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Nonclinical cardiovascular safety evaluation of romosozumab, an inhibitor of sclerostin for the treatment of osteoporosis in postmenopausal women at high risk of fracture.
Turk, James R; Deaton, Aimee M; Yin, Jun; Stolina, Marina; Felx, Melanie; Boyd, Gabrielle; Bienvenu, Jean-Guy; Varela, Aurore; Guillot, Martin; Holdsworth, Gill; Wolfreys, Alison; Dwyer, Denise; Kumar, Sheetal V; de Koning, Emily M; Qu, Yusheng; Engwall, Michael; Locher, Kathrin; Ward, Lucas D; Glaus, Charles; He, Yudong D; Boyce, Rogely Waite.
Affiliation
  • Turk JR; Translational Safety and Bioanalytical Sciences, Amgen Research, Thousand Oaks, CA, USA. Electronic address: jturk@amgen.com.
  • Deaton AM; Translational Safety and Bioanalytical Sciences, Amgen Research, Cambridge, MA, USA.
  • Yin J; Genome Analysis Unit, Amgen Research, South San Francisco, CA, USA.
  • Stolina M; Cardiometabolic Disorders Research, Amgen Research, Thousand Oaks, CA, USA.
  • Felx M; Charles River Laboratories Montreal ULC, Senneville, QC, Canada.
  • Boyd G; Charles River Laboratories Montreal ULC, Senneville, QC, Canada.
  • Bienvenu JG; Charles River Laboratories Montreal ULC, Senneville, QC, Canada.
  • Varela A; Charles River Laboratories Montreal ULC, Senneville, QC, Canada.
  • Guillot M; Charles River Laboratories Montreal ULC, Senneville, QC, Canada.
  • Holdsworth G; UCB Pharma, Slough, UK.
  • Wolfreys A; UCB Pharma, Slough, UK.
  • Dwyer D; Cardiometabolic Disorders Research, Amgen Research, Thousand Oaks, CA, USA.
  • Kumar SV; Translational Safety and Bioanalytical Sciences, Amgen Research, Cambridge, MA, USA.
  • de Koning EM; Translational Safety and Bioanalytical Sciences, Amgen Research, Cambridge, MA, USA.
  • Qu Y; Translational Safety and Bioanalytical Sciences, Amgen Research, Thousand Oaks, CA, USA.
  • Engwall M; Translational Safety and Bioanalytical Sciences, Amgen Research, Thousand Oaks, CA, USA.
  • Locher K; Translational Safety and Bioanalytical Sciences, Amgen Research, South San Francisco, CA, USA.
  • Ward LD; Translational Safety and Bioanalytical Sciences, Amgen Research, Cambridge, MA, USA.
  • Glaus C; Cardiometabolic Disorders Research, Amgen Research, Thousand Oaks, CA, USA.
  • He YD; Translational Safety and Bioanalytical Sciences, Amgen Research, Thousand Oaks, CA, USA; Genome Analysis Unit, Amgen Research, South San Francisco, CA, USA.
  • Boyce RW; Translational Safety and Bioanalytical Sciences, Amgen Research, Thousand Oaks, CA, USA.
Regul Toxicol Pharmacol ; 115: 104697, 2020 Aug.
Article in En | MEDLINE | ID: mdl-32590049
ABSTRACT
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.
Subject(s)
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cardiovascular System / Adaptor Proteins, Signal Transducing / Bone Density Conservation Agents / Antibodies, Monoclonal Type of study: Clinical_trials / Etiology_studies / Risk_factors_studies Limits: Animals / Female / Humans / Male Language: En Journal: Regul Toxicol Pharmacol Year: 2020 Document type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cardiovascular System / Adaptor Proteins, Signal Transducing / Bone Density Conservation Agents / Antibodies, Monoclonal Type of study: Clinical_trials / Etiology_studies / Risk_factors_studies Limits: Animals / Female / Humans / Male Language: En Journal: Regul Toxicol Pharmacol Year: 2020 Document type: Article