Duchenne Agent DYNE-251 Demonstrates Functional Improvement in Phase 1/2 DELIVER Trial

Wildon Farwell, MD, MPH

Building upon previously announced data in January, newly reported topline findings from the phase 1/2 DELIVER study (NCT05524883) continued to highlight treatment benefits of DYNE-251 (Dyne Therapeutics), an investigational therapeutic in development for Duchenne muscular dystrophy (DMD). All told, treatment with the agent once every 4 weeks for 6 months (Q4W) resulted in compelling impact on key disease biomarkers as well as functional improvements and favorable safety profiles.¹

DELIVER consists 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, which is designed to be registrational, enrolled ambulant and nonambulant males with DMD between the ages of 4 and 16 who have mutations amenable to exon 51 skipping. Dyne plans to continue to engage with global regulators to pursue an expedited approval pathway for both DYNE-251 and DYNE-101, the company’s other investigational agent currently in development for myotonic dystrophy type 1.

DYNE-251 consists of a phosphorodiamidate morpholino oligomer (PMO) conjugated to a fragment antibody that binds to the transferrin receptor 1 (TfR1) which is highly expressed on muscle. In DELIVER, those on 10 mg/kg of DYNE-251 Q4W demonstrated a mean absolute dystrophin level of 3.22% of normal and a 2.97% change from baseline at 6 months. When adjusting for muscle content, those treated with the agent reached 7.64% mean absolute dystrophin, which was considered greater than levels reported by peptide conjugate PMOs in clinical development.

"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,” Wildon Farwell, MD, MPH, chief medical officer at Dyne, said in a statement.¹ "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."

READ MORE: FDA Grants Breakthrough Therapy Designation for AOC 1001 in Myotonic Dystrophy Type 1

The reported efficacy data included 8 males with DMD who were randomly assigned to either DYNE-251 (n = 6) or placebo (n = 2) once every 4 weeks for 6 months. Additional data showed that the levels of dystrophin expression seen with DYNE-251 exceeded levels reported in a clinical trial for etelpirsen (Exondys 51; Sarepta Therapeutics), the first approved exon 51-skipping agent for DMD. In comparison, eteplirsen reached a mean absolute unadjusted dystrophin level of 0.30% of normal and a 0.06% change from baseline after 6 months.

After 6 months of treatment, patients on 10 mg/kg DYNE-251 Q4W demonstrated improvement across multiple functional end points, including North Star Ambulatory Assessment, Stride Velocity 95th Centile, 10-Meter Walk/Run Time, and Time to Rise from Floor. In terms of safety, which included 48 patients enrolled through the 40-mg/kg–Q8W cohort of the MAD portion of DELIVER, continued to highlight DYNE-251’s favorable profile, with the majority of treatment-emergent adverse events (TEAEs) mild or moderate in severity. Of note, there were no related serious TEAEs identified.

DELIVER includes dose cohorts of 0.7 mg/kg (n = 6), 1.4 mg/kg (n = 6), 2.8 mg/kg (n = 6) and 5 mg/kg (n = 6), and dose optimization cohorts of 10 mg/kg (n = 8), 20 mg/kg (n = 8), and 40 mg/kg (n = 8). Enrollment has been completed through the 40 mg/kg cohort, with approximately 480 doses administered to date, representing 35 patient-years of follow-up. The trial is designed to be registrational, potentially leading to an FDA approval of DNYE-251. To date, Dyne has confirmed that the FDA precedent for using dystrophin as a surrogate biomarker for accelerated approval remains available.

In the previously announced data in January, those in the 5 mg/kg cohort of DELIVER demonstrated a mean absolute exon skipping level of 0.90% and a 0.80% change. Treatment with DYNE-251 demonstrated at least a 2.5-fold higher dystrophin expression at 6 months than the eteplirsen study. Measured by Western blot, patients on the agent had a mean absolute dystrophin level of 0.88% of normal and a 0.28% change from baseline whereas eteplirsen reached a mean absolute dystrophin level of 0.30% of normal and a 0.06% change from baseline.²

REFERENCES
1. Dyne Therapeutics Announces New Clinical Data from ACHIEVE Trial of DYNE-101 in DM1 and DELIVER Trial of DYNE-251 in DMD Demonstrating Compelling Impact on Key Disease Biomarkers and Improvement in Multiple Functional Endpoints. News release. May 20, 2024. Accessed May 22, 2024. https://www.globenewswire.com/news-release/2024/05/20/2884726/0/en/Dyne-Therapeutics-Announces-New-Clinical-Data-from-ACHIEVE-Trial-of-DYNE-101-in-DM1-and-DELIVER-Trial-of-DYNE-251-in-DMD-Demonstrating-Compelling-Impact-on-Key-Disease-Biomarkers-a.html
2. Dyne Therapeutics announces positive initial clinical data from ACHIEVE trial in DM1 patients and DELIVER trial in DMD patients demonstrating promise of the FORCE platform in developing therapeutics for rare muscle diseases. News release. Dyne Therapeutics. January 3, 2024. Accessed May 22, 2024. https://www.globenewswire.com/news-release/2024/01/03/2803115/0/en/Dyne-Therapeutics-Announces-Positive-Initial-Clinical-Data-from-ACHIEVE-Trial-in-DM1-Patients-and-DELIVER-Trial-in-DMD-Patients-Demonstrating-Promise-of-the-FORCE-Platform-in-Devel.html