PEPR124 (RT001): A repurposed small molecule drug as a mutation agnostic and safe therapeutic for Duchenne Muscular Dystrophy

Topic:

Translational Research

Poster Number: LB435

Author(s):

Srinivas Gullapalli, M.Pharm, PhD, Peptris Technologies, India, Srikant Viswanadha, MS, PhD, Advait Enterprises / Revio Therapeutics, India, Reem Bou Akar, MS, PhD, INSERM U955, Faculty of Medicine Université Paris-Est Créteil Val de Marne (UPEC), France, Anand Budni, BE, Peptris Technologies, India, Amit Mahajan, BE, Peptris Technologies, India, Jitesh Doshi, Msc, Peptris Technologies, India, Indhumathy Murugan, MTech, PhD, Peptris Technologies, India, Gayathri Warrier, MSc, Peptris Technologies, India, Girdhari Roy, M.Pharm, PhD, Advait Enterprises / Revio Therapeutics, India, Sreevatsa Natarajan, B.Pharm, MSc, MS, Advait Enterprises / Revio Therapeutics, India, Venkatasubramanian Narayanan, MSc, Peptris Technologies, India, Frédéric Relaix, MSc, PhD, INSERM U955, Faculty of Medicine Université Paris-Est Créteil Val de Marne (UPEC), France, Shridhar Narayanan, B.Pharm, MS, PhD, Peptris Technologies, India

Duchenne Muscular Dystrophy (DMD) is an X-linked recessive rare disease primarily affecting boys. DMD is characterized by progressive muscle wasting due to mutations in the dystrophin gene. Presently approved treatments only delay the disease and come with heavy burden of adverse effects (Ex: Corticosteroids – Cushing’s syndrome, osteoporosis, weight gain and stunted growth; Givinostat – thrombocytopenia, leukopenia and QTc prolongation). There is still an unmet medical need for effective and safe small molecule therapeutics for DMD patients, irrespective of their mutation status.
Peptris, using its proprietary AI/ML platform – pepAI, predicted PEPR124(RT001) (an already approved drug) to upregulate utrophin, a functional paralog of dystrophin, with the potential to compensate for its loss. Further, PEPR124(RT001) upregulated utrophin in C2C12 mouse skeletal muscle myoblasts and in human induced pluripotent stem cells (hIPSC – derived from DMD patient).
In a 28-day study in D2-Mdx mouse model of DMD, PEPR124(RT001) at 50mg/kg (p.o., q.d.) significantly improved various muscle strength/function and showed improvement in histopathology parameters as compared to disease control.
Further, in a 90-day chronic study in D2-Mdx model, RT001 (25, 50 & 100 mg/kg, p.o., q.d.) and the positive standard deflazacort (5 mg/kg, p.o. q.d.) significantly improved various muscle strength/function-related parameters in treadmill test (distance travelled, time to exhaustion), grip strength and hanging tests compared to disease control mice. The combination of RT001 and deflazacort also resulted in significantly superior efficacy in hanging latency and in reducing the serum creatine kinase (CK) compared to either of the treatments during the course of the study. Unlike deflazacort, RT001 as a single-agent had no adverse effect on the body weight growth of DMD mice throughout the study.
RT001, a repurposed, mutation agnostic and safe therapeutic, if successful in clinic, could be a significant breakthrough in DMD, that can be fast-tracked via US-505(b)(2)/EU-Hybrid pathway for quicker patient access.