Solid Biosciences’ Gene Therapy SGT-003 Produces Microdystrophin Expression in Patients With DMD
With regard to safety, the company characterized SGT-003 as well-tolerated.
Solid Biosciences SGT-003, an investigational next-generation adeno-associated virus (AAV) vector-based gene therapy, has produced expression of microdystrophin in patients being treated for Duchenne muscular dystrophy (DMD) in the phase 1/2 INSPIRE DUCHENNE clinical trial (NCT06138639).1
The efficacy set for the interim data announced by the company includes 2 boys who were 5 years of age at the time of dosing and 1 boy who was 7 years of age at the time of dosing. As of 90 days posttreatment, the 3 boys showed microdystrophin expression at mean levels 110% of normal according to Western blot and at mean levels 108% of normal according to mass spectrometry. In addition, a mean 78% dystrophin-positive fibers were seen via immunofluorescence and the mean number of vector copies per nucleus was 18.7. A mean 42% neuronal nitric oxide synthase (nNOS)-positive fibers and a mean 70% beta sarcoglycan-positive fibers were also reported.
Solid also reported data on biomarkers of muscle injury and stress for the 3 patients at 90 days posttreatment, noting a mean 57% reduction in serum creatine kinase (CK) (IU/L), a 45% mean reduction in serum aspartate aminotransferase (AST) (IU/L), a 54% mean reduction in Serum alanine transaminase (ALT) (IU/L), and a 60% mean reduction in serum lactate dehydrogenase (LDH) (IU/L). A 42% mean reduction in serum titin (pmol/L) and a 59% mean reduction in embryonic myosin heavy chain (eMHC) positive fibers were also reported.
Furthermore, for the 2 patients who had at least 180 days of posttreatment follow-up at the data cut-off, a mean increase in cardiac function from baseline, as measured by left ventricular ejection fraction, was observed at this time point. For 1 patient who had elevated levels of serum cardiac hs-troponin I (hs-cTnI) at baseline, a reduction of 36% in these levels was seen at 90 days posttreatment.
“We are extremely pleased to present our initial clinical data from the INSPIRE DUCHENNE trial,” Bo Cumbo, BS, the president and chief executive officer of Solid Biosciences, said in a statement.1 “When starting this trial, we committed to comprehensively analyzing the effects of SGT-003. To that end, 3 different measurement methodologies showed what we believe to be potential best-in-class expression of our differentiated microdystrophin transgene. Significant reductions observed in all evaluated clinical biomarkers of muscle damage associated with Duchenne provide preliminary evidence of a beneficial effect in muscle integrity, including potential early signals of a positive cardiac benefit of SGT-003 in these young boys. In mid-2025, we plan to request a meeting with the FDA to discuss the potential for an accelerated approval regulatory pathway for SGT-003.”
Solid reported safety results for all 6 patients who have been dosed in the trial as of the February 11, 2025 data cut-off. Each of these patients had at least 20 days of posttreatment follow-up at the time.
The company characterized SGT-003 as well-tolerated. There were no serious adverse events (SAEs), no suspected unexpected serious adverse reactions (SUSARs), no hospitalizations, no hepatic transaminitis, no elevated gamma-glutamyl transferase levels, and no indication of thrombotic microangiopathy or atypical hemolytic uremic syndrome. Furthermore, all treatment-related AEs were resolved without sequelae and no additional immunomodulatory agents were needed to manage AEs. A grade 1 case of mild, transient hs-troponin I elevation occurred in a single patient and was deemed an AE of special interest, but resolved without treatment. The most common AEs reported among the treated patients were nausea/vomiting, transient thrombocytopenia, infusion related hypersensitivity reaction, and fever. With regard to transient thrombocytopenia it was noted that a grade 3 episode occurred and with regard to infusion related hypersensitivity reaction it was noted that a grade 3 episode of prolonged fever occurred. Both of these grade 3 events resolved within days without treatment.
“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,” INSPIRE DUCHENNE investigator Craig McDonald, MD, the chair of the Department of Physical Medicine & Rehabilitation at UC Davis Health, added to the 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 binding domain, which is unique to SGT-003, may play in improving clinical outcomes.”
SGT-003 uses the company’s proprietary AAV-SLB101 capsid to deliver h-µD5, a transgene encoding for a microdystrophin protein containing the R16 and R17 nNos binding protein domains.2 The investigational new drug application enabling the launch of INSPIRE DUCHENNE was cleared by the FDA in November 2023, and the trial itself began on May 6, 2024. Notably, a month prior to the IND clearance for INSPIRE DUCHENNE, in October 2023, Solid announced that it was deprioritizing its earlier-generation lead candidate gene therapy SGT-001, which was also being developed for the treatment of DMD, in favor of advancing SGT-003.3 SGT-001, which utilizes an AAV9 vector that contains a muscle-specific promoter and microdystrophin, is being evaluated in the phase 1/2 IGNITE-DMD clinical trial (NCT03368742). IGNITE-DMD is no longer recruiting new patients, but will continue long-term tracking of the patients that have been treated.
