Whether long-term treatment with the twice-yearly, siRNA therapeutic inclisiran, which reduces hepatic production of proprotein convertase subtilisin/kexin type 9 (PCSK9), results in sustained ...reductions in LDL cholesterol with an acceptable safety profile is not known. The aim of this study was to assess the effect of long-term dosing of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol.
ORION-3 was a 4-year open-label extension study of the placebo-controlled, phase 2 ORION-1 trial, conducted at 52 sites across five countries. Patients with prevalent atherosclerotic cardiovascular disease or high-risk primary prevention and elevated LDL cholesterol despite maximally tolerated statins or other LDL-lowering treatments, or with documented statin intolerance, who had completed the ORION-1 trial were eligible. Patients receiving inclisiran in ORION-1 received twice-yearly 300 mg subcutaneous inclisiran sodium throughout ORION-3 (inclisiran-only arm), whereas patients receiving placebo in ORION-1 first received subcutaneous evolocumab 140 mg every 2 weeks until day 360 thereafter transitioning to inclisiran twice-yearly for the remainder of ORION-3 study (switching arm). The primary efficacy endpoint was the percentage change in LDL cholesterol with inclisiran from the start of ORION-1 through to day 210 of the open label extension phase in the inclisiran-only arm (approximately 570 days of total inclisiran exposure in the modified intention-to-treat population). Secondary and exploratory endpoints included changes in LDL-C cholesterol and PCSK9 concentrations levels up to day 1440 (4 years) in each arm, and safety. ORION-3 is registered with ClinicalTrials.gov, NCT03060577.
Of the original ORION-1 cohort of 497 patients, 290 of 370 patients allocated to drug continued into the inclisiran-only arm and 92 of 127 patients allocated to placebo entered the switching-arm in the ORION-3 extension study conducted between March 24, 2017, and Dec 17, 2021. In the inclisiran-only arm, LDL cholesterol was reduced by 47·5% (95% CI 50·7–44·3) at day 210 and sustained over 1440 days. The 4-year averaged mean reduction of LDL-C cholesterol was 44·2% (95% CI: 47·1–41·4), with reductions in PCSK9 ranging from 62·2% to 77·8%. Adverse events at the injection site were reported in 39 (14%) of 284 patients in the inclisiran-only arm and 12 (14%) of 87 patients in the switching arm. The incidence of treatment-emergent serious adverse events possibly related to the study drug was 1% (three of 284) in the inclisiran-only arm and 1% (one of 87) in the switching arm.
Twice-yearly inclisiran provided sustained reductions in LDL cholesterol and PCSK9 concentrations and was well tolerated over 4 years in the extension study. This is the first prospective long-term study to assess repeat hepatic exposure to inclisiran.
Novartis Pharma.
Urate production by human heart Huizer, T; de Jong, J W; Nelson, J A ...
Journal of molecular and cellular cardiology,
07/1989, Volume:
21, Issue:
7
Journal Article
Peer reviewed
Open access
Xanthine oxidoreductase has been demonstrated in the heart of various species. However, its presence in human heart is still debated. In the literature, high to undetectable levels have been ...reported. We studied the arterial-venous urate difference across the heart of patients undergoing both routine cardiac catheterization and percutaneous transluminal coronary angioplasty. Urate is the end product of the reaction catalysed by xanthine oxidoreductase. In 10 patients, studied before angioplasty, the plasma urate level in the great cardiac vein exceeded the arterial one by 26 +/- 10 nmol/ml (P = 0.028). In a further 13 patients, urate production was maximal immediately after the last of four consecutive occlusions (23 +/- 8 nmol/ml, P = 0.018) and concomitant with increased coronary sinus hypoxanthine levels. We conclude that xanthine oxidoreductase is probably present in the heart of patients, suffering from ischemic heart disease, and responsible for the increase in urate production during transient myocardial ischemia.
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