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 safe and effective small molecule therapies except for Corticosteroids (Ex. Deflazacort) and recently approved Givinostat which are known for dose-limiting and severe adverse effects upon chronic treatment. There is a high unmet medical need to have safe, effective, mutation-agnostic and affordable small molecule drug options.
Utrophin upregulation attracted as an alternate therapeutic approach to offset disease pathology and symptoms of lack of functional Dystrophin protein. Aryl hydrocarbon receptor (AhR) antagonist (Ex. Ezutromid) as an Utrophin up-regulator showed some promise in a Ph2 clinical trial in ameliorating disease symptoms and improving motor functions in DMD patients. However, Ezutromid failed in a 48-week Phase 2 clinical trial because of its poor pharmacokinetic (PK) properties.
We previously, showed that PEPR112 (identified using our proprietary pepAI platform) was a more potent antagonist of AhR (IC50 – 1.53 uM) in a cell-based gene reporter assay and an utrophin upregulation (1.62 fold) in C2C12 mouse skeletal muscle myoblasts compared to Ezutromid (AhR antagonist IC50 – 4.16 uM). Now, we have characterized the ‘in vivo’ efficacy of PEPR112 in the mouse D2-Mdx model of DMD. PEPR112 was found to significantly improve skeletal muscle function and strength parameters in a dose dependent manner along with amelioration of tissue inflammation and fibrosis in histological analysis.
PEPR112 is an US FDA approved oral generic drug with good 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 could provide a potential of access to patients with quicker time of development in a cost-effective manner.