Sarepta Therapeutics announced that at the 23rd International Congress of the World Muscle Society in Mendoza, Argentina, Jerry Mendell, MD, of Nationwide Children’s Hospital presented positive updated results from its gene therapy clinical trial assessing AAVrh74.MHCK7.micro-Dystrophin in individuals with Duchenne muscular dystrophy (DMD). Dr. Mendell presented the following updated data on the four patients enrolled in the study:

All patients showed robust expression of transduced micro-dystrophin, which is properly localized to the muscle sarcolemma, as measured by immunohistochemistry. Mean gene expression for the study, as measured by percentage of micro-dystrophin positive fibers was 81.2% and the mean intensity of the fibers was 96.0% compared to normal control. All post-treatment biopsies showed robust levels of micro-dystrophin as measured by Western blot, with a mean of 74.3% compared to normal utilizing Sarepta’s method, or 95.8% compared to normal pursuant to Nationwide Children’s quantification of Sarepta’s method that adjusts for fat and fibrotic tissue.

Gene expression for the fourth patient was robust, as follows:

  • As measured by immunohistochemistry, micro-dystrophin positive fibers was 96.2% and the mean intensity of the fibers was 160.0% compared to normal control.
  • As measured by Western blot, patient 4 showed robust levels of micro-dystrophin, with 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 that adjusts for fat and fibrotic tissue.
  • In all patients, expression of micro-dystrophin was associated with significant expression and up-regulation of the dystrophin-associated protein complex, an additional indication of functionality of dystrophin.
  • All patients showed significant decreases of serum creatine kinase (CK) levels at last measure, with a mean reduction of CK of over 78% from baseline.

Dr. Mendell also provided an update on functional endpoints for all four patients, including North Star Ambulatory Assessment (NSAA), Time to Rise, 4 Stairs Up, and 100M. Patients showed improvements across all measured functions, with boys showing an average NSAA raw score improvement of 6.5 points from baseline to last measure, or on a linearized NSAA basis, 12 points of improvement in the first 90 days. While results suggest functional improvements across all measures significantly greater than natural history predictions, it should be cautioned that this is a small, uncontrolled data set and these positive results must be reconfirmed in the larger, controlled registration trial.

No serious adverse events (SAEs) were observed in the study. Three patients had elevated gamma-glutamyl transferase (GGT) that resolved with increased steroids within a week. There were no other significant laboratory findings. Patients had transient nausea generally during the first week of therapy coincident with increased steroid dosing.

Dr. Mendell, the study’s principal investigator, in collaboration with Louise Rodino-Klapac, Ph.D., empirically optimized the AAVrh74.MHCK7 specifically for DMD:

  • The AAVrh74 vector is designed to be systemically and robustly delivered to skeletal, diaphragm and cardiac muscle without promiscuously crossing the blood brain barrier, making it an ideal candidate to treat peripheral neuromuscular diseases.
  • 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 DMD, who typically die from pulmonary or cardiac complications. In pre-clinical models, micro-dystrophin expression in the heart was observed to be up to 120% of the micro-dystrophin levels observed in skeletal muscles.
  • The transgene was designed to maintain spectrin-like repeats 2 and 3, which has been reported to be critical to maintaining the protective functional characteristics of dystrophin.

Dr. Mendell stated, “The goal of this study was to validate what we observed in pre-clinical models. 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.”