SGT-003 Gene Therapy Shows Potential in DMD

Patients with Duchenne muscular dystrophy (DMD) treated with SGT-003, an investigational gene therapy, showed microdystrophin expression at 90 days post treatment in the INSPIRE DUCHENNE trial (NCT06138639), Solid Biosciences announced in a press release.¹ The initial data from the phase 1/2 trial also suggest the therapy was well tolerated, with no serious adverse events (AEs).

In the INSPIRE DUCHENNE trial, interim 90-day biopsy data showed an average microdystrophin expression of 110% among the first 3 participants in the study. | Image credit: RFBSIP - stock.adobe.com

DMD is a rare, inherited condition characterized by progressive muscle weakness caused by alterations of the dystrophin protein, with symptom onset usually occurring in early childhood.² SGT-003 is a next-generation adeno-associated virus (AAV) vector–based gene therapy that contains “a differentiated microdystrophin construct and a proprietary, next-generation capsid, AAV-SLB101, which was rationally designed to target integrin receptors,” according to the press release.¹ In nonclinical studies, the AAV-SLB101 capsid demonstrated enhanced cardiac and skeletal muscle activity with decreased liver targeting.

In the phase 1/2 INSPIRE DUCHENNE trial, interim 90-day biopsy data showed an average microdystrophin expression of 110% among the first 3 participants in the study based on western blot testing.

“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,” Craig McDonald, MD, chair of the Department of Physical Medicine & Rehabilitation at UC Davis Health and investigator in the INSPIRE DUCHENNE trial, said in a statement.¹ “In the landscape of genetic therapies for Duchenne, individual microdystrophin constructs likely have unique efficacy and safety profiles. I am very encouraged by the initial results reported today and look forward to seeing additional data and longer-term functional data that I believe will further inform our understanding of the role that the nNOS [neuronal nitric oxide synthase] binding domain, which is unique to SGT-003, may play in improving clinical outcomes.”

Participants in the study also experienced improvements in biomarkers for muscle injury and stress, including a 57% mean reduction in serum creatine kinase, 45% mean reduction in aspartate aminotransferase, 54% mean reduction in alanine transaminase, and a 60% mean reduction in lactate dehydrogenase. There was also a mean 42% reduction in serum titin and 59% reduction in embryonic myosin heavy chain–positive fibers, both markers of muscle breakdown and dystrophic regeneration.

The study is also tracking measures of cardiac function, which improved at the time of the interim data cutoff. At 180 days, mean cardiac function increased by 8% from baseline based on left ventricular ejection fraction measurements from 2 patients—the third had not reached day 180 follow-up at the time of the February 11, 2025, data cutoff. One participant who entered the trial with elevated serum cardiac hs-troponin I (hs-cTnI) levels experienced a 36% reduction at day 90. Additionally, 2 of the 6 total participants so far had elevated troponin at baseline that had reduced after treatment with SGT-003.

“While loss of normal dystrophin is the defining molecular hallmark of Duchenne, there is growing understanding within the community that the success of microdystrophin gene therapy extends beyond expression, and will also depend on signals of restoration and preservation of muscle health, which were observed in these early clinical data,” Gabriel Brooks, MD, chief medical officer at Solid Biosciences, said in the statement.¹ “We are highly encouraged by the safety and tolerability profile observed, which has been consistent with AAV-based gene therapies. Additionally, though the trial was geared to follow cardiac measures for safety, we were gratified to observe early signs of cardiac benefit, including a decline in hs-troponin I levels in the participant with elevated levels at baseline, and improvements in cardiac function by echocardiography at day 180 in two participants with borderline low ejection fraction.”

Among the first 6 participants dosed, SGT-003 was well tolerated, with no severe AEs, no suspected unexpected serious adverse reactions observed, and no evidence of thrombotic microangiopathy, atypical hemolytic uremic syndrome, or hemolysis. Notably, none of the AEs seen required the use of immunomodulatory agents such as eculizumab, sirolimus, or rituximab. The most common AEs were nausea/vomiting, transient thrombocytopenia, infusion-related hypersensitivity reaction, and fever.

References

1. Solid Biosciences reports positive initial clinical data from next-generation Duchenne gene therapy candidate SGT-003. News release. Solid Biosciences. February 18, 2025. Accessed February 26, 2025. https://investors.solidbio.com/news-releases/news-release-details/solid-biosciences-reports-positive-initial-clinical-data-next

2. Duchenne muscular dystrophy (DMD). Muscular Dystrophy Association. Accessed February 26, 2025. https://www.mda.org/disease/duchenne-muscular-dystrophy