P.13.14 Future clinical and biomarker development for SMTC1100, the first utrophin modulator to enter clinical trials for Duchenne Muscular Dystrophy (DMD)

Abstract

Utrophin modulation i.e. the re-programming of utrophin transcription such that utrophin RNA and protein is continually expressed in mature fibres is expected to be disease modifying in all genetic forms of DMD. SMTC1100 is a small molecule utrophin modulator demonstrating significant benefit on the muscular dystrophy in the dystrophin deficient mdx mouse. These data led to the nomination of SMTC1100 as the candidate for evaluation in DMD clinical trials. In 2012 we reported that SMTC1100 successfully completed a Phase 1 healthy volunteer trial in which an oral paediatric formulation was deemed safe and well tolerated with plasma levels well above those determined to be efficacious in cells and animals. Plans for the first patient trials of SMTC1100 have been developed consisting of two components; a safety and dose finding study in DMD boys in late 2013 followed by a proof of concept study in 2014. In order for proof of concept to be demonstrated in patients, a multicomponent biomarker strategy has been implemented that comprises of two modules; the increase of utrophin levels and evidence of reduction in muscle regeneration. To demonstrate increased utrophin derived from drug treatment above that normally found in regenerating DMD muscle, we aim to quantify utrophin RNA, total utrophin protein and utrophin fibre localisation derived from pre- and post-dose biopsies. To determine a reduction in the rate of degeneration, i.e. increase in mature fibre survival, changes in the percentage of newly regenerating fibres as determined by the presence of neonatal and foetal myosin will be calculated from the biopsies. Using serum and urine samples we will quantify the levels of specific miRNAs associated with fibre leakage and peptide markers of active fibrosis which characterises fibre damage and degeneration respectively. We will present the patient clinical trial plans and data from candidate biomarkers tested both in DMD samples and dystrophin deficient animals.