Duchenne Muscular Dystrophy Gene Therapy Shows Positive Results


In a small trial, the AAVrh74.MHCK7.micro-dystrophin therapy has shown high levels of transduced micro-dystrophin expression.

Dr Jerry Mendell

Jerry Mendell, MD, from Nationwide Children's Hospital

Jerry Mendell, MD

Sarepta Therapeutics’ micro-dystrophin gene therapy has reported positive results in a group of pediatric patients with Duchenne muscular dystrophy (DMD), according to the company.

Ultimately, the therapy showed that in 4 patients there was a robust expression of transduced micro-dystrophin, as measured by immunohistochemistry. The mean gene expression for the study, as measured by the percentage of micro-dystrophin positive fibers, was 81.2%, and the mean intensity of the fibers was 96.0% compared to normal control.

As measured by Western blot, the levels of micro-dystrophin were reported as 74.3% compared to normal using Sarepta’s method, equivalent to 95.8% compared to normal pursuant to Nationwide Children’s quantification of Sarepta’s method, which adjusts for fat and fibrotic tissue.

The data on the AAVrh74.MHCK7.micro-dystrophin therapy was presented by Jerry Mendell, MD, from Nationwide Children’s Hospital, at the 23rd International Congress of the World Muscle Society in Mendoza, Argentina. Previously, it was reported that the therapy showed significant decreases of serum creatine kinase (CK) levels, with a nearly 100% reduction in the mean by day 60 (87% reduction) in 3 patients.

“The goal of this study was to validate what we observed in pre-clinical models,” Mendell said in a statement. “We observed efficient transduction of our vector, AAVrh74, to all muscle types; robust expression in skeletal muscles via the MHCK7 promoter; a reduction in creatine kinase levels; and a favorable safety profile. Similar to pre-clinical models, we also observed in this early study that robust expression has the potential to positively impact the natural course of disease progression.”

The fourth patient’s gene expression was also robust, with a percentage of micro-dystrophin positive fibers of 96.2% and a mean intensity of the fibers of 160.0% compared to normal control. As measured by Western blot, the fourth patients showed a mean of 182.7% compared to normal utilizing Sarepta’s method, or 222% compared to normal pursuant to Nationwide Children’s quantification of Sarepta’s method.

“The encouraging results that we previously saw and reinforced in the fourth patient strengthen our resolve to rapidly move to a confirming trial and, assuming successful, to bring this therapy to the Duchenne community around the world with a sense of urgency,” Doug Ingram, Sarepta’s president and chief executive officer, said.

The AAVrh74.MHCK7.micro-dystrophin vector consists of a rhesus monkey-derived AAV vector, which shows lower immunogenicity rates in existing early-stage clinical studies than expected with other AAV vectors. The MHCK7 cassette allows for AAVrh74 to effectively enter skeletal, diaphragm, and cardiac muscle preferentially via the blood, making it an ideal candidate for neuromuscular diseases.

The presentation by Mendell also included updates for functional endpoints as measured by the North Star Ambulatory Assessment (NSAA), Time to Rise, 4 Stairs Up, and 100M. The patients showed improvements across all of these functions, with boys showing an average NSAA raw score improvement of 6.5 points from baseline. On a linearized NSAA basis, they showed 12 points of improvement in the first 90 days.

Additionally, no serious adverse events were observed. Three patients had elevated gamma-glutamyl transferase which resolved with increased steroids within 7 days. Patients had transient nausea generally during the first week of therapy parallel with increased steroid dosing.

Mendell noted in his presentation that although the results suggest the functional improvements across all measures are significantly greater than natural history predictions, caution is advised, as this is a small, uncontrolled data set, and the positive results must be reconfirmed in the larger, controlled registration trial.

“These results create for us an obligation to patients around the globe living with and being damaged by this cruel disease,” Ingram said. “We are investing our energy, resources, and creativity to moving the development forward, planning meetings with the FDA and other agencies around the world to take their input, building a compelling access and reimbursement package, and establishing sufficient manufacturing capacity to fully serve the community if our program is successful.”


Sarepta Therapeutics Announces that at the 23rd International Congress of the World Muscle Society, Jerry Mendell, M.D., Presented Positive Updated Results from the Four Children Dosed in the Gene Therapy Micro-dystrophin Trial to Treat Patients with Duchenne Muscular Dystrophy [press release]. Cambridge, MA: Sarepta Therapeutics; Published October 3, 2018. globenewswire.com/news-release/2018/10/03/1601085/0/en/Sarepta-Therapeutics-Announces-that-at-the-23rd-International-Congress-of-the-World-Muscle-Society-Jerry-Mendell-M-D-Presented-Positive-Updated-Results-from-the-Four-Children-Dosed.html. Accessed October 4, 2018.

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