Rimeporide (EMD 87580)

Rimeporide (EMD 87580), a potential disease modifying drug for Duchenne muscular dystrophy (DMD)

Florence Porte-Thomé, EspeRare Foundation

28th March 2015

EspeRare proposes to reposition Rimeporide, an inhibitor of Na/H-exchanger-1 initially developed for heart failure, for development in Duchenne muscular dystrophy (DMD) and other muscular dystrophies. The proposal is based on preclinical data including research with in vitro primary cultures of myoblasts and in vivo studies covering progressive cardiomyopathy and muscular dystrophy in various rodent models including mdx mice. It has been demonstrated that Rimeporide regulates sodium, pH, calcium overload, reduces inflammation in a number of muscles; decreases skeletal, diaphragm, and cardiac fibrosis as well as muscle cell degeneration. The preclinical data package has allowed Orphan Drug Designation granting by the European Medicines Agency in April 2015. Non- invasive biomarkers qualification to measure intracellular pH and sodium concentration with Magnetic Resonance Spectroscopy (MRS) is ongoing. Safety and Pharmacokinetics (PK) have already been established in several phase I trials in adults. EspeRare plans a 4-week multiple ascending dose phase IB trial in 6-14 year old Duchenne boys investigating safety, tolerability, PK and pharmacodynamic action as measured by MRS and multiple biochemical and immunological biomarkers.

TACT welcomes the pathophysiological concept and the scientific approach to first verify that in a Golden Retriever Muscular Dystrophy (GRMD) study and then to repeat this in a first human phase IB trial together with dosing and safety investigations.  However, TACT advises to ensure appropriate statistical power of the GRMD study to secure translatability of data to DMD boys. For further drug development, the MRS data and other biomarkers will necessarily have to be validated with functional clinical outcome measures as the latter are required for marketing authorisation. At this time to strengthen the positioning of Rimeporide as a cardiac and/or skeletal muscle disease modifying agent, the TACT proposes further preclinical explorations addressing complementary PK and dose-dependent effects on muscle function in mdx mice.  This will contribute to strengthen the rationale for the primary efficacy outcome criteria for a pivotal clinical trial in patients with DMD.

12 Apr 2017