Dialing in on a new DMD target

OXFORD, U.K.—The 15^th Action Duchenne International Conference 2017, an event that unites individuals with Duchenne and Becker muscular dystrophy (and their families) with experts and industry members focused on tackling the diseases, met in Birmingham, U.K., this past November. Among the industry members in attendance were Summit Therapeutics plc and collaborators from the University of Oxford, who presented data supporting utrophin modulation as a universal treatment for Duchenne muscular dystrophy (DMD).

The preclinical data in question were presented by Prof. Kay Davies of the University of Oxford, scientific advisor and co-founder of Summit. The data revealed that continuous expression of utrophin in a dystrophin-deficient environment can reduce mitochondrial aberration and oxidative stress—the former drives the latter, which contributes to DMD muscle damage. Davies also covered previously published preclinical results related to utrophin modulators, including ezutromid, that captured the candidates’ potential to prevent molecular disease. Ezutromid is the company’s lead utrophin modulator.

Davies commented in a press release that, “My team at the University of Oxford continues to gather scientific evidence showing how utrophin can substitute for dystrophin in animal muscle and prevent many of the molecular hallmarks of DMD from occurring in these animal models. Importantly, these underlying changes in muscle health have the potential to lead to functional benefits, providing hope for a universal, disease-modifying treatment for families living with Duchenne.”

As explained by Glyn Edwards, CEO of Summit, “Utrophin and dystrophin both act as molecular shock absorbers in normal muscle function. This helps the muscle fibers to deal with the shock of muscle contractions. The difference is when they perform this function—utrophin is present along the muscle fiber when a muscle is first forming or repairing. As the muscle matures, utrophin production is switched off and dystrophin production is switched on to take its place. Utrophin has additional roles in mature muscles where the nerve meets the muscle (neuromuscular junction) and where the tendon meets the muscle (myotendinous junction). It is also expressed in other cells throughout the body.”

An advantage of targeting utrophin rather dystrophin, says Edwards, is that it could help all DMD patients, regardless of their specific dystrophin mutation.

“Many of the dystrophin-restoration approaches are specific to certain dystrophin mutations and therefore can only treat a subset of patients,” Edwards tells DDNews. “Based on our animal work, we believe that utrophin can substitute for dystrophin and could work as a stand-alone therapy for DMD. We also believe that utrophin modulation could work in combination with dystrophin restoration therapies and other therapies in development for DMD.”

“There are a finite number of sites along the muscle fibers where either utrophin or dystrophin could be present,” he adds. “The current generation of dystrophin-restoration therapies does not appear to restore dystrophin to 100 percent, meaning there are some sites along the muscle that are vacant. The potential is for utrophin to fill some of those vacant sites. We don’t believe there would be any complications with expressing both utrophin and dystrophin at once, and have observed this in animal studies, but this would need to be tested in a clinical setting. We are first focused on showing benefit with utrophin modulation alone.”

The recent presentation also covered Summit’s ongoing Phase 2 proof-of-concept trial, PhaseOut DMD, which is evaluating ezutromid in 40 patients with DMD. The company announced on Nov. 20 that it had completed the initial 24 weeks of dosing of ezutromid for the clinical trial.

“These new preclinical data from Prof. Davies’ team at the University of Oxford provide another piece of evidence highlighting the potential of utrophin modulation in being able to treat this devastating muscle wasting disease,” said Dr. David Roblin, chief operating officer and medical officer at Summit. “We remain on track to report the first results of ezutromid treatment in boys with DMD in PhaseOut DMD in the first quarter of 2018, and if results provide evidence of the mechanism of utrophin modulation in patients, we believe it would represent a major advancement for ezutromid. It would bring closer to all patients a therapy that has the potential to be disease modifying in DMD.”

Edwards says that pending positive results from PhaseOut DMD, Summit plans to conduct a placebo-controlled trial to secure “accelerated and conditional approvals in the U.S. and EU, respectively.”

“We also have a pipeline of future generation utrophin modulators under development with the University of Oxford,” he adds. “These are much earlier in development, but we’ve identified a series of molecules that may have a different mechanism to ezutromid.”