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Gene expression, dystrophin production, and dystrophin localization in patients with Duchenne muscular dystrophy amenable to skipping exon 53 treated with Golodirsen

Muscle biopsy results from 4053-101 study, a phase 1/2 first-in-human study conducted in Europe to assess the safety, tolerability, pharmacokinetics, and efficacy of Golodirsen in 25 boys with confirmed deletions of the DMD gene amenable to skipping exon 53, were presented.

The study comprised two parts. In part 1, 12 patients were randomized to receive a dose titration of Golodirsen ( 8 patients ) or placebo ( 4 patients ).
At the end of part 1 ( dose titration ), all 12 patients continued on Golodirsen and an additional 13 patients started Golodirsen ( part 2 ).
In part 2, all 25 patients were treated for an additional 48 weeks at the time of muscle biopsy. The analysis included biopsies of the bicep muscle at baseline and on-treatment at the part 2 week 48 time point.

All 25 participants displayed an increase in skipping exon 53 ( p less than 0.001 ) over baseline levels, representing a 100% response rate as measured by RT-PCR and demonstrating proof of mechanism.
Mean dystrophin protein increased to 1.019% of normal compared to a mean baseline of 0.095% of normal ( p less than 0.001 ) as measured by Western blot, the primary biological endpoint in the study, representing a 10.7 fold increase from baseline.

The study also showed a statistically significant increase in dystrophin immunofluorescence as measured by immunohistochemistry ( IHC ), the secondary biological endpoint in the study, confirming sarcolemma-associated protein expression and distribution.

Dystrophin is a protein found in muscle cells that, while present in extremely small amounts ( about 0.002% of total muscle protein ), is crucial in strengthening and protecting muscle fibers.
A devastating and incurable muscle-wasting disease, Duchenne muscular dystrophy ( DMD ) is associated with specific errors in the gene that codes for dystrophin, a protein that plays a key structural role in muscle fiber function.
Progressive muscle weakness in the lower limbs spreads to the arms, neck and other areas of the body.
The condition is universally fatal, and death usually occurs before the age of 30 generally due to respiratory or cardiac failure.

Golodirsen uses phosphorodiamidate morpholino oligomer ( PMO ) chemistry and exon-skipping technology to skip exon 53 of the DMD gene.
Golodirsen is designed to bind to exon 53 of dystrophin pre-mRNA, resulting in exclusion, or skipping, of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 53 skipping.
Exon skipping is intended to allow for production of an internally truncated dystrophin protein.

The 4053-101 study was conducted as part of the SKIP-NMD project.
Part 1 is a randomized, placebo-controlled dose-titration to assess safety, tolerability and pharmacokinetics of four dose levels of Golodirsen in genotypically-confirmed DMD patients with deletions amenable to exon 53 skipping.
Part 2 is an open-label evaluation of Golodirsen in patients from part 1, along with newly enrolled DMD patients with deletions amenable to exon 53 skipping. Paired muscle biopsies of the biceps brachii at baseline and on-treatment were obtained to evaluate the biological endpoints from 25 patients treated with 30 mg/kg of Golodirsen administered weekly by intravenous infusion during part 2 of the trial. The study is scheduled to continue for 144 weeks to evaluate safety and clinical endpoints.

Duchenne muscular dystrophy is an X-linked rare degenerative neuromuscular disorder causing severe progressive muscle loss and premature death.
One of the most common fatal genetic disorders, DMD affects approximately one in every 3,500 - 5,000 male births worldwide. ( Xagena )

Source: Sarepta Therapeutics, 2017