Diabetes Care Volume 42, January 2019 173 Inclisiran Lowers LDL-C and Lawrence A. Leiter,1 Hwee Teoh,1,2 David Kallend,3 R. Scott Wright,4 PCSK9 Irrespective of Diabetes Ulf Landmesser,5 Peter L.J. Wijngaard,3 John J.P. Kastelein,6 and Kausik K. Ray7 Status: The ORION-1 Randomized Clinical Trial Diabetes Care 2019;42:173–176 | https://doi.org/10.2337/dc18-1491 OBJECTIVE To evaluate the efficacy and safety of inclisiran by diabetes status. RESEARCH DESIGN AND METHODS ORION-1 (ClinicalTrials.gov, NCT02597127) randomized 501 subjects with athero- sclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalents and high LDL cholesterol (LDL-C), despite maximally tolerated LDL-C–lowering therapies, to one 1 or two doses of placebo or inclisiran. Levels of lipids and proprotein convertase Division of Endocrinology and Metabolism, Li Ka Shing Knowledge Institute of St. Michael’s Hos- subtilisin/kexin type 9 (PCSK9) at baseline and day 180 were compared. pital, University of Toronto, Toronto, Ontario, Canada RESULTS 2Division of Cardiac Surgery, Keenan Research Inclisiran was associated with marked declines in LDL-C (median 228% to 252%, P < Centre for Biomedical Science and Li Ka Shing 0.0001 and 228% to 255%, P < 0.005 for all doses in the without- and with-diabetes Knowledge Institute of St. Michael’s Hospital, Toronto, Ontario, Canada groups, respectively) and PCSK9. The inclisiran-treated groups also had lower 3The Medicines Company, Parsippany, NJ apolipoprotein B, non-HDL cholesterol, and lipoprotein(a) but higher HDL choles- 4Department of Cardiology, Mayo Clinic, Roches- terol. Inclisiran had an adverse profile similar to that of placebo, and adverse events ter, MN NOVEL COMMUNICATIONS IN DIABETES 5 were proportionally balanced in the baseline with- and without-diabetes groups. Departmentof Cardiology,Charite-Universit´ ats-¨ medizin Berlin, Berlin Institute of Health and CONCLUSIONS German Center for Cardiovascular Research, Partner Site Berlin, Berlin, Germany PCSK9-targeted siRNA-driven strategies may provide a novel therapeutic option 6Department of Vascular Medicine, Academic for managing dyslipidemia in the presence and absence of diabetes. Medical Center, University of Amsterdam, Am- sterdam, the Netherlands 7Department of Primary Care and Public Health, Imperial Centre for Cardiovascular Disease Pre- Many individuals at high cardiovascular risk have LDL cholesterol (LDL-C) levels vention, Imperial College London, London, U.K. exceeding recommended targets (1,2). Diabetes is a risk factor for atherosclerotic Correspondingauthor:LawrenceA.Leiter,leiterl@ cardiovascular disease (ASCVD), and guidelines underscore timely initiation of smh.ca – appropriately aggressive LDL-C lowering pharmacotherapy in individuals who co- Received 12 July 2018 and accepted 21 October present with diabetes and dyslipidemia (3–5). 2018 Although statins remain the cornerstone of LDL-C–lowering strategies, maximally Clinical trial reg. no. NCT02597127, clinicaltrials tolerated doses of statins are not always sufficiently efficacious even when used with .gov nonstatin lipid-lowering agents. The discovery that proprotein convertase subtilisin/ This article contains Supplementary Data online kexin type 9 (PCSK9) modulates the degradation of LDL receptors (LDLRs) (6), and at http://care.diabetesjournals.org/lookup/suppl/ the linking of PCSK9 polymorphisms with serum LDL-C levels and cardiovascular out- doi:10.2337/dc18-1491/-/DC1. comes (7) signaled a new era of lipid-lowering options. Novel approaches involving © 2018 by the American Diabetes Association. monoclonal antibodies that interfere with PCSK9-LDLR interaction or RNA interfer- Readers may use this article as long as the work is properly cited, the use is educational and not ence preventing PCSK9 synthesis are associated with substantial LDL-C declines for profit, and the work is not altered. More infor- among individuals with suboptimal LDL-C levels despite being on optimal background mation is available at http://www.diabetesjournals statin therapy with or without other lipid-lowering agents (8–13). Furthermore, .org/content/license. 