Treatment with Vyondys 53 (golodirsen) for 48 weeks increases levels of dystrophin protein by 16-fold in boys with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping, updated results of a Phase 1/2 trial show.
Also, the newly produced protein was correctly located in the membrane of muscle cells.
The trial (NCT02310906) is ongoing to assess the therapy’s long-term efficacy over 144 weeks.
The study’s early results were published an article, “Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy,” in the journal Neurology.
Vyondys 53, by Sarepta Therapeutics, is an exon-skipping therapy delivered into the blood (intravenously). It was designed to mask the mutated exon 53 in the messenger RNA produced from the DMD gene, to generate a shorter but working version of dystrophin. Approximately 8% of all DMD patients have mutations in exon 53. Exons are the tiny bits of DNA containing information to produce proteins.
The study was divided in two parts. In part 1, participants were randomly assigned to receive either Vyondys 53 or a placebo for 12 weeks. Those on Vyondys 53 received a dose of 4 mg/kg for at least two weeks, followed by three increasing doses of 10, 20, or 30 mg/kg each for two weeks. The primary goal of part 1 was to assess the treatment’s safety, tolerability, and processing inside the body, or its pharmacokinetics.
In total, 12 boys from 6–15 years old with mutations amenable to exon 53 skipping were included — eight on Vyondys 53 and four on placebo.
All patients who completed part 1 plus 13 more patients took part in part 2, an open-label (no placebo group) phase where all will receive weekly 30 mg/kg doses of Vyondys 53 for 168 weeks (approximately three years and three months). An additional group of untreated patients with a DMD mutation not amenable to exon 53 skipping (meaning a mutation in a different exon) was also recruited as a control.
The main goal of part 2 is to assess the therapy’s efficacy at week 144. An earlier time point, week 48, was used to assess the production of dystrophin in muscle biopsies.
Safety findings from part 1 were consistent with those previously observed in pediatric patients with DMD, with all patients reporting at least one treatment-emergent adverse event (TEAE), but none was serious. Also, none of the participants discontinued the treatment due to adverse effects. Two patients had moderate TEAEs: an infection caused by Staphylococcus aureus and fever.
Pharmacokinetics analysis showed that Vyondys 53 was excreted within four hours following administration. The treatment’s average half-life (the time it took for its amount in the body to be reduced by half) was 3.09 hours. According to the team, this short half-life indicates that no accumulation of Vyondys 53 occurs in the blood with weekly dosing.
After 48 weeks of treatment, levels of dystrophin increased by 16-fold compared to the start of the study (baseline), corresponding to a mean of 1.019% of normal dystrophin protein. In addition, produced dystrophin after Vyondys 53 was correctly located at the sarcolemma (membrane of the muscle cell).
Also at week 48, the researchers saw a significant increase of over 13-fold in the number of muscle fibers containing dystrophin compared to the start of the trial.
By skipping over exon 53, Vyondys 53 also restored the cell machinery’s ability to produce protein in all treated patients.
Overall, these findings show that “golodirsen [Vyondys 53] was well-tolerated; muscle biopsies from golodirsen-treated patients showed increased exon 53 skipping, dystrophin production, and correct dystrophin sarcolemmal localization,” the researchers wrote.
While these findings are promising, they added that “a longer duration of treatment is needed to characterize the clinical benefits of exon skipping.”
“This study is ongoing and efficacy, additional safety, and functional outcomes will be described in a separate publication when the week 144 data cut has been performed,” they wrote.
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