Pharmacodynamics of sustained levels of PTH following palopegteriparatide treatment in adults with hypoparathyroidism.

Purpose: Palopegteriparatide is a prodrug of parathyroid hormone (PTH) (1-34), administered once daily. It is designed to provide active PTH within the physiologic range for 24 hours/day. The effects of palopegteriparatide on serum and urine markers were explored to determine if the pharmacodynamic profile of palopegteriparatide reflects continuous disease control in adults with hypoparathyroidism. Methods: A 24-hour sub-study was conducted during the PaTH Forward trial. Eligible participants were those who completed the Week 58 visit and received stable doses of palopegteriparatide for the prior week. Upon admission to the clinical research unit, participants received their usual dose of palopegteriparatide. Plasma PTH, serum calcium (albumin-adjusted), and serum phosphate concentrations were evaluated at 4-hour intervals. Urinary calcium, phosphate, and citrate concentrations were determined from each of six 4-hour collection periods. Descriptive statistics were performed. Results: Palopegteriparatide doses ranged from 12 to 33 µg/day and resulted in continuous exposure to active PTH within the estimated normal range over 24 hours. Mean serum calcium and serum phosphate were maintained near or within the normal ranges. Median urine calcium concentration was stable in the normal range for all 4-hour collection periods. Urine phosphate concentrations showed minor variability across collection intervals, and urine citrate was maintained above the lower limit of normal. Conclusion: Palopegteriparatide provided continuous exposure to active PTH within the physiological range. The expected pharmacodynamic effects of continuous PTH exposure on serum and urine chemistries were consistent with the efficacy and safety of palopegteriparatide demonstrated in the published PaTH Forward and PaTHway clinical trials.