Introduction: Upacicalcet is a novel injectable calcimimetic. This phase 3 multicenter open-label study aimed to assess the long-term efficacy and safety of upacicalcet in hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT). Methods: Japanese HD patients with serum intact parathyroid hormone (iPTH) levels >240 pg/mL and corrected calcium (cCa) levels >= 8.4 mg/dL were enrolled. Upacicalcet with a dose range of 25-300 mu g was administered after each dialysis for 52 weeks. The main efficacy endpoint was the percentage of patients achieving the target iPTH level (60-240 pg/mL). Results: A total of 157 patients were enrolled, of whom 138 completed the study. Overall, 94.2% of patients achieved the target serum iPTH level at week 52. Neither symptomatic hypocalcemia nor cCa level <7.5 mg/dL occurred despite the negligible increase of concomitant vitamin D receptor activators and calcium carbonate. Upacicalcet improved the control of serum phosphate (P) and calcium levels regardless of baseline PTH levels and decreased intact fibroblast growth factor-23 levels. The largest parathyroid glands shrank, irrespective of their baseline volume or prior calcimimetic usage. Upacicalcet was well tolerated, with no adverse events requiring dose reduction. Conclusion: This is the first study to show that a calcimimetic improves serum P and cCa control without inducing severe hypocalcemia in patients with iPTH levels <= 300 pg/mL. Upacicalcet is efficacious in HD patients with mild-to-severe SHPT, with few safety concerns.

ABSTRACT 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.

Background Secondary hyperparathyroidism is a major complication of patients undergoing hemodialysis (HD). Upacicalcet, a new injectable calcimimetic, acts on calcium-sensing receptors to suppress parathyroid hormone (PTH) secretion. We examined the efficacy and safety of upacicalcet in patients with secondary hyperparathyroidism receiving HD. Methods In this phase 3, double-blind, placebo-controlled study, we randomized Japanese patients undergoing HD with serum intact PTH (iPTH) concentrations >240 pg/ml and corrected calcium concentrations ≥8.4 mg/dl. Either upacicalcet or placebo was administered after each HD session for 24 weeks. The primary outcome was the percentage of participants achieving the target mean serum iPTH concentration (60–240 pg/ml) at weeks 22–24. Results A total of 103 participants received upacicalcet, and 50 participants received the placebo. The percentage of participants achieving mean serum iPTH concentrations of 60–240 pg/ml during the evaluation period was 67% (69/103) in the upacicalcet group and 8% (4/50) in the placebo group. The difference between the two groups was 59% (95% confidence interval, 48% to 71%). Upacicalcet also decreased serum fibroblast growth factor-23, bone-specific alkaline phosphatase, total type 1 procollagen-N-propeptide, and tartrate-resistant acid phosphatase-5b concentrations. Adverse events were reported in 85% (88/103) and 72% (36/50) participants in the upacicalcet and placebo groups, respectively. The incidence of upper gastrointestinal adverse events, such as nausea and vomiting, was similar between the two groups. Serum corrected calcium concentrations <7.5 mg/dl were observed in 2% of participants in the upacicalcet group and no participants in the placebo group. Conclusions Upacicalcet, a novel injectable calcimimetic, is effective and safe for secondary hyperparathyroidism patients receiving HD. Clinical Trial Registry Name and Registration Number Phase 3 Study of SK-1403, NCT03801980.

Upacicalcet is a new renally excreted and injectable calcimimetic agent. We evaluated the pharmacokinetics, pharmacodynamics, safety, and tolerability of single and multiple intravenous administration of upacicalcet in patients with secondary hyperparathyroidism undergoing hemodialysis. This study was a multicenter, randomized, placebo-controlled, double-blinded, dose-escalation study consisting of a single-dose study and a multiple-dose study. The single-dose study consisted of seven dose steps from 0.025 to 0.8 mg. For each step, six patients were randomly assigned 2:1 to receive upacicalcet or a placebo. The multiple-dose study occurred over 3 weeks in three-dose steps from 0.05 to 0.2 mg. For each step, 12 patients were randomly assigned 3:1 to receive upacicalcet or a placebo. The plasma concentration of upacicalcet increased in a dose-dependent manner and was maintained for the next dialysis. Upacicalcet was approximately 80% removed by a single dialysis and did not increase in the plasma concentration with repeated administration. Serum intact parathyroid hormone and corrected calcium (Ca2+) levels tended to decrease in response to the plasma concentration of upacicalcet. In the single-dose study, upper gastrointestinal symptoms were observed as a non-serious and mild adverse drug reaction in the groups receiving upacicalcet ≥ 0.4 mg. In the multiple-dose study, abdominal discomfort occurred in each patient in the 0.1 mg and 0.2 mg groups. Upacicalcet for patients with secondary hyperparathyroidism undergoing hemodialysis could be a calcimimetic agent that acts in a dose-dependent manner and persistently until the next dialysis session. No safety or tolerability issues specific to upacicalcet were found.

BACKGROUND AND OBJECTIVE:Upacicalcet sodium hydrate is a novel small-molecule calcimimetic and has potential as a therapeutic agent for secondary hyperparathyroidism. We assessed the pharmacokinetics, pharmacodynamics, safety, and tolerability of a single intravenous dose of upacicalcet in Japanese healthy adults.METHOD:This was a single-center, double-blinded, randomized, placebo-controlled, dose-escalation study. For each cohort, eight subjects were randomly assigned at a ratio of 3:1 to receive a single injection of placebo or upacicalcet 0.01, 0.1, 1.0, or 2.5 mg.RESULT:The plasma concentration of upacicalcet increased in a dose-dependent manner. Upacicalcet rapidly disappeared from plasma after administration. The half-life of upacicalcet was approximately 1-2 h. The major excretion route of upacicalcet was via urine. Serum intact parathyroid hormone decreased in accordance with the upacicalcet dose, from the lowest dose of 0.01 mg. Gastrointestinal disorders occurred in one patient in the 1.0 mg group and in five patients in the 2.5 mg group. All adverse events were nonserious, and no symptomatic hypocalcemia occurred.CONCLUSION:This study showed that upacicalcet acted as a calcimimetic and was excreted in the urine unchanged with little metabolism. Moreover, upacicalcet is a small molecule and has a small volume of distribution. In addition, less than 50% of upacicalcet binds to human plasma proteins. These findings suggest that upacicalcet administered to patients undergoing hemodialysis might be expected to have a long excretion period and sustained pharmacological effect.

Hyperuricemia is supposed to be an independent risk factor for kidney dysfunction in diabetic patients. We attempted to examine the uric acid-lowering effect and the renoprotective effect of topiroxostat, a selective xanthine oxidoreductase inhibitor, in patients with diabetic nephropathy and hyperuricemia in this pilot study.