P50 A phase 1/2 randomized, placebo-controlled, multiple ascending dose study (ACHIEVE) of DYNE-101 in individuals with myotonic dystrophy type 1 (DM1)

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 drives disease progression. As there are no approved disease-modifying therapies, treatment of DM1 is limited to symptom management. The FORCE™ 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. The safety, tolerability, pharmacodynamics, and pharmacokinetics of DYNE-101 are being investigated in an ongoing, randomized, double-blinded, placebo-controlled, multiple ascending dose (MAD) Phase 1/2 study (ACHIEVE) in adults with DM1 aged 18-49 years (NCT05481879). The primary outcome is the number of participants with treatment-emergent adverse events. Change from baseline in splicing index in skeletal muscle assessed by biopsies at baseline, 12, and 24 weeks is a secondary outcome. In the 24-week MAD portion of ACHIEVE, ∼72 participants will be enrolled 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 mg/kg DYNE-101 cohort will be dosed every 4 weeks. Participants who receive 3.4, 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 subsequent 24-week open-label extension and 96-week long-term extension periods. Initial safety, tolerability, and splicing data from the MAD portion are expected in the second half of 2023. 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 drives disease progression. As there are no approved disease-modifying therapies, treatment of DM1 is limited to symptom management. The FORCE™ 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. The safety, tolerability, pharmacodynamics, and pharmacokinetics of DYNE-101 are being investigated in an ongoing, randomized, double-blinded, placebo-controlled, multiple ascending dose (MAD) Phase 1/2 study (ACHIEVE) in adults with DM1 aged 18-49 years (NCT05481879). The primary outcome is the number of participants with treatment-emergent adverse events. Change from baseline in splicing index in skeletal muscle assessed by biopsies at baseline, 12, and 24 weeks is a secondary outcome. In the 24-week MAD portion of ACHIEVE, ∼72 participants will be enrolled 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 mg/kg DYNE-101 cohort will be dosed every 4 weeks. Participants who receive 3.4, 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 subsequent 24-week open-label extension and 96-week long-term extension periods. Initial safety, tolerability, and splicing data from the MAD portion are expected in the second half of 2023.