Dyne Therapeutics has announced new clinical data from its Phase 1/2 DELIVER trial, showcasing significant dystrophin expression and functional improvements in patients with Duchenne muscular dystrophy (DMD) treated with DYNE-251. The investigational antisense oligonucleotide (ASO) is designed for patients amenable to exon 51 skipping. These promising results have led the company to initiate registrational cohorts within the trial, with an update on the registration path expected by the end of 2024.
The DELIVER trial includes 6-month biomarker and functional data from eight patients in the 20 mg/kg cohort and 12-month functional data from six patients in the 10 mg/kg cohort. Patients treated with DYNE-251 in the 20 mg/kg cohort achieved a mean absolute dystrophin expression of 3.71% of normal, which is more than 10 times higher than the 0.3% reported in a previous study of eteplirsen (Exondys 51; Sarepta Therapeutics), a current standard of care. After adjusting for muscle content, the mean absolute dystrophin expression reached 8.72%.
Functional Improvements and Safety
Across both the 20 mg/kg and 10 mg/kg DYNE-251 cohorts, researchers reported meaningful improvements in multiple functional endpoints, including the North Star Ambulatory Assessment, Stride Velocity 95th Centile, 10-Meter Walk/Run Time, and Time to Rise from Floor. The 10 mg/kg cohort showed continued improvement in all reported measures from 6 to 12 months. Notably, the changes from baseline in both cohorts achieved the minimal clinically important difference as defined by the European Medicines Agency.
According to Wildon Farwell, MD, MPH, chief medical officer at Dyne, these data reinforce the potential to transform the treatment landscape for individuals with Duchenne. He stated, "In DELIVER, DYNE-251 achieved the highest level of dystrophin expression reported for an exon 51 skipping therapy and improvement in multiple functional endpoints across multiple cohorts that continued with time on therapy."
Safety and tolerability data from 54 participants in the DELIVER trial indicated a favorable safety profile, with most treatment-emergent adverse events being mild or moderate. There were no reports of related serious treatment-emergent adverse events, except in two patients who received the 40 mg/kg dose, with events potentially related to the study drug, from which they recovered. Approximately 675 doses have been administered in the DELIVER trial, representing over 50 patient-years of follow-up.
Trial Design and Endpoints
DELIVER is a phase 1/2 global trial that includes a 24-week multiple ascending dose (MAD) randomized placebo-controlled period, a 24-week open-label extension, and a 96-week long-term extension. The trial is enrolling ambulant and non-ambulant patients with DMD, aged 4 to 16, who have mutations amenable to exon 51 skipping. The primary endpoints are safety, tolerability, and change from baseline in dystrophin levels, measured by Western blot. Secondary endpoints include measures of muscle function, exon skipping, and pharmacokinetics.
Ongoing ACHIEVE Trial in Myotonic Dystrophy Type 1 (DM1)
Dyne Therapeutics is also advancing its phase 1/2 ACHIEVE trial of DYNE-101 in myotonic dystrophy type 1 (DM1). Topline data from the ACHIEVE trial showed that DYNE-101 treatment resulted in robust muscle delivery and dose-dependent splicing correction, along with improvements in multiple functional endpoints and patient-reported outcomes among individuals with DM1. Dyne continues to pursue an accelerated approval pathway for DYNE-101, potentially leveraging splicing as a surrogate biomarker.
