Use of simvastatin as a potential treatment for Duchenne muscular dystrophy

Jorge Quiroz, Solid Biosciences

1st April 2016

This proposal is to conduct a 12 month dose escalation trial of simvastatin (a specific inhibitor of HMG-CoA reductase) in non-ambulant DMD patients aged 10 years and older. The proposed primary outcome measure is cardiac MRI. In this study, initial pharmacokinetic measurements will also be obtained from 16 subjects (8 treated and 8 placebo) to ensure appropriate exposure in DMD boys.

The rationale supporting the trial is based on the preclinical work performed at the University of Washington (Whitehead NP et al., Proc Natl Acad Sci U S A. 2015 Oct 13;112(41):12864-9). These results showed beneficial effects of simvastatin on specific muscle force, decreased fibrosis and decreased inflammation in the mdx mouse. Importantly, they showed beneficial effects of simvastatin in mdx mice with treatment at 3 weeks, 12 weeks and 52 weeks of age.  The proposed mechanism of action includes reduced oxidative stress and normalized autophagy.

Simvastatin is a ready to use drug that is already approved for use in man. There is clinical evidence of safety in a paediatric population (for familial hypercholesterolaemia). TACT felt that the pre-clinical mdx mouse data for skeletal and diaphragm muscle was very strong.

The TACT panel agreed with the applicant that the overall rationale for use in DMD is promising and recommended confirmatory pre-clinical studies conducted by an independent laboratory. In addition, suggestions were made about additional animal models that be considered. Advice was given on outcome measures (primary and secondary) to be selected. TACT strongly recommended early pre-IND engagement with regulatory authorities.

12 Apr 2017