SRP-9003 Gene Therapy for LGMD2E Shows Benefits After 1 Year

A single administration of the gene therapy SRP-9003 at a low dose continues to lead to significant improvements in functional measures in three children with limb girdle muscular dystrophy (LGMD) type 2E, one-year data from a Phase 1/2 trial show.

When administered at a high dose in three other children, SRP-9003 also increased the number of muscle fibers containing beta-sarcoglycan, a protein that plays a key role in muscle integrity and whose levels are diminished in people with LGMD2E. Treatment also lowered the levels of creatine kinase (CK) in the blood, a marker of muscle damage.

SRP-9003, formerly known as MYO-101, is an investigational gene therapy currently being developed by Sarepta Therapeutics. It uses a harmless adeno-associated viral vector (AAV), called AAVrh74, to deliver a functional copy of the SGCB gene, which encodes beta-sarcoglycan, to muscle cells. AAVrh74 was selected due to the vector’s lower likelihood of inducing an immune response compared to other AAVs, Sarepta said.

The main goal of the therapy is to increase the production of beta-sarcoglycan in both cardiac and skeletal muscles to reverse the symptoms of LGMD2E.

A Phase 1/2 trial (NCT03652259) is currently testing the treatment’s safety and effectiveness in six children with LGMD2E, ages 4–13, with significant symptoms of the disease. SRP-9003 is given by intravenous infusion, or directly into the bloodstream.

The study comprises two groups, each with three children: in the first group, children received a low dose of 5×10¹³ vector genomes (vg)/kg. In the second group, a higher dose of of 2×10¹⁴ vg/kg was used.

Nine-month data from the three children in the low-dose group showed that SRP-9003 led to significant improvements in several functional measures, including the North Star Assessment for Dysferlinopathy (NSAD, a 54-point scale assessing motor abilities), the time-to-rise, the four-stair climb, and the 10-meter and 100-meter walk tests.

Treatment also lowered CK levels by approximately 82%. No new safety signals were identified.

One-year results from this first group showed that SRP-9003 continues to lead to significant improvements in all previously assessed functional measures.

No new treatment-related safety signals were identified since the last update. No reductions in platelet counts or signs of complement system activation — a complex system comprising more than 30 blood proteins that form part of the body’s immune defenses — were reported.

“We were very encouraged by the previously reported results from our first cohort of patients treated with a lower dose of SRP-9003, including impressive expression, good tolerability, and positive functional signals, which continue impressively at one year,” Doug Ingram, president and CEO of Sarepta, said in a press release.

The company also announced preliminary data from muscle biopsies taken from the three children in the second group after two months of treatment. Those on the high dose had a stronger, dose-dependent increase than children who took the low dose in the number of muscle fibers containing beta-sarcoglycan.

On average, 72.3% of muscle fibers were positive for beta-sarcoglycan in children from the high-dose group following treatment, while about 50% of those in children from the low-dose group contained the protein.

Additional analyses also revealed that SRP-9003 increased the levels of beta-sarcoglycan, which reached approximately 62.1% of levels in healthy people.

“We are pleased that these data show robust expression, similar to what we observed in the micro-dystrophin program [in DMD], for the protein that is missing in children with LGMD2E, and remain hopeful that this brings us one step closer to a therapy that can help improve both prognosis and quality of life,” said Jerry Mendell, MD, principal investigator at the Center for Gene Therapy at Nationwide Children’s Hospital, and the study’s lead investigator.

Treatment also lowered CK levels in all three children by an average of 89.1% after three months, from the beginning of the study to the last assessment at day 90.

Most adverse events observed among the three children from the second group were mild or moderate in severity. One serious adverse event — dehydration caused by vomiting — was reported and rapidly resolved with standard treatment.

“We are excited to have been able to achieve even more impressive expression and other biomarkers in our higher-dose cohort for SRP-9003, along with good tolerability,” added Ingram.

Sarepta is now planning to use these findings as a basis to define the best dose at which SRP-9003 should be administered to patients in future studies.

“The safety and efficacy results with these two doses of SRP-9003 provide us with additional experience and confidence … as we select the dose for the pivotal trial of SRP-9003 and work to quickly develop this therapy for patients who currently have no treatment options,” Ingram said.