Trial Results in DMD Heralded as 'Proof of Concept'

The Dec. 27 issue of the prestigious New England Journal of Medicine featured encouraging results of a phase 1 clinical trial of an exon skipping compound in four boys with Duchenne muscular dystrophy (DMD). Preliminary findings from this trial, conducted in the Netherlands, were announced in May (see Progress Reports).

Judith van Deutekom, formerly at Leiden University in the Netherlands and now at Prosensa in Leiden, received MDA funding to work on preclinical development of exon skipping for DMD and is the first author on this study. The clinical trial was funded by several European agencies and Prosensa, which produced the therapeutic compound.

Exon skipping is a strategy to restore production of the needed protein, which in DMD is dystrophin, by telling muscle cells to ignore (skip) a part of the genetic instructions that contain an error (mutation) and to synthesize dystrophin from the remaining instructions. The skipping is achieved by blocking the mutation-containing part of the gene with an antisense oligonucleotide, or AON.

The hoped-for result, which occurred in this trial in all four participants, is the production of smaller-than-normal, but potentially functional, dystrophin protein molecules.

Two of the participants were 10 and 11 years old, and two were 13. None had any detectable dystrophin in muscle biopsy samples prior to treatment, and all had mutations that were potentially correctable by skipping over a part of the dystrophin gene known as exon 51, which Prosensa’s PRO051 AON was designed to block.

Each boy received four injections of PRO051 in a muscle at the front of the lower leg. A biopsy a month later showed dystrophin production that was between 3 percent and 12 percent of a normal level of the protein. No functional changes were observed, but none were expected from this low dose and restricted area of injection. The results are considered “proof of concept,” however, for exon skipping via antisense as a strategy to treat DMD.

The investigators did not observe any problems related to safety of PRO051, although one participant reported pain at the injection site, two reported a few days of flulike symptoms after the injections, and one experienced mild diarrhea for a day.

Importantly, there were no apparent inflammatory or toxic responses to the compound.

In an accompanying editorial, long-time DMD researcher Eric Hoffman, now at Children’s National Medical Center in Washington, describes the promise of the Dutch study, as well as the hurdles yet to be cleared.

Hoffman, who has been awarded several MDA grants, notes that an exon skipping compound, to be truly useful, would have to be delivered systemically to all muscles, without toxicity, and that several compounds (perhaps dozens) would have to be designed for the hundreds of different dystrophin mutations in boys with DMD.

If each AON compound has to be put through the full gamut of Food and Drug Administration approval tests, he says, the regulatory hurdles for this treatment strategy will be formidable. Instead, he suggests, perhaps the FDA will consider approving such compounds as a class of drugs, rather than as individual therapeutic agents.

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