Efficacy and Safety of Upacicalcet in Hemodialysis Patients with Secondary Hyperparathyroidism

Abstract

Key Points These 2 phase 3 trials assessed upacicalcet, an intravenous calcimimetic, in hemodialysis patients with secondary hyperparathyroidism. ≥30% reduction in intact parathyroid hormone levels occurred in 42% (Parathyroid Hormone [PTH] Attenuation Trial in Hemodialysis-1) and 44% (Parathyroid Hormone [PTH] Attenuation Trial in Hemodialysis-2) with upacicalcet versus 17% and 17%, respectively, with placebo (strata-adjusted; both P < 0.001). Asymptomatic hypocalcemia was more frequent with upacicalcet, and symptomatic hypocalcemia was infrequent; gastrointestinal events were similar to placebo. Background Secondary hyperparathyroidism is a common complication in patients with CKD undergoing hemodialysis. We examined the efficacy and safety of upacicalcet, an intravenous calcimimetic, versus placebo on serum intact parathyroid hormone (iPTH) levels in patients receiving hemodialysis. Methods Parathyroid Hormone (PTH) Attenuation Trial in Hemodialysis (PATH)-1 and PATH-2 were identical, randomized, phase 3, double-blind, placebo-controlled trials conducted in parallel in 768 patients receiving hemodialysis with secondary hyperparathyroidism and serum iPTH levels ≥400 to ≤1500 pg/ml. Participants received intravenous upacicalcet ( n =510) or placebo ( n =258) after hemodialysis for 27 weeks; dosing was titrated using iPTH and corrected serum calcium. Calcium supplementation or changes in active vitamin D sterols for corrected serum calcium <8.3 mg/dl without hypocalcemia symptoms were restricted. The primary outcome was the proportion of participants achieving ≥30% decrease from baseline in mean iPTH during the efficacy assessment period, weeks 22–27. Results The strata-adjusted proportions of participants achieving the primary outcome were significantly higher with upacicalcet versus placebo: in PATH-1, 42.1% versus 16.8%, for a difference in proportions of 25.3% (95% confidence interval, 16.2 to 34.5, P < 0.001); in PATH-2, 43.5% versus 17.4%, for a difference in proportions of 26.1% (95% confidence interval, 17.4 to 34.8, P < 0.001). Serious adverse events were similar between upacicalcet and placebo (PATH-1, 26% versus 24%; PATH-2, 23% versus 22%). Rates of gastrointestinal symptoms were similar between treatment groups. Corrected calcium <7.5 mg/dl occurred in 31% versus 12% in PATH-1 and 45% versus 19% in PATH-2; dose interruptions occurred in 44% versus 24% and 52% versus 27%, respectively. Investigator-attributed symptomatic hypocalcemia was reported in 0.8% and 2% of upacicalcet-treated participants, respectively, and in no placebo patients. Conclusions In 2 phase 3 trials, upacicalcet significantly reduced iPTH versus placebo. Asymptomatic hypocalcemia and dose interruptions were more frequent in patients receiving upacicalcet, while symptomatic hypocalcemia was infrequent and gastrointestinal adverse event rates were similar to placebo. Clinical Trial registry name and registration number: PATH-1 NCT05832931 and PATH-2 NCT05836220.