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Abstract Details

ACHIEVE Trial, a Randomized, Placebo-Controlled, Multiple Ascending Dose Study of DYNE-101 in Individuals with Myotonic Dystrophy Type 1 (DM1)
Child Neurology and Developmental Neurology
ES2 - Emerging Science 2 (6:18 PM-6:24 PM)
009

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 FORCETM 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.

Authors/Disclosures
Daniel Wolf, PhD (Dyne Therapeutics, Inc.)
PRESENTER
Dr. Wolf has received personal compensation for serving as an employee of Dyne Therapeutics. Dr. Wolf has received personal compensation for serving as an employee of Sarepta Therapeutics. Dr. Wolf has stock in Dyne Therapeutics. Dr. Wolf has stock in Sarepta Therapeutics.
Chris Mix, MD (Dyne Therapeutics) Dr. Mix has received personal compensation for serving as an employee of Dyne Therapeutics. Dr. Mix has stock in Dyne Therapeutics.
Baoguang Han (Dyne Therapeutics, Inc.) Baoguang Han has received personal compensation for serving as an employee of Dyne-Therapeutics-INC. Baoguang Han has stock in Dyne-Therapeutics-INC.
Ashish Dugar, PhD (Dyne Therapeutics) Dr. Dugar has received personal compensation for serving as an employee of Dyne Therapeutics.
Wildon Farwell, MD Dr. Farwell has received personal compensation for serving as an employee of Biogen. Dr. Farwell has received stock or an ownership interest from Biogen.