DMD Trial: AVI4658 Increased Dystrophin Production

The biopharmaceutical company AVI BioPharma has announced additional encouraging results from its clinical trial of AVI4658, an experimental treatment for Duchenne muscular dystrophy (DMD).

The new results show that, at higher doses, AVI4658 can result in substantial production of the needed dystrophin protein in muscle fibers.

The company has not yet released results of any tests of muscle function in the 19 children in this trial.

AVI4658 is an antisense oligonucleotide that sticks to genetic instructions at a predetermined location, blocking the instructions and causing muscle cells to ignore (skip) them. AVI4658 is designed to correct DMD caused by mutations in the dystrophin gene in or near a section called exon 51. (Lack of dystrophin is the underlying cause of this X-chromosome-linked genetic muscle disease.)

The new information supplements preliminary data presented in April 2010 at the American Academy of Neurology meeting in Toronto. At that time, the company reported that the drug appeared safe and resulted in production of dystrophin in some participants in this trial. (See More Good News About Exon Skipping.)

About the new findings

On June 2, 2010, the company announced muscle biopsy sample results from the 19 participants in the phase 1b/2 clinical trial, which was conducted at two centers in the United Kingdom. The trial participants were boys with DMD ages 5-15 with mutations in the area of exon 51.

The announcement included biopsy results on participants who completed 12 weekly intravenous infusions of AVI4658 at one of six different doses (0.5, 1, 2, 4, 10 or 20 milligrams per kilogram of body weight).

In summary, here's what AVI found:

• Muscle biopsy samples from all 12 trial participants completing 12 weekly doses in the 2-, 4-, 10- and 20-milligram-per-kilogram group showed skipping of exon 51 of the dystrophin gene.
• All eight participants in the 10- and 20-milligram groups, and one person in the 2-milligram-per-kilogram group, showed some increases in the number of muscle fibers producing dystrophin.
• Three trial participants, one each in the 2-, 10- and 20-milligram groups, showed substantial increases in the number of fibers producing dystrophin before and after treatment. One person, in the 20-milligram-per-kilogram group, had a post-treatment biopsy sample showing dystrophin production in 55 percent of his sampled muscle fibers, compared to 3 percent prior to treatment.
• No dystrophin was detected in participants receiving 0.5 milligrams or 1 milligram of AVI4658 per kilogram of body weight. These were the two lowest dosage levels.
• The drug was generally well tolerated in all patients.
• No unwanted immune responses were noted.

Meaning for people with DMD

This and other exon skipping trial results (see Progress in Exon Skipping for DMD) bode well for this strategy in DMD in children and young adults whose disease results from mutations in the area of exon 51 of the dystrophin gene.

AVI BioPharma plans to open a U.S. trial as soon as regulatory hurdles have been cleared. The first trial site is slated to be Nationwide Children's Hospital in Columbus, Ohio.

More information, including questions and answers about AVI4658 and an archived conference call that took place June 2, 2010, can be found on the AVI BioPharma website.