The following is a summary of “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 February 2023 issue of Diabetes and Endocrinology by Ray, et al.

It is unknown if the siRNA therapy inclisiran, which is administered twice yearly, can lower LDL cholesterol with an acceptable safety profile over the long term by decreasing hepatic production of proprotein convertase subtilisin/kexin type 9 (PCSK9). This research was aimed at investigating the effects of chronic inclisiran administration in patients with high cardiovascular risk and raised LDL cholesterol. ORION-3 was a placebo-controlled, phase 2 extension study that spanned 4 years and 52 sites in 5 nations. Individuals who had completed the ORION-1 study and had either prevalent atherosclerotic cardiovascular disease or high-risk primary prevention with higher LDL cholesterol despite maximally tolerated statins or other LDL-lowering therapies, or with confirmed statin intolerance, were considered. In ORION-1, patients who received inclisiran were given 300 mg of subcutaneous inclisiran sodium twice yearly for the duration of ORION-3 (inclisiran-only arm). 

Those who received placebo 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). The percentage change in LDL cholesterol from the beginning of ORION-1 to day 210 of the open label extension phase in the inclisiran-only arm was the primary effectiveness objective (approximately 570 days of total inclisiran exposure in the modified intention-to-treat population). Alterations in LDL-C and PCSK9 concentrations were assessed up to day 1,440 (4 years) in each group as a secondary endpoint. In the ORION-3 extension study run from March 24, 2017, to December 17, 2021, 290 of 370 patients allocated to drug continued into the inclisiran-only arm, and 92 of 127 patients randomised to placebo entered the switching-arm. 

LDL cholesterol was lowered by 47.5% (95% CI 50.7%-44.3%) at day 210 and was maintained over 1440 days in the inclisiran-only group. Reductions in PCSK9 ranged from 62% to 78% over the course of 4 years, with an average mean reduction in LDL-C cholesterol of 44% (95% CI: 47%-44%). In the inclisiran-only group, 39 patients (14%) had injection-site adverse events, while the switching group reported 12 cases (14%) of injection-site adverse events. In the inclisiran-only arm, 1% (3 of 284) and 1% (1 of 87) of patients experienced significant adverse events that might be attributed to the study medicine, respectively. During the course of the extension study’s 4 years, twice-yearly dosing with inclisiran resulted in significant decreases in LDL cholesterol and PCSK9 concentrations and was well tolerated by all patients. The following study was funded by Novartis Pharma.