Arrowhead Pharmaceuticals, Inc. announced that it has dosed the first subjects in a Phase 1/2a double-blinded, placebo-controlled, dose-escalating study (NCT06138743) to evaluate single and multiple ascending doses of ARO-DM1, the company?s investigational RNA interference (RNAi) therapeutic, in up to 48 subjects with type 1 myotonic dystrophy (DM1). DM1 is the most common adult-onset muscular dystrophy. Patients with DM1 have muscle weakness and wasting, myotonia, cataracts, and often develop cardiac conduction abnormalities.

Additionally, patients may become physically disabled and have a shortened life span. There is currently no approved disease-modifying therapy for DM1. Treatments have focused on symptomatic management, including physical therapy, exercise, ankle-foot orthoses, and assistive devices, such as wheelchairs.

ARO-DM1 is designed to reduce expression of the dystrophia myotonica protein kinase (DMPK) gene in the muscle. Pathogenesis of DM1 is driven by an expanded CUG trinucleotide repeat in the 3?-untranslated region of DMPK transcripts. These abnormal transcripts cause mis-regulated splicing, known as spliceopathy, for certain messenger RNAs which are directly linked to the clinical manifestations of DM1.

Preclinical data recently presented at the 2024 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference showed that in nonhuman primates, ARO-DM1 achieved greater than 80% silencing of DMPK in skeletal muscle, which was maintained for longer than 85 days. In a mouse model of DM1 harboring a pathogenic DMPK transgene, a modified species-specific version of ARO-DM1 (S-ARO-DM1) decreased the DMPK-CUG expression and corrected the spliceopathies.