Investigational Limb-Girdle Muscular Dystrophy Gene Therapy Positive in Phase 1/2


Data show the therapy’s positive safety and expression results from a small number of clinical trial participants with limb-girdle muscular dystrophy type 2E out to 1 year.

Dr Jerry Mendell

Jerry Mendell, MD, principal investigator at the Center for Gene Therapy in the Abigail Wexner Research Institute at Nationwide Childrens Hospital

Jerry Mendell, MD

New study results (NCT03652259) investigating the potential of SRP-9003, a gene therapy for limb-girdle muscular dystrophy type 2E (LGMD2E), show the therapy’s positive safety and expression results from a small number of clinical trial participants, according to manufacturer Sarepta.1

The results show 60-day safety and expression data for 3 participants on a high dose of SRP-9003 (5x1013 vg/kg; Cohort 2), as well as 1-year functional data from 3 participants in a low-dose group (2x1014 vg/kg; Cohort 1).

“LGMD2E is a devastating neuromuscular disease that causes significant disability in the children we see and currently lacks treatment options beyond tailored physical therapy,” Jerry Mendell, MD, principal investigator, Center for Gene Therapy, Abigail Wexner Research Institute, Nationwide Children’s Hospital, said in a statement. “We are pleased that these data show robust expression, similar to what we observed in the micro-dystrophin program, 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.”

In Cohort 1, all 3 participants continued to show improvements from baseline across all functional measures, including the North Star Assessment for Limb-Girdle Muscular Dystrophies, time-to-rise, four-stair climb, 100-meter walk test and 10-meter walk test at the Year-1 time point.

In Cohort 2, there was a strong, dose-dependent increase in transduction as well as expression transduction and expression when compared with the low-dose cohort. All 3 participants showed robust mean expression of 72.3% of transduced ß-sarcoglycan (beta-SG), properly localized to the muscle sarcolemma, and measured by immunohistochemistry (IHC). According to Sarepta, those data exceeded the pre-defined measure of success for the study, defined as 50% positive fibers—previously achieved in Cohort 1 (51%; mean intensity, 47%).2

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Additionally, mean fiber intensity in Cohort 2, also measured by IHC, was 73.1% compared to normal control. All participants in the cohort showed robust quantification of beta-SG, as measured by Western blot, with mean beta-SG of 62.1% of normal control. Serum creatine kinase levels from pre-treatment to 90 days were reduced by a mean of 89.1%.

Adverse events (AEs) in Cohort 2 were deemed mostly mild to moderate in severity. There was 1 serious AE: dehydration resulting from vomiting 3 days after infusion. This resolved in 2 days with ondansetron, promethazine, and intravenous fluids.

SRP-9003 is a gene construct that transduces skeletal and cardiac muscle, delivering a gene that codes for the full-length beta-sarcoglycan protein, the absence of which is the sole cause of progressive degeneration and a shortened lifespan characterized by the disease. LGMD2E is an autosomal recessive subtype of LGMD which progresses to loss of ambulation in the teenage years and often death prior to age 30; there is currently no available treatment.

“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 1 year,” Doug Ingram, President and CEO, Sarepta, said in a statement. “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. The SRP-9003 gene construct, vector and promoter were designed with the goal of robustly delivering to skeletal and cardiac muscles a gene coding for the missing beta-sarcoglycan protein that causes LGMD2E. These data support the conclusion that the therapy is achieving its intended purpose, driving robust expression in the muscles where it is needed.”

Ingram noted that SRP-9003 utilizes the same vector—AAVrh74—and same promoter—MHCK7—as its investigational Duchenee muscular dystrophy (DMD) treatment, SRP-9001. Additionally, he said that Cohort 2 received a dose similar to that in the ongoing SRP-9001 studies.

“The safety and efficacy results with these 2 doses of SRP-9003 provide us with additional experience and confidence with the rh74 vector and the MHCK7 promoter 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.

In October 2019, Sarepta had announced 9-month results, in which all 3 participants had improvements from baseline in the North Star Assessment for Dysferlinopathy (NSAD), time to rise, 4-stair climb, 100-meter walk test, and 10-meter walk test scores, with results distinct with what an age-matched, natural history group would predictably show. Natural history patients with LGMD2E begin showing neuromuscular symptoms such as difficulty running, jumping, and climbing stairs prior to age 10. As well, creatine kinase, the enzyme biomarker strongly associated with muscle damage, was significantly reduced.3

Sarepta had also previously shared expression results from the study, which found that in 2-month post-treatment muscle biopsies, clinical trial participants showed a mean of 51% beta-sarcoglycan positive fibers, as measured by IHC, substantially exceeding the pre-defined 20% measure for success. Mean fiber intensity compared to normal control was 47%, as measured by IHC.

Sarepta noted that the final dose for registration trial will be selected by Q3, and informed by this data, while the company engages with global regulatory agencies to discuss its pivotal trial designs. The initiation of a registrational study in 2021 is anticipated as well.2


1. Sarepta Therapeutics Announces Positive Expression and Functional Data From the SRP-9003 Gene Therapy Trial to Treat Limb-Girdle Muscular Dystrophy Type 2E [press release]. Cambridge, MA: Sarepta Therapeutics; Published Jun 8, 2020. Accessed June 9, 2020.

2. Sarepta Therapeutics. Clinical Update: SRP-9003 Beta-Sarcoglycanopathy Gene Therapy Program Limb-Girdle Muscular Dystrophy Type 2E. Cambridge, MA; Published June 8, 2020. Accessed June 9, 2020.

3. 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 [press release]. Cambridge, MA: Sarepta Therapeutics; Published October 4, 2019. Accessed June 9, 2020.

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