Repurposing a novel parathyroid hormone analogue to treat hypoparathyroidism

Abstract

BACKGROUND AND PURPOSEHuman 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 APPROACHA 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 RESULTSThe 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 IMPLICATIONSWe 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.

Design and Preclinical Development of TransCon PTH, an Investigational Sustained-Release PTH Replacement Therapy for Hypoparathyroidism

“…(18,19) Similarly, a PTH(1-34) peptide backbone with specific amino acid substitutions coupled to a 2 kDa PEG increased sCa to levels comparable to sham controls in a 2-week study in TPTx rats. (20) increase in sCa levels 6 and/or 10 hours after administration, neither compound demonstrated sustained sCa levels within the normal range/comparable to sham controls throughout the entire dosing interval as was found in TPTx animals dosed with TransCon PTH. An additional compound, a PEGylated PTH(1-34) fragment, has also demonstrated promising sustained effects on systemic calcium and phosphate levels beyond 24 hours after a single i.v.…”

“…Two 4‐week studies in TPTx rats, one testing an orally administered small‐molecule PTH1R agonist and the other a long‐acting PTH molecule (LA‐PTH) administered s.c., have reported the ability to restore sCa levels and lower sP . Similarly, a PTH(1–34) peptide backbone with specific amino acid substitutions coupled to a 2 kDa PEG increased sCa to levels comparable to sham controls in a 2‐week study in TPTx rats . However, despite the observed increase in sCa levels 6 and/or 10 hours after administration, neither compound demonstrated sustained sCa levels within the normal range/comparable to sham controls throughout the entire dosing interval as was found in TPTx animals dosed with TransCon PTH.…”

Study on Rapid Intraoperative Parathyroid Hormone to Identify and Protect Parathyroid Gland during Total Thyroidectomy

“…PTH is a linear peptide with 84 amino acids secreted by the host cells of parathyroid gland, and its biological activity is determined by the 1-27 amino acid residues at the n-terminal. Its half-life was about 5min in plasma, and it was mainly inactivated in kidney [12] . Its main function is to regulate the metabolism of calcium and phosphorus in the body.…”

Repositioning an Immunomodulatory Drug Vidofludimus as a Farnesoid X Receptor Modulator With Therapeutic Effects on NAFLD

“…Repositioning of drugs through identification of their potentials for functionally interacting with unintended targets, offers an increasing productivity than traditional drug development (Hu et al, 2014;Wang et al, 2014;Bao et al, 2016;Krishnan et al, 2018). This strategy can not only improve the optimization of current drugs, but also lead to new therapeutic switching.…”