Hypoparathyroidism is a complex endocrine disorder characterized by deficiency of parathyroid hormone (PTH) and calcitriol and resulting in abnormal calcium and phosphate homeostasis, neuromuscular symptoms, and impaired health-related quality of life. Conventional therapy of hypoparathyroidism includes oral calcitriol (or its analogue alfacalcidol)—because its endogenous production is insufficient in the face of PTH deficiency—and oral calcium. This approach does not mimic normal physiology and has inherent limitations, i.e. increased risk of nephrolithiasis, nephrocalcinosis, and chronic kidney disease, failure of restoration of normal bone turnover and improvement in quality of life.
In 2015, the US Food and Drug Administration approved the once-daily subcutaneous (SC) administration of recombinant human rhPTH (1-84) (Natpar®) as an adjunctive treatment for adult patients with chronic hypoparathyroidism who cannot be adequately controlled with active vitamin D and calcium supplements. However, in October 2022 termination of production of the substance with availability only until the end of 2024 owing to unsolvable problems during production was announced; see https://www.takeda.com/en-us/newsroom/statements/2022/takeda-to-discontinue-manufacturing-of-natpar-natpara for further details.
A new substance to treat chronic hypoparathyroidism was developed recently and the 26-week results from the phase-3 PaTHway trial were published in 2023 and recently reported in national and international congresses. The double-blind, placebo-controlled, 26-week, phase-3 PaTHway trial assessed the efficacy and safety of PTH replacement therapy for hypoparathyroidism patients with the investigational drug TransCon PTH® (palopegteriparatide). TransCon PTH® consists of a parent drug, PTH(1‐34), transiently conjugated to a methoxypolyethylene glycol (mPEG) carrier through a linker. It is administered as an once‐daily SC injection designed to provide stable PTH levels within the normal physiological range over 24 h/d. PTH replacement therapy with TransCon PTH® robustly improved and maintained mean serum calcium levels in the normal range at all study visits, while allowing independence from conventional therapy. TransCon PTH® treatment was well-tolerated, normalized the mean 24-hour urine calcium excretion, and led to improvements in health-related quality of life (HRQoL) and hypoparathyroidism-related symptoms, functioning, and well-being. These promising results are particularly important for patients not adequately controlled under conventional therapy and currently treated with rhPTH (1-84) (Natpar®).