AMG 416 (velcalcetide) is a novel peptide for the treatment of secondary hyperparathyroidism in a single-dose study in hemodialysis patients

Abstract

AMG 416 (velcalcetide), a novel peptide agonist of the calcium-sensing receptor, lowers plasma parathyroid hormone in preclinical uremic animal models and in normal healthy individuals. Here, we studied its efficacy in hemodialysis patients suffering from secondary hyperparathyroidism. Major inclusion criteria were hemodialysis for at least 3 months, serum parathyroid hormone over 300 pg/ml, a corrected serum calcium of 9.0 mg/dl or more, and stable doses of vitamin D analogs for at least 3 weeks prior to screening. Twenty-eight patients were enrolled in one of five cohorts (5, 10, 20, 40, 60 mg). Cohorts 1-3 (four patients each) were treated in a two-period crossover design, while cohorts 4 and 5 (eight patients each) were randomized 1:1 to AMG 416 or placebo. Patients were admitted to a clinical research unit following hemodialysis and studied for 3 days prior to discharge for hemodialysis. Single intravenous doses of AMG 416 from 5 to 60 mg were well tolerated, and plasma levels increased in a dose-related manner. AMG 416 treatment was associated with significant, dose-dependent reductions in serum parathyroid hormone and fibroblast growth factor 23. Compared with placebo, all dose groups of 10 mg or more were associated with attenuation in the rise in serum phosphate during the interdialytic period. Dose-dependent reductions in serum calcium were observed and were well tolerated. Thus, AMG 416 represents a novel therapeutic approach for the treatment of secondary hyperparathyroidism in hemodialysis patients.

Rates and Outcomes of Parathyroidectomy for Secondary Hyperparathyroidism in the United States

“…for sHPT or in patients intolerant of or nonresponsive to oral or intravenous active vitamin D analogs and/or cinacalcet (22,23). Although many studies have highlighted the risks associated with sHPT, relatively few published studies have reported risks associated with the parathyroidectomy procedure itself.…”

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

“…AMG 416 acts in a fashion similar to the phenylalkylamine CaSR agonist, cinacalcet (Sensipar/Mimpara; Amgen Inc.) by decreasing circulating levels of parathyroid hormone (PTH), calcium, and phosphorus in dialysis patients with secondary HPT (Block et al, 2004;Lindberg et al, 2005;Moe et al, 2005;Martin et al, 2014b;Bell et al, 2015). However, AMG 416 differs from cinacalcet in its chemical class, intravenous route of administration, extended half-life, and thrice weekly dosing following each hemodialysis session (Martin et al, 2014b).…”

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

“…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).…”