Dyne Reports Positive Phase 1/2 Data for Duchenne Agent DYNE-251

Wildon Farwell, MD, MPH

Newly announced initial data from the phase 1/2 DELIVER trial (NCT05524883) showed that treatment with DYNE-251 (Dyne Therapeutics) was safe among patients with Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping, with a compelling efficacy profile that was comparable, if not better, than standard-of-care eteplirsen (Exondys 51; Sarepta Therapeutics).¹

DYNE-251, an investigational agent, consists of a phosphorodiamidate morpholino oligomer (PMO) conjugated to a fragment antibody that binds to the transferrin receptor 1 which is highly expressed on muscle. DELIVER, a global, randomized, placebo-controlled, registrational study, consists of a 24-week multiple ascending dose (MAD) period, a 24-week open-label extension, and 96-week long-term extension, similar to Dyne’s ACHIEVE trial (NCT05481879) of DYNE-101.

The initial efficacy assessment included 6 male patients with DMD amenable to exon 51 skipping enrolled in the 5 mg/kg (approximate PMO dose) cohort of the MAD portion of the trial. After 6 months of treatment, those on DYNE-251 demonstrated a mean absolute exon skipping level of 0.90% and a 0.80% change. Eteplirsen, the only approved therapy for patients with DMD amenable to exon 51 skipping, showed a 0.59% mean absolute exon skipping level and a 0.40% change from baseline in the previously completed PROMOVI phase 3 trial (NCT05481879).

"Treatment with DYNE-251 surpassed the level of dystrophin production reported for the standard of care for DMD exon 51 with a fraction of the dose. Underpinning these results are favorable safety profiles, which are critical in the development of therapies for chronic diseases," Wildon Farwell, MD, MPH, chief medical officer, Dyne, said in a statement.¹ "We are grateful to the participants, clinicians and the community for their ongoing partnership as we collectively strive to transform the treatment of rare muscle diseases."

In the study, patients received intravenous DYNE-251 or placebo every 4 weeks. The trial 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 20 mg/kg cohort, with 40 total patients enrolled and approximately 275 doses administered to date.

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. For context, at a regimen of 5 mg/kg Q4W for 6 months, DYNE-251 is administered 4 times less frequent than eteplirsen and has 24-fold lower PMO dose in comparison.

Additional findings from the study showed a 22.2% mean level of dystrophin positive fibers (PDPF) and a 19.8% change from baseline after 6 months of DYNE-251. In comparison, eteplirsen demonstrated a 19.6% mean level of PDPF and a 10.7% change.

Safety and tolerability assessments, which comprised of 45 patients enrolled through the 5.4 mg/kg Q8W cohort of the MAD portion, further demonstrated DYNE-251’s safety profile. The most common treatment-emergent adverse events (TEAEs) included headache (16%), nasopharyngitis (16%), vomiting (14%), infusion related reactions (11%), fall (11%), and cough (11%), all of which were mild or moderate in intensity. 1 serious TEAE of dehydration because of gastroenteritis was observed but not related to the study drug.

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With nearly 275 doses administered to date, Dyne believes the safety profile of DYNE-251 to date has supported dosing up to 20 mg/kg. In the trial, no participants experienced anemia, thrombocytopenia, or kidney injury. Furthermore, no participant had clinically meaningful changes in electrolytes, including magnesium.

"We are excited that Dyne’s first clinical data in two programs have demonstrated proof-of-concept and validated the promise of the FORCE™ platform in developing targeted therapeutics for rare muscle diseases. In addition to the opportunity with our co-lead programs, this clinical validation reinforces the potential of FORCE to deliver for patients in other areas, including building a global DMD franchise, addressing FSHD and exploring diseases involving the CNS," Joshua Brumm, president and chief executive officer, Dyne, said in a statement.¹ "The safety profiles for both DYNE-101 and DYNE-251 have supported dose escalation to a combined 10 cohorts and the administration of nearly 600 doses across both the ACHIEVE and DELIVER trials."

He added, "This positions us to optimize dose and dose regimen in both trials with the goal of initiating registrational cohorts as we end 2024. We anticipate reporting data for multiple, higher dose cohorts from both trials in the second half of 2024, while continuing to pursue expedited regulatory pathways and working to help address the urgent need for therapeutics for people living with DM1 and Duchenne."

REFERENCE
1. 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 January 5, 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