Palopegteriparatide in Adults With Hypoparathyroidism: 3.5-Year Results From the Phase 3 PaTHway Trial

CONTEXT: Palopegteriparatide offers a parathyroid hormone (PTH) replacement option that addresses the multiorgan consequences of hypoparathyroidism. OBJECTIVE: Evaluate the long-term safety and efficacy of palopegteriparatide in adults with hypoparathyroidism. DESIGN: Phase 3 trial with a 26-week, randomized, double-blind, placebo-controlled period followed by a 156-week, open-label extension (OLE). SETTING: Twenty-one North American and European sites. PARTICIPANTS: Eighty-two adults with hypoparathyroidism were randomized and received study drug and 73 completed Week 182. INTERVENTION(S): Palopegteriparatide initiated at 18 µg/day (or corresponding volume of placebo) with progressive titration for 26 weeks, followed by a 156-week OLE period during which all received titrated palopegteriparatide treatment. MAIN OUTCOME MEASURE(S): Efficacy assessments included independence from conventional therapy (≤600 mg/day of elemental calcium and no active vitamin D) and maintenance of normocalcemia (8.3 to 10.6 mg/dL [2.07 to 2.64 mmol/L]). Renal endpoints, skeletal measures, and patient-reported outcomes were monitored at prespecified intervals. Safety assessments included adverse events (AEs) and laboratory monitoring. RESULTS: At Week 182, 96% of participants (70/73) were independent from therapeutic doses of calcium, 100% (73/73) were independent from active vitamin D, and 89% (65/73) were normocalcemic. Mean bone turnover marker values increased from and stabilized above baseline values. Mean bone mineral density (BMD) Z-scores trended towards age- and sex-matched norms, remaining above zero. Early normalization of mean 24-hour urine calcium excretion, gains in mean estimated glomerular filtration rate (eGFR), and improvement in patient-reported outcomes were preserved through Week 182. Most AEs were mild-to-moderate. CONCLUSION: Palopegteriparatide demonstrated durable safety and efficacy as a PTH replacement therapy in adults with hypoparathyroidism over 3.5 years.