Velcalcetide (AMG 416), a novel peptide agonist of the calcium-sensing receptor, reduces serum parathyroid hormone and FGF23 levels in healthy male subjects

Abstract

ContextVelcalcetide, also known as AMG 416, is a novel, long-acting selective peptide agonist of the calcium sensing receptor. It is being developed as an intravenous treatment of secondary hyperparathyroidism (SHPT) in hemodialysis patients with chronic kidney disease—mineral and bone disorder.ObjectiveTo assess the safety, tolerability, pharmacokinetics and pharmacodynamics of velcalcetide in healthy male volunteers.MethodsThe study was a double-blind, randomized, placebo-controlled, single-dose, dose-escalation study in healthy males aged 18–45 years conducted at a single center. Each cohort included eight subjects randomized 6:2 to velcalcetide or placebo.InterventionVelcalcetide at 0.5, 2, 5 and 10 mg or placebo was administered intravenously.OutcomesMeasurements included plasma ionized calcium (iCa), serum total calcium, intact parathyroid hormone (iPTH), phosphorus and fibroblast growth factor-23 (FGF23), 1,25-dihydroxyvitamin D, calcitonin and urine creatinine, calcium and phosphorus and plasma pharmacokinetics for velcalcetide. Vital signs, safety biochemical and hematological indices, and adverse events were monitored throughout the study.ResultsIntravenous administration of velcalcetide was well tolerated with no adverse reaction of nausea, vomiting or diarrhea reported. Velcalcetide mediated dose-dependent decreases in serum iPTH at 30 min, FGF23 at 24 h and iCa at 12 h post dose (P < 0.05) and in urine fractional excretion of phosphorus and increases in tubular reabsorption of phosphorus. Velcalcetide plasma exposure increased in a dose-related manner and the terminal elimination of half-life was comparable across the dose range evaluated and ranged from 18.4 to 20.0 h.ConclusionSingle IV doses of velcalcetide were well tolerated and associated with rapid, sustained, dose-dependent reductions in serum PTH. The results support further evaluation of velcalcetide as a treatment for SHPT in hemodialysis patients.

Nonclinical Pharmacokinetics, Disposition, and Drug-Drug Interaction Potential of a Novel D-Amino Acid Peptide Agonist of the Calcium-Sensing Receptor AMG 416 (Etelcalcetide)

“…AMG 416, administered i.v. three times weekly at the end of each hemodialysis session in CKD patients, has demonstrated PTHlowering effect and improved treatment adherence with reduced adverse events (Martin et al, 2014;Bell et al, 2015;Cozzolino et al, 2015).…”

Clinical and Practical Use of Calcimimetics in Dialysis Patients With Secondary Hyperparathyroidism

“…This subgroup probably represents those patients with the highest bone-derived P load. Decreasing levels of FGF23 have also been described with cinacalcet and AMG-416 (36,98). This possible mechanism for a beneficial effect of cinacalcet on vascular calcification and CV outcomes awaits further investigation, as well as other off-target effects of cinacalcet that cannot be just neglected (74).…”

“…Consequently, cinacalcet is currently indicated for the treatment of SHPT in dialysis patients and is shown to reduce hypercalcemia in patients with parathyroid carcinoma and in selected cases of primary hyperparathyroidism (34,35). AMG-416 is currently in development and represents a novel, third-generation intravenous long-acting selective peptide agonist of the CaR (36,37).…”

Critical Cysteine Residues in Both the Calcium-Sensing Receptor and the Allosteric Activator AMG 416 Underlie the Mechanism of Action

“…values of 6.2 6 0.8%, 12.3 6 0.6%, 25.2 6 1.3% (all P , 0.0001; paired Student's t test) for 0.3 mg/kg, 1 mg/kg, and 3 mg/kg dose groups, respectively. Lastly, data from healthy young male human subjects (Martin et al, 2014a) show significant reductions in blood ionized calcium levels of 16.3 6 1.0% (mean 6 S.E.M. ; P , 0.0001; The pCaSR was completely sequenced to explore whether the lack of PD response to AMG 416 in pigs was associated with receptor composition.…”

“…AMG 416 administration leads to dose-dependent suppression of PTH in normal and uremic rats (Walter et al, 2013), healthy adults (Martin et al, 2014a), and patients with secondary HPT on hemodialysis (Martin et al, 2014b). AMG 416 also reduces serum phosphorus and calcium levels in patients with secondary HPT on hemodialysis (Martin et al, 2014b).…”