• Kausik K Ray, Ulf Landmesser, Lawrence A Leiter, David Kallend, Robert Dufour, Mahir Karakas, Tim Hall, Roland P T Troquay, Traci Turner, Frank L J Visseren, Peter Wijngaard, R Scott Wright, and John J P Kastelein.
• From the Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College London, London (K.K.R.), and Knowle House Surgery, Plymouth (T.H.) - both in the United Kingdom; the Department of Cardiology, Charité-Universitätsmedizin Berlin, Berlin Institute of Health and German Center for Cardiovascular Research, Berlin (U.L.), and University Heart Center Hamburg, Department of General and Interventional Cardiology, Hamburg (M.K.) - all in Germany; the Division of Endocrinology and Metabolism, Li Ka Shing Knowledge Institute and Keenan Research Centre for Biomedical Science, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.); the Medicines Company, Parsippany, NJ (D.K., P.W.); Institut de Recherches Cliniques de Montréal, University of Montreal, Montreal (R.D.); the Department of Cardiology and Interventional Cardiology, VieCuri Medical Center for Northern Limburg, Venlo (R.P.T.T.), University Medical Center, Utrecht (F.L.J.V.), and the Department of Vascular Medicine, Academic Medical Center-University of Amsterdam, Amsterdam (J.J.P.K.) - all in the Netherlands; the Metabolic and Atherosclerosis Research Center, Medpace, Cincinnati (T.T.); and the Department of Cardiology, Mayo Clinic, Rochester, MN (R.S.W.).
• N. Engl. J. Med. 2017 Apr 13; 376 (15): 1430-1440.

BackgroundIn a previous study, a single injection of inclisiran, a chemically synthesized small interfering RNA designed to target PCSK9 messenger RNA, was found to produce sustained reductions in low-density lipoprotein (LDL) cholesterol levels over the course of 84 days in healthy volunteers.MethodsWe conducted a phase 2, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial of inclisiran administered as a subcutaneous injection in patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels. Patients were randomly assigned to receive a single dose of placebo or 200, 300, or 500 mg of inclisiran or two doses (at days 1 and 90) of placebo or 100, 200, or 300 mg of inclisiran. The primary end point was the change from baseline in LDL cholesterol level at 180 days. Safety data were available through day 210, and data on LDL cholesterol and proprotein convertase subtilisin-kexin type 9 (PCSK9) levels were available through day 240.ResultsA total of 501 patients underwent randomization. Patients who received inclisiran had dose-dependent reductions in PCSK9 and LDL cholesterol levels. At day 180, the least-squares mean reductions in LDL cholesterol levels were 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6% after two doses (P<0.001 for all comparisons vs. placebo). The two-dose 300-mg inclisiran regimen produced the greatest reduction in LDL cholesterol levels: 48% of the patients who received the regimen had an LDL cholesterol level below 50 mg per deciliter (1.3 mmol per liter) at day 180. At day 240, PCSK9 and LDL cholesterol levels remained significantly lower than at baseline in association with all inclisiran regimens. Serious adverse events occurred in 11% of the patients who received inclisiran and in 8% of the patients who received placebo. Injection-site reactions occurred in 5% of the patients who received injections of inclisiran.ConclusionsIn our trial, inclisiran was found to lower PCSK9 and LDL cholesterol levels among patients at high cardiovascular risk who had elevated LDL cholesterol levels. (Funded by the Medicines Company; ORION-1 ClinicalTrials.gov number, NCT02597127 .).

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