers and lack of an immune response. Adding to my
level of confidence in our approach is the restoration of the
dystrophin related protein complexes necessary for proper muscle
cell function that were previously absent from these patients. I'm
eager to continue our clinical program in an effort to develop a
disease modifying therapy where currently no such therapies are
available."
A review of the data from all patients who completed the trial
establishes support for the following conclusions:
- AVI-4658 was well tolerated in all patients. Adverse events
were mostly mild or moderate in intensity, not dose-related, and
none were considered probably related to study drug. There were
also no drug-related serious adverse events or severe adverse
events.
- Substantial and novel dystrophin expression and
dystrophin-positive fiber generation reaching up to 55%, although
variable among patients, tended to be greatest in the highest two
cohorts.
- Dystrophin expression was correctly localized and was
accompanied by restoration of the Dystrophin-associated
Glycoprotein Complex (DGC), a protein complex necessary for the
proper function of muscle cells.
- Reductions in key inflammatory markers, including CD3, CD4 and
CD8 counts, potentially suggest an alteration in the underlying
degenerative disease process.
- There was no immune response to newly made dystrophin.
- There was general stability in exploratory markers of patient
clinical performance, including cardiac, pulmonary and muscle
functional assessments.
Phase 1b/2 Trial Results
Evaluation of safety measurements over the 26-week course of the
study demonstrate that AVI-4658 was well tolerated in all patients
treated, with 219 doses of AVI-4658 successfully administered in
this study. Adverse events were consistent with those typically
seen in chronic pediatric trials and with the underlying disease of
the patients enrolled. Adverse events were generally mild or
moderate. None of the adverse events, serious adverse events or the
single severe adverse event reported was considered by the
investigators to be probably related to treatment with AVI-4658.
There was also no dose-dependent increase in the frequency or
severity of any events. Laboratory assessments for this population
were generally stable throughout the course of the study, notably
across measurements of coagulation, renal function, clinical
chemistry and hematology.
In the study, treatment with AVI-4658 also appeared to have a
favorable impact on immunological and inflammatory markers.
Restoration of dystrophin was followed by an absence of
anti-dystrophin antibodies, suggesting no immunologic reaction to
the newly produced dystrophin. There was also an overall reduction
in T cell infiltration and inflammatory markers, including CD3, CD4
and CD8 cell counts, in the patient muscle biopsies from the top
two cohorts.
Treatment with AVI-4658 in all eight patients in the 10 mg/kg
and 20 mg/kg cohorts showed consistent skipping of exon 51, which
is believed necessary to restore the messenger RNA (mRNA) reading
frame leading to expression of a truncated but functional
dystrophin protein in a substantial subgroup of patients with
specific mutations. All patients in these cohorts also 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 levels 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 also
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.
Dystrophin expression in patients, although variable, tended to
be greatest in the 10 mg/kg and 20 mg/kg cohorts. These cohorts,
both quantitatively and qualitatively, had more uniform and
widespread dystrophin-positive fiber distribution than patients who
received lower doses. Additionally, the greatest response measured
by Western blot was reported in the 20 mg/kg cohort.
Restoration of dystrophin was correctly localized within muscle
cells in patients and was observed to be accompanied by restoration
of the DGC. Loss of dystrophin results in the loss of the DGC,
which is necessary for the proper function of muscle cells.
Exploratory clinical performance measurements, including the 6
Minute Walk Test, 10 Meter Walk Test, NorthStar Ambulatory
Assessment and evaluations of cardiac and pulmonary function,
generally demonstrated stability in patient performance. Given the
size and duration limitations of this open label trial, definitive
assessment of the treatment impact on measures of clinical
performance will need to be further evaluated in additional
clinical studies.
Phase 1b/2 Trial Design
Study 28 was 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 five and 15 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 slow 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 were followed for an
additional 14 weeks. Muscle biopsies were taken before treatment
and at week 14, two weeks after administration of the final dose.
The primary objective of the trial was to assess the safety of
AVI-4658 at these doses over the 26-week duration of the trial.
