A phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of etelcalcetide (ONO-5163/AMG 416), a novel intravenous calcimimetic, for secondary hyperparathyroidism in Japanese haemodialysis patients.

BACKGROUND: Secondary hyperparathyroidism (SHPT) is a major complication associated with chronic kidney disease. We evaluated the efficacy and safety of etelcalcetide (ONO-5163/AMG 416), a novel intravenous calcimimetic, in Japanese haemodialysis patients with SHPT. METHODS: In this phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group study, etelcalcetide was administered three times per week at an initial dose of 5 mg, and subsequently adjusted to doses between 2.5 and 15 mg at 4-week intervals for 12 weeks. A total of 155 SHPT patients with serum intact parathyroid hormone (iPTH) levels ≥300 pg/mL were assigned to receive etelcalcetide (n = 78) or placebo (n = 77). The primary endpoint was the proportion of patients with decreased serum iPTH to the target range proposed by the Japanese Society for Dialysis Therapy (60-240 pg/mL). The major secondary endpoint was the proportion of patients with ≥30% reductions in serum iPTH from baseline. RESULTS: The proportion of patients meeting the primary endpoint was significantly higher for etelcalcetide (59.0%) versus placebo (1.3%). Similarly, the proportion of patients meeting the major secondary endpoint was significantly higher for etelcalcetide (76.9%) versus placebo (5.2%). Serum albumin-corrected calcium, phosphorus and intact fibroblast growth factor-23 levels were decreased in the etelcalcetide group. Nausea, vomiting and symptomatic hypocalcaemia were mild with etelcalcetide. Serious adverse events related to etelcalcetide were not observed. CONCLUSIONS: This study demonstrated the efficacy and safety of etelcalcetide. As the only available intravenous calcium-sensing receptor agonist, etelcalcetide is likely to provide a new treatment option for SHPT in haemodialysis patients.

Impairment of α1-adrenoceptor-mediated contractile activity in caudal arterial smooth muscle from type 2 diabetic Goto-Kakizaki rats.

1. In the present study, we compared the responsiveness of de-endothelialized caudal artery smooth muscle strips, isolated from Type 2 diabetic Goto-Kakizaki (GK) and normal Wistar rats, to alpha(1)-adrenoceptor stimulation (cirazoline) and membrane depolarization (K(+)). 2. The contractile and myosin 20 kDa light chain (LC(20)) phosphorylation responses to 0.3 micromol/L cirazoline of caudal artery strips isolated from 12-week-old GK rats were significantly reduced compared with those of age-matched Wistar rats, whereas the contractile and LC(20) phosphorylation responses to 60 mmol/L K(+) were unaltered. 3. Stimulation of fura 2-AM-loaded strips from GK rats with 0.3 micromol/L cirazoline induced a significantly smaller rise in [Ca(2+)](i) (by approximately 20%) compared with that in strips from Wistar rats, whereas comparable Ca(2+) transients were evoked by K(+) in both. 4. Using quantitative polymerase chain reaction, no significant differences were detected in the mRNA expression of alpha(1A)-, alpha(1B)- and alpha(1D)-adrenoceptor subtypes between GK and Wistar rats. 5. Cirazoline (1 micromol/L)- and caffeine (20 mmol/L)-induced contractions in the absence of extracellular Ca(2+) were unaltered in GK rats, suggesting that the release of Ca(2+) from the sarcoplasmic reticulum in response to cirazoline does not differ between GK and Wistar rats. 6. The results of the present study suggest that Ca(2+) entry from the extracellular space via alpha(1)-adrenoceptor-activated, Ca(2+)-permeable channels, but not via membrane depolarization and voltage-gated L-type Ca(2+) channels, is impaired in caudal artery smooth muscle of GK rats.