The impact of parathyroid hormone replacement with palopegteriparatide on synthesis of 1,25-dihydroxy vitamin D in hypoparathyroidism.

Abstract

Introduction: Parathyroid hormone (PTH) is the primary regulator of calcium and phosphate balance via direct action on the kidneys and bones and indirect action on the intestine. Hypoparathyroidism is caused by insufficient levels of PTH, leading to 1,25-dihydroxy vitamin D (1,25[OH]₂D) deficiency. PTH-induced 1,25(OH)₂D production is a highly regulated process essential for physiological functions that is reduced or absent in hypoparathyroidism.

Areas covered: Physiological synthesis of 1,25(OH)₂D requires 25-hydroxy vitamin D (25[OH]D) 1-α-hydroxylation via the renal CYP27B1 enzyme. Enzyme activity is dependent on CYP27B1 transcription, which is induced by specific PTH-1 receptor (PTH1R) activation that results in endosomal-derived intracellular cyclic adenosine monophosphate formation. Palopegteriparatide, a prodrug of PTH(1-34) used as replacement therapy in hypoparathyroidism, is designed to provide active PTH that exerts its physiological effect through the same affinity and binding to receptors as endogenous PTH. Throughout 3.5 years in the phase 3 PaTHway trial, 25(OH)D and 1,25(OH)₂D levels were maintained within normal limits as a result of restoring endogenous production of 1,25(OH)₂D and physiological signaling with palopegteriparatide treatment, thereby facilitating independence from active vitamin D.

Expert opinion: 1,25(OH)₂D production can be compromised by even small changes to PTH that bias the physiological interaction between PTH and PTH1R. Thus, ensuring formation of 1,25(OH)₂D should be a key outcome of interest in drug development of PTH replacement therapies. Data from clinical trials demonstrate active PTH released from palopegteriparatide interacts with PTH1R to ensure adequate 1,25(OH)₂D synthesis, enabling independence from active vitamin D analogues, and confirms its position as a PTH replacement therapy.