SOURCE: AVI BioPharma, Inc.

AVI BioPharma, Inc.

June 02, 2010 07:00 ET

AVI-4658 Demonstrates First Ever Reported Generation of Greater Than 50% Dystrophin-Positive Muscle Fibers in a Patient Following Systemic Administration in Duchenne Muscular Dystrophy; All Patients in Two Highest Dose Cohorts Generated New Dystrophin-Positive Fibers

AVI-4658 Oligomer Demonstrates Dose Response

Conference Call Scheduled Today at 8:30 AM Eastern Time

BOTHELL, WA--(Marketwire - June 2, 2010) -  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, 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

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 Junín, influenza, HCV or Dengue viruses. For more information, visit

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