Duchenne Muscular Dystrophy Gene Therapy SGT-001 Continues to Show Efficacy, Safety Following Protocol Amendment

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Participants in both the low- and high-dose cohorts showed improved functional outcomes at 1-year post-dose.

Twelve-month data from the ongoing IGNITE-DMD clinical trial (NCT03368742) presented at the 24th Annual Meeting of the American Society of Gene & Cell Therapy (ASGCT), May 12-15, demonstrate the continued efficacy and safety of SGT-001 gene therapy for the treatment of Duchenne muscular dystrophy (DMD).1

“The totality of the functional and biomarker data, as well as the patient reported outcome measures reported suggest that SGT-001 may provide benefit to patients with Duchenne, a serious disease for which there is no cure,” said Barry Byrne, MD, PhD, associate chair of pediatrics and director of the Powell Gene Therapy Center at the University of Florida, and principal investigator of IGNITE DMD, in a statement. 

IGNITE-DMD is an open-label, phase 1/2, ascending-dose study investigating the safety and efficacy of a single intravenous infusion of SGT-001, an adeno-associated virus serotype 9 microdystrophin gene therapy for DMD. “SGT-001 is designed to deliver a functional surrogate of the dystrophin protein absent in DMD. This unique microdystrophin construct includes the neuronal nitric oxide synthase (nNOS) binding domain, which has been shown to protect muscles from ischemic damage in preclinical studies,” first author Carl Morris, PhD, chief scientific officer, Solid Biosciences, and colleagues wrote. 

Morris and colleagues assessed primary outcomes such as safety evaluations and measurement of microdystrophin expression by Western blot. Secondary outcomes included pulmonary function, disease biomarkers, and quality of life measures.

Following the observation of low microdystrophin expression in the first 3 participants administered the initial dose of 5 x 1013 vg/kg, the dose was escalated to 2 x 1014 vg/kg for the next 3 patients. At day 90 post-administration, the 3 high-dose participants exhibited 5% to 17.5% of normal microdystrophin expression levels by Western blot and 20% to 70% of positive muscle fibers by immunofluorescence. 

The investigators also saw restored sarcolemmal localization of β-sarcoglycan and nNOS in microdystrophin-positive muscle fibers, which are critical associated proteins, signifying increased molecular function. At 1-year post-treatment, levels of serum creatine kinase were substantially decreased. 

Serious treatment-related adverse events did occur, including complement-mediated inflammatory response, thrombocytopenia, and transient increases in hepatic transaminases, but these all resolved. Following these events, subsequent participants will receive prophylactic administration of complement inhibitors and increased glucocorticoid dose since implemented in the clinical protocol.

Overall, North Star Ambulatory Assessment (NSAA) scores suggest a clinical benefit of treatment with SGT-001 compared with the natural history of the disease. Notably, participants in the untreated control cohort exhibited a mean decline of 4.0 points from baseline to 1 year, while patients in the low-dose and high-dose cohorts demonstrated a mean improvement of 1.0 point and 0.3 points, respectively, over the same period of time. Compared with a decline of 8.5 meters from baseline to 1 year on the 6 Minute Walk Test in the untreated cohort, participants in the low- and high-dose cohorts exhibited mean improvements of 37 meters and 49.7 meters, respectively. Additionally, meaningful improvements were seen on the Pediatrics Outcomes Data Collection Instrument as well as increases in forced vital capacity at 1-year post-treatment.

Together, these data support further exploration of SGT-001 for the treatment of DMD. Solid previously reported in March 2021 that patient 7 has been dosed under the amended study protocol and experienced mild to moderate adverse events, all of which resolved.2 

REFERENCES
1. Morris CA, Clary CM, Redican S, et al. IGNITE-DMD phase I/II study of SGT-001 microdystrophin gene therapy for Duchenne muscular dystrophy. Presented at: 2021 American Society of Gene & Cell Therapy Annual Meeting; May 12-15, 2021. Abstract 263
2. Byrne B, Salabarria S, Berthy J, et al. IGNITE-DMD: phase I/II ascending dose study of single IV infusion of SGT-001 microdystrophin gene therapy for DMD-ne year efficacy and safety results. Presented at: MDA Clinical and Scientific Conference 2021; March 15–18, 2021. Poster 61.
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