Duchenne Muscular Dystrophy (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 transcriptionally reprogramming the temporal and spatial expression of the dystrophin-related protein utrophin, we aim to develop a pharmacological therapy applicable to all DMD patients by targeting the primary defect and restoring sarcolemmal stability. In partnership with Summit Therapeutics, the 2-aryl benzoxazole utrophin modulator ezutromid (formerly SMT C1100), which demonstrates reduced dystrophic symptoms in the mdx mouse, has progressed to human clinical trials. As a potential First-In-Class molecule, ezutromid is currently being evaluated in an open label Phase 2 study in DMD patients. Interim twenty-four week data was made available in January 2018 which excitingly demonstrated a combination of reduced muscle fibre damage and increased levels of utrophin, providing the first evidence of ezutromid target engagement and proof of mechanism. The successful clinical progression to date of ezutromid provides crucial proof-of-concept for the strategy which is being undertaken, and a comprehensive pipeline of future generation utrophin modulators is being developed. A series of Second Generation Utrophin Modulators which are structurally related to ezutromid, but with improved physicochemical and metabolism profiles have also been evaluated in the mdx mouse, and results were published. In parallel, novel utrophin modulator chemotypes have been discovered using an alternative in vitro dystrophin null myoblast screening assay where a reporter gene has been directly knocked into a utrophin exon. Multiple new structural classes which significantly increase utrophin expression in both murine and human DMD myoblasts have been identified and are now being optimised. Importantly, our data suggests that some of these small molecules modulate utrophin transcription through an alternative regulatory mechanism to ezutromid. These new compounds exhibit favourable solubility, stability, oral absorption and are well tolerated in the mdx mouse. This talk will provide an update on progress of our utrophin modulator drug pipeline, and studies directed towards identifying their mechanism of action.

Small molecule utrophin modulators for the therapy of Duchenne muscular dystrophy (DMD)

256th National Meeting (2018)

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