P.317Rimeporide, a repositioned NHE-1 inhibitor for DMD: a preclinical trial in GRMD dogs

Abstract

In DMD, the muscle pH and the intracellular calcium are increased, as part of the many disturbances observed in the myofiber subsequent to dystrophin deficiency. The pharmacological inhibition of NHE-1 is thought to directly regulate the pH, and indirectly decrease calcium concentration by downregulating NCX. Promising data obtained in dystrophic rodent models prompted us to perform a preclinical study in GRMD dogs, a large size animal model faithfully reproducing the DMD disease course. Twenty-four GRMD dogs were included in a double blinded randomized placebo-controlled study (n=12 per arm), and followed over 10 months, from the age of 2 months. In the treated group, dogs received rimeporide at a dose of 10 mg/kg PO twice daily. Extensive functional evaluation was performed including iterative clinical scoring, gait analysis, respiratory inductance plethysmography, muscle ultrasound, force measurement, ECG and histopathological evaluation of skeletal muscles. Echocardiography and skeletal muscle and cardiac NMRI and NMRS were also performed but will not be reported here. The overall tolerance was good in long-term treated growing dogs. Rimeporide significantly improved skeletal muscle relaxation, suggesting the NCX bystander effect of the rimeporide-mediated NHE-1 inhibition had been achieved. A trend towards decreased hypertrophy of the sartorius cranialis and atrophy of the biceps femoris was observed. However, no significant effect on the disease course could be evidenced from a more global point of view, assessed by several aforementioned evaluation methods. Histological quantifications on skeletal muscle biopsies did not reveal any significant treatment effect. PK/PD studies should help to understand if a suboptimal drug exposure could explain the low efficacy observed in GRMD dogs. This study, together with good tolerance demonstrated during a phase I dose escalation study in DMD patients, should help supporting the design of future clinical trial phases.