Dyne Therapeutics initiates Phase III FORZETTO trial of z-rostudirsen in Duchenne muscular dystrophy

Dyne Therapeutics (Nasdaq: DYN) has announced the initiation of the Phase III FORZETTO trial of zeleciment rostudirsen (z-rostudirsen; DYNE-251) in Duchenne muscular dystrophy, with the first site now open for enrollment and a biologics license application for US accelerated approval planned for later this quarter.

The FORZETTO trial is a global, randomized, double-blind, placebo-controlled Phase III study evaluating z-rostudirsen in approximately 90 ambulatory male participants aged 4 to 18 years with DMD amenable to exon 51 skipping, randomized 1:1 to 20 mg/kg intravenous z-rostudirsen or placebo every four weeks for 72 weeks.

As per the press release, the primary endpoint is change from baseline in rise from floor velocity at Week 73, a measure of lower limb muscle strength and motor coordination widely used in DMD clinical trials. Secondary endpoints include stride velocity 95th centile, North Star Ambulatory Assessment total score, 10-meter walk/run velocity, four-stair climb velocity, and forced vital capacity percent predicted, alongside patient-reported outcomes. Participants completing the placebo-controlled period are eligible to enter a 96-week open-label extension.

The Dyne Therapeutics Phase III trial design was aligned with the US FDA and is intended to serve as both a confirmatory trial supporting conversion of accelerated approval to traditional approval in the US and as the basis for ex-US marketing applications.

Supporting data from the DELIVER trial

The FORZETTO trial enrollment and the planned z-rostudirsen BLA approval submission are grounded in data from the registrational expansion cohort of the Phase I/II DELIVER trial. In that cohort, z-rostudirsen 20 mg/kg every four weeks (n=21) produced an improvement in rise from floor velocity of 0.04 rise/sec compared with pooled placebo (n=18; nominal p < 0.05) at six months. That improvement exceeded the published minimal clinically important difference of 0.023 rise/sec established by Duong et al. in the Journal of Neuromuscular Diseases.

It is important to note that this result comes from a post-hoc analysis; the prespecified statistical analysis plan for the DELIVER trial did not include formal hypothesis testing for functional endpoints. The company has described the safety profile from DELIVER as favorable, based on data as of August 2025, though detailed safety breakdowns have not been disclosed in the current announcement.

Z-rostudirsen and the exon 51 skipping approach

Z-rostudirsen is a phosphorodiamidate morpholino oligomer conjugated to an antigen-binding fragment that targets transferrin receptor 1, a protein highly expressed on muscle cells. The TfR1-directed delivery is designed to substantially improve uptake of the oligonucleotide into muscle tissue and the central nervous system compared with unconjugated PMO chemistries, enabling production of near-full-length dystrophin across both compartments.

The exon 51 skipping mechanism works by binding the dystrophin pre-mRNA at splice sites flanking exon 51, causing that exon to be excluded during splicing. In the approximately 13% of DMD patients whose mutations are amenable to exon 51 skipping, this restores the mRNA reading frame and allows expression of a truncated but partially functional dystrophin protein.

DMD affects approximately 12,000 individuals in the US and 16,000 in the EU. Caused by mutations in the DMD gene that result in near-complete absence of dystrophin, the disease typically presents between ages 3 and 5 with progressive muscle weakness and can also involve cognitive impairment and neuropsychiatric features.

Z-Rostudirsen DMD trial in competitive context

The only FDA-approved therapy targeting the exon 51 skipping population is Sarepta Therapeutics' Exondys 51 (eteplirsen), which received accelerated approval in September 2016 on the basis of dystrophin production as a surrogate endpoint. Eteplirsen's approval has faced ongoing scrutiny given modest dystrophin restoration levels and the absence of confirmed clinical benefit in pivotal trials; no EMA approval has been granted for any exon 51 skipping therapy.

Z-rostudirsen's TfR1-conjugate delivery platform is the central mechanistic distinction from eteplirsen, which relies on unconjugated PMO chemistry. The DELIVER data suggest that the conjugate approach may translate to functionally meaningful dystrophin restoration, though cross-trial comparisons are limited by differences in study design, patient populations, and endpoints. Whether the functional signal from DELIVER holds in the larger, randomized FORZETTO setting will be the critical question for both the traditional approval pathway and any ex-US regulatory submissions.

Beyond the exon 51 space, Sarepta's Elevidys (delandistrogene moxeparvovec), a gene therapy approved for broader DMD populations in the US, represents a different competitive dynamic — one based on a single-dose micro-dystrophin delivery approach rather than chronic exon skipping. The Duchenne muscular dystrophy treatment landscape is therefore evolving along multiple mechanistic axes simultaneously, with the DMD gene therapy clinical trial field increasingly testing whether repeated dosing of targeted oligonucleotides or one-time gene delivery offers the more durable functional benefit.

Z-rostudirsen holds Breakthrough Therapy, Fast Track, and Rare Pediatric Disease designations from the FDA, as well as Orphan Drug designation from the FDA, EMA, and Japan's Ministry of Health, Labour and Welfare.

Dyne plans to submit the BLA for US accelerated approval based on DELIVER trial data later in Q2 2026, with the FORZETTO trial design to be presented at the International Congress on Neuromuscular Diseases in Florence on July 8, 2026.

---

This article was generated with AI assistance and reviewed and edited by the AllSci editorial team Explore more at AllSci News: https://allsci.com/news/

---

Spot something wrong? Report an issue with this article