Z-Rostudirsen Meets Primary End Point in Phase 1/2 DELIVER Trial for Duchenne Muscular Dystrophy

Topline results from the registrational expansion cohort (REC) of Dyne Therapeutics’ phase 1/2 DELIVER trial (NCT05524883) showed that zeleciment rostudirsen (z-rostudirsen), formally known as DYNE-251, met its primary end point in dystrophin expression among patients with Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping. The company noted that it plans to initiate a global phase 3 study of z-rostudirsen and submit a biologics license application to the FDA for accelerated approval in the second quarter of 2026.¹

In the REC of the DELIVER trial, researchers enrolled 32 ambulant and nonambulant boys with DMD aged 4 to 16 years at baseline who had mutations amenable to exon 51 skipping. Among these, 24 participants were randomized to receive 20 mg/kg z-rostudirsen every 4 weeks, and 8 were randomized to placebo. Findings showed that the REC met its primary end point, showing a statistically significant increase in muscle content-adjusted dystrophin expression to 5.46% of normal relative to baseline at 6 months (P <.0001).

All told, these data replicated the 7-fold increase in muscle-content adjusted dystrophin expression observed at 6 months among participants receiving 20 mg/kg z-rostudirsen in the multiple-ascending dose (MAD) portion of the DELIVER trial. When unadjusted for muscle content, the mean absolute dystrophin expression among patients treated with 20 mg/kg z-rostudirsen was 2.87% of normal (P <.0001), compared with 0.3% of normal reported in a U.S. clinical trial of the weekly standard of care for DMD exon 51.

"The Duchenne community has long awaited therapies that deliver meaningful and sustained functional improvement,” principal investigator Perry Shieh, MD, PhD, a neurologist and professor of neurology and pediatrics at the David Geffen School of Medicine at UCLA, said in a statement.¹ "Our scientific understanding of the disease has led to a strong belief that restoring a sufficient level of near-full-length dystrophin expression in individuals with DMD could have the potential to significantly alter the trajectory of this disease."

Shieh added, "I am highly encouraged by these new results from the placebo-controlled Registrational Expansion Cohort and the longer-term portions of DELIVER, and I look forward to being able to offer z-rostudirsen to eligible DMD patients, if approved."

At 6 months, the company observed functional improvements across multiple clinical end points relative to baseline and declines in the pooled placebo group. Improvement relative to placebo was reported across all 6 prespecified functional end points from the topline readout of the REC. Notably, Time to Rise (TTR) Velocity and 10-Meter Walk/Run (10MWR) Velocity showed improvement relative to placebo at 6 months (both, placebo, n = 18; z-rostudirsen, n = 21; P <.05). The North Star Ambulatory Assessment (NSAA) also demonstrated functional improvement from baseline and relative to placebo, as did Stride Velocity 95th Centile (SV95C; placebo n = 12; z-rostudirsen n = 20) and Performance of Upper Limb (PUL2.0; placebo n = 23; z-rostudirsen n = 22).

A post hoc analysis comparing the REC group with the pooled placebo group at 6 months generated a nominal P <.05 for TTR Velocity and 10MWR Velocity. Additional findings showed that lung function was preserved in the z-rostudirsen treated group at 6 months as measured by Forced Vital Capacity Percent Predicted (FVC%p; placebo n = 20; z-rostudirsen n = 15), whereas FVC%p declined in the pooled placebo group.

"With its high level of dystrophin expression, favorable safety profile, convenient monthly dosing regimen, and functional improvement as assessed by six prespecified clinical measures, z-rostudirsen has the potential to transform the care of those living with DMD amenable to exon 51 skipping," John Cox, president and chief executive officer at Dyne, said in a statement.¹ "With these unprecedented clinical data in hand, we are on track to submit for U.S. Accelerated Approval in Q2 2026, positioning us for a potential Q1 2027 launch, assuming Priority Review, into an established market of approximately 1,600 people with significant unmet need."

"In anticipation of approval, we have built a management team of medical, commercial and CMC experts to enable a capital efficient and successful launch. With this clinical validation, we are now in a position to leverage these capabilities and relationships in DMD to advance a broader portfolio of potential exon-skipping therapies with a total population of more than 4,000 individuals. Beyond the opportunity in DMD, we believe the compelling clinical results from our DELIVER study validate the power of our FORCE platform and its ability to deliver multiple potential products that could offer meaningful and sustained benefits for those living with other challenging neuromuscular diseases," Cox added in a statement.¹

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Additionally, Dyne reported long-term clinical data from the ongoing open-label extension (OLE) and long-term extension (LTE) portions of the DELIVER study. All told, the company noted sustained functional outcomes from baseline in TTR Velocity, 10MWR Velocity, NSAA, SV95C, PUL2.0, and FVC%p. These results included 24-month data from 6 participants treated with z-rostudirsen in the 10 mg/kg MAD cohort who were dose-escalated to 20 mg/kg during the OLE, 18-month data from 6 participants treated in the 20 mg/kg MAD cohort, and pooled 18-month data from both cohorts.

In terms of safety and tolerability, the data were based on 86 participants enrolled in the DELIVER trial and followed for up to 36 months, including participants initially enrolled in the MAD cohorts (n = 54) and REC (n = 32) who transitioned to the OLE and LTE portions. The company reported that a-rostudirsen’s safety profile remained consistent with prior observations, and most related treatment-emergent adverse events (TEAEs) were mild or moderate. The most commonly reported related TEAEs were pyrexia and headache. In the REC, Dyne did not observe any related serious TEAEs.

Since the last safety update, findings showed that only 2 participants in the OLE/LTE portion of the trial experienced malaise and pyrexia, which were reported as related serious TEAEs; both fully recovered and have continued treatment without interruption. Approximately 1441 doses of z-rostudirsen, including 1062 at the 20 mg/kg dose, have been administered to date in the DELIVER trial, representing 113 patient-years of follow-up.

Earlier this year, the FDA granted breakthrough therapy designation to z-rostudirsen based on prior data from the DELIVER trial.² Following the news, Doug Kerr, MD, PhD, chief medical officer at Dyne Therapeutics, spoke NeurologyLive^® to discuss the mechanism and rationale behind z-rostudirsen in the treatment of DMD. Throughout the conversation, he talked about the previously announced data for the early- and late-stage cohorts, which showed sustained and clinically meaningful functional improvement, along with robust dystrophin expression.

REFERENCES
1. Dyne Therapeutics Announces Positive Topline Results from Phase 1/2 DELIVER Trial of Z-Rostudirsen in Duchenne Muscular Dystrophy (DMD). News release. December 8, 2025. Accessed December 10, 2025. https://investors.dyne-tx.com/news-releases/news-release-details/dyne-therapeutics-announces-positive-topline-results-phase-12
2. Dyne Therapeutics Announces FDA Breakthrough Therapy Designation for DYNE-251 in Duchenne Muscular Dystrophy (DMD). News release. Dyne Therapeutics. August 4, 2025. Accessed December 10, 2025. https://investors.dyne-tx.com/news-releases/news-release-details/dyne-therapeutics-announces-fda-breakthrough-therapy-0