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

Abstract

CONTEXT:

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.

INTERVENTION:

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

OUTCOMES:

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.

CONCLUSION:

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.

• Authors: Kevin J Martin, Gregory Bell, Karen Pickthorn, Saling Huang, Andrew Vick, Peter Hodsman, Munro Peacock
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 29 Issue 2 Pg. 385-92 (Feb 2014) ISSN: 1460-2385 [Electronic] England
• PMID: 24235081 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• FGF23 protein, human
• Parathyroid Hormone
• Peptides
• Receptors, Calcium-Sensing
• Fibroblast Growth Factors
• etelcalcetide hydrochloride
• Fibroblast Growth Factor-23

Topics

• Adolescent
• Adult
• Biomarkers (blood)
• Chronic Kidney Disease-Mineral and Bone Disorder (blood, complications, drug therapy)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Fibroblast Growth Factor-23
• Fibroblast Growth Factors (blood, drug effects)
• Follow-Up Studies
• Humans
• Hyperparathyroidism, Secondary (blood, drug therapy, etiology)
• Injections, Intravenous
• Male
• Middle Aged
• Parathyroid Hormone (blood)
• Peptides (pharmacokinetics, pharmacology)
• Receptors, Calcium-Sensing (agonists)
• Reference Values
• Renal Insufficiency, Chronic (blood, complications, drug therapy)
• Time Factors
• Treatment Outcome
• Young Adult