Lipid-efficacy RCT · N Engl J Med 2020
ORION-9 trial
Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia.
The bottom line
In patients with heterozygous familial hypercholesterolemia, twice-yearly inclisiran injections significantly lowered LDL cholesterol compared with placebo, with a similar safety profile and a convenient infrequent dosing schedule.
Primary lipid endpoint metUS status: US-approved
At a glance
- Medicine
- Inclisiran sodium 300 mg subcutaneous injection on days 1, 90, 270, and 450
- Compared with
- Matching placebo
- People
- 482
- Who took part
- Adults with heterozygous familial hypercholesterolemia; median age 56 years, 47% men, mean baseline LDL cholesterol 153 mg/dl
- Design
- phase 3, double-blind, randomized, placebo-controlled trial (1:1)
- Follow-up
- Through day 540
- Main question
- Percent change from baseline in LDL cholesterol level on day 510, and time-adjusted percent change from baseline in LDL cholesterol level between day 90 and day 540
Main result
At day 510, the percent change in the LDL cholesterol level was a reduction of 39.7% (95% CI, -43.7 to -35.7) in the inclisiran group and an increase of 8.2% (95% CI, 4.3 to 12.2) in the placebo group, for a between-group difference of -47.9 percentage points (95% CI, -53.5 to -42.3; P<0.001). The time-averaged percent change in the LDL cholesterol level between day 90 and day 540 was a reduction of 38.1% (95% CI, -41.1 to -35.1) in the inclisiran group and an increase of 6.2% (95% CI, 3.3 to 9.2) in the placebo group, for a between-group difference of -44.3 percentage points (95% CI, -48.5 to -40.1; P<0.001).
Effect on LDL cholesterol
Reduction of 39.7% at day 510 and time-averaged reduction of 38.1% (day 90-540) with inclisiran vs increases of 8.2% and 6.2% respectively with placebo; between-group differences of -47.9 and -44.3 percentage points
Other results
There were robust reductions in LDL cholesterol levels in all genotypes of familial hypercholesterolemia.
Safety
Adverse events and serious adverse events were similar in the two groups.
In the trial's own words
“At day 510, the percent change in the LDL cholesterol level was a reduction of 39.7% (95% confidence interval [CI], -43.7 to -35.7) in the inclisiran group and an increase of 8.2% (95% CI, 4.3 to 12.2) in the placebo group, for a between-group difference of -47.9 percentage points (95% CI, -53.5 to -42.3; P<0.001).”
Quoted from the abstract of N Engl J Med 2020, checked word for word against PubMed. PubMed 32197277 · Full paper (DOI)
How this medicine works, where it stands and what it costs: Inclisiran (Leqvio)
Common questions
What did the ORION-9 trial find?
In patients with heterozygous familial hypercholesterolemia, twice-yearly inclisiran injections significantly lowered LDL cholesterol compared with placebo, with a similar safety profile and a convenient infrequent dosing schedule.
Who was in ORION-9?
482 people. Adults with heterozygous familial hypercholesterolemia; median age 56 years, 47% men, mean baseline LDL cholesterol 153 mg/dl.
What was ORION-9's main result?
At day 510, the percent change in the LDL cholesterol level was a reduction of 39.7% (95% CI, -43.7 to -35.7) in the inclisiran group and an increase of 8.2% (95% CI, 4.3 to 12.2) in the placebo group, for a between-group difference of -47.9 percentage points (95% CI, -53.5 to -42.3; P<0.001). The time-averaged percent change in the LDL cholesterol level between day 90 and day 540 was a reduction of 38.1% (95% CI, -41.1 to -35.1) in the inclisiran group and an increase of 6.2% (95% CI, 3.3 to 9.2) in the placebo group, for a between-group difference of -44.3 percentage points (95% CI, -48.5 to -40.1; P<0.001).
How much did LDL cholesterol change in ORION-9?
Reduction of 39.7% at day 510 and time-averaged reduction of 38.1% (day 90-540) with inclisiran vs increases of 8.2% and 6.2% respectively with placebo; between-group differences of -47.9 and -44.3 percentage points
Related trials
- HAUSER-RCT (2020)In pediatric patients with heterozygous familial hypercholesterolemia already on lipid-lowering therapy, adding monthly evolocumab substantially lowered LDL cholesterol compared with placebo with a similar adverse event rate.
- ORION-10/11 (2020)Twice-yearly inclisiran injections lowered LDL cholesterol by about 50% compared with placebo in statin-treated patients with atherosclerotic cardiovascular disease, with mostly mild injection-site reactions as the main safety difference.
- ODYSSEY OUTCOMES (2018)In post-ACS patients already on high-intensity statins, adding alirocumab reduced recurrent cardiovascular events and all-cause death compared with placebo.
- 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.
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