title: Nonclinical Safety Profile of Etelcalcetide, a Novel Peptide Calcimimetic for the Treatment of Secondary Hyperparathyroidism.
abstract: Etelcalcetide is a novel d-amino acid peptide that functions as an allosteric activator of the calcium-sensing receptor and is being developed as an intravenous calcimimetic for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on hemodialysis. To support clinical development and marketing authorization, a comprehensive nonclinical safety package was generated. Primary adverse effects included hypocalcemia, tremoring, and convulsions. Other adverse effects were considered sequelae of stress associated with hypocalcemia. Cardiovascular safety evaluations in the dog revealed an anticipated prolongation of the corrected QT interval that was related to reductions in serum calcium. Etelcalcetide did not affect the human ether-a-go-go gene ion channel current. Etelcalcetide was mutagenic in some strains of Salmonella, however, based on the negative results in 2 in vitro and 2 in vivo mammalian genotoxicity assays, including a 28-day Muta mouse study, etelcalcetide is considered nongenotoxic. Further support for a lack of genotoxicity was provided due to the fact that etelcalcetide was not carcinogenic in a 6-month transgenic rasH2 mouse model or a 2-year study in rats. There were no effects on fertility, embryo-fetal development, and prenatal and postnatal development. All of the adverse effects observed in both rat and dog were considered directly or secondarily related to the pharmacologic activity of etelcalcetide and the expected sequelae associated with dose-related reductions in serum calcium due to suppression of parathyroid hormone secretion. These nonclinical data indicate no safety signal of concern for human risk beyond that associated with hypocalcemia and associated QT prolongation.
authors.affiliation: Comparative Biology and Safety Sciences, Amgen Inc, Thousand Oaks, CA, USA mfielden@amgen.com.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Fielden
authors.affiliation: Comparative Biology and Safety Sciences, Amgen Inc, Thousand Oaks, CA, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Dean
authors.affiliation: Comparative Biology and Safety Sciences, Amgen Inc, Thousand Oaks, CA, USA.
authors.forename: Kurt
authors.initials: K
authors.lastname: Black
authors.affiliation: Comparative Biology and Safety Sciences, Amgen Inc, Thousand Oaks, CA, USA.
authors.forename: Satin G
authors.initials: SG
authors.lastname: Sawant
authors.affiliation: Pharmacokinetics and Drug Metabolism, Amgen Inc, Thousand Oaks, CA, USA.
authors.forename: Raju
authors.initials: R
authors.lastname: Subramanian
authors.affiliation: Cardiometabolic Disorders, Amgen Inc, Thousand Oaks, CA, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Tomlinson
authors.affiliation: Cardiometabolic Disorders, Amgen Inc, Thousand Oaks, CA, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Walter
authors.affiliation: Comparative Biology and Safety Sciences, Amgen Inc, Thousand Oaks, CA, USA.
authors.forename: Cameron
authors.initials: C
authors.lastname: Zimmermann
authors.affiliation: MPI Research Inc, Mattawan, MI, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Griggs
authors.affiliation: BioReliance, Rockville, MD, USA.
authors.forename: Marie E
authors.initials: ME
authors.lastname: McKeon
authors.affiliation: Charles River Laboratories Inc, Horsham, PA, USA.
authors.forename: Elise M
authors.initials: EM
authors.lastname: Lewis
authors.affiliation: Covance Laboratories Ltd, Harrogate, United Kingdom.
authors.forename: Carol
authors.initials: C
authors.lastname: Beevers
authors.affiliation: Comparative Biology and Safety Sciences, Amgen Inc, Thousand Oaks, CA, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Pyrah
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000097:blood; D004285:Dogs; D000072237:ERG1 Potassium Channel / Q000502:physiology; D005260:Female; D057809:HEK293 Cells; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000188:drug therapy; D006996:Hypocalcemia / Q000139:chemically induced; D008297:Male; D008822:Mice, Transgenic; D009152:Mutagenicity Tests; D010455:Peptides / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity*; D011817:Rabbits; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced; D014202:Tremor / Q000139:chemically induced
chemical_list: D000072237:ERG1 Potassium Channel; C000606913:KCNH2 protein, human; D010455:Peptides; C583569:etelcalcetide hydrochloride; D002118:Calcium
keywords: calcimimetic; calcium-sensing receptor; etelcalcetide; hypocalcemia; nonclinical safety profile