Discussion
hypoparathyroidism, normocalcemia, hypercalcemia, PaTHway, hypocalcemia
DISEASE, HYPOPARATHYROIDISM, HYPERCALCEMIA, SECONDARY, ADVERSE EVENT, HYPOCALCEMIA
In this randomized trial of women and men with chronic hypoparathyroidism, 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. Treatment with TransCon PTH additionally resulted in significant improvement in physical functioning and well‐being, as well as potential longer‐term benefits evident in the normalization of urinary calcium excretion. TransCon PTH treatment was safe and well‐tolerated, with no participants discontinuing therapy because of a related adverse event. Unique to this trial was the ability to titrate the dose of TransCon PTH offering an individualized approach to improve treatment outcomes.Significantly more participants treated with TransCon PTH (79%, In the phase 2 PaTH Forward trial, TransCon PTH was associated with normalization of renal absorption of filtered calcium from baseline (415 mg/24 h) to week 26 (178 mg/24 h).Individuals with hypoparathyroidism often experience physical and cognitive symptoms that impact multiple dimensions of health and well‐being that persist despite conventional therapy and improvements in serum calcium.TransCon PTH was well‐tolerated with a safety profile as expected. Most AEs were mild or moderate in severity and no TRAEs led to withdrawal from the trial. There was a numerically greater incidence of hypercalcemia with TransCon PTH within the first 3 months of treatment and a consistently greater incidence of hypocalcemia with placebo throughout the trial. The majority of participants (57 of 61) receiving TransCon PTH remained on a stable dose of study drug for a minimum of 4 weeks before assessment of the primary endpoint, supporting a durable treatment effect.Potential limitations of this trial merit consideration. Real‐time measurement of serum calcium was not available, and therefore, symptoms suggestive of calcium abnormalities could not be universally confirmed with laboratory studies before treatment with PRN conventional therapy. Participants and investigators were blinded to the allocation of study drug but were aware of calcium and active vitamin D doses for safety reasons. The substantial reduction in conventional therapy in participants treated with TransCon PTH has the potential for a degree of functional unblinding and may have contributed to changes in patient‐reported outcomes. Evaluation of long‐term effects of treatment and event‐driven evaluation of end‐organ outcomes were limited by trial duration, though data from the ongoing open‐label extensions of the PaTH Forward and PaTHway trials will permit further assessment.The participant population of the PaTHway trial is consistent with previous clinical trials in hypoparathyroidism and representative of previously reported cohorts of this disease, supporting the generalizability of these results to the broader population of adults with chronic hypoparathyroidism.The PaTHway trial met all primary and key secondary endpoints with statistically significant differences from placebo. In this randomized trial of adults with hypoparathyroidism dependent on conventional therapy, the ability to maintain normocalcemia while gaining independence from active vitamin D and elemental calcium (>600 mg/d) was significantly greater among the participants who received TransCon PTH compared with those receiving placebo. TransCon PTH treatment was well‐tolerated, normalized mean 24‐hour urine calcium excretion, and led to improvements in HRQoL and hypoparathyroidism‐related symptoms, functioning, and well‐being. The results of the PaTHway trial both confirm and extend findings from initial reports of the efficacy of treatment with TransCon PTH in restoring physiological functions of PTH in individuals with chronic hypoparathyroidism.