174 Inclisiran Lowers LDL-C in Diabetes Diabetes Care Volume 42, January 2019 interventions targeting PCSK9 have dem- RESULTS Inclisiran therapy was also associated onstrated cardiovascular benefit in in- Of the 501 subjects randomized, 497 re- with decreases in total cholesterol, dividuals with stable cardiovascular ceived their assigned study agent. A total atherogenic apolipoprotein B, non-HDL disease (9,10) and recent acute coro- of 67 had diabetes at baseline (n = 25 and cholesterol, and lipoprotein(a), as well as nary syndromes (12,13) regardless of 42 for the one-dose and two-dose sub- a trend toward increases in HDL choles- whether they have diabetes (10,12). studies, respectively) and 415 did not terol, regardless of baseline diabetes Inclisiran is a synthetic siRNA that (n = 218 and 197 for the one-dose and status or whether they were assigned drives PCSK9-specific mRNA degradation two-dose substudies). The baseline clin- to the one-dose or two-dose regimen in the liver. The ORION-1 trial (Clinical- ical characteristics were generally similar (Supplementary Table 1). Trials.gov, NCT02597127) reported that between the placebo- and inclisiran- There were no clinically meaningful people with ASCVD or ASCVD risk equiv- treated groups, with minor exceptions. changes in HbA1c 180 days after treat- alents along with high LDL-C, despite The placebo group tended to have higher ment initiation, and this persisted over management with maximally tolerated BMI, and the inclisiran group with di- the course of the study. The overall LDL-C–lowering therapies, had signifi- occurrences of adverse events were abetes tended to be older. Median HbA1c cantly lower LDL-C following inclisiran values in the groups without diabetes similar in subjects with and subjects therapy (8,11). This post hoc analysis were ;5.6% (36 mmol/mol), while those without diabetes. There were no cases evaluated whether ORION-1 subjects in the groups with diabetes ranged be- of myopathyand nopersistent elevations with and without diabetes at baseline tween 7.6% (60 mmol/mol) and 8.5% of liver function tests considered to be responded differently to inclisiran with (69 mmol/mol). related to inclisiran in subjects with or fi respect to changes in lipid pro les, safety, Inclisiran treatment was associated without diabetes. and glycemic control. with robust reductions in mean LDL-C levels from day 14 until day 210 regard- CONCLUSIONS RESEARCH DESIGN AND METHODS less of baseline diabetes status (Table 1). We report that, regardless of diabetes Details for the ORION-1 trial have pre- The LDL-C nadirs with the one-dose in- status, silencing of the PCSK9 pathway via viously been published (8). Subjects were clisiran regimens normally occurred at siRNA technology on a maximally toler- randomized to either one dose of pla- day 30; LDL-C remained significantly be- ated statin background 1) yields rapid, cebo or inclisiran (200, 300, or 500 mg) low baseline levels at day 180. The significant, and extended lowering of on day 1 or two doses of placebo or groups assigned to the two-dose incli- LDL-C levels with one to two injections; inclisiran (100, 200, or 300 mg inclisiran siran regimens demonstrated further 2) improves atherogenic lipid and lipo- on days 1 and 90). For this analysis, the LDL-C lowering after the second dose protein profiles; and 3) is safe and well subjects were divided into those with or of inclisiran. The maximal changes in tolerated, including neutral effects on without diabetes at baseline. The primary LDL-C between the baseline visits and glycemia and inflammatory markers. efficacy end point was the percent change those after the second inclisiran doses The novel approach of using PCSK9- from baseline LDL-C at day 180. Second- were greater than those noted for the directed monoclonal antibodies pro- ary efficacy end points included the per- one-dose regimens and displayed a vides an option for people who are at cent change in lipid measures. Adverse slower return to baseline values for up very high risk and who have been unable events were documented up to day 210. to 210 days. to achieve their LDL-C goals. Importantly, Table 1—Similar lowering of LDL-C levels between the baseline and day 180 visits for the group without and group with diabetes Without diabetes (N = 415 [86% of cohort]) With diabetes (N = 67 [14% of cohort]) Baseline % LDL-C change, Baseline % LDL-C change, LDL-C, mmol/L, LS mean LDL-C,(mmol/L), LS mean n (%) median (IQR) (95% CI) P (vs. placebo) n (%) Median, (IQR) (95% CI) P (vs. placebo) One dose Placebo 57 (26) 3.1 (2.5, 3.8) 2.8 (22.5, 8.2) NA 6 (24) 2.3 (2.1, 2.9) 24.3 (220.9, 12.2) NA Inclisiran 200 mg 53 (24) 3.1 (2.6, 3.5) 228.0(233.6, 222.4) ,0.0001 7 (28) 2.9 (2.7, 3.0) 227.6(242.9, 212.3) 0.0670 300 mg 54 (25) 2.8 (2.2, 3.8) 236.9(242.4, 231.4) ,0.0001 6 (24) 2.7 (2.2, 3.4) 252.0(268.5, 235.5) 0.0009 500 mg 54 (25) 3.5 (2.7, 4.4) 241.4(247.0, 235.9) ,0.0001 6 (24) 3.6 (2.3, 4.3) 245.8(262.3, 229.3) 0.0031 Two dose Placebo 52 (26) 2.8 (2.3, 3.8) 2.3 (22.4, 7.1) NA 9 (21) 3.3 (3.0, 3.6) 21.2 (212.7, 10.3) NA Inclisiran 100 mg 49 (25) 3.1 (2.3, 3.8) 235.1(240.0, 230.2) ,0.0001 10 (24) 3.3 (3.0, 3.6) 237.2(248.1, 226.3) 0.0001 200 mg 44 (22) 3.1 (2.3, 4.4) 243.6(248.8, 238.4) ,0.0001 16 (38) 3.0 (2.8, 3.8) 248.3(257.0, 239.7) ,0.0001 300 mg 52 (26) 3.1 (2.5, 4.1) 252.3(257.1, 247.5) ,0.0001 7 (17) 2.9 (2.5, 4.7) 255.0(268.0, 242.0) ,0.0001 Data are presented for the modified intention-to-treat population.