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


OBJECTIVE
To assess the safety, tolerability, pharmacokinetics and pharmacodynamics of velcalcetide in healthy male volunteers.


METHODS
The 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.


METHODS
Velcalcetide at 0.5, 2, 5 and 10 mg or placebo was administered intravenously.


RESULTS
Measurements 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.


RESULTS
Intravenous 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.


CONCLUSIONS
Single 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.
Division of Nephrology, Saint Louis University School of Medicine, Saint Louis, MO 63103, USA.
Kevin J
KJ
Martin
Gregory
G
Bell
Karen
K
Pickthorn
Saling
S
Huang
Andrew
A
Vick
Peter
P
Hodsman
Munro
M
Peacock
D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000097:blood; D012080:Chronic Kidney Disease-Mineral and Bone Disorder / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood* / Q000187:drug effects; D005500:Follow-Up Studies; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D010281:Parathyroid Hormone / Q000097:blood*; D010455:Peptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D044169:Receptors, Calcium-Sensing / Q000819:agonists*; D012016:Reference Values; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000150:complications* / Q000188:drug therapy; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
D015415:Biomarkers; C000717427:FGF23 protein, human; D010281:Parathyroid Hormone; D010455:Peptides; D044169:Receptors, Calcium-Sensing; D005346:Fibroblast Growth Factors; C583569:etelcalcetide hydrochloride; D000089703:Fibroblast Growth Factor-23
AMG 416; FGF23; calcimimetic; parathyroid hormone; velcalcetide