Solid Biosciences Inc. has announced positive initial data from its Phase 1/2 INSPIRE DUCHENNE trial evaluating SGT-003, a next-generation gene therapy candidate for Duchenne muscular dystrophy (DMD). The early results indicate promising microdystrophin expression and improvements in muscle health biomarkers, suggesting a potential new treatment option for this debilitating genetic disorder. The company plans to discuss a potential accelerated approval pathway with the FDA in mid-2025.
The INSPIRE DUCHENNE trial is an ongoing, first-in-human, open-label, single-dose, multicenter study designed to assess the safety, tolerability, and efficacy of SGT-003 in pediatric patients with DMD. The trial involves a one-time intravenous infusion of SGT-003 at a dose of 1E14 vg/kg. As of the data cutoff date of February 11, 2025, six participants had been dosed, with enrollment continuing to reach a target of approximately 20 participants by the fourth quarter of 2025.
Key Findings from the INSPIRE DUCHENNE Trial
Interim data from the first three participants dosed in the trial revealed an average microdystrophin expression of 110%, as measured by western blot. Mass spectrometry analysis showed an average microdystrophin expression of 108%. These results indicate that SGT-003 is effectively delivering and expressing the microdystrophin gene in patients' muscles.
In addition to microdystrophin expression, the trial also demonstrated improvements in several biomarkers indicative of muscle health and resilience. Specifically, researchers observed mean reductions in markers of muscle injury and stress, including:
- Serum creatine kinase (CK): -57%
- Serum aspartate aminotransferase (AST): -45%
- Serum alanine transaminase (ALT): -54%
- Serum lactate dehydrogenase (LDH): -60%
Furthermore, the study reported mean reductions in markers of muscle breakdown and dystrophic regeneration:
- Serum titin: -42%
- Embryonic myosin heavy chain (eMHC) positive fibers: -59%
Cardiac Benefits
Encouragingly, early signals of potential cardiac benefit were also observed. At Day 180, mean cardiac function increased by 8% (N=2) from baseline, as measured by left ventricular ejection fraction. Additionally, in one participant with elevated baseline levels of serum cardiac hs-troponin I (hs-cTnI), a reduction of -36% was observed at Day 90.
Safety and Tolerability
SGT-003 was generally well-tolerated in the first six participants dosed. Adverse events (AEs) were consistent with those typically observed in AAV gene therapy, including nausea, vomiting, fever, and transient declines in platelets in some participants. Importantly, no serious adverse events (SAEs) or suspected unexpected serious adverse reactions (SUSARs) were reported, and none of the observed AEs required the use of additional immunomodulatory agents.
Expert Commentary
"The robust microdystrophin expression, improvements in markers of muscle integrity and health, and favorable safety profile observed in this cohort of participants as of the data cutoff date of February 11, 2025, are very promising," said Craig McDonald, MD, Chair, Department of Physical Medicine & Rehabilitation at UC Davis Health and investigator in the INSPIRE DUCHENNE trial. He added that he looks forward to seeing additional data and longer-term functional data that will further inform our understanding of the role that the nNOS binding domain, which is unique to SGT-003, may play in improving clinical outcomes.
The Current Landscape of DMD Treatment
Duchenne muscular dystrophy is a severe genetic disorder affecting approximately 1 in every 3,500 to 5,000 live male births. It is characterized by progressive muscle degeneration and weakness due to mutations in the DMD gene, which prevents the body from producing dystrophin, a protein essential for muscle function. Currently, there is no cure for DMD, and treatments are focused on managing symptoms and slowing disease progression.
Sarepta Therapeutics’ Elevidys (delandistrogene moxeparvovec-rokl) is the only FDA-approved gene therapy for DMD, designed to deliver a gene that leads to the production of microdystrophin. While Elevidys has shown sustained microdystrophin expression and improvements in some clinical measures, it has also faced scrutiny due to mixed results in clinical trials.
Solid Biosciences hopes that SGT-003, with its differentiated microdystrophin construct and next-generation capsid, may offer improved efficacy and clinical outcomes for patients with DMD. The company plans to request a meeting with the FDA in mid-2025 to discuss the potential for an accelerated approval pathway for SGT-003.
