SRP-9003 elicited sustained protein expression in muscle tissue and stabilized North Star Assessment for Dysferlinopathies scores at 2 years in patients with limb-girdle muscular dystrophy Type 2E.
The AAV-based gene therapy SRP-9003 elicited sustained protein expression in muscle tissue and stabilized North Star Assessment for Dysferlinopathies (NSAD) scores at 2 years in patients with limb-girdle muscular dystrophy Type 2E (LGMD2E), according to updated findings from a phase 1/2 study presented at the 2021 Muscular Dystrophy Association (MDA) Annual Clinical and Scientific Conference.
In a low-dose cohort with 2 years of follow-up, mean beta-sarcoglycan (beta-SG) expression was 54% by western blot in patients receiving SRP-9003, which was an increase from 36% at day 60. In a high-dose cohort, the 60-day beta-SG expression was 62%. Two-year findings were not yet available. There was a mean improvement from baseline in NSAD score at 2 years of 5.7 points with low-dose SRP-9003. In the high-dose arm, there was a 4.0-point increase at 1 year.
SRP-9003 elicited improvements for functional measures in all patients in the phase 1/2 study. These included improvements in time-to-rise, four-stair climb, 100-meter walk test, and 10-meter walk test. These improvements were more pronounced in the high-dose group. Across all 6 patients in the phase 1/2 study, a comparison to historical controls showed a marked improvement in NSAD score with SRP-9003. For those treated with SRP-9003, the mean improvement in NSAD was 4.6 points compared with a decline of 4.6 points for matched historical controls, for an absolute difference of 9.2 points.
“This data is the first look at longer-term expression data with any gene therapy for muscular dystrophy,” Louise Rodino-Klapac, PhD, executive vice president and chief scientific officer, Sarepta Therapeutics, the company developing the therapy, said in a statement. “The meaningful and sustained levels of beta-sarcoglycan protein expression at 2 years and continued strength of the functional outcomes measured are tremendously positive and support continued advancement of this investigational treatment for patients.”
LGMD2E is characterized by mutations in the sarcoglycan beta (SGCB) gene, disrupting production of key proteins in the dystrophin-associated protein complex (DAPC). SRP-9003 was developed to restore function to SGCB, through transfer of a SGCB transgene mediated by the AAVrh74 vector. The therapy is targeted to cardiac and skeletal muscle expression specifically through the MCHK7 promoter.
"LGMD2E is one of the most severe forms of LGMD and causes significant disability in children while frequently leading to early mortality and the data continue to suggest this treatment could bring much needed hope to these patients," Rodino-Klapac said.
The phase 1/2 study contained 2 cohorts, each exploring a different dose of the gene therapy. In cohort 1, patients received 1.85 × 1013 vg/kg as a single intravenous infusion and in cohort 2 treatment was given at 7.41×1013 vg/kg. The dose in the second cohort was based on safety and efficacy findings from cohort 1. The study enrolled children between the ages of 4 and 15 years with significant symptoms.
In cohort 1 (n = 3) there were 24 months of follow-up. The percent of immunofluorescent (IF)-positive fibers for beta-SG expression was 48%. At 60 days, this was 51%, showing stabilization with additional follow up. The mean fluorescent beta-SG intensity at 2 years was 35% and was found to be localized to muscle sarcolemma, suggesting efficacy of the MCHK7 promoter. At 60 days, the intensity was 47%. By PCR, there were 0.59 vector copies per nucleus at 60 days and 0.13 at 2 years.
In cohort 2 (n = 3) there were 12 months of follow up. At 60 days, approximately 72% of fibers had beta-SG expression with a mean fluorescent intensity of 73%. There were 4.24 vector copies per nucleus. Other proteins encoded by the SGCD gene were also elevated, namely delta-SG and gamma-SG, which could indicate a reconstitution of the DAPC. Expression for these proteins was 65.3% mean positive fibers and 103% intensity for delta-SG and 60% mean positive fibers and 97% intensity for gamma-SG.
“In cohort 2, we also saw strong expression of delta-sarcoglycan and gamma-sarcoglycan proteins in addition to beta-sarcoglycan, which suggests that SRP-9003 is working to restore the dystrophin associated protein complex, or DAPC, which provides biological support for the sustained functional benefits observed in both cohorts," Rodino-Klapac said.
Adverse events remained consistent with the additional follow-up, and there were no new safety events. Earlier in the study, in cohort 1, there were 2 cases of liver enzyme elevation, 1 of which was deemed a serious adverse event (SAE). There was 1 elevation in liver enzyme in cohort 2. All of these cases occurred when patients were tapered off steroids and both resolved with supplemental steroid treatment. In cohort 2, there was 1 SAE of dehydration due to vomiting 3 days post-infusion.