PCO-371: A Comprehensive Review of an Investigational Oral PTHR1 Agonist

1. Introduction to PCO-371

1.1. Overview and Rationale for Development

PCO-371 (also known as PCO371 or PC-0371) is an orally bioavailable, non-peptide small molecule that was developed as an agonist for the parathyroid hormone receptor type 1 (PTHR1).[1] The primary therapeutic motivation behind its development was to address disorders related to parathyroid hormone (PTH) function, with a particular focus on hypoparathyroidism. Hypoparathyroidism is a rare endocrine condition characterized by deficient endogenous PTH production, leading to hypocalcemia, hyperphosphatemia, and a range of associated symptoms and complications.[2] Conventional management of hypoparathyroidism typically involves supplementation with calcium and active vitamin D analogues, which can be challenging to optimize and may lead to long-term complications such as hypercalciuria, nephrocalcinosis, and renal insufficiency.[7] While PTH peptide analogues (e.g., teriparatide, abaloparatide, palopegteriparatide) offer hormone replacement, they necessitate parenteral administration, which can be burdensome for patients requiring chronic therapy.[6] PCO-371 was therefore conceived as an orally administered agent that could potentially overcome the limitations of both conventional supplementation and injectable PTH therapies by providing a more convenient and physiological means of PTHR1 activation.[2]