Repurposing a novel parathyroid hormone analogue to treat hypoparathyroidism.

Therapeutic Approaches

Abstract

BACKGROUND AND PURPOSE: Human parathyroid hormone (PTH) is critical for maintaining physiological calcium homeostasis and plays an important role in the formation and maintenance of the bone. Full-length PTH and a truncated peptide form are approved for treatment of hypoparathyroidism and osteoporosis respectively. Our initial goal was to develop an improved PTH therapy for osteoporosis, but clinical development was halted. The novel compound was then repurposed as an improved therapy for hypoparathyroidism. EXPERIMENTAL APPROACH: A longer-acting form of PTH was synthesised by altering the peptide to increase cell surface residence time of the bound ligand to its receptor. In vitro screening identified a compound, which was tested in an animal model of osteoporosis before entering human trials. This compound was subsequently tested in two independent animal models of hypoparathyroidism. KEY RESULTS: The peptide identified, LY627-2K, exhibited delayed internalization kinetics. In an ovariectomy-induced bone loss rat model, LY627-2K demonstrated improved vertebral bone mineral density and biomechanical properties at skeletal sites and a modest increase in serum calcium. In a Phase I clinical study, dose-dependent increases in serum calcium were reproduced. These observations prompted us to explore a second indication, hypoparathyroidism. In animal models of this disease, LY627-2K restored serum calcium, comparing favourably to treatment with wild-type PTH. CONCLUSIONS AND IMPLICATIONS: We summarize the repositioning of a therapeutic candidate with substantial preclinical and clinical data. Our results support its repurposing and continued development, from a common indication (osteoporosis) to a rare disease (hypoparathyroidism) by exploiting a shared molecular target.

Authors

Krishnan, Venkatesh; Ma, Yanfei L; Chen, Catherine; Thorne, Natasha; Bullock, Heather; Tawa, Gregory; Javella-Cauley, Christy; Chu, Shaoyou; Li, Weiming; Kohn, Wayne; Adrian, Mary D; Benson, Charles; Liu, Lifei; Sato, Masahiko; Zheng, Wei; Pilon, Andre; Yang, Nora; Bryant, Henry U;

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