Emerging Therapies in Hypoparathyroidism and Renal Outcomes of PTH Replacement

Dr. Lubitz explains that eneboparatide is distinct from palopegteriparatide in its mechanism of prolonged action. Rather than relying on a prodrug approach to extend half-life, eneboparatide is a synthetically designed 36-amino acid PTH/PTHrP hybrid peptide engineered to have exceptionally high affinity for the R0 conformation of the PTH-1 receptor. This enables prolonged intracellular signaling well beyond its short plasma half-life, allowing for once-daily subcutaneous administration. It received FDA fast track designation in 2024 and is currently in phase 3. Phase 2 open-label data showed 88% of patients were free of conventional therapy at three months. Early blinded phase 3 data showed 31.1% of the treatment group achieved independence from conventional therapy versus 5.9% on placebo. The safety profile was consistent with other PTH replacement therapies, including injection site reactions, and expected hypercalcemia and hypocalcemia events.

Dr. Shoback then compares renal outcomes across trials. In the Pathway phase 3 trial of palopegteriparatide (two-year data), 80–90% of patients achieved calcium targets, 97% were independent of conventional therapy, eGFR increased on average by approximately 9 mL/min/1.73 m²—with those entering with a GFR below 60 gaining nearly 14 mL/min—and urinary calcium declined by more than 50% and was sustained throughout. For eneboparatide in its shorter-term phase 2 study, urinary calcium reductions were dramatic and rapid (over 50%), and eGFR improved by approximately 6 mL/min, with those with reduced baseline GFR gaining approximately 11 mL/min. Dr. Shoback characterizes these consistent renal improvements across both agents as a highly important clinical finding for this rare disease.

In the next episode, "Multisystem Complications: Guiding Treatment Selection in Hypoparathyroidism," Dr. Khosravi explains how the severity and breadth of multisystem complications—from basal ganglia calcifications to cardiovascular effects and quality of life—guide the decision to transition from conventional therapy to PTH replacement.