Second generation arylhydrocarbon receptor antagonist, utrophin modulators for the treatment of Duchenne muscular dystrophy

Utrophin is a protein closely related to dystrophin, which is the protein that is absent in the muscle-wasting condition Duchenne muscular dystrophy (DMD). Utrophin has the potential to act as a substitute for dystrophin in patients and ameliorate the disease. Ezutromid was developed from work in our labs as the first drug designed to treat DMD by increasing the amount of utrophin in muscle.
Summit Therapeutics began a clinical trial to test whether ezutromid would be a beneficial treatment for boys with DMD. The clinical trial showed promising results after 24 weeks of treatment. However, the drug wasn't effective over a longer period and in 2018, Summit discontinued its development.
We therefore sought to understand how ezutromid works to uncover new opportunities for alternative drugs that might act in a similar yet more effective way and provide long term increases in utrophin. We demonstrated that ezutromid binds to and switches off a protein, called the arylhydrocarbon receptor (AhR), leading to more utrophin production. Since our project began we have discovered two new types of alternative molecules which switch off AhR and increase utrophin production. We have also shown that an alternative AhR binding molecule is beneficial in the mdx mouse model of DMD. We expect these molecules will overcome the limitations of ezutromid and we will continue to develop these molecules into a new candidate drug as a utrophin replacement therapy.

Our overall objective is to identify a small molecule drug which increases utrophin levels in muscle as an effective treatment of DMD. There is no curative treatment available for DMD, only supportive approaches and genetic approaches with very limited efficacy.
Ezutromid was identified through a phenotypic screening approach, and developed as our first-in-class utrophin modulator. The Phase 2 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. We have since been able to rationalise the lack of sustained efficacy, and demonstrated 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, thereby confirming AhR as a viable target for utrophin functional replacement therapies. This work paves the way for the first target-based disease modifying drug discovery program in DMD. We have already identified second generation lead molecules as AhR antagonists with better efficacy and improved properties compared to ezutromid. This proposal is to support a lead optimization campaign on our lead molecules to drive towards the identification of an IND-ready development candidate for the treatment of all DMD patients irrespective of their mutation.