Eighteen of 19 patients received at least 10 of the 12 doses
planned in this trial. Secondary trial objectives included
assessment of plasma pharmacokinetics, urinary elimination and
exploratory endpoints evaluating biological activity and clinical
performance.
The clinical trial of AVI-4658 was 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 Francesco 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 were provided in part
by the UK Medical Research Council.
Phase 2 Trial Plans
AVI is currently preparing to initiate a Phase 2 clinical trial
intended to evaluate higher weekly doses of AVI-4658 of 50 mg/kg
and 100 mg/kg, subject to review of the trial protocol by the U.S.
Food and Drug Administration (FDA) under the Company's open
Investigational New Drug application (IND) and by the Institutional
Review Board of Nationwide Children's Hospital, Columbus, Ohio, the
planned clinical site. AVI received permission from the FDA to
conduct studies in the U.S. under an IND that was opened in July
2010. The highest weekly dose evaluated in Study 28 was 20 mg/kg.
The Phase 2 study is scheduled to start in late 2010.
The design for the Phase 2 clinical trial was discussed recently
at an expert panel assembled by AVI to review Study 28 data and
future clinical plans in DMD. As a result of the input from the
expert panel, the planned study will be a randomized, double blind,
placebo-controlled Phase 2 trial assessing the safety, tolerability
and pharmacokinetics of AVI-4658 as well as biological activity of
the compound as determined by levels of dystrophin restoration in
patients. The study will also assess exploratory parameters of
clinical performance. The study will be conducted in ambulatory
patients with DMD between the ages of five and 15 who have an error
in the gene coding for dystrophin that can be treated by skipping
exon 51. Patients will be dosed once per week for 12 weeks. After
completion of dosing, patients will be followed for an additional
14 weeks.
About AVI-4658
AVI-4658 is AVI's lead drug candidate being developed as a
systemically administered treatment for a substantial subgroup of
patients with DMD. It is an RNA-based therapeutic employing AVI's
novel phosphorodiamidate morpholino oligomer (PMO) based chemistry
which can work by exon skipping. AVI has exclusive worldwide rights
to intellectual property under a license from the University of
Western Australia. The lead inventor on the patent is Prof. Steve
Wilton, Winthrop Professor, University of Western Australia,
President, Australian Gene Therapy Society, and Head, Molecular
Genetic Therapeutics Group, Centre for Neuromuscular and
Neurological Disorders, Australian Neuromuscular Research
Institute.
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.
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
novel RNA-based therapeutics for rare and infectious diseases, as
well as other select disease targets. Applying pioneering
technologies developed and optimized by AVI, the Company is able to
target a broad range of diseases and disorders through distinct
RNA-based mechanisms of action. Unlike other RNA-based approaches,
AVI's technologies can be used to directly target both messenger
RNA (mRNA) and precursor messenger RNA (pre-mRNA) to either
down-regulate (inhibit) or up-regulate (promote) the expression of
targeted genes or proteins. By leveraging a highly differentiated
RNA antisense-based technology platform, AVI has built a pipeline
of potentially transformative therapeutic agents, including one in
the clinical development stage for the treatment of Duchenne
muscular dystrophy.
Forward-Looking Statements and
Information
This press release contains statements that are forward-looking,
including statements about the development of AVI 4658, other
antisense-based technology and the efficacy, potency and utility of
our product candidates in the treatment of rare and infectious
diseases, and its potential to treat a broad number of human
diseases. These forward-looking statements involve risks and
uncertainties, many of which are beyond AVI's control. Known risk
factors include, among others: clinical trials may not demonstrate
safety and efficacy of any of AVI's drug candidates, including AVI
4658, and/or AVI's antisense-based technology platform; any of
AVI's drug candidates, including AVI 4658, may fail in development,
may not receive required regulatory approvals, or be delayed to a
point where they do not become commercially viable. Any of the
foregoing risks could materially and adversely affect AVI's
business, results of operations and the trading price of its common
stock. For a detailed description of risks and uncertainties AVI
faces, you are encouraged to review the official corporate
documents filed with the Securities and Exchange Commission. AVI
does not undertake any obligation to publicly update its
forward-looking statements based on events or circumstances after
the date hereof.
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