Dyne Therapeutics announced on the 20th of May, positive clinical data from its ongoing Phase 1/2 ACHIEVE trial of DYNE-101 in patients with myotonic dystrophy type 1 (DM1) and its ongoing Phase 1/2 DELIVER trial of DYNE-251 in patients with Duchenne muscular dystrophy (DMD) who are amenable to exon 51 skipping. New data from both trials demonstrated a compelling impact on key disease biomarkers as well as improvement in multiple functional endpoints and favourable safety profiles.
We are excited to report new clinical data from both our ACHIEVE and DELIVER trials demonstrating meaningful impact on key biomarkers and functional improvement in multiple clinical endpoints that matter to patients. We believe these data reflect the best-in-class potential for these product candidates and reinforce the opportunity to transform the treatment of DM1 and DMD as well as the potential of the FORCE platform to address other rare muscle diseases
John Cox, Dyne’s president and chief executive officer.
We believe the breadth and depth of these data are truly differentiating. Our robust preclinical work is translating into clinical benefit along with favourable safety profiles for both DYNE-101 and DYNE-251. In ACHIEVE, treatment with DYNE-101 demonstrated consistent, dose-dependent splicing correction, which led to an improvement in muscle strength, function, and patient reported outcomes. In DELIVER, treatment with DYNE-251 resulted in dystrophin expression that exceeded levels that have been reported for the standard of care for DMD as well as trends in functional improvement earlier than expected. The DM1 and Duchenne communities have waited too long for new and better therapeutic options. Building on the strength of these encouraging data and recent regulatory interactions, we look forward to continuing to engage with global regulatory authorities throughout this year to pursue expedited approval pathways and address the urgent unmet medical needs in these communities. We are thankful to the participants and clinicians in these trials and the communities for their continued partnership.
Wildon Farwell, M.D., MPH, Dyne’s chief medical officer
The DELIVER Clinical Trial for DMD
DELIVER is a Phase 1/2 global clinical trial evaluating DYNE-251 (an investigational exon 51 skipping therapeutic) consisting of a 24-week multiple ascending dose (MAD) randomised placebo controlled period, a 24-week open-label extension and a 96-week long-term extension. The trial, which is designed to be registrational, is enrolling ambulant and non-ambulant males with Duchenne muscular dystrophy (DMD) who are ages 4 to 16 and have mutations amenable to exon 51 skipping. The primary endpoints are safety, tolerability and change from baseline in dystrophin levels as measured by Western blot. Secondary endpoints include measures of muscle function, exon skipping and pharmacokinetics.
Key Findings from DELIVER
Efficacy Data:
Dyne reported efficacy data from 8 male patients with DMD amenable to exon 51 skipping enrolled in the 10 mg/kg (approximate PMO dose) cohort of the randomised, placebo-controlled MAD portion of the DYNE-251 DELIVER trial. Patients were randomised to receive either DYNE-251 (n=6) or placebo (n=2) once every four weeks for 6 months.
10 mg/kg of DYNE-251 Q4W demonstrated dose-dependent exon skipping and dystrophin expression. DYNE-251 reached levels of dystrophin expression that exceeded levels reported in a clinical trial for the current weekly standard of care for DMD exon 51, eteplirsen, at 6 months1 with a 12-fold lower PMO dose. DYNE-251 also demonstrated encouraging trends in multiple functional endpoints.
Dystrophin Expression (measured by Western blot):
Patients treated with 10 mg/kg of DYNE-251 Q4W had a mean absolute dystrophin level of 3.22% of normal and a 2.97% change (unadjusted for muscle content) from baseline at 6 months. Eteplirsen reached a mean absolute unadjusted dystrophin level of 0.30% of normal and a 0.06% change from baseline at 6 months.1 When adjusting for muscle content, the DYNE-251 treated group reached 7.64% mean absolute dystrophin, which is greater than levels reported by peptide conjugate PMOs in clinical development.3
Function:
Trends in improvement were observed in multiple functional endpoints in the 10 mg/kg DYNE-251 Q4W group at 6 months, including North Star Ambulatory Assessment (NSAA), Stride Velocity 95th Centile (SV95C), 10-Meter Walk/Run Time, and Time to Rise from Floor.
Safety and Tolerability Data:
Dyne also reported safety and tolerability data from 48 patients enrolled through the 40 mg/kg Q8W cohort of the MAD portion of the DELIVER trial. DYNE-251 demonstrated a favourable safety profile.4 The majority of treatment emergent adverse events were mild or moderate and no related serious treatment emergent adverse events have been identified.
Enrolment is complete through the 40 mg/kg cohort. Approximately 480 doses have been administered to date, representing over 35 patient-years of follow-up, supporting dose escalation up to 40 mg/kg.
Dyne plans to continue to engage with global regulators this year on ACHIEVE and DELIVER, and anticipates providing an update on the path to registration for both DYNE-101 and DYNE-251 by the end of 2024. Both trials are designed to be registrational, and the company is pursuing expedited approval pathways for both programs.
If you would like to know more about ACHIEVE and DELIVER, follow the below link:
Would you like to know more about Duchenne muscular dystrophy? Increase your knowledge and understanding of Duchenne with our bite-sized science video series.
Section 1 – Facts about Duchenne muscular dystrophy
Section 2 – Signs and Symptoms of Duchenne muscular dystrophy
Section 3 – Diagnosis of Duchenne muscular dystrophy
Section 4 – Crucial Genetic Terminology
Section 5 – Genetics – Blueprint of Duchenne muscular dystrophy
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