Abstract Details

DM1 is a severe neuromuscular disease caused by expanded CUG triplets in the dystrophia myotonica protein kinase (DMPK) RNA, which sequester splicing proteins into toxic nuclear foci resulting in a spliceopathy that ultimately drives disease progression. As there are no available disease-modifying therapies, treatment of DM1 is limited to symptom management.

The FORCE^TM platform was developed to overcome limitations of oligonucleotide delivery to muscle by harnessing the expression of transferrin receptor (TfR)1 on muscle cells. DYNE-101 is a TfR1-targeting antigen-binding fragment conjugated to a gapmer antisense oligonucleotide (ASO) that targets nuclear DMPK RNA. In preclinical models, DYNE-101 had a favorable safety profile and was shown to reduce mutant DMPK RNA, foci formation, and correct splicing defects, suggesting a potential effect in individuals with DM1.

To evaluate DYNE-101 in adults living with myotonic dystrophy type 1 (DM1).

ACHIEVE is a randomized, double-blinded, placebo-controlled, multiple ascending dose (MAD) Phase 1/2 study assessing safety, tolerability, pharmacodynamics, efficacy, and pharmacokinetics of DYNE-101 administered intravenously to adults with DM1 aged 18-49 years (NCT05481879). The study consists of three periods: MAD/placebo-controlled (24 weeks), open-label extension (OLE, 24 weeks), and long-term extension (LTE, 96 weeks). The primary outcome is the number of participants with treatment-emergent adverse events. Change from baseline in splicing index in skeletal muscle is a secondary outcome.

ACHIEVE will enroll ~64 participants in 4 cohorts of ascending doses of DYNE-101 (1.8, 3.4, 6.8, and 10.2 mg/kg approximate ASO equivalent doses). Participants in the 1.8 and 3.4 mg/kg DYNE-101 cohorts will be dosed every 4 weeks. Participants who receive 6.8 and 10.2 mg/kg DYNE-101 will be dosed every 4 or 8 weeks. All participants will receive the highest safe and tolerable dose of DYNE-101 during the OLE and LTE periods.

The ACHIEVE study will inform further clinical development of DYNE-101 for the treatment of DM1.