Exon-Skipping Drug Delivers Again

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Interim results from a human clinical trial of the exon-skipping compound AVI4658 in boys with Duchenne muscular dystrophy (DMD) show that when the compound is delivered to the whole body via the bloodstream — rather than simply injected into a foot muscle as in a previous trial — it appears safe and leads to production of the missing muscle protein dystrophin.

Exon skipping is among the most promising strategies for treatment of DMD, and the AVI4658 results bode well for this compound and others of its type. Restoration of dystrophin, a key component of muscle, theoretically could restore muscle function or halt its deterioration in DMD.

AVI BioPharma of Bothell, Wash., announced the results in a press release on Dec. 22, 2009, based on a clinical trial held in the United Kingdom. (See Systemic Treatment with AVI4658 Demonstrates RNA Exon Skipping and Dystrophin Protein Expression in Duchenne Muscular Dystrophy Patients.)

A U.S. trial of AVI4658 will begin in spring 2010 at Nationwide Children's Hospital in Columbus, Ohio, under the direction of neurologist Jerry Mendell, who co-directs the MDA clinic at that institution. (See First Human Exon Skipping Trial in U.S. Planned for 2010 and Exon Skipping - AVI BioPharma Trial to Skip Exon 51 in DMD.) In the U.S. trial, the compound will be delivered either intravenously to the whole body or by subcutaneous (under the skin) injection to a small region of the body.

About AVI4658

DMD is caused by a mutation in the gene for the muscle protein dystrophin. Without dystrophin, muscle fibers are abnormally fragile and break down under the stress of contractions.

AVI4658, which is based in part on MDA-supported basic-science research, is designed to coax cells to skip (ignore) the part of the dystrophin gene called exon 51. It’s estimated that approximately 13 percent of DMD patients have a genetic mutation in the exon-51 area of the gene and potentially could be helped by AVI4658. (To find the location of a mutation in the dystrophin gene, it’s necessary to undergo DNA testing.)

About this trial

The newly announced trial results reflect an ongoing phase 1b/2 clinical trial of AVI4658 for the systemic (whole body) treatment of DMD. (See AVI4658: Dose-Ranging Study to Induce Dystrophin Expression.)

The interim results are for participants in the first four of six dosage groups who have completed 12 weeks of treatment with different doses of AVI6458 (0.5, 1, 2 or 4 milligrams per kilogram of body weight) and have undergone muscle biopsies.

The post-treatment muscle biopsy samples reveal that the three trial participants who received 2 and 4 milligrams per kilogram of intravenous AVI4658 showed final instructions (messenger RNA) for dystrophin that reflect skipping of exon 51, accompanied by production of dystrophin protein.

One trial participant, in the 2-milligram dosage group, showed significant production of dystrophin with treatment, encouraging the investigators, who said that they expect even greater levels of dystrophin production with higher doses.

No dystrophin was seen in the biopsy samples from patients who received 0.5 milligrams or 1 milligram per kilogram of AVI4658.

Nineteen patients are now enrolled in this trial, with some receiving dosages of 10 and 20 milligrams per kilogram of of intravenous AVI4658.

Implications for people with DMD

At this time, the strategy only applies to people who can benefit from skipping exon 51. However, if this approach proves successful, other exon-skipping compounds can be developed targeting other dystrophin mutations.

See the clinical trials section of the MDA Web site for news about exon skipping trials and opportunities to participate in them as information becomes available.