Rare Daily Staff

Sarepta Therapeutics reported nine-month functional results from three limb-girdle muscular dystrophy type 2E clinical trial participants who received it experimental gene therapy SRP-9003.

SRP-9003 is 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 limb-girdle muscular dystrophy type 2E (LGMD2E).

Limb girdle muscular dystrophies (LGMD) 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, 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’s 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.

In the first cohort of the SRP-9003 study, three participants ages 4 to 13 were treated with an infusion of SRP-9003. Improvements in functional outcomes were observed at nine months for all three participants compared to the natural history of the disease and a significant reduction in mean creatine kinase, a biomarker strongly associated with muscle damage, compared to baseline. The results follow positive and robust expression (51 percent beta-sarcoglycan positive fibers) and biomarker data presented earlier in 2019.

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.

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, but 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.

“LGMD2E is a devastating neuromuscular disease with no current treatment options so we are very pleased to observe a functional improvement in study participants who received SRP-9003,” said Jerry Mendell, principal investigator at the Center for Gene Therapy in the Abigail Wexner Research Institute at Nationwide Children’s Hospital and lead investigator for the study.

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. 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.

“We have now observed consistent functional improvements, in addition to high levels of expression of the missing protein of interest and strong results in related biomarkers, in both of our first cohorts for Duchenne muscular dystrophy (SRP-9001) and LGMD2E (SRP-9003),” said Doug Ingram, Sarepta’s president and CEO. “We intend to test one higher dose of SRP-9003 in LGMD2E participants, select our clinical dose and then advance our SRP-9003 program, along with our other five LGMD programs, as rapidly as possible.”

Photo: Doug Ingram, Sarepta’s president and chief executive officer

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