A Treatment for Patients with Jansens Metaphyseal Chondrodysplasia (JMC)

National Center For Advancing Translational Sciences

Investigators

Abstract

The lead collaborators identified the first, and most frequent, PTHR1 mutation of JMC (H223R) and generated a corresponding transgenic mouse model (C1HR) recapitulating some of the JMC skeletal phenotype. They also identified through in vitro studies PTHR1 inverse agonist ligands that can suppress the high basal activity of the mutant receptors causing JMC. These inverse agonists, based on fragments of PTH or the PTH-related protein (PTHrP), were then tested in vivo in the C1HR mouse. One of these PTH inverse agonists (PTH-IA) was found to significantly improve the bone and mineral ion defects in the mutant mice, supporting the hypothesis that a PTH-IA could be developed as a therapy for JMC. TRND scientists initiated a preclinical development campaign to advance the PTH-IA candidate to clinical evaluation. The team standardized a process to manufacture PTH-IA drug substance and has produced a clinical-grade (Good Manufacturing Practice, GMP) formulation for toxicology testing and clinical trials. In-use testing and stability studies have been performed on the formulated drug product, and Good Laboratory Practice (GLP) toxicology studies in adult rats have been completed to assess its safety. The team is organizing relevant regulatory documentation to compile an Investigational New Drug (IND) application, including the clinical protocol and operations plans for the trial planned for the NIH Clinical Center. Bioanalytical methods development for clinical sample analysis is underway, and a GLP toxicology study in juvenile animals is being conducted to support eventual trials in pediatric patients. Orphan Drug and Rare Pediatric Disease Designations were granted by the FDA for PTH-IA and JMC, and a natural history study in JMC patients is ongoing at the NIH Clinical Center.