Development of next generation utrophin modulators for Duchenne muscular dystrophy: learning from clinical setbacks

Speaker - Angela Russell, University of Oxford

Abstract: 

Duchenne muscular dystrophy (DMD) is an X-linked progressive muscle wasting disorder caused by mutations in the dystrophin locus leading to absence of the associated protein, dystrophin. There is currently no cure for DMD, although various promising approaches (e.g. exon skipping, gene therapy) are being developed. We and others have demonstrated that DMD pathology in preclinical models can be prevented through functional replacement of dystrophin with its autosomal paralogue, utrophin. Our long-term therapeutic aim is to develop a small molecule drug to increase utrophin levels at the muscle membrane in DMD patients.

In partnership with Summit Therapeutics ezutromid, identified through a phenotypic screening approach, was progressed to human clinical trials as our first-in-class utrophin modulator. The clinical trial showed promising efficacy and evidence of target engagement after 24 weeks of treatment, but these effects were not seen after the full 48 weeks of the trial. Without knowledge of the mechanism of action of ezutromid, it was difficult to rationalise the lack of sustained clinical efficacy, and development of ezutromid was discontinued.

This talk will provide an overview of the early discovery and the clinical translation of ezutromid, our follow up work to rationalise the lack of sustained efficacy in the clinic, and our development of follow-on compounds to overcome the limitations of ezutromid. Our demonstration through a series of target identification and validation studies that ezutromid binds to the arylhydrocarbon receptor (AhR) with high affinity, and antagonism of AhR by ezutromid leads to utrophin upregulation will be described, confirming AhR as a viable target for utrophin functional replacement therapies. The identification of new lead molecule AhR antagonists with better efficacy and improved properties compared to ezutromid will also be described, as will the implementation of an alternative screening strategy leading to the discovery of new molecules with a distinct mechanism of action to ezutromid.

Bio: 

Angela is a Professor of Medicinal Chemistry jointly between the Departments of Chemistry and Pharmacology at the University of Oxford. She gained her DPhil in Organic Chemistry in 2004, and in 2007 she was awarded a Research Councils’ UK Fellowship. in 2018 she was promoted to Professor of Medicinal Chemistry, only the 5th female full professor in Oxford Chemistry’s 100+ year history.

Her research concerns the discovery and translation of new molecules and mechanisms to manipulate cell fate, particularly for degenerative diseases. She has founded three companies MuOx Ltd (acquired by Summit Therapeutics plc), Oxstem Ltd and Kodiform Therapeutics Ltd to translate her research towards new treatments and taken two products to clinical trial, one in Duchenne muscular dystrophy, the other in COVID-19. In 2016 she was named as a Rising Star in the UK Biobeat report, recognizing 50 outstanding women entrepreneurs and business leaders who are recognised for their contributions to global health innovation. Her pioneering work to develop a therapy for Duchenne muscular dystrophy has been recognized through a Harrington Rare Diseases scholarship award in 2020, and the RSC Jeremy Knowles Award in 2024.

https://russellchem.web.ox.ac.uk/