source: Neuromuscular Disorders
T. Gidaro, L. Servais, S. Previtali, A. Zambon, J. Pitchforth, K. Maresh, J. Diaz, C. Laveille, J. Gray, F. Porte-Thomé, H. Gheit, M. Annoussamy, V. Che, D. Duchene, M. Sora, S. Gerevini, N. Vidal, K. Groves, J. Brimble, F. Muntoni
In Duchenne muscular dystrophy, impaired sodium and calcium handling are associated with severe osmotic oedema, muscle weakness, inflammation and fibrosis. Rimeporide, a safe and potent NHE-1 inhibitor, represents a novel target for DMD patients. Rimeporide is an orally available drug showing to promote compelling cardioprotective effect in the dystrophic hamsters with dilated cardiomyopathy. In mdx mice Rimeporide demonstrated promising data on skeletal muscle function, fibrosis and inflammation in skeletal, cardiac and diaphragm muscles. Altogether, these data show that Rimeporide may be a successful pharmacological approach to the cardiac, skeletal and respiratory dysfunctions observed in DMD regardless of the patient’s mutation. The safety, tolerability and pharmacokinetic of Rimeporide involving more than 150 healthy adults has shown that Rimeporide was well tolerated over a dose range of 50 to 600 mg per day. Recently, an open label, oral ascending dose study in 20 patients with DMD (6 to 14 years old) is ongoing in Europe to evaluate the safety, tolerability and pharmacokinetic (NCT02710591). The boys are exposed to one of the 4 dose cohorts (75 mg to 900 mg per day) for a 4 week treatment with Rimeporide. The study also explores a panel non-invasive biomarkers including serum biomarkers of inflammation and fibrosis. To date, 15 patients have completed treatment in the first three cohorts. There has been no significant safety signal to date. The pharmacokinetic profile was in line with the concentration observed in healthy adults and a dose linear increase was observed. Safety, PK and exploratory biomarkers will be presented for the 4 dose cohorts.
I-Motion, France; San Raffaele Scientific Institute, Italy; Dubowitz Neuromuscular Unit, UK; Hospital de la Santa Creu I Sant Pau, Spain; Calvagone, France; EspeRare Foundation, Switzerland; Somers Clinical Research Facility, UK