Nonclinical cardiovascular safety evaluation of romosozumab, an inhibitor of sclerostin for the treatment of osteoporosis in postmenopausal women at high risk of fracture.
Adaptor Proteins, Signal Transducing
/ antagonists & inhibitors
Animals
Antibodies, Monoclonal
/ pharmacology
Bone Density Conservation Agents
/ pharmacology
Cardiovascular System
/ drug effects
Drug Evaluation, Preclinical
Female
Fractures, Bone
/ prevention & control
Humans
Macaca fascicularis
Male
Mice, Inbred C57BL
Mice, Knockout, ApoE
Osteoporosis
/ drug therapy
Rats, Sprague-Dawley
Risk
ApoE knockout mouse
Atherosclerosis
Cardiovascular safety
Risk assessment
Romosozumab
Sclerostin antibody
Journal
Regulatory toxicology and pharmacology : RTP
ISSN: 1096-0295
Titre abrégé: Regul Toxicol Pharmacol
Pays: Netherlands
ID NLM: 8214983
Informations de publication
Date de publication:
Aug 2020
Aug 2020
Historique:
received:
18
02
2020
revised:
20
05
2020
accepted:
29
05
2020
pubmed:
27
6
2020
medline:
26
3
2021
entrez:
27
6
2020
Statut:
ppublish
Résumé
Romosozumab (EVENITY™ [romosozumab-aqqg in the US]) is a humanized monoclonal antibody that inhibits sclerostin and has been approved in several countries for the treatment of osteoporosis in postmenopausal women at high risk of fracture. Sclerostin is expressed in bone and aortic vascular smooth muscle (AVSM). Its function in AVSM is unclear but it has been proposed to inhibit vascular calcification, atheroprogression, and inflammation. An increased incidence of positively adjudicated serious cardiovascular adverse events driven by an increase in myocardial infarction and stroke was observed in romosozumab-treated subjects in a clinical trial comparing alendronate with romosozumab (ARCH; NCT01631214) but not in a placebo-controlled trial (FRAME; NCT01575834). To investigate the effects of sclerostin inhibition with sclerostin antibody on the cardiovascular system, a comprehensive nonclinical toxicology package with additional cardiovascular studies was conducted. Although pharmacodynamic effects were observed in the bone, there were no functional, morphological, or transcriptional effects on the cardiovascular system in animal models in the presence or absence of atherosclerosis. These nonclinical studies did not identify evidence that proves the association between sclerostin inhibition and adverse cardiovascular function, increased cardiovascular calcification, and atheroprogression.
Identifiants
pubmed: 32590049
pii: S0273-2300(20)30123-9
doi: 10.1016/j.yrtph.2020.104697
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Antibodies, Monoclonal
0
Bone Density Conservation Agents
0
romosozumab
3VHF2ZD92J
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
104697Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: James R Turk, Marina Stolina, Denise Dwyer, Sheetal V Kumar, Emily M de Koning, Yusheng Qu, and Michael Engwall are employees and stockholders of Amgen Inc. AMD, JY, KL, LW, CG, YDH, and RWB are former Amgen employees.. Melanie Felx, Gabrielle Boyd, Jean-Guy Bienvenu, Aurore Varela, and Martin Guillot are employees of Charles River Laboratories Montreal ULC, which received funding from Amgen Inc., Astellas, and UCB Pharma to conduct this research. Gill Holdsworth and Alison Wolfreys are employees and stockholders of UCB Pharma.