Golodirsen Shows Potential to Treat DMD


Sarepta Therapeutics has announced encouraging results from a phase 1/2 clinical trial that suggest the experimental treatment golodirsen potentially may be effective as a treatment for Duchenne muscular dystrophy (DMD). The trial, conducted in Europe, was the first to test the drug in people with DMD.

Golodirsen is an “exon skipping” drug designed to slow disease progression in DMD. Administered by intravenous infusion, it targets a section of genetic code called exon 53, and may help up to 8 percent of boys with DMD. Another Sarepta drug, eteplirsen (brand name Exondys 51), which is based on the same strategy as golodirsen, was approved by the U.S. Food and Drug Administration in 2016 to treat boys with DMD caused by a mutation amenable to skipping exon 51.

Results demonstrated increase in dystrophin protein production

In the trial, conducted in Europe to assess the safety, tolerability, pharmacokinetics (how the drug is absorbed, distributed and metabolized in the body) and efficacy of golodirsen in 25 boys with DMD, treatment with the golodirsen for approximately one year was associated with a significant boost in dystrophin protein production. Muscle biopsies confirmed that all participants responded to the drug, with increased levels of exon 53 skipping compared to measurements taken at baseline (prior to beginning treatment).

A 10.7-fold increase in levels of dystrophin protein was seen, equating to a rise from an initial average among patients of 0.095 percent of normal protein levels to a mean of 1.019 percent.

As was reported in Sarepta’s press release, “This is now the second exon-skipping agent to have shown a statistically significant increase in dystrophin production, validating the exon-skipping approach to treating boys with amenable mutations,” said pediatric neurologist and principal investigator for the study Francesco Muntoni.

Exon skipping prompts the production of shortened protein

Golodirsen uses Sarepta Therapeutics’ exon-skipping technology to target exon 53 of the DMD gene.

Exon skipping is a treatment strategy in which sections of genetic code are “skipped” (spliced out, or left out) during the protein manufacturing process, allowing cells to create shortened but partially functional dystrophin protein, the muscle protein missing in DMD. Exon skipping is not a cure for DMD, but potentially could lessen the severe muscle weakness and atrophy that is the hallmark of the disease.

Just as individuals with DMD caused by a mutation that would be amenable to skipping exon 51 could benefit from treatment with Exondys 51, those with DMD caused by a mutation that would be impacted by skipping exon 53 potentially could benefit from treatment with golodirsen.

Although treatment with golodirsen would not cure Duchenne, it could slow progression of the disease which, in turn, could extend the length of time individuals with DMD could walk, eat independently and breathe without assistance.

MDA has been central to development of the exon skipping approach from the beginning, having funded foundational work upon which the strategy was built. Laboratory development of exon skipping began in the 1990s, and MDA has funded extensive research into the strategy since that time.

Looking ahead

The 25 boys with DMD who participated in the phase 1/2 clinical trial will continue to be evaluated for a total of 144 weeks. The study is expected to be completed in May 2019, and Sarepta has said it plans to release study data at a future medical or scientific conference.

The safety and efficacy of golodirsen also is being evaluated in the ongoing phase 3 ESSENCE study in boys with DMD gene deletions amenable to skipping exons 45 or 53. This trial currently is recruiting approximately 100 people to participate at sites across the United States, Canada and Europe. For more information about this trial, visit clinicaltrials.gov and enter NCT02500381 into the search box.