Stan Froehner’s group at the University of Washington recently reported preclinical efficacy data on the approved drug, Simvastatin, in the mdx mouse model of Duchenne (see PPMD's blog from the last day of the World Muscle Society meeting). These results have now been pusblished in the Proceedings of the National Academy of Sciences.
Simvastatin may seem an unlikely therapeutic candidate for Duchenne—statins are linked to drug-induced myopathy in a small minority of normal adult patients. However, several studies show that the HMG-CoA reductase inhibitors, such as Simvastatin, also are anti-inflammatory, anti-fibrotic, and reduce oxidative stress—all activities potentially beneficial in Duchenne. Extensive experience with Simvastatin in treatment of pediatric hypercholesterolemia also provides a wealth of safety data in children. In rigorous acute and chronic studies in mdx mice, Simvastatin was shown to have potent effects on inflammation (70% reduction), fibrosis (50% reduction in diaphragm) muscle force (40% increase). A compelling finding was that Simvastatin reversed the extensive fibrosis seen in old mdx mouse diaphragm. In the mdx, dosing with Simvastatin did not impair muscle regeneration or activate pathways associated with the statin myotoxicity seen in adults.
With the caveat that the mdx mouse is simply a model of Duchenne, and findings may or may not translate to human, Simvastatin targets key pathogenic pathways that are operative in Duchenne and thus may prove effective in slowing progression, particularly in a combination therapy approach.