Lipid-efficacy RCT · N Engl J Med 2017
ORION-1 trial
Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol.
The bottom line
In this phase 2 trial, inclisiran produced substantial, dose-dependent, and durable reductions in LDL cholesterol and PCSK9 levels in high cardiovascular risk patients, with an acceptable safety profile, but the trial was not designed to assess cardiovascular outcomes.
Primary lipid endpoint metUS status: US-approved
At a glance
- Medicine
- Single dose of 200, 300, or 500 mg inclisiran, or two doses (days 1 and 90) of 100, 200, or 300 mg inclisiran, subcutaneous injection
- Compared with
- Placebo (single dose or two doses)
- People
- 501
- Who took part
- Patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels
- Design
- Phase 2, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial
- Follow-up
- Safety data through day 210; LDL cholesterol and PCSK9 data through day 240
- Main question
- Change from baseline in LDL cholesterol level at 180 days
Main result
At day 180, the least-squares mean reductions in LDL cholesterol levels were 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6% after two doses (P<0.001 for all comparisons vs. placebo).
Effect on LDL cholesterol
Least-squares mean LDL-C reductions at day 180: 27.9-41.9% after a single dose; 35.5-52.6% after two doses; two-dose 300-mg regimen produced greatest reduction, with 48% of patients achieving LDL-C below 50 mg/dL (1.3 mmol/L) at day 180; at day 240, PCSK9 and LDL-C remained significantly lower than baseline with all regimens.
Other results
Not reported
Safety
Serious adverse events occurred in 11% of patients who received inclisiran and in 8% of patients who received placebo. Injection-site reactions occurred in 5% of the patients who received injections of inclisiran.
In the trial's own words
“At day 180, the least-squares mean reductions in LDL cholesterol levels were 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6% after two doses (P<0.001 for all comparisons vs. placebo).”
Quoted from the abstract of N Engl J Med 2017, checked word for word against PubMed. PubMed 28306389 · Full paper (DOI)
How this medicine works, where it stands and what it costs: Inclisiran (Leqvio)
Common questions
What did the ORION-1 trial find?
In this phase 2 trial, inclisiran produced substantial, dose-dependent, and durable reductions in LDL cholesterol and PCSK9 levels in high cardiovascular risk patients, with an acceptable safety profile, but the trial was not designed to assess cardiovascular outcomes.
Who was in ORION-1?
501 people. Patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels.
What was ORION-1's main result?
At day 180, the least-squares mean reductions in LDL cholesterol levels were 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6% after two doses (P<0.001 for all comparisons vs. placebo).
How much did LDL cholesterol change in ORION-1?
Least-squares mean LDL-C reductions at day 180: 27.9-41.9% after a single dose; 35.5-52.6% after two doses; two-dose 300-mg regimen produced greatest reduction, with 48% of patients achieving LDL-C below 50 mg/dL (1.3 mmol/L) at day 180; at day 240, PCSK9 and LDL-C remained significantly lower than baseline with all regimens.
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