Open-label extension · Lancet Diabetes Endocrinol 2023
ORION-3 trial
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.
The bottom line
Twice-yearly inclisiran produced durable, substantial LDL cholesterol and PCSK9 lowering over 4 years of repeated hepatic dosing and was well tolerated with low rates of serious drug-related adverse events.
Sustained effectUS status: US-approved
At a glance
- Medicine
- Twice-yearly 300 mg subcutaneous inclisiran sodium (inclisiran-only arm); placebo arm from ORION-1 received evolocumab 140 mg every 2 weeks until day 360 then transitioned to twice-yearly inclisiran (switching arm)
- Compared with
- Within-patient comparison from ORION-1 baseline; switching arm initially evolocumab
- People
- 497
- Who took part
- 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
- Design
- 4-year open-label extension of placebo-controlled phase 2 trial, inclisiran-only arm and switching arm (evolocumab then inclisiran)
- Follow-up
- approximately 570 days of total inclisiran exposure for primary endpoint; up to 1440 days (4 years) for secondary/exploratory endpoints
- Main question
- 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
Main result
LDL cholesterol was reduced by 47·5% (95% CI 50·7-44·3) at day 210 and sustained over 1440 days
Effect on LDL cholesterol
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%
Other results
Changes in LDL-C cholesterol and PCSK9 concentrations up to day 1440 (4 years) in each arm; secondary/exploratory, not a mortality endpoint
Safety
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.
In the trial's own words
“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%.”
Quoted from the abstract of Lancet Diabetes Endocrinol 2023, checked word for word against PubMed. PubMed 36620965 · Full paper (DOI)
How this medicine works, where it stands and what it costs: Inclisiran (Leqvio)
Common questions
What did the ORION-3 trial find?
Twice-yearly inclisiran produced durable, substantial LDL cholesterol and PCSK9 lowering over 4 years of repeated hepatic dosing and was well tolerated with low rates of serious drug-related adverse events.
Who was in ORION-3?
497 people. 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.
What was ORION-3's main result?
LDL cholesterol was reduced by 47·5% (95% CI 50·7-44·3) at day 210 and sustained over 1440 days
How much did LDL cholesterol change in ORION-3?
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%
Related trials
- LIBerate-HeFH (2023)In patients with heterozygous familial hypercholesterolaemia needing more LDL-C lowering, adding monthly subcutaneous lerodalcibep to therapy produced a large, highly significant LDL-C reduction versus placebo over 24 weeks with a safety profile similar to placebo aside from mild injection site reactions.
- MK-0616 phase 2b (2023)In this phase 2b trial, the oral PCSK9 inhibitor MK-0616 produced large, dose-dependent LDL-C reductions compared with placebo and was well tolerated over 8 weeks of treatment plus 8 weeks of follow-up.
- FOURIER-OLE (2022)Long-term evolocumab treatment after FOURIER maintained very low LDL-C with a persistently favorable safety profile over more than 8 years, and earlier initiation of evolocumab was associated with fewer cardiovascular events, including cardiovascular death, compared with delayed treatment start.
- HUYGENS (2022)Adding evolocumab to statin therapy after NSTEMI led to greater regression and stabilization of coronary plaque on imaging (thicker fibrous caps, smaller lipid cores, less plaque burden) compared with placebo.
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