Navigating Hypoparathyroidism: Understanding the Multisystem Burden and Optimizing Patient Care - Episode 11
Palopegteriparatide in Hypoparathyroidism: Mechanism, Long-Term Efficacy, and Clinical Experience
In this episode, Dr. Cusano asks Dr. Sara Lubitz to explain the mechanism of action and administration of palopegteriparatide, then turns to Dr. Dolores Shoback for a review of long-term clinical trial data and patient-reported outcomes.
Dr. Lubitz explains that palopegteriparatide is a prodrug consisting of three components: PTH 1–34 as the parent drug, an inert carrier, and a TransCon linker that auto-cleaves under physiologic pH and temperature to release PTH 1–34, which then binds to the PTH-1 receptor. This mechanism results in an apparent half-life of approximately 60 hours, enabling once-daily subcutaneous injection via a pre-filled multi-dose pen.
Dr. Shoback reviews four-year data from the Path Forward phase 2 study, presented at the Joint Congress of the European Society for Pediatric Endocrinology and European Society of Endocrinology in 2025. At four years, over 90% of patients were independent of conventional therapy and 98% had normal serum calcium. Bone density T and Z scores declined from their elevated baseline toward normal values, and bone turnover markers normalized over time. Estimated GFR rose on average by 7.5 mL/min/1.73 m²—a statistically and clinically significant improvement. No new or worsening safety signals were identified.
On patient-reported outcomes, SF-36 scores moved from below the US population average into the normal range within weeks of initiating therapy and remained there throughout the four years. Scores on the hypoparathyroidism-specific HPES improved early and were sustained. Notably, patients with the greatest symptom burden at baseline showed the largest quality-of-life gains—which Dr. Shoback describes as particularly encouraging news for the most affected patients. She reports that her own clinical experience with palopegteriparatide has been uniformly excellent: patients who had carried a heavy symptom burden were able to dramatically reduce their medication load and report substantially improved day-to-day functioning.
In the next episode, "Emerging Therapies in Hypoparathyroidism and Renal Outcomes of PTH Replacement," Dr. Lubitz introduces eneboparatide and its unique mechanism of action, and Dr. Shoback compares the renal outcomes—including eGFR improvements and urinary calcium reductions—seen across both PTH replacement therapies in clinical trials.
