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A potential gene therapy known as SRP-9003 led to sustained production of beta-sarcoglycan in muscle fibers and functional improvements over two years in children with limb-girdle muscular dystrophy type 2E (LGMD2E), early data from a Phase 1/2 trial showed.
Beta-sarcoglycan is the protein missing in people with LGMD2E.
“This data is the first look at longer-term expression data with any gene therapy for muscular dystrophy,” Louise Rodino-Klapac, PhD, chief scientific officer and executive vice president of Sarepta Therapeutics, the therapy’s developer, said in a press release.
“The meaningful and sustained levels of beta-sarcoglycan protein expression at two years and continued strength of the functional outcomes measured are tremendously positive, and support continued advancement of this investigational treatment for patients,” Rodino-Klapac said.
The data were presented at the 2021 MDA Virtual Clinical & Scientific Conference in an oral presentation titled “Safety, β-sarcoglycan Expression, and Functional Outcomes from Systemic Gene Transfer of rAAVrh74.MHCK7.SGCB in Limb-Girdle Muscular Dystrophy Type 2E.”
LGMD2E (also called LGMDR4) is caused by variants in the SGCB gene, which carries instructions for the protein beta-sarcoglycan. This protein is found on the membrane of muscle cells as part of a larger protein complex that helps stabilize dystrophin proteins, strengthening and protecting muscle fibers.
SRP-9003 uses a modified and harmless adeno-associated virus (AAV) to deliver a healthy copy of the SGCB gene to muscle cells.
The therapy is being evaluated in a Phase 1/2 trial (NCT03652259) that involves six children with LGMD2E, ages 4–13. The enrolled patients carry two mutated SGCB gene copies, one from each parent, and do not have antibodies against the AAV vector used in SRP-9003.
Three of the children — those in group 1 — received low dose SRP-9003 by direct (intravenous, or into-the-vein) infusion into the bloodstream of 1.85e13 vector genomes (vg)/kg. Meanwhile, the three in group 2 were given a higher dose of 7.41e013 vg/kg.
The low-dose patients also received the immunosuppressive agent prednisone one day before and for 30 days after infusion; the dose was then tapered. The high-dose group received the same prednisone regimen for 60 days before tapering.
Safety and tolerability are the trial’s primary outcome measures, or main goals. Secondary assessments include beta-sarcoglycan expression (production) in muscle fibers, assessed by biopsy before treatment and at 60 days and two years post-treatment, as well as functional tests such as the North Star Assessment for Dysferlinopathy, known as NSAD, and timed tests. The 54-point NSAD scale assesses motor abilities, while the timed tests include evaluations of time-to-rise, a four-stair climb, and a 10-meter and 100-meter walk.
New data from biopsies taken at 60 days in the low dose group showed the mean level of beta-sarcoglycan was 36% of normal control, which increased to 54% at two years. An alternate test showed 51% of muscle fibers were positive for beta-sarcoglycan at 60 days and sustained at 48% for two years.
In the high dose group, and as previously reported, biopsies taken at 60 days showed mean beta-sarcoglycan levels at 62% of normal and 72% by the alternative measure. These data showed a “dose-response with regards to cohort [group] 1 and cohort 2, but the cohort 1 sustained expression over two years was a very good finding,” said Rodino-Klapac, who presented the updates.
In the high dose group, after 60 days, SRP-9003 also increased the production of other sarcoglycan complex proteins (gamma- and delta-sarcoglycan) that are diminished or absent with a loss of beta-sarcoglycan.
This 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.
In the low dose group, the mean NSAD score improved by 3.0 points at six months and 5.7 points at one year, which was sustained through two years. The high dose group showed an increased NSAD score of 3.7 points at six months and 4.0 points at one year. Of note, two-year results are not yet available for the high-dose participants.
Across all patients, a mean decrease in timed tests showed functional improvement for the low-dose group at six months, one and two years, and in the high-dose group at six months and one year.
An evaluation of all SRP-9003-treated children showed a mean improvement of 4.6 NSAD points over two years, compared with an untreated natural history group, which declined by 4.6 points over the same period. This translates to a clinically meaningful difference of 9.2 points between the two groups.
A 77% decrease in the muscle damage marker creatine kinase was seen in the low-dose group at two years. A 74% reduction was seen in the high dose group at one year.
In a review of recent safety findings, two participants in the low-dose group had elevated liver enzymes during or after the prednisone tapering phase. One case was designated a serious adverse event. Both were resolved after further steroid treatment. One child experienced mild vomiting for one day.
In the high-dose group, most adverse events were mild to moderate, including vomiting and pain in the extremities. One child experienced dehydration due to vomiting three days post-infusion, while another had mildly elevated liver damage marker GGT. All were resolved with treatment.
In both groups, no discontinuations were reported due to adverse events, and no abnormal lab tests were observed, including no reduction in platelet counts or immune activation. One child died unexpectedly due to a recreational accident not related to therapy.
“This interim analysis reinforces the favorable safety profile of systemically administered SRP-9003,” the scientists concluded. “The observed durable treatment effect provides proof of concept and supports further clinical assessment [of] SRP-9003 gene therapy patients with LGMD2E/R4.”
Added Rodino-Klapac: “The data continue to suggest this treatment could bring much needed hope to [LGMD2E] patients.”
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