TransCon PTH as a Hormone Replacement Therapy for Patients with Hypoparathyroidism: 6-Month Update from the PaTH Forward Open-Label Extension

Background: Hypoparathyroidism (HP) is characterized by insufficient levels of parathyroid hormone (PTH), resulting in hypocalcemia, hyperphosphatemia, hypercalciuria, and a reduced quality of life (QoL). PTH replacement therapy should restore physiologic levels of PTH and restore downstream physiologic levels of calcitriol, promoting independence from Ca and active vitamin D supplements and normalization of QoL. TransCon PTH is an investigational long-acting prodrug of PTH(1–34) for the treatment of HP. During the initial 4-week fixed-dose period of the PaTH Forward Trial, TransCon PTH enabled 82% of subjects to achieve independence from standard of care (SoC; no active vitamin D and Ca ≤ 500 mg/day) compared to 15% with placebo. Here, we report 6-month (Week 26) results from the open-label extension (OLE). Methods: PaTH Forward is a phase 2, double-blind, placebo-controlled trial evaluating TransCon PTH in adult HP patients treated with SoC. Subjects received fixed doses of TransCon PTH 15, 18, or 21 µg PTH(1–34)/day or placebo for 4 weeks, followed by an OLE period during which TransCon PTH dose was titrated (6–30 µg PTH[1–34]/day) per individual dosing requirement. Safety and efficacy endpoints were evaluated at predefined timepoints over the OLE. Endpoints were evaluated at Week 26 including 1) sCa, 2) 24-hour uCa, 3) independence from active vitamin D, and 4) independence from therapeutics doses of oral calcium. QoL was assessed by the SF-36 and the Hypoparathyroidism Patient Experience Scales (HPES). Results: All 59 subjects completed the initial 4-week period and continued in the OLE; 58 subjects continue in the OLE beyond 6 months (1 withdrew unrelated to safety or efficacy). TransCon PTH enabled independence from SoC (no active vitamin D and Ca ≤ 500 mg/day) in 91% of subjects and independence from all supplements (no active vitamin D and no Ca) in 76% of subjects by Week 26. Mean 24-hour uCa decreased from a baseline mean of 415 mg/24h to 178 mg/24h by Week 26 (n = 44) while maintaining sCa, and reducing sP and CaxP to fall within the normal range. The mean scores for all SF-36 summary and domains increased from below normal at baseline to within the normal range by Week 26. The HPES Symptom and Impact scores continuously improved through 26 weeks for TransCon PTH and placebo subjects switching to TransCon PTH. TransCon PTH continued to be well-tolerated with no treatment-related serious or severe adverse events. Conclusions: Results from the OLE of the PaTH Forward Trial demonstrated that TransCon PTH continued to enable independence from active vitamin D and Ca supplements for most subjects while maintaining normal sCa, sP, uCa, and demonstrating enhanced quality of life, supporting its potential as a hormone replacement therapy for patients with HP. TransCon PTH will be further evaluated in the phase 3 PaTHway Trial.