Pharmacology of AMG 416 (Velcalcetide), a Novel Peptide Agonist of the Calcium-Sensing Receptor, for the Treatment of Secondary Hyperparathyroidism in Hemodialysis Patients

Abstract

A novel peptide, AMG 416 (formerly KAI-4169, and with a United States Adopted Name: velcalcetide), has been identified that acts as an agonist of the calcium-sensing receptor (CaSR). This article summarizes the in vitro and in vivo characterization of AMG 416 activity and the potential clinical utility of this novel compound. AMG 416 activates the human CaSR in vitro, acting by a mechanism distinct from that of cinacalcet, the only approved calcimimetic, since it can activate the CaSR both in the presence or the absence of physiologic levels of extracellular calcium. Administration of AMG 416 in vivo into either normal or renally compromised rats results in dose-dependent reductions in parathyroid hormone (PTH) levels and corresponding decreases in serum calcium, regardless of the baseline level of PTH. Treatment of 5/6 nephrectomized rats with AMG 416 resulted in dramatic improvements in their metabolic profile, including lower PTH and serum creatinine levels, reduced amounts of vascular calcification, attenuated parathyroid hyperplasia, and greater expression of the parathyroid gland regulators CaSR, vitamin D receptor, and FGF23 receptor compared with vehicletreated animals. No drug accumulation was observed under this dosing regimen, and the terminal half-life of AMG 416 was estimated to be 2-4.5 hours. As a long-acting CaSR agonist, AMG 416 is an innovative new therapy for the treatment of hemodialysis patients with secondary hyperparathyroidism.

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

“…Peptides AMG 416 (Ac-c[C]arrrar-NH 2 ; 1048 Da), KP-2067 (Ac-carrrar-NH 2 ; 929 Da), and KP-2140 (Ac-arrrar-NH 2 ; 826 Da) were synthesized using the methods described previously (Walter et al, 2013). Lower case single letters in sequences represent D-amino acids and upper case is an L-amino acid.…”

“…Analysis of KP-2067 and KP-2140 in a Stable Cell Line Expressing hCaSR Dose-response curves for KP-2067, KP-2140, and calcium were measured in a clonal cell line of HEK293T stably transfected with the human CaSR (Multispan, Hayward, CA) and as previously described for AMG 416 (Walter et al, 2013).…”

“…AMG 416 is a synthetic eight-amino acid peptide calcimimetic that activates the CaSR in the presence of extracellular calcium in vitro but also demonstrates lower activity when extracellular calcium is absent (Walter et al, 2013). 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 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).…”

Etelcalcetide: A New Intravenous Calcimimetic for the Treatment of Secondary Hyperparathyroidism in Haemodialysis Patients

“…Questi recettori sono espressi nelle Etelcalcetide: un nuovo calciomimetico per la terapia dell'iperparatiroidismo secondario nei pazienti in emodialisi Monica Limardo, Giuseppe Pontoriero sviluppato con l'obiettivo di migliorare la tollerabilità gastrointestinale, la compliance al trattamento e conseguentemente l'efficacia della terapia calciomimetica. Infatti, è stato ipotizzato che la somministrazione endovenosa non esponga il lume gastrointestinale a una concentrazione significativa di calciomimetico come nel caso di Cinacalcet (7); inoltre, in studi sulla distribuzione del farmaco, Etelcalcetide non sembra superare in maniera significativa la barriera emato-encefalica e ciò potrebbe mitigare i rischi di eventuali effetti gastrointestinali mediati dal sistema nervoso centrale (6). Un beneficio aggiuntivo per i pazienti potrebbe essere trovato nella riduzione del numero di compresse da assumere al domicilio.…”