by: Parent Project Muscular Dystrophy
Dyne Therapeutics, Inc. has announced positive new clinical data from its ongoing Phase 1/2 DELIVER trial of DYNE-251 in patients with Duchenne who are amenable to exon 51 skipping. DYNE-251 is an exon skipping product that combines a PMO to enable skipping of exon 51 with a fragment antibody (Fab) to increase targeted delivery of the drug to muscle. It is designed to enable targeted muscle tissue delivery and promote exon skipping in the nucleus, allowing muscle cells to create a truncated, functional dystrophin protein, with the goal of stopping or reversing disease progression.
Dyne reports that patients treated with 20 mg/kg of DYNE-251 every four weeks had a mean absolute dystrophin expression of 3.71% of normal (unadjusted for muscle content), more than 10-fold higher than the 0.3% reported in a clinical trial of the once weekly standard of care, eteplirsen.
According to Dyne, treatment with DYNE-251 resulted in meaningful improvements in multiple functional outcome measures, such as the North Star Ambulatory Assessment (NSAA), 10-Meter Walk/Run Time (10-MWR), Time to Rise from Floor, and Stride Velocity 95th Centile (SV95C), a digital outcome measure approved as a primary endpoint for Duchenne clinical trials in Europe.
The company has indicated that it is moving quickly to initiate registrational cohorts in DELIVER, and continues to pursue expedited approval pathways and plans to provide an update on the path to registration by the end of this year.
PPMD is pleased to learn this news and we look forward to further updates from Dyne.
Read Dyne’s press release here.
Read Dyne’s community letter:
September 3, 2024
A Letter to the Duchenne Muscular Dystrophy Community From Dyne Therapeutics
At Dyne we are working to advance our proprietary FORCETM platform to overcome the limitations of muscle tissue delivery, with the stated mission to deliver life-transforming therapies for people living with serious muscle diseases. Our initial focus includes programs for myotonic dystrophy type 1 (DM1), Duchenne muscular dystrophy (DMD) and facioscapulohumeral muscular dystrophy (FSHD), with the hope of delivering on a shared goal with the community- stopping or reversing disease progression. You can learn more about the FORCETM platform and our pipeline priorities here: https://www.dyne-tx.com/our-forcetm-platform/. Our purpose and our passion are fueled by our continuous engagement and active dialogue with the communities we serve.
Recognizing a shared sense of urgency with the DMD community to accelerate potential therapies that drive functional benefit for patients via restoration of near full- length dystrophin, and in keeping with a commitment to maintain an active dialogue with the community, we are sharing new clinical data from the on-going DYNE-251 Phase1/2DELIVERtrial. Themostrecentupdateincludesefficacyandsafetydata from participants enrolled in the 20 mg/kg (approximate PMO dose) study group, or cohort, of the on-going randomized, placebo-controlled multiple ascending dose (MAD) portion of the DYNE-251 DELIVER trial. Participants were randomized to receive either DYNE-251 or placebo once every four weeks (Q4W) for 6 months. We also report 12- month data from the 10 mg/kg Q4W study group receiving DYNE-251. The clinical data demonstrate consistency of benefit at 10 mg/kg Q4W and 20 mg/kg Q4W giving us confidence that exon 51 skip-amenable patients may benefit from treatment.
Key findings from DELIVER include:
Function
- Improvements were observed in multiple functional endpoints in the 20 mg/kg Q4W DYNE-251 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.
- Continued benefit was seen in multiple functional endpoints in the 10 mg/kg Q4W DYNE-251 group from 6 months to 12 months1.
- Meaningful improvement in SV95C was seen in both 10 mg/kg and 20 mg/kg study groups following Q4W dosing. SV95C is a digital, objective outcome measure of ambulatory performance in patients’ normal daily environment and is approved as a primary endpoint for Duchenne clinical trials in Europe.
Dystrophin expression measured by Western blot
- Patients treated with 20 mg/kg Q4W of DYNE-251 had a mean absolute dystrophin level of 3.71% of normal at 6 months. When adjusting for muscle content, the DYNE-251 treated group reached 8.72% mean absolute dystrophin.
Safety & Tolerability Data
Patient safety is the top priority for Dyne, its investigators and all aspects of the clinical research studies we conduct. Overall, the safety profile has been favorable for DYNE- 251 based on 54 participants enrolled thus far in DELIVER with approximately 675 doses administered to date.
- The majority of treatment emergent adverse events (TEAEs) were mild or moderate. There have been three serious treatment-emergent adverse events potentially related to study drug in two participants in the 40 mg/kg study group. Both participants are home and well.
- Other than two participants with serious TEAEs in the 40 mg/kg Q4W cohort, no participants have demonstrated persistent related anemia or thrombocytopenia or demonstrated kidney injury. Additionally, no participants have demonstrated clinically meaningful changes in electrolytes, including magnesium.
- All participants in DELIVER are now being dosed at 20 mg/kg; including participants dose escalated following the placebo-controlled period from starting doses lower than 20 mg/kg and participants initiated at 40 mg/kg who are now being dosed at 20 mg/kg following evaluation of the safety profile at 40 mg/kg.
Thank You
We are now moving to initiate registrational study groups in DELIVER. We continue to pursue expedited approval pathways, and we look forward to sharing this encouraging data, program updates and additional details with the community throughout the remainder of the year.
Our therapy development efforts would not be possible without the generous participation of community members like you. The insights and expertise provided have contributed to the development of our science and the design of our programs. Your participation in clinical research advances collective knowledge critical for current and future drug development. We recognize and acknowledge the time, hard work and thought provided by community participants and we are deeply grateful. Thank you.
With gratitude, Dyne Therapeutics
1During the open label extension period (OLE), all participants in the 10 mg/kg cohort were dose escalated to 20 mg/kg Q4W regimen. 2DYNE-251 safety data as of August 21, 2024.
