Vesleteplirsen

Dyne Therapeutics’ z-rostudirsen shows cardiopulmonary improvements in Duchenne muscular dystrophy trial Dyne Therapeutics, a Massachusetts-based biotech, unveiled new cardiopulmonary data from the ongoing Phase I/II DELIVER trial of zeleciment rostudirsen (z-rostudirsen, DYNE-251) in Duchenne muscular dystrophy (DMD). The 24-month analyses showed improvements in heart and lung function relative to expected declines documented in published natural history studies, extending previously reported findings on muscle function. Cardiorespiratory failure is the leading cause of death in DMD, making these readouts particularly relevant to the clinical trajectory of this asset. DELIVER is a global, randomized, placebo-controlled, double-blind Phase I/II trial evaluating z-rostudirsen in individuals with DMD mutations amenable to exon 51 skipping. The study included a multiple ascending dose portion that identified 20 mg/kg administered intravenously every four weeks as the registrational dose. The primary endpoint for the registrational expansion cohort was change from baseline in dystrophin protein levels measured by Western blot at six months. The placebo-controlled portion of this cohort has been completed. The new 24-month analyses reported improvement from baseline in forced vital capacity percent predicted (FVC%p), circumferential strain (an early marker of cardiac performance), and left ventricular ejection fraction, each compared against expected worsening drawn from published natural history data. Safety data from 86 participants followed for up to 36 months showed most treatment-related adverse events were mild or moderate, with pyrexia and headache the most common. No related serious adverse events were observed in the registrational expansion cohort. Participants from earlier portions of the study could enroll in open-label and long-term extension phases. The company noted that most participants at the 24-month timepoint had initiated treatment at doses of 0.7-2.8 mg/kg before transitioning to the registrational dose, meaning the observed long-term efficacy may not fully reflect continuous dosing at 20 mg/kg. Doug Kerr, chief medical officer of Dyne, stated that the company attributes the cardiopulmonary findings to its FORCE delivery platform’s ability to reach cardiac, trunk, and diaphragm muscle as well as the central nervous system. Z-rostudirsen has received Breakthrough Therapy, Fast Track, and Rare Pediatric Disease designations from the US FDA, along with Orphan Drug designation from the US FDA, the European Medicines Agency, and Japan’s Ministry of Health, Labour and Welfare. The company has indicated that data from the registrational expansion cohort are intended to support a potential US accelerated approval submission, though no specific filing timeline was disclosed. Z-rostudirsen is a phosphorodiamidate morpholino oligomer (PMO) conjugated to an antibody fragment (Fab) that binds transferrin receptor 1 (TfR1). TfR1 is expressed on skeletal muscle, cardiac muscle, and CNS cells; binding facilitates receptor-mediated uptake of the antisense payload into these tissues. Once inside the cell, the PMO component binds DMD gene pre-mRNA and induces skipping of exon 51, restoring the reading frame and enabling production of a truncated but partially functional dystrophin protein. Approximately 13% of DMD patients carry mutations amenable to this approach. DMD affects roughly 12,000 individuals in the US and 16,000 in the EU. Symptoms typically emerge between ages three and five, progressing from proximal muscle weakness to loss of ambulation and eventual cardiorespiratory compromise. Several exon-skipping therapies have received US FDA approval, though earlier-generation unconjugated PMOs such as eteplirsen (Exondys 51, Sarepta Therapeutics) have faced scrutiny over low levels of dystrophin restoration. The antibody-conjugated design of z-rostudirsen is intended to overcome the poor tissue uptake that has limited unconjugated PMOs. Key competing assets include: Sarepta Therapeutics’ eteplirsen (Exondys 51), an unconjugated PMO targeting exon 51, approved by the US FDA in 2016 under accelerated approval. It remains on the market but has generated debate over the magnitude of dystrophin increase achieved. Sarepta Therapeutics’ delandistrogene moxeparvovec (Elevidys), a mutation-agnostic gene therapy delivering a micro-dystrophin transgene via AAV, granted accelerated approval by the US FDA in 2023 for ambulatory DMD patients aged four to five, later expanded. It targets a broader mutation population rather than a single exon. Among next-generation delivery approaches, no antibody/Fab-conjugated PMO targeting exon 51 appears to be in active clinical development besides z-rostudirsen; prior enhanced-delivery exon 51 programs such as Sarepta’s SRP-5051 and PepGen’s PGN-EDO51 have been discontinued. Dyne is also building a broader DMD franchise with preclinical exon-skipping programs applying the FORCE platform. Your email address will not be published. Required fields are marked * Comment * Name * Email * Website