More Good News about Exon Skipping

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AVI4658, an experimental treatment for patients with Duchenne muscular dystrophy (DMD) caused by certain mutations in the gene for the muscle protein dystrophin, has shown promising results when delivered intravenously to 19 trial participants.

Principal investigator Francesco Muntoni, a professor of pediatric neurology at the Dubowitz Neuromuscular Centre in London, presented results Wednesday, April 14, 2010, at the annual meeting of the American Academy of Neurology (AAN), held in Toronto.

Muntoni elaborated on results of this systemic trial of AVI4658 that were released in December (see Exon Skipping Drug Delivers Again).

The drug was tested in the United Kingdom. U.S. testing is planned.

About AVI4658

AVI4658, developed by AVI BioPharma of Bothell, Wash., belongs to a class of experimental drugs known as "exon skipping" constructs, also known as "antisense oligonucleotides."

AVI4658 is designed to cause muscle cells to ignore ("skip") a section of the gene for the muscle protein dystrophin known as exon 51. Other studies have suggested that skipping exon 51 can lead to dystrophin protein production in patients with mutations in this region of the dystrophin gene.

Any of a large number of mutations in the dystrophin gene that result in the absence of functional dystrophin protein can cause DMD.

About the new trial results

Nineteen boys ages 5-15 with dystrophin mutations in the area of exon 51 received weekly intravenous infusions of AVI4658 for 12 weeks at one of six dosage levels. Each group received the construct at a higher dosage level than the previous group.

The investigators wanted to evaluate the safety and tolerability of the drug, as well as how the drug interacted with the body's tissues and whether it affected function in any of the trial participants.

The drug was very well tolerated, with no adverse events, although one child experienced worsening of his cardiac muscle deterioration (cardiomyopathy) and withdrew from the study. It is not known whether the drug had anything to do with this problem.

Skipping of exon 51 with production of dystrophin was seen in all boys who received AVI4658 at the third and fourth dosage levels, and in at least one trial participant who received the drug at the second dosage level. Analysis has not yet been completed for the fifth and sixth (highest) dosage groups.

One set of pre- and post-treatment muscle biopsy slides was presented at the AAN meeting. In the pretreatment sample, there were a few fibers producing dystrophin. Post-treatment, there was dystrophin present at a level of 21 percent of normal, a significant improvement. Full data will be available later in 2010.

Muntoni indicated that the level of dystrophin achieved by at least some trial participants may be sufficient to enable muscle protection and clinical benefit.

No results of clinical function were presented.

AVI is planning a long-term study of intravenous AVI4658.

Meaning for people with DMD

Exon skipping is an extremely promising strategy for people with certain types of mutations that cause DMD. (See Progress in Exon Skipping for DMD for results of another trial of exon skipping, conducted by Prosensa and GlaxoSmithKline.)

The fact that this drug is apparently safe and that it resulted in skipping of exon 51 and dystrophin production in several trial participants is extremely encouraging, as is AVI's continued commitment to development of this drug.

That the drug can be effective when given intravenously is also extremely important, as delivery directly to muscle, via injections, would be cumbersome and uncomfortable for patients.

A trial of AVI4658 at Nationwide Children's Hospital in Columbus, Ohio, under the direction of neurologist Jerry Mendell, who co-directs the MDA clinic at that institution, is planned for later this year.

 Editor's note: This article was updated June 2, 2010, to reflect that there were only 19 trial participants, not 24, per AVI BioPharma's June 2 announcement. For more details on the results of this 19-person trial, see DMD Trial: AVI4658 Increased Dystrophin Production.