Sarepta therapeutics announces positive functional results from the srp-9003 (myo-101) gene therapy trial to treat limb-girdle muscular dystrophy type 2e, or beta-sarcoglycanopathy
Sarepta therapeutics, inc. announced the nine-month functional results from three limb-girdle muscular dystrophy type 2e (lgmd2e) clinical trial participants who received srp-9003. srp-9003 is an investigational gene therapy intended to transduce skeletal and cardiac muscle with a gene that codes for the full-length, native beta-sarcoglycan protein, the lack of which is the sole cause of lgmd2e. in cohort 1 of the srp-9003 study, three participants ages 4-13 were treated with an infusion of srp-9003 at a dose of 5x1013vg/kg. improvements in functional outcomes were observed at day 270 (nine months) for all three participants. at day 270, mean creatine kinase (ck) was significantly reduced compared to baseline. ck is an enzyme biomarker strongly associated with muscle damage. at day 270, all three participants showed improvements from baseline across all functional measures, including the north star assessment for dysferlinopathy (nsad), time to rise, four-stair climb, 100-m walk test and 10-meter walk test. these results are distinctly different from what an age-matched, natural history group would predict. no new safety signals were observed and the safety profile seen to date supports the ability to dose escalate in the next cohort of the study. as previously disclosed, two participants in the study had elevated liver enzymes, one of which was designated a serious adverse event (sae), as the participant had associated transient increase in bilirubin. both events occurred when the participants were tapered off oral steroids and, in both instances, elevated liver enzymes returned to baseline and symptoms resolved following supplemental steroid treatment. sarepta had previously shared expression results from the study, which found that in two-month post-treatment muscle biopsies, clinical trial participants showed a mean of 51% beta-sarcoglycan positive fibers, as measured by immunohistochemistry (ihc), substantially exceeding the pre-defined 20% measure for success. mean fiber intensity, as measured by ihc, was 47% compared to normal control. srp-9003 uses the aavrh74 vector, which is designed to be systemically and robustly delivered to skeletal, diaphragm and cardiac muscle without promiscuously crossing the blood brain barrier, making it an ideal candidate to treat peripheral neuromuscular diseases. as a rhesus monkey-derived aav vector, aavrh74 has lower immunogenicity rates than reported with other common human aav vectors. the mhck7 promoter has been chosen for its ability to robustly express in the heart, which is critically important for patients with lgmd2e, many of whom die from pulmonary or cardiac complications. this first-in-human study is evaluating a single intravenous infusion of srp-9003 among children with lgmd2e between the ages of four and 15 years with significant symptoms of disease. limb girdle muscular dystrophies are genetic diseases that cause progressive, debilitating weakness and wasting that begin in muscles around the hips and shoulders before progressing to muscles in the arms and legs. patients with lgmd2e begin showing neuromuscular symptoms such as difficulty running, jumping and climbing stairs before age 10. the disease, which is an autosomal recessive subtype of lgmd, progresses to loss of ambulation in the teen years and often leads to death before age 30. there is currently no treatment or cure for lgmd2e. sarepta has five lgmd gene therapy programs in development, including subtypes for lgmd2e, lgmd2d, lgmd2c, lgmd2b and lgmd2l, and holds an option for a sixth program for lgmd2a.
