Efficacy and Safety of Parathyroid Hormone Replacement With TransCon PTH in Hypoparathyroidism: 26-Week Results From the Phase 3 PaTHway Trial

Abstract

Conventional therapy for hypoparathyroidism consisting of active vitamin D and calcium aims to alleviate hypocalcemia but fails to restore normal parathyroid hormone (PTH) physiology. PTH replacement therapy is the ideal physiologic treatment for hypoparathyroidism. The double-blind, placebo-controlled, 26-week, phase 3 PaTHway trial assessed the efficacy and safety of PTH replacement therapy for hypoparathyroidism individuals with the investigational drug TransCon PTH (palopegteriparatide). Participants (n = 84) were randomized 3:1 to once-daily TransCon PTH (initially 18 μg/d) or placebo, both co-administered with conventional therapy. The study drug and conventional therapy were titrated according to a dosing algorithm guided by serum calcium. The composite primary efficacy endpoint was the proportion of participants at week 26 who achieved normal albumin-adjusted serum calcium levels (8.3-10.6 mg/dL), independence from conventional therapy (requiring no active vitamin D and ≤600 mg/d of calcium), and no increase in study drug over 4 weeks before week 26. Other outcomes of interest included health-related quality of life measured by the 36-Item Short Form Survey (SF-36), hypoparathyroidism-related symptoms, functioning, and well-being measured by the Hypoparathyroidism Patient Experience Scale (HPES), and urinary calcium excretion. At week 26, 79% (48/61) of participants treated with TransCon PTH versus 5% (1/21) wiplacebo met the composite primary efficacy endpoint (p < 0.0001). TransCon PTH treatment demonstrated a significant improvement in all key secondary endpoint HPES domain scores (all p < 0.01) and the SF-36 Physical Functioning subscale score (p = 0.0347) compared with placebo. Additionally, 93% (57/61) of participants treated with TransCon PTH achieved independence from conventional therapy. TransCon PTH treatment normalized mean 24-hour urine calcium. Overall, 82% (50/61) treated with TransCon PTH and 100% (21/21) wiplacebo experienced adverse events; most were mild (46%) or moderate (46%). No study drug-related withdrawals occurred. In conclusion, TransCon PTH maintained normocalcemia while permitting independence fromThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Evaluation and Management of Hypoparathyroidism Summary Statement and Guidelines from the Second International Workshop

“…TransCon PTH was safe and effective and well tolerated over 26 weeks. (109) These results support TransCon PTH as a potential hormone-replacement therapy for adults with HypoPT. (106) Open-label trials have reported improvements in QoL with both rhPTH (1-84) (72,73,110) and PTH (1-34).…”

Hyper- und Hypokalzämie: Was gibt es zu beachten?

“…Nachfolgepräparate, insbesondere das sog. TransCon PTH, befinden sich allerdings in der Vorbereitung und klinischen Prüfung [13].…”

Management of Hypoparathyroidism

“…Studies with PTH (1-84) therapy demonstrated significant improvements in QoL (49) and this was also observed with the TransCon PTH molecule which has a 60-hour half-life and is currently in phase 3 trials. (50)…”

“…No study drug-related withdrawals occurred. (86) An injectable long-acting PTH analogue (LA-PTH), a hybrid molecule with both PTH and PTHrP homology, increased serum calcium and reduced serum phosphorus in a thyroparathyroidectomized rat model of HypoPT and had prolonged effects on serum calcium in monkeys. (87,88) Phase-1 trial data with this drug, AZP-3601, has been presented.…”