Treatment with DYNE-251 revealed dose dependent exon skipping and dystrophin expression as well as improvement in multiple functional end points in both cohorts of the phase 1/2 DELIVER trial.
Wildon Farwell, MD, MPH
(Credit: Dyne Therapeutics)
New data from the ongoing phase 1/2 DELIVER trial (NCT05524883) assessing Dyne Therapeutics’ DYNE-251, an investigational phosphorodiamidate morpholino oligomer (PMO), displayed significant dystrophin expression among treated patients with Duchenne muscular dystrophy (DMD) who are amenable to exon 51 skipping. These results as well as regulatory interactions have led the company to initiate registrational cohorts in the trial with plans to offer an update on the path to registration for DYNE-251 by year-end of 2024.1
This trial update includes 6-month biomarker and functional data from 8 patients randomized to receive DYNE-251 or placebo once every 4 weeks in the 20 mg/kg cohort, and 12-month functional data from 6 patients in the 10 mg/kg cohort. In the 20 mg/kg cohort, those treated with DYNE-251 had a mean absolute dystrophin expression of 3.71% of normal, which was more than 10-fold higher than the 0.3% reported in a previously completed study of eteplirsen (Exondys 51; Sarepta Therapeutics), a standard of care option. Notably, patients treated with DYNE-251 reached 8.72% mean absolute dystrophin after adjusting for muscle content.
“We believe these data reinforce the opportunity to transform the treatment paradigm for individuals living with Duchenne. 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,” Wildon Farwell, MD, MPH, chief medical officer at Dyne, said in a statement.1 “Our goal has always been to drive dystrophin levels that lead to functional benefit for patients – these data suggest that the distribution across cardiac, diaphragm and other skeletal muscles observed preclinically with the FORCE platform is translating in the clinic.”
DELIVER is a phase 1/2 global trial consisting of 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 currently enrolling ambulant and non-ambulant patients with DMD who are ages 4 to 16 and have mutations amenable to exon 51 skipping. The primary end points of the trial are safety, tolerability and change from baseline in dystrophin levels, measured by Western blot. Additionally, secondary end points for the study include measures of muscle function, exon skipping and pharmacokinetics.
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Across both the 20 mg/kg and 10 mg/kg DYNE-251 cohorts, investigators reported meaningful improvements in multiple functional end points including North Star Ambulatory Assessment, Stride Velocity 95th Centile, 10-Meter Walk/Run Time, Time to Rise from Floor. Researchers also observed continued improvement in all reported measures from 6 months to 12 months in the 10 mg/kg cohort. Notably, the change from baseline reported from patients in the 10 mg/kg and 20 mg/kg cohorts of the trial achieved the published minimal clinically important difference as defined by the European Medicines Agency.1
Safety and tolerability data were based on 54 participants enrolled in DELIVER. Treatment with DYNE-251 showed a favorable safety profile, and most treatment emergent adverse events (AEs) reported by participants were mild or moderate. Investigators noted no reports of related serious treatment emergent AEs other than in 2 patients who received the 40 mg/kg dose level, with events potentially related to the study drug, who recovered. According to the company’s update, there have been approximately 675 doses administered to date in the DELIVER trial, which as noted represents over 50 patient-years of follow-up.
“Importantly, treatment with DYNE-251 resulted in meaningful improvements in SV95C, a digital outcome measure approved as a primary endpoint for Duchenne clinical trials in Europe. With these exciting data, we are moving quickly to initiate registrational cohorts in DELIVER, and we continue to pursue expedited approval pathways and plan to provide an update on our path to registration by the end of this year,” Farwell said in a statement.1
The company is also executing its ongoing phase 1/2 ACHIEVE trial (NCT05481879) of DYNE-101 in myotonic dystrophy type 1 (DM1). In May 2024, topline data reported from ACHIEVE showed that treatment with DYNE-101 resulted in robust muscle delivery and dose-dependent, consistent splicing correction while also showing improvement in multiple functional end points and patient-reported outcomes among those with DM1.2
In the recent efficacy data, which includes 40 adults with DM1 enrolled in the randomized, placebo-controlled MAD portion of ACHIEVE, the therapy continued to demonstrate a dose-dependent splicing correction. Specifically, patients in the 5.4-mg/kg–Q8W cohort had a 27% mean splicing correction from baseline across a broad, 22-gene panel at 3 months, with all participants showing splicing correction.
More specifically, the efficacy analysis comprised of 16 patients in the 1.8 mg/kg Q4W cohort who had 12-month data, 16 patients in the 3.4 mg/kg Q4W cohort with 6-month data, and 8 participants from the 5.4 mg/kg Q8W cohort. Results showed that DYNE-101-treated patients showed improvement in muscle strength as measured by Quantitative Myometry Testing, and early sustained potential benefit in 10-Meter Walk/Run test and 5 Times Sit to Stand Test. Those on the therapy also saw improvements in patient-reported outcomes, specifically the Myotonic Dystrophy Type 1 Activity and Participation Scale.
Myotonia, a common complication of DM1, was also improved through DYNE-101. All told, those in the 1.8 mg/kg Q4W group had a mean 3.1-second benefit in myotonia at 3 months that increased to 4.4 seconds at 12 months. Additionally, the 5.4-mg/kg–Q8W cohort had a mean 4.5-second improvement in myotonia at 3 months. During the treatment period, patients on the agent also saw improvement in Myotonic Dystrophy Health Index (MDHI), a patient-reported outcome, and the 17 subscales within it, which include peripheral muscles, central nervous system, and gastrointestinal measures.
In its previous announcement, the company also wrote that enrollment through the 6.8-mg/kg–Q8W cohort is complete, with approximately 500 total doses of DYNE-101 administered to date. Based on dialogue with the Center for Drug Evaluation and Research division of the FDA, Dyne continues to pursue an accelerated approval pathway for the therapy, including leveraging splicing as a potential surrogate biomarker.
