New orally available compounds which modulate utrophin expression for the therapy of Duchenne muscular dystrophy (DMD)

DMD is a devastating X-linked muscle-wasting disease caused by lack of the cytoskeletal protein dystrophin. There is currently no cure for DMD although various promising approaches (e.g. exon skipping, read through of stop codons, gene therapy) are being developed. By pharmacologically modulating the dystrophin-related protein utrophin, we aim to develop a therapy applicable to all DMD patients by targeting the primary defect and restoring sarcolemmal stability. In partnership with Summit plc we previously developed SMT C1100; a small molecule utrophin modulator that reduced dystrophic symptoms in the mdx mouse. As a potential first-in-class molecule, SMT C1100 recently successfully completed a Phase 1a trial. DMD patients are currently being dosed in an ongoing Phase 1b trial for which a multicomponent biomarker strategy has been implemented with a quantification of utrophin level, regeneration, fibrosis, inflammation and analysis of specific miRNAs. The successful clinical progression to date provides crucial proof-of-concept for the strategy we developed. We are now optimising next generation utrophin modulator molecule which were discovered using an improved drug screening assay based on immortalised myoblasts from the utrophin luciferase knock-in mouse. This enables us to screen utrophin in its genomic context, better mimicking the in vivo situation and enabling identification of compounds which modulate utrophin through regulatory pathways outside of the 8.4 kb promoter fragment used in our previous screen. Thus, we identified multiple structural classes which significantly modulate utrophin expression in both mouse and human DMD myoblasts. New compounds exhibit favourable solubility, stability, oral absorption and are well tolerated in the mouse and structure–activity studies are underway, with the objective to improve compound effectiveness. The two of the best new utrophin modulators are currently being studied in pre-clinical in vivo studies in mdx mice.