Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol

Ray, K. K. et al. (2020) Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. New England Journal of Medicine, 382(16), pp. 1507-1519. (doi: 10.1056/NEJMoa1912387) (PMID:32187462)

Abstract

Background: Inclisiran inhibits hepatic synthesis of proprotein convertase subtilisin–kexin type 9. Previous studies suggest that inclisiran might provide sustained reductions in low-density lipoprotein (LDL) cholesterol levels with infrequent dosing. Methods: We enrolled patients with atherosclerotic cardiovascular disease (ORION-10 trial) and patients with atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent (ORION-11 trial) who had elevated LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose. Patients were randomly assigned in a 1:1 ratio to receive either inclisiran (284 mg) or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter over a period of 540 days. The coprimary end points in each trial were the placebo-corrected percentage change in LDL cholesterol level from baseline to day 510 and the time-adjusted percentage change in LDL cholesterol level from baseline after day 90 and up to day 540. Results: A total of 1561 and 1617 patients underwent randomization in the ORION-10 and ORION-11 trials, respectively. Mean (±SD) LDL cholesterol levels at baseline were 104.7±38.3 mg per deciliter (2.71±0.99 mmol per liter) and 105.5±39.1 mg per deciliter (2.73±1.01 mmol per liter), respectively. At day 510, inclisiran reduced LDL cholesterol levels by 52.3% (95% confidence interval [CI], 48.8 to 55.7) in the ORION-10 trial and by 49.9% (95% CI, 46.6 to 53.1) in the ORION-11 trial, with corresponding time-adjusted reductions of 53.8% (95% CI, 51.3 to 56.2) and 49.2% (95% CI, 46.8 to 51.6) (P<0.001 for all comparisons vs. placebo). Adverse events were generally similar in the inclisiran and placebo groups in each trial, although injection-site adverse events were more frequent with inclisiran than with placebo (2.6% vs. 0.9% in the ORION-10 trial and 4.7% vs. 0.5% in the ORION-11 trial); such reactions were generally mild, and none were severe or persistent. Conclusions: Reductions in LDL cholesterol levels of approximately 50% were obtained with inclisiran, administered subcutaneously every 6 months. More injection-site adverse events occurred with inclisiran than with placebo. (Funded by the Medicines Company; ORION-10 and ORION-11 ClinicalTrials.gov numbers, NCT03399370. opens in new tab and NCT03400800. opens in new tab.)

• Item Type: Articles
• Additional Information: Ian Ford is a member of the Independent Data Monitoring Committee of the ORION-10 and ORION-11 Investigators.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Ford, Professor Ian
• Authors: Ray, K. K., Wright, R. S., Kallend, D., Koenig, W., Leiter, L. A., Raal, F. J., Bisch, J. A., Richardson, T., Jaros, M., Wijngaard, P. L.J., Kastelein, J. J.P., and ORION-10 and ORION-11 Investigators,
• Subjects: R Medicine > R Medicine (General)
• College/School: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Robertson Centre
• Journal Name: New England Journal of Medicine
• Publisher: Massachusetts Medical Society
• ISSN: 0028-4793
• ISSN (Online): 1533-4406
• Copyright Holders: Copyright © 2020 Massachusetts Medical Society
• First Published: First published in New England Journal of Medicine 382(16): 1507-1519
• Publisher Policy: Reproduced in accordance with the publisher copyright policy