Craig McDonald, MD | Image credit: UC Davis Health

Background information on SGT-003

On February 18, 2025, Solid Biosciences reported positive interim data for the Duchenne muscular dystrophy (DMD) gene therapy candidate, SGT-003, which has been granted rare pediatric disease designation from the FDA.^1,2

In the phase 1/2 INSPIRE DUCHENNE trial, data from the first 3 patients dosed revealed an average microdystrophin expression of 110%, as measured by western blot, and improvements in multiple biomarkers that are indicators of muscle health and resilience.¹

In the trial—a first in human, open-label, single-dose, multicenter trial evaluating safety, tolerability, and efficacy of SGT-003—a dose of 1E14vg/kg is administered as a one-time infusion. The trial remains ongoing, with at least 10 total participants expected to be dosed by the second quarter of 2025, according to a press release from Solid Biosciences at the time of data announcement.²

In the Q+A interview below, Craig McDonald, MD, chair, Department of Physical Medicine & Rehabilitation, UC Davis Health and investigator in the INSPIRE DUCHENNE trial, breaks down the results and what the gene therapy candidate means for the DMD patient population.

Data, previously reported by Contemporary Pediatrics, featured:

Muscle integrity biomarker evaluation at day 90 among the first 3 patients revealed mean reductions that were observed in markers of muscle injury and stress. Data included:

• Serum creatine kinase (CK) (IU/L): -57%
• Serum aspartate aminotransferase (AST) (IU/L): -45%
• Serum alanine transaminase (ALT) (IU/L): -54%
• Serum lactate dehydrogenase (LDH) (IU/L): -60%

Mean reductions observed in markers of muscle breakdown and dystrophic regeneration included:

• Serum titin (pmol/L): -42%
• Embryonic myosin heavy chain (eMHC) positive fibers: -59%

Measure of potential cardiac benefit included:

• At Day 180, mean cardiac function increased by 8% (n = 2) from baseline as measured by left ventricular ejection fraction
• The third participant had not reached Day 180 follow up as of the data cutoff date of February 11, 2025

Reduction in serum cardiac hs-troponin I (hs-cTnI) of -36% observed at Day 90 in 1 participant who entered the trial with elevated hs-cTnI levels:

• Two of the first 3 participants entered the study with normal baseline cTnI levels
• Two participants in total (n = 6) had elevated troponin at baseline that reduced below initial baseline values post-dose

Q+A

Contemporary Pediatrics:

For this initial data, what is your biggest takeaway from the ongoing phase 1/2 trial and the data reported? Specifically, though a specialty disease, what should general providers know about the disease and this data?

Craig McDonald, MD:

It is important to understand that DMD is an unyielding disease of degraded muscle integrity and degeneration that ultimately leads to loss of ambulation and cardiac and respiratory failure, all because of mutations in the dystrophin gene that lead to loss of functional dystrophin protein.

Providers should continue to refer any patient with a new or suspected Duchenne diagnosis to an appropriate specialist for further evaluation and discussion of treatment options, including potential participation in an appropriate clinical trial.

The data that Solid Biosciences recently announced for their Duchenne gene therapy candidate, SGT-003, are very encouraging. While early, these initial 90-day data from the INSPIRE DUCHENNE clinical trial represent a comprehensive dataset, encompassing 3 different measurements of microdystrophin expression as well as improvements in multiple muscle health biomarkers, many of which have not historically been shared for other Duchenne gene therapies.

The consistency and robustness of these findings appear to suggest that treatment with SGT-003, which is comprised of a novel capsid and a unique microdystrophin transgene containing the nNOS binding domain (R16/R17), may lead to a differentiated safety and efficacy profile for patients.

In particular, the vector copies per nucleus (VCN) data that were reported indicate that the capsid, AAV-SLB101, achieved high levels of transduction that clearly translated into a high percentage of microdystrophin positive fibers and robust microdystrophin expression.

Contemporary Pediatrics:

Can you explain the muscle integrity biomarkers and what the data reported explains/means for the patient population?

McDonald:

The 90-day data reported in the first 3 patients dosed suggests that SGT-003 may be having a positive biochemical effect on acute and chronic markers of muscle damage, which ultimately contribute to muscle maturation and preservation.

In these first 3 patients, Solid saw consistent reductions across several markers of acute muscle damage, including CK, ALT, AST, which are leaked upon skeletal muscle injury, as well as reductions in chronic markers of damage, including titin and LDH. These reductions could indicate an enhancement in muscle integrity and resilience after treatment.

What I find to be particularly intriguing is that these reductions in acute and chronic injury markers seem to point to a significant reduction (59%) in embryonic myosin heavy chain (eMHC) between baseline and Day 90. This reduction in eMHC is an elegant signal that muscle fibers are not breaking down, and that there appears to be an increased stabilization of the sarcolemma membrane, indicating a potential lack or reduction of ongoing contraction-induced injury, and ultimately a reduced need for muscle fiber repair and regeneration.

This could have important implications for preservation of a patient’s reservoir of muscle stem cells, also known as satellite cells, and potentially, for durability of the treatment effect. The data are early and in a small number of participants, but they are certainly promising.

Additionally, the early cardiac effect that the Solid team shared, including reductions in elevated troponin levels in 2 patients dosed to date, as well as stabilized mean left ventricular ejection fraction (LVEF) in an additional 2 patients, are incredibly encouraging to me, given that a leading cause of mortality for Duchenne patients is cardiomyopathy.

These findings are early and need to be investigated further, but if replicated in additional patients, this could represent an additional point of differentiation in the Duchenne gene therapy landscape.

Contemporary Pediatrics:

Overall for this debilitating disease, how encouraging are these initial results, and with more patients expected to be dosed in the next quarter, what observations are you and colleagues looking for / will be tracking.

McDonald:

I believe these initial data present a unique and robust dataset, with compelling early signals of potentially beneficial treatment effects. Importantly, SGT-003 has had a favorable safety profile to date, with no serious adverse events (SAEs) observed.

I am eager to see additional participant data and, eventually, longer-term functional data from the INSPIRE STUDY that I believe will help to further inform our understanding of SGT-003’s effectiveness and ability to alter the course of the disease.

Craig McDonald discloses he is an INSPIRE DUCHENNE clinical trial investigator and a clinical consultant for Solid Biosciences.

References:

1. Fitch, J. Positive initial data reported for SGT-003 to treat Duchenne muscular dystrophy. Contemporary Pediatrics. February 18, 2025. Accessed March 26, 2025. https://www.contemporarypediatrics.com/view/positive-initial-data-reported-for-sgt-003-to-treat-duchenne-muscular-dystrophy

2. Solid Biosciences Reports Positive Initial Clinical Data from Next-Generation Duchenne Gene Therapy Candidate SGT-003. Solid Biosciences. Press release. February 18, 2025. Accessed March 26, 2025. https://investors.solidbio.com/news-releases/news-release-details/solid-biosciences-reports-positive-initial-clinical-data-next