Clinical Unmet Needs in Hypoparathyroidism and Current Pipeline Agents

Abstract Hypoparathyroidism is a disease characterized by inadequate or absent parathyroid hormone (PTH) levels. It manifests with hypocalcemia, hyperphosphatemia, and elevated urinary fractional excretion of calcium. The conventional therapy with calcium supplementation and active vitamin D analogs is limited by the pill burden, unstable calcium concentrations, and significant renal and bone complications. Hence, the development of replacement therapies utilizing PTH or PTH-related receptor modulators has emerged as a promising therapeutic avenue. rhPTH (1-84) (NATPARA®) is a once-daily injection of full-length recombinant human parathyroid hormone that was initially approved by the U.S. Food and Drug Administration(FDA) in 2015 for hypoparathyroidism. However, it was recalled from the U.S. market in 2019, and its production will cease globally by the end of 2024. TransCon™ PTH, known as palopegteriparatide, utilizes an innovative technology to provide a sustained release of PTH (1-34) prodrug. It has received approval from the European Medicines Agency and is currently undergoing FDA review. Eneboparatide is a PTH receptor 1 agonist, designed to stimulate a specific receptor configuration.Encaleret is a negative allosteric modulator of the calcium-sensing receptor and rescues the secretion of naive PTH inAutosomal Dominant Hypocalcemia type 1. MBX 2109 is an investigational once-weekly PTH prodrug that addresses thefrequent administration challenge. EB612, the tablet form of PTH(1-34), is the first oral hormone replacement treatment for hypoparathyroidism. Recent developments in the management of chronic hypoparathyroidism hold promise as a therapeutic approach to restore physiological function, manage symptoms, and prevent associated complications. Cite this article as: Cetin E, Pedersen B, Furkan Burak M. Clinical unmet needs in hypoparathyroidism and current pipeline agents. Endocrinol Res Pract. 2024;28(4): 240-246.