Nonclinical cardiovascular safety evaluation of romosozumab, an inhibitor of sclerostin for the treatment of osteoporosis in postmenopausal women at high risk of fracture

Romosozumab is a humanized monoclonal antibody that inhibits sclerostin, an extracellular inhibitor of the canonical Wnt signaling pathway, expressed in osteocytes. Romosozumab results in increased bone formation and decreased bone resorption and has been approved in several countries for the treatment of osteoporosis in postmenopausal women at high risk of fracture. Sclerostin is also expressed in aortic vascular smooth muscle cells, the function of which is unclear but has been proposed to be an inhibitor of vascular calcification, atheroprogression, and associated inflammation. A slight increase in serious cardiovascular adverse events (CV AEs) was observed in romosozumab-treated subjects in a clinical trial comparing alendronate with romosozumab (ARCH; NCT01631214) but was not observed in a placebo-controlled trial (FRAME; NCT01575834). To investigate biological plausibility of the role of romosozumab in cardiovascular disease, a comprehensive nonclinical package with additional cardiovascular studies was conducted including studies in two murine models of atherosclerosis. Results of these studies demonstrated that the effects of romosozumab or a surrogate sclerostin antibody were either a direct or indirect consequence of its pharmacodynamic effects on bone. There were with no functional or morphologic effects on the cardiovascular system in animal models in the presence or absence of atherosclerosis. The totality of these nonclinical data has not identified a biologically plausible mechanism to explain the increase in serious CV AEs in the ARCH trial. Overall design: The objective of this substudy was to evaluate transcriptional changes in the aorta in response to sclerostin antibody (Scl-Ab) treatment in high fat diet-fed ovariectomized (OVX) wild-type (WT) and Apolipoprotein E (ApoE) knockout mice. RNA-seq analyses were applied to satellite animals in the vehicle, Scl-Ab–treated WT, and HFD-fed ApoE-OVX groups. All groups of satellite animals were analyzed in the AngII-infused ApoE KO study.