Development of a PTH Receptor Inverse Agonist (PTH-IA) as a new investigational drug for treatment of patients with Jansen Metaphyseal Chondrodysplasia (JMC)

Authors

• R Stan
• RM Lomash
• A Khatri
• T Gardella
• H Jueppner
• S Jha
• MT Collins
• EA Ottinger

Abstract

Jansen Metaphyseal Chondrodysplasia (JMC) is a rare disease of skeletal development and mineral ion balance caused by heterozygous, autosomal-dominant activating mutations in the Parathyroid Hormone Receptor Type 1 (PTHR1). PTH-IA, an inverse agonist at the PTHR1, was tested in a mouse model of JMC and found to significantly improve bone histology, limb length, and bone turnover, without evidence of side effects, supporting the hypothesis that PTH-IA could be developed as a therapy for JMC.
Scientists within NCATS Therapeutic Development Branch initiated the preclinical development in collaboration with Massachusetts General Hospital, NIDDK, and NIDCR to advance the PTH-IA candidate to clinical evaluation. The preclinical team standardized a process to manufacture GMP grade PTH-IA drug substance and assessed its safety in a GLP toxicology study. A clinical formulation of PTH-IA has been developed and its potency and stability have been verified. All study results and clinical development plans were reviewed by the FDA as part of an Investigational New Drug application, and the project has been deemed as “safe to proceed.” Preparations for clinical trials are ongoing, with the first-in-human study starting in 2024 at the NIH Clinical Center. PTH-IA has received the Orphan Drug Designation and qualifies as a drug for Rare Pediatric Disease. Information gained from an active natural history study of parathyroid-hormone related disorders will further inform the PTH-IA clinical trial.
Here we share how a collaborative ecosystem between a patient advocacy group (The Jansen’s Foundation), academic researchers, drug developers and clinicians can help move such a program forward.

Scientific Focus Area: Clinical Research

This page was last updated on Tuesday, August 6, 2024