Plenary Poster 30th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting 2020

Sclerostin Antibody Does Not Affect Endpoints Related to Atheroprogression, Plaque Calcification, or Inflammation in Murine Models of Atherosclerosis (#26)

Rogely Boyce 1 , Aimee Deaton 2 , Jun Yin 3 , Marina Stolina 1 , Melanie Felx 4 , Gabrielle Boyd 4 , Jean-Guy Bienvenu 4 , Aurore Varela 4 , Martin Guillot 4 , Gill Holdsworth 5 , Alison Wolfreys 5 , Denise Dwyer 1 , Sheetal Kumar 2 , Emily de Koning 2 , Kathrin Locher 1 , Luke Ward 1 , Charles Glaus 1 , Yudong He 3 , James Turk 1
  1. Amgen Inc, Thousand Oaks, CA, USA
  2. Amgen Inc, Cambridge, MA, USA
  3. Amgen Inc, San Francsico, CA, USA
  4. Charles River Laboratories Montreal ULC, Senneville, QC, Canada
  5. UCB Pharma, Slough, UK

Sclerostin has been proposed to inhibit vascular calcification, atheroprogression, and inflammation. To investigate the effects of sclerostin inhibition by Scl-Ab (humanised sclerostin antibody) on vasculature in the presence of vascular disease, studies were conducted in ovariectomised ApoE knockout (ApoE KO-OVX) mice fed a high-fat diet—model of severe atherosclerosis and the bone-vascular axis of postmenopausal women, and angiotensin-infused male ApoE knockout (AngII ApoE KO) mice—model of atherosclerosis and aortic aneurysm.

First study: Scl-Ab (Scl-Ab VI; 10 mg/kg/wk) or vehicle was administered for 3, 8, or 16 wk to ApoE KO- and wild-type (WT)-OVX mice. Alendronate (0.02mg/kg/twice wk) or saline was administered for 16 wk to ApoE KO-OVX mice (comparator). Evaluated endpoints: aortic total and mineralised plaque volume (by μCT); plaque histopathology; serum biomarkers of inflammation, bone formation and endothelial/platelet activation; and aortic transcriptional changes (by RNA Seq). Second study: Male ApoE KO mice were infused with AngII at approximately 1 µg/kg/min for 4 wk, and administered Scl-Ab (Scl-Ab VI; 10 mg/kg/wk) or vehicle. WT mice were infused with and administered vehicle. At 4 wk, aortic total and mineralised plaque volume, serum inflammation biomarkers, bone mass, aortic transcriptional changes, and aortic aneurysm incidence were evaluated.

Collective data showed robust expected effects on cardiovascular endpoints in vehicle-treated ApoE KO-OVX and AngII ApoE KO vs WT mice. Scl-Ab promoted bone formation but did not affect total/mineralised plaque volume, plaque histopathology, serum biomarkers of inflammation and endothelial/platelet activation, atheroprogression-related signalling pathways, or aortic aneurysm incidence compared with respective vehicle-treated mice. Alendronate had no meaningful effects on atheroprogression-related endpoints.

Sclerostin inhibition by Scl-Ab at systemic exposures predicted to be 4-fold greater than romosozumab clinical exposure at 210 mg QM has no effect on atheroprogression-related endpoints, plaque calcification, or inflammation in 2 murine models of atherosclerosis.

Study was sponsored by Amgen Inc. and UCB Pharma