SGT-001 Shows Improvements in Key DMD Measures, Microdystrophin Expression

Barry Byrne, MD, PhD

Data from a recent interim analysis of the open-label phase 1/2 IGNITE-DMD (NCT03368742) suggest that intravenous SGT-001 (Solid Biosciences) is well-tolerated and efficacious in Duchenne muscular dystrophy (DMD).

These findings were presented virtually by principal investigator Barry Byrne, MD, PhD, professor and associate chair, pediatric research, University of Florida Health, at the Muscular Dystrophy Association’s (MDA) Scientific and Clinical Conference 2021, March 15-18.

“Boys with Duchenne rarely run, and so it's been very rewarding to hear from families, [about] these newfound abilities to run and other skills have led to the ability to participate in sports or even ride a bike. These moments are a really important part of childhood, so I've been very gratified to share these moments with the families,” Byrne said during his presentation.

IGNITE-DMD is an ascending dose study investigating safety and efficacy of SGT-001, an AAV9 microdystrophin gene therapy for DMD. The therapy is designed to deliver a functional surrogate of the DMD gene, including the nitric oxide synthase (nNOS) binding domain thought to protect muscle from ischemic damage.

READ MORE: Casimersen Shows Safe and Effective Profile in Multiple DMD Studies

Byrne and colleagues assessed primary outcomes such as measurement of muscle biopsy microdystrophin expression by Western blot, scores on North Star Ambulatory Assessment (NSAA), 6-minute walk test (6MWT) distance, and safety evaluations. The 3 patients in cohort A received the initial dose of 5 x 10¹³ vg/kg, the 3 in cohort B received a 4-fold escalated dose of 2 x 10¹⁴ vg/kg, and 3 control patients were also assessed. Cohort B’s dose was escalated after evaluating microdystrophin expression.

The researchers found that all subjects in Cohort B showed an average level of microdystrophin expression around 10% of normal dystrophin at day 90. Immunofluorescence analyses revealed microdystrophin and associated proteins such as β-sarcoglycan and nNOS were localized in membranes in around 20-70% of muscle fibers positive for microdystrophin, demonstrating molecular function.

Creatine kinase (CK) levels decreased by 55% (standard deviation [SD], 7.5) in cohort B at 1 year. Levels increased by 166% (SD, 147) in cohort A and by 17% (SD, 67) in controls.

Meaningful improvements at 1 year were seen on the Pediatrics Outcomes Data Collection Instrument (PODCI) test, with global score increases of 13 points, 11 points, and 27 points in cohort B; and 18 points, 6 points, and 9 points in cohort A; compared to score reductions of 18 points and 10 points in patients with data in the control group.

Improvements were seen as well in forced vital capacity (FVC) compared to natural history. The mean change in predicted FVC was –9.6%, –7.6%, and –15.0% in controls; 8.9%, 5.3%, and –2.4% in cohort A; and 3.1%, 36.7%, and 10.2% in cohort B.

From baseline to 1-year, average NSAA score change was –1 point and –7 points in controls, –3 points and 5 points in cohort A; and 1 point, –1 point, and 1 point in cohort B. The mean change in 6MWT distance was –8 and –9 meters in controls, 12 and 62 in cohort A, and 12, 85, and 52 in cohort B. 

Treatment emergent adverse events (TEAEs) included nausea (n = 6), emesis (n = 5) and fever (n = 4) within 72 hours of dosing. Other AEs included thrombocytopenia, elevation of d-dimer associated with microangiopathy, and acute kidney injury in 2 participants.

Two serious AEs (SAEs) resulted from activation of the terminal pathway (C5b9) of the classical complement system, which occurred in all participants. An episode of transaminitis and hyperbilirubinemia 4 weeks after dosing which resolved after a transient increase of corticosteroids was another SAE and 1 more unrelated to SGT-001 occurred. All AEs resolved.

Further data detailing results in NSAA, 6MWT, timed function tests, biomarker and outcomes will be reported at a later date.

“The overall data supports the role of this microdystrophin in providing a benefit to patients, as shown by the trends of the assessments that have been described: a reduction in CK, minor but sustained improvements in North Star, increased 6MWT distance as well as improvements in FVC, and all of the domains of the quality-of-life measures that we assessed,” Byrne concluded his presentation.

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REFERENCE

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-One year efficacy and safety results. Presented at MDA Clinical and Scientific Conference 2021; March 15–18. Poster 61.