Solid Biosciences is monitoring the long-term cardiac effects of its investigational adeno-associated virus (AAV) vector-based gene therapy, SGT-001, for Duchenne muscular dystrophy (DMD) in the phase 1/2 IGNITE-DMD clinical trial (NCT03368742). The study, initiated in December 2017, is a randomized-controlled, single-ascending dose trial designed to evaluate the safety and efficacy of SGT-001. Although the trial reached its primary completion date on October 17, 2024, long-term follow-up is ongoing, with an estimated completion date of October 15, 2026, where patients are expected to be followed for about 5 years after their treatment with SGT-001.
IGNITE-DMD Trial Design and Endpoints
The IGNITE-DMD trial initially included three arms: two experimental arms receiving different doses of SGT-001 and an untreated control group. However, the protocol was amended to remove the control arm after four patients were dosed. The trial is being conducted at two locations: the David Geffen School of Medicine at UCLA and the University of Florida.
SGT-001 utilizes an AAV9 vector containing a muscle-specific promoter and microdystrophin, a truncated, functional version of the dystrophin gene, which is mutated in DMD patients. It is administered as a single dose via intravenous infusion.
The primary efficacy endpoint of IGNITE-DMD is the change from baseline in microdystrophin protein levels in muscle biopsies at 12 months post-treatment. The study also monitors multiple primary safety endpoints, including the incidence of adverse events, clinical laboratory abnormalities, vital sign abnormalities, physical examination abnormalities, and electrocardiogram (ECG) abnormalities, all within 12 months after treatment.
Patient Eligibility
The trial enrolled boys aged 4 to 17 years with clinically diagnosed DMD, a documented mutation in the dystrophin gene predictive of DMD, and absence of dystrophin protein as assessed by muscle biopsy. Ambulatory status was also considered, with adolescents required to be non-ambulatory and children required to be ambulatory. Patients also needed to have anti-AAV9 antibodies below a protocol-specific threshold, stable cardiac and pulmonary function, and be on a stable dose of oral corticosteroids for at least 12 weeks.
Exclusion criteria included abnormal liver or renal function, clinically significant coagulation abnormalities, impaired cardiovascular or respiratory function, significant spinal deformity, a BMI in the 95th percentile or greater, use of other investigational drugs, or use of drugs affecting dystrophin or utrophin expression. Patients weighing over 30 kg were also ineligible.
Long-Term Cardiac MRI Findings
Long-term follow-up results from seven patients treated with SGT-001 were presented at the 2024 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference. The data indicated that in six of the seven patients, left ventricular end diastolic volume (LVEDV) remained normal throughout the study, ranging from 56 to 108 mL/m2 (median, 67.2 mL/m2). Ejection fraction (EF) also remained in the normal range in these patients, ranging from 51% to 72% (median, 61.8%). The remaining patient, who had an elevated LVEDV at baseline, experienced a further increase at year 5.
According to a poster presented by Stephanie Salabarria, BHSc, and colleagues, "This is the first study that describes longitudinal cardiac MRI findings in DMD subjects that have received microdystrophin gene therapy. We observed that cardiac function was preserved as the individuals age with expected worsening of DMD-related cardiomyopathy. Further studies are needed to better understand the effects of the DMD gene therapy in the heart and carefully quantify the extent of cardiac gene transfer."
Shift to SGT-003
Solid Biosciences announced in October 2023 that it would deprioritize further development of SGT-001 and focus on SGT-003, a next-generation gene therapy for DMD. SGT-003 received FDA IND clearance and is currently being evaluated in the phase 1/2 INSPIRE-DUCHENNE clinical trial (NCT06138639).
Gabriel Brooks, MD, Chief Medical Officer of Solid Biosciences, stated, "We are very encouraged that dosing has been well tolerated with no observed serious adverse events and that the safety results were consistent with the IND-enabling nonhuman primate toxicology study. To date, in this study of SGT-003, immunosuppression was achieved with steroids alone. SGT-003 leverages a rationally designed, novel capsid, AAV-SLB101, with the intent to target and more potently transduce muscle... We firmly believe Duchenne patients remain in need of better treatment options, and SGT-003 with its proprietary capsid, enhanced manufacturing process and differentiated transgene (uniquely containing the nNOS binding domain and flexible construct design), represents a potential next-generation therapy."
