Duchenne Muscular Dystrophy (DMD) is an X-linked, chromosomal recessive rare disease primarily affecting only boys. DMD is characterized by devastatingly progressive muscle wasting & weakness due to mutation(s) in the dystrophin gene. Currently, there are no affordable and effective small molecule therapies to cure / treat except for limited symptomatic management. Ezutromid, an Aryl hydrocarbon receptor (AhR) antagonist, attracted attention as a promising therapeutic approach due to its ability for utrophin (a surrogate of dystrophin) upregulation, leading to enhanced muscle tissue function and decreased inflammation & dystrophy in DMD patients. However, Ezutromid failed in a 48-week Phase 2 clinical trial because of its poor pharmacokinetic (PK) properties.
Using our proprietary AI/ML platform – pepAI, we discovered a repurposable drug (PEPR112) which upregulates the utrophin expression through AhR antagonism and potentially enhances muscle function in DMD patients. We discovered PEPR112 to be a potent antagonist of AhR in a cell-based gene reporter assay and found it to be a potent utrophin upregulator in C2C12 mouse skeletal muscle myoblasts compared to Ezutromid. In addition, PEPR112 significantly improved the locomotion of larvae of zebrafish DMD model, particularly in dark phase, on day 6 post fertilization (dpf) in a dose dependent manner.
PEPR112 is an US FDA approved oral generic drug with excellent PK and broader safety profile including in paediatric population (3 to 16 years).
Our findings show that the repurposing of PEPR112 as a drug to upregulate utrophin for the treatment of DMD represents a significant breakthrough in the field of DMD therapeutics and could reduce the time and cost of development to give a quick access to DMD patients, a potential therapeutic intervention.