Solid Biosciences Tracking Long-Term Effects of Duchenne Muscular Dystrophy Gene Therapy in Phase 1/2 IGNITE-DMD Study

Solid Biosciences’ SGT-001, an investigational adeno-associated virus (AAV) vector-based gene therapy for Duchenne muscular dystrophy (DMD), is currently being evaluated in the phase 1/2 IGNITE-DMD clinical trial (NCT03368742).^1,2 Following up on World Duchenne Awareness Day, observed annually on September 7 by the clinician and patient communities, CGTLive® has decided to take a closer look at this study.

IGNITE-DMD, which was initiated on December 6, 2017, takes the form of a randomized-controlled, single-ascending dose study. Participants were assigned to either of 2 experimental arms in which they received either a lower dose or a higher dose of the gene therapy product. A third arm, serving as an untreated control group, was originally included in the protocol. Patients in this control group who were treatment eligible were to receive treatment with the gene therapy after 1 year. Although, according to the clinicaltrials.gov page for the study, which was most recently updated on August 12, 2024, the protocol was amended to remove the control arm after 4 patients were dosed.

The study includes 2 locations: the David Geffen School of Medicine at UCLA in Los Angeles, California, and the University of Florida in Gainesville, Florida. Although the trial reached its primary completion date on October 17, 2024, long-term follow-up is ongoing, and the study has an estimated completion date of October 15, 2026. Patients are expected to be followed for about 5 years after their treatment with SGT-001.

SGT-001 utilizes an AAV9 vector that contains a muscle-specific promoter and microdystrophin, a truncated, functional version of the dystrophin gene, which is rendered nonfunctional by mutation in patients with DMD. It is delivered as a single dose via intravenous infusion.

IGNITE-DMD's primary efficacy end point is the change from baseline in microdystrophin protein levels in muscle biopsies at 12 months posttreatment. The study includes multiple primary safety end points: the incidence of adverse events, clinical laboratory abnormalities, abnormalities in vital signs, abnormalities in physical examinations, and abnormalities on electrocardiogram (ECG) tests. All primary safety end points have a timeframe of 12 months after treatment.

The trial was open to boys aged 4 to 17 years who have clinically diagnosed DMD and a documented mutation in the dystrophin gene that is predictive of DMD, along with absence of dystrophin protein as assessed by muscle biopsy in patients who are ambulatory. Furthermore, patients were required to have antiAAV9 antibodies at levels below a protocol-specific threshold, stable cardiac and pulmonary function, and to be on a stable daily dose or otherwise equivalent dose of oral corticosteroids for at least 12 weeks. Adolescents were required to be nonambulatory by protocol-specified criteria and children were required to be ambulatory by protocol-specified criteria.

(Click to enlarge)

Patients with a history of or current medical conditions or physical examination, ECG, or laboratory findings that could interfere with safety, study completion, or interpretation of the trial’s results were not eligible for participation in IGNITE-DMD. Additional specified exclusion criteria included: abnormal liver or renal function; clinically significant coagulation abnormalities; impaired cardiovascular function, as assessed by cardiac MRI or echocardiogram; impaired respiratory function, as assessed by forced vital capacity percent predicted or the need for daytime ventilatory support; significant spinal deformity; presence of spinal rods; a BMI in the 95th percentile or greater for a patient’s age; use of any other investigational drug during the 3 months before screening or within 5 half-lives before the screening; or use of any drugs that affect dystrophin or utrophin expression in the 6 months before screening. The clinicaltrials.gov page also notes that additional criteria for inclusion or exclusion may apply and that patients weighing over 30 kg would not be eligible for treatment.

Long-term follow-up results from 7 patients treated with the gene therapy in the trial were presented earlier this year in a poster at the 2024 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, held March 3-6, in Orlando, Florida. First author Stephanie Salabarria, BHSc, a clinical research coordinator III at the University of Florida, and colleagues pointed out that for 6 of the 7 patients left ventricular end diastolic volume (LVEDV) remained normal throughout the study, ranging from 56 to 108 mL/m2 (median, 67.2 mL/m2). Similarly, in these same patients, ejection fraction (EF) also stayed in the normal range, ranging from 51% to 72% (median, 61.8%). The other patient, who had a 94.7 mL/m2 LVEDV at baseline, had a 118.76 mL/m2 LVEDV at year 5.

“This is the first study that describes longitudinal cardiac MRI findings in DMD subjects that have received microdystrophin gene therapy,” Salabarria and colleagues wrote in the poster.¹ “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.”

Notably, Solid Biosciences announced in October 2023 that it would be deprioritizing further development of SGT-001.² The company stated in November 2023 that it would instead focus its efforts on further development of SGT-003, a next-generation gene therapy for DMD that had just received clearance of an investigational new drug (IND) application from the FDA at that time.³ SGT-003 is now being evaluated in the phase 1/2 INSPIRE-DUCHENNE clinical trial (NCT06138639).⁴

“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,” Gabriel Brooks, MD, the chief medical officer of Solid Biosciences, said in an August 13, 2024, statement.⁴ “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 believe that the safety data seen to date are encouraging for not only SGT-003, but also our proprietary capsid, AAV-SLB101. 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.”

REFERENCES
1. Salabarria S, Shih R, Leon C, et al. Evaluation of long-term cardiac MRI outcome following micro-dystrophin gene therapy in subjects with Duchenne muscular dystrophy receiving SGT-001. Presented at: 2024 MDA Clinical and Scientific Conference; March 3-6; Orlando, FL. Poster #M184
2. Solid Biosciences announces acquisition of AavantiBio and concurrent $75 million private placement. News release. Solid Biosciences Inc. September 30, 2022. Accessed September 9, 2024. https://www.solidbio.com/about/media/press-releases/solid-biosciences-announces-acquisition-of-aavantibio-and-concurrent-75-million-private-placement
3. Solid Biosciences announces IND clearance by FDA for Duchenne muscular dystrophy gene therapy candidate SGT-003. News release. Solid Biosciences Inc. November 14, 2023. Accessed September 9, 2024. https://www.solidbio.com/about/media/press-releases/solid-biosciences-announces-ind-clearance-by-fda-for-duchenne-muscular-dystrophy-gene-therapy-candidate-sgt-003
4. Solid Biosciences Reports Second Quarter 2024 Financial Results and Provides Business Updates. News release. Solid Biosciences Inc. August 13, 2024. Accessed September9, 2024. https://investors.solidbio.com/news-releases/news-release-details/solid-biosciences-reports-second-quarter-2024-financial-results