The following is a summary of the “Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial,” published in the January 2023 issue of Diabetes and Endocrinology by Ray, et al.
The siRNA therapy inclisiran is administered twice yearly and decreases hepatic production of proprotein convertase subtilisin/kexin type 9 (PCSK9), but it is unclear if this results in sustained reductions in LDL cholesterol with a tolerable risk profile over the long term. Study participants had high cardiovascular risk and elevated LDL cholesterol, and researchers wanted to see how inclisiran would fare when given to them over several years. ORION-3 was a placebo-controlled, phase 2 extension study that spanned four years and 52 sites in five countries. Eligible patients included those who had completed the ORION-1 trial, had atherosclerotic cardiovascular disease, were at high risk for developing a such illness, and had elevated LDL cholesterol despite maximally tolerated statins or other LDL-lowering treatments or who had documented statin intolerance.
Patients in the inclisiran arm of ORION-1 were given 300 mg subcutaneous inclisiran sodium twice yearly for the duration of ORION-3 (inclisiran-only arm), while those in the placebo arm of ORION-1 were given subcutaneous evolocumab 140 mg every 2 weeks until day 360, and then switched to inclisiran twice yearly for the rest of the study (switching arm). Percentage change in LDL cholesterol in the inclisiran-only arm from the beginning of ORION-1 to day 210 of the open-label extension phase was the primary efficacy endpoint (approximately 570 days of total inclisiran exposure in the modified intention-to-treat population). Alterations in LDL-C cholesterol and PCSK9 concentrations up to day 1,440 (4 years) in each arm and safety served as secondary and exploratory endpoints. The ORION-3 study is a part of a larger research program with a unique identifier on ClinicalTrials.gov: NCT03060577.
Between March 24, 2017, and December 17, 2021, 290 of 370 patients from the original ORION-1 cohort of 497 continued into the inclisiran-only arm, and 92 of 127 patients from the placebo arm entered the switching arm of the ORION-3 extension study. LDL cholesterol was reduced by 47.5% (95% CI 50.7-44.3) at day 210 and remained low for 1,440 days in the inclisiran-only group. Reductions in PCSK9 ranged from 62% to 78% over 4 years, with an average mean reduction in LDL-C cholesterol of 44% (95% CI: 47%-44%). 39 (14%) of 284 patients in the inclisiran-only arm and 12 (14%) of 87 patients in the switching arm reported injection-site adverse events. Only 1% (3/284 people) of those assigned to the inclisiran-only group and 1% (1/87) of those assigned to the switching group experienced treatment-emergent serious adverse events that could be attributed to the study drug. The extension study found that twice-yearly inclisiran was safe and effective in lowering LDL cholesterol and PCSK9 concentrations for 4 years. Repeated infusions of inclisiran into the liver are evaluated in this first prospective, long-term study.