Phase 2 study of upacicalcet in Japanese haemodialysis patients with secondary hyperparathyroidism: an intraindividual dose-adjustment study.

Background: Upacicalcet is a novel small-molecule calcimimetic agent developed for intravenous injection. Here, we evaluated the long-term efficacy and safety of upacicalcet treatment via intraindividual dose adjustment in haemodialysis patients with secondary hyperparathyroidism (SHPT). Methods: A phase 2, multicentre, open-label, single-arm study was conducted. Upacicalcet was administered for 52 weeks; the starting dose was 50 µg thrice a week, and then adjusted to 25, 50, 100, 150, 200, 250, or 300 µg, according to the dose-adjustment method set in the protocol. The primary endpoint was the percentage of patients with serum intact parathyroid hormone (iPTH) level achieving a target range of 60-240 pg/mL (target achievement rate) at week 18. Results: A total of 58 patients were administered upacicalcet. The target achievement rate of serum iPTH level at week 18 was 57.9%, which increased to 80.8% at week 52. The serum-corrected calcium (cCa) level decreased immediately after upacicalcet administration, but no further decrease was observed. Adverse events were observed in 94.8% of patients, and adverse drug reactions (ADRs) occurred in 20.7% of patients. The most common ADR was decreased adjusted calcium in eight patients; dizziness occurred as a serious ADR in one patient. The serum cCa level of patients who interrupted upacicalcet treatment at a serum cCa level of <7.5 mg/dL recovered to ≥7.5 mg/dL immediately after the interruption. Conclusions: In haemodialysis patients with SHPT, upacicalcet doses of 25-300 µg for 52 weeks were found to be highly effective and well-tolerated, with minor safety concerns.

Pharmacological profile of upacicalcet, a novel positive allosteric modulator of calcium-sensing receptor, in vitro and in vivo.

Upacicalcet (formerly SK-1403/AJT240) is a novel non-peptide calcimimetic agent that acts as a calcium-sensing receptor (CaSR) agonist for the treatment of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). We compared upacicalcet with other calcimimetics (etelcalcetide or cinacalcet) and examined its in vitro and in vivo characteristics in terms of its human CaSR agonistic activity, its efficacy in normal and CKD rats after a single administration, and its effect on gastric emptying in rats. Upacicalcet activated human CaSR depending on the extracellular calcium (Ca2+) concentration without exhibiting an agonistic action when the extracellular Ca2+ level was below the physiological level. On the other hand, etelcalcetide had an agonistic activity even in the absence of physiological levels of extracellular Ca2+. The intravenous administration of upacicalcet to normal and double-nephrectomized rats dose-dependently (0.03-3mg/kg and 0.3-30mg/kg, respectively) decreased the serum intact parathyroid hormone (iPTH) and serum Ca2+ levels; however, the effect of upacicalcet on the reduction in serum Ca2+ disappeared at extracellular Ca2+ levels below the physiologically range, even when administered at a dose higher (100-fold) than the effective dose. Furthermore, upacicalcet did not affect gastric emptying in normal rats when administered up to a dose of 10mg/kg (300-fold higher than the dose affecting serum iPTH levels), while the administration of cinacalcet significantly slowed gastric emptying by approximately 50%. These findings suggest that upacicalcet has potential as an alternative calcimimetic agent with good pharmacological properties and a lower risk of hypocalcemia and gastrointestinal complications.

Upacicalcet, a positive allosteric modulator of the calcium-sensing receptor, prevents vascular calcification and bone disorder in a rat adenine-induced secondary hyperparathyroidism model.

Secondary hyperparathyroidism (SHPT) is a major comorbidity of chronic kidney disease (CKD). Chronic elevation of PTH levels is associated with cortical bone deterioration and increase in the risk of fractures in CKD patients. Here, we evaluated the effect of repeated administration of upacicalcet, a novel positive allosteric modulator of the calcium-sensing receptor, in a rat model of adenine-induced renal failure, by determining serum levels of intact PTH (iPTH), calcium, phosphorus, creatinine, and urea nitrogen. Furthermore, parathyroid hyperplasia (parathyroid gland weight and Ki-67-positive cell density), ectopic calcification (calcium content in the thoracic aorta, kidney and heart and positive von Kossa staining in the thoracic aorta), and bone morphometry parameters (cortical porosity and fibrosis volume) were evaluated. Rats treated with either 0.2 mg/kg or 1 mg/kg upacicalcet exhibited significantly lower serum iPTH levels than CKD-control rats, as early as 7 days after the first dose. Repeated administration of upacicalcet reduced serum iPTH levels and inhibited parathyroid hyperplasia in rats with adenine-induced severe renal failure. Moreover, it suppressed ectopic calcification and cortical pore formation. In contrast, serum calcium and phosphorus levels were not significantly affected, suggesting a low risk of hypocalcemia, which often occurs with SHPT treatment. In conclusion, repeated administration of upacicalcet decreased serum iPTH levels and suppressed parathyroid hyperplasia in the adenine-induced CKD rat model of SHPT. Furthermore, ectopic calcification and cortical pore formation were suppressed without significant changes in blood mineral parameters. Upacicalcet safely inhibited the progression of SHPT in an adenine-induced CKD rat model.