DMD Trial Results Demonstrate Decrease in Creatine Kinase Levels

Results of a Phase 1/2a gene therapy clinical trial assessing AAVrh74.MHCK7.microdystrophin in children with Duchenne muscular dystrophy (DMD) revealed a significant decrease in levels of serum creatine kinase (CK), an enzyme biomarker associated with muscle damage caused by DMD, according to an announcement from Sarepta Therapeutics.

Sarepta Therapeutics, a commercial stage biopharmaceutical company, presented preliminary data on the first 3 patients enrolled in their clinical trial at the company’s R&D Day. Jerry Mendell, MD, of Nationwide Children’s Hospital, announced the main findings, including:

• All patients demonstrated robust expression of transduced microdystrophin as measured by immunohistochemistry. The mean gene expression of microdystrophin positive fibers was 76.2% and the mean intensity of the fibers was 74.5% compared with the control.
• All posttreatment biopsies showed robust levels of microdystrophin with a mean of 38.2% compared with normal utilizing Sarepta’s method, or 53.7% compared with normal pursuant to Nationwide children’s quantification of Sarepta’s method that is adjusted for fat and fibrotic tissue.
• An average of 1.6 vector copies per cell nucleus were measured in patients.
• All patients demonstrated significant decreases of serum CK levels, with a mean reduction of 87% at Day 60.

“I have been waiting my entire 49-year career to find a therapy that dramatically reduces CK levels and creates significant levels of dystrophin. Although the data are early and preliminary, these results, if they persist and are confirmed in additional patients, will represent an unprecedented advancement in the treatment of DMD,” Mendell stated. “I look forward to treating more patients in the clinical study to generate the data necessary to bring this therapy to patients with DMD, with the goal of dramatically changing the course of the disease.”

The trial also did not result in any serious adverse events. Overall, 2 patients had elevated gamma-glutamyl transferase, which resolved within a week using increased steroids. Patients also had transient nausea during the first week of therapy with the increased steroid dosing.

Mendell and Louise Rodino-Klapac, PhD, empirically optimized the AAVrh74.MHCK7 specifically for DMD, according to the study. They described that the AAVrh74 vector can be systemically and robustly delivered to skeletal, diaphragm, and cardiac muscle without excessively crossing the blood brain barrier. Additionally, the MHCK7 promoter has been chosen due to its ability to robustly express in the heart, which is important for patients with DMD because they typically die from pulmonary or cardiac complications.

“While these are early days and work remains to fully understand the full potential of gene therapies, these first signals are encouraging. We remain hopeful that this will lead to a viable treatment for Duchenne,” concluded Pat Furlong, Parent Project Muscular Dystrophy’s founding president and chief executive officer.