Over a 2-year period, SRP-9003 elicited sustained protein expression in muscle tissue and stabilized North Star Assessment for Dysferlinopathies scores.
Findings from a phase 1/2 study of the AAV-based gene therapy SRP-9003 suggest that treatment with the Sarepta Therapeutics agent resulted in 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). The study enrolled children between the ages of 4 and 15 years with significant symptoms.1
The updated data were presented at the Muscular Dystrophy Association (MDA) 2021 Clinical and Scientific Conference, March 15-18, by Louise Rodino-Klapac, PhD, executive vice president and chief scientific officer, Sarepta Therapeutics. The study included 2 cohorts, both with a different dose of the gene therapy. Cohort 1 (n = 3) included patients who received 1.85 × 1013 vg/kg as a single intravenous infusion, and cohort 2 (n = 3) included those who received it at a dose of 7.41×1013 vg/kg—a dose selected based on findings from cohort 1.
All told, SRP-9003 elicited improvements for functional measures in all patients in the phase 1/2 study, including scores in time-to-rise, four-stair climb, 100-meter walk, and 10-meter walk tests. These were most pronounced in the high-dose group.
In the low-dose cohort of the therapy with 2 years of follow-up, with data showing that mean beta-sarcoglycan (beta-SG) expression was 54% by western blot in treated patients—up from 36% at day 60. Similarly, in the high-dose cohort, the beat-SG expression was 62% at day 60, though long-term follow-up data were unavailable.
NSAD scores improved from baseline by a mean of 5.7 points with low-dose SRP-9003 after 2 years, while in the high-dose arm, there was a 4.0-point increase at 1 year. Across all 6 patients in the study, comparison to historical controls showed a clear improvement in NSAD scores. 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.2 “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 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 added.
The percent of immunofluorescent (IF)-positive fibers for beta-SG expression was 48% in cohort 1. At 60 days, this was 51%, with stabilization observed after additional follow-up. The mean fluorescent beta-SG intensity at 2 years was 35%, with localization to muscle sarcolemma observed, 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 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 (AEs) were 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 AE. 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.
LGMD2E is characterized by mutations in the sarcoglycan beta (SGCB) gene, disrupting the production of key proteins in the dystrophin-associated protein complex (DAPC). SRP-9003 was developed to restore function to SGCB, through the transfer of an SGCB transgene mediated by the AAVrh74 vector. The therapy is targeted to cardiac and skeletal muscle expression specifically through its MCHK7 promoter.