P.337Dystrophin restoration by exon 53 skipping in patients with Duchenne muscular dystrophy after viltolarsen treatment: phase 2 study update

Abstract

Duchenne muscular dystrophy (DMD) results in the loss of motor functional ability and early mortality due to the absence of dystrophin in muscle. Restoration of an out-of-frame deletion in the dystrophin mRNA to yield a truncated, in-frame transcript can be accomplished by "exon skipping." Viltolarsen is a novel antisense oligonucleotide that promotes exon 53 skipping in the dystrophin mRNA. Viltolarsen provides the potential to treat DMD patients who have dystrophin deletions comprising exons 43-52, 45-52, 47-52, 48-52, 49-52, 50-52, or 52 alone. A completed Phase 2 study, NS-065/NCNP-01-201 (ClinicalTrials.gov Identifier: NCT02740972), enrolled 16 DMD patients with dystrophin mutations amenable to exon 53 skipping and demonstrated safety and tolerability of viltolarsen, as previously presented. In this study, target engagement by viltolarsen was demonstrated in RNA and protein extracted from patient muscle demonstrating skipping of exon 53 with accompanying expression of a truncated dystrophin protein. For each patient, the expected truncated dystrophin protein was observed by western blot, mass spectrometry and immunofluorescence, comparing a pre-treatment baseline muscle sample to a follow up sample after 24 weeks of treatment. The mass spectrometry demonstration of muscle dystrophin expression, using an assay validated for this study, is novel. All participants from the completed study then enrolled in a Phase 2 extension study NS-065/NCNP-01-202 (ClinicalTrials.gov Identifier: NCT03167255). The present report focuses on additional exploratory investigations into safety and timed function and strength measures observed after 73 weeks of total treatment with viltolarsen.