Repurposing a novel parathyroid hormone (PTH) analog to treat hypoparathyroidism

Background and Purpose Human parathyroid hormone (PTH) is critical for maintaining physiologic calcium homeostasis, and plays an important role in the formation and maintenance of 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 asset was then repurposed as an improved therapy for hypoparathyroidism. Experimental Approach To create a longer-acting form of PTH, changes were introduced to the peptide to increase cell surface residence time of the bound ligand to its receptor. In vitro screening identified a candidate, which was tested in an animal model of osteoporosis prior to entering human trials. The candidate was subsequently tested in two independent animal models of hypoparathyroidism. Key Results A peptide was identified, termed LY627-2K, with 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 recapitulated. These observations prompted us to explore a second indication, hypoparathyroidism. In animal models of this disease, LY627-2K restored serum calcium, comparing favorably 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 the rationale for repurposing and continued development, pivoting from a common indication, osteoporosis, to a rare disease, hypoparathyroidism, by exploiting a shared molecular target.