Intravenous AVI4658 Shows Safety, Benefit in DMD

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The experimental drug AVI4658, in development by AVI BioPharma to treat Duchenne muscular dystrophy (DMD) caused by specific genetic mutations, was well tolerated and resulted in increased production of the needed dystrophin protein. Measured aspects of cardiac, pulmonary and skeletal muscle function remained stable.

The investigators noted a reduction in markers of inflammation and no immune response to the newly produced protein. (An immune response to a therapeutic protein that the body considers "foreign" is a potential problem in therapies that encourage new protein production.)

The encouraging results for this phase 1b-2 trial were announced at the 15th International Congress of the World Muscle Society, held in Kumamoto, Japan, Oct. 12-16, 2010, and in an AVI BioPharma press release Oct. 15. (See AVI BioPharma's Investigational Drug Candidate AVI-4658 Demonstrates Broadly Favorable Profile of Safety and Tolerability, New Dystrophin Expression, Stable Clinical Performance and Inflammatory Modulation in the Treatment of Duchenne Muscular Dystrophy.)

AVI says it will now proceed with plans to move to a phase 2 trial for AVI4658, using higher doses of this investigational drug.

About AVI4658

AVI4658 is a so-called antisense oligonucleotide and exon-skipping compound. It encourages cells to "ignore," or "skip," parts of genetic instructions that contain erroneous information, splice remaining correct pieces of information around the skipped section, and then synthesize a functional protein from them. Exons are specific regions of a gene.

AVI4658 targets exon 51 of the dystrophin gene and is designed to cause dystrophin protein production in the muscle fibers of patients who have genetic mutations in or around this exon.

About the new findings

The results announced this week for this AVI4658 study follow initial findings announced in June 2010 on the first 12 weeks of this trial. (See DMD Trial: AVI4658 Increased Dystrophin Production and Dose-Ranging Study of AVI-4658 to Induce Dystrophin Expression in Selected Duchenne Muscular Dystrophy Patients.)

AVI reported in June that some trial participants showed variable to substantial increases in dystrophin protein production in muscle biopsy samples.

The new report includes data from an additional 14 weeks of follow-up (for a total of 26 weeks) in 19 people with DMD between the ages of 5 and 15 with an error in the dystrophin gene that could potentially be treated by skipping exon 51. The trial was conducted at two sites in the United Kingdom.

Each participant in this open-label trial received a slow intravenous infusion of AVI4658 once a week for 12 weeks at one of six dosage levels — 0.5, 1, 2, 4, 10 or 20 milligrams per kilogram of body weight. (Open-label trials are those in which investigators and participants know what treatment is being given to each participant.)

Each person was then followed for an additional 14 weeks during which no treatment was given.

Muscle biopsies were taken before treatment and then at week 14, two weeks after the final intravenous infusion of AVI4658.

The primary goal of the trial was to assess safety. Additional objectives included measurements of how the body metabolized the drug, the biological activity of the drug, including dystrophin production in muscle fibers resulting from its administration, and any changes in function in the trial participants.

In summary, the trial found:

• AVI4658 was well tolerated by all participants during the 26 weeks of the study.
• Three participants, one each from the 2-milligram, 10-milligram and 20-milligram dosage levels, showed substantial levels of new dystrophin-postive muscle fibers.
• The dystrophin protein was correctly located in the fibers and was accompanied by restoration of associated proteins that normally attach to dystrophin.
• There was no immune response seen to the newly made dystrophin protein.
• Reductions in key markers of inflammation suggested a favorable alteration in the underlying DMD disease process.
• Functional measurements of walking ability, cardiac function and pulmonary function showed general stability; AVI notes longer and larger studies will be needed to measure the impact of AVI4658 on function.

Meaning for people with DMD

These results are extremely encouraging though far from definitive for the future of AVI4658 and perhaps other exon-skipping compounds aimed at increasing dystrophin production in people with DMD.

In particular, they offer at least preliminary reassurance that DMD patients will not mount an unwanted immune response to newly synthesized dystrophin following this type of treatment.

AVI plans to start a phase 2 trial, employing higher weekly intravenous doses of AVI4658, at Nationwide Children's Hospital in Columbus, Ohio, later in 2010.

The new trial will evaluate doses of 50 and 100 milligrams of AVI4658 per kilogram of body weight and will be double-blind and placebo-controlled. This means there will be a placebo group receiving an inert, look-alike substance and that neither the investigators nor the participants will know each person's group assignment until after the study has been completed.

MDA will continue to follow the progression of AVI4658 through the regulatory process and keep the community informed about trial opportunities.