Exon 45 Skipping Therapy for DMD Shows Safety in Small Trial

A potential exon-skipping therapy for Duchenne muscular dystrophy (DMD) called DS-5141 showed a good safety profile with repeat dosing in a small clinical trial, according to a press release.

The Phase 1/2 clinical trial (NCT02667483) tested DS-5141 for a first time in Duchenne patients amenable to exon 45 skipping. No safety concerns, including clinically significant adverse events, were reported, and no one stopped treatment early.

DMD is caused by mutations in the DMD gene, which encodes the instructions necessary to produce dystrophin, a protein that is important for muscle health.

DS-5141 is specifically an exon-skipping therapy. Within a cell’s DNA, the protein-coding parts of genes are located in discrete segments called exons. When the DNA is “read,” these exons are strung together in the messenger RNA, which in turn is used to produce a protein.

DS-5141 allows the cells to skip over exon 45 when the DMD gene is read, thereby allowing a cell to produce a shortened — but functional — version of the dystrophin protein in people whose mutation is amenable to this approach.

The investigational therapy is being jointly developed by Daiichi Sankyo and the Orphan Disease Treatment Institute in Tokyo, which specializes in Duchenne treatments.

The trial enrolled seven boys with DMD at two sites in Japan. DS-5141 was administered by subcutaneous (under-the-skin) injection once weekly for 12 weeks, followed by once weekly for 48 weeks. Four different doses are reported to have been tested, ranging from 0.1 mg/kg to 6 mg/kg, but dosing was not specified in the summary results announced by Daiichi Sankyo.

Main trial goals were to evaluate the safety and tolerability of the investigational therapy, as well as its pharmacokinetic profile — how the medication moves into, through, and is processed by the body.

Another primary goal was to assess the expression of dystrophin protein. As announced in an earlier report, protein expression was detected in some, but not all, of the treated participants. The recent release noted “a clear increase” of dystrophin expression in “several patients.”

A secondary goal was to assess the production of DMD gene messenger RNA with exon 45 skipping. This was found in all participants.

Further analyses of trial data are ongoing.

“Daiichi Sankyo will continue to investigate this study’s result in detail as part of its efforts to provide new treatment options for patients with DMD,” the company stated.