A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia–5 - ORION-5

Contribution To Literature:

The ORION-5 trial indicated that inclisiran is not superior to placebo in reducing LDL-C between baseline and day 150 among patients with HoFH who are already on maximal doses of statins and other lipid-lowering therapy.


The goal of the trial was to assess the safety and efficacy of inclisiran in lowering low-density lipoprotein cholesterol (LDL-C) among patients with homozygous familial hypercholesterolemia (HoFH).

Study Design

Eligible patients were randomized in a 2:1 fashion to either inclisiran 300 mg (n = 37) or matching placebo (n = 19). All patients were on maximally tolerated statin. The study drug was administered as a subcutaneous injection on day 1 and day 90. Part 2 consisted of an 18-month open-label, single-arm phase in which patients already receiving inclisiran continued treatment, and placebo-treated patients from part 1 were transitioned to inclisiran and received their first dose of inclisiran subcutaneously on day 180. All patients in part 2 received subsequent doses of inclisiran on days 270, 450, and 630, with an end-of-study visit on day 720.

  • Total number of enrollees 56
  • Duration of follow-up: 24 months
  • Mean patient age: 43 years
  • Percentage female: 61%

Inclusion criteria:

  • Age ≥18 years
  • HoFH diagnosed by history of an untreated LDL-C concentration >500 mg/dL together with either xanthoma before 10 years of age or evidence of heterozygous familial hypercholesterolemia in both parents
  • LDL-C ≥130 mg/dL despite receiving a maximally tolerated dose of statin therapy with or without ezetimibe

Exclusion criteria:

  • Patients receiving anti-PCSK9 (proprotein convertase subtilisin/kexin type 9) therapies within 90 days of screening

Other salient features/characteristics:

  • Known atherosclerotic cardiovascular disease: 68%
  • High-intensity statins: 100%, ezetimibe: 66%, apheresis: 36%
  • Baseline LDL-C: 315.3 mg/dL
  • Lipoprotein(a): 85 nmol/L
  • Apolipoprotein B (apoB): 203.1 mg/dL

Principal Findings:

The primary outcome, least squares mean LDL-C change, for inclisiran vs. placebo, 0.7 vs. 2.39; difference = −1.68 (95% confidence interval [CI] −29.19, 25.83; p = 0.90).

Secondary outcomes for inclisiran vs. placebo:

  • Placebo-corrected absolute change in LDL-C level from baseline to day 150: 6.47 mg/dL (p = 0.87)
  • Placebo-corrected percentage changes from baseline to day 150 for apoB (−4.3%; p = 0.68), non–HDL-C (−2.1%; p = 0.87), and total cholesterol (−0.8%; p = 0.94) 
  • Placebo-corrected percentage change in PCSK9 level from baseline to day 180 ranged between −60.6% and −92.3%

In a subgroup analysis by genotype that evaluated the reduction in LDL-C level from baseline to day 150 by underlying causal sequence variations of HoFH, the placebo-corrected percentage reduction in LDL-C level from baseline to day 150 was numerically greater in the compound heterozygous LDLR group (−26.5%; n = 15; p = 0.47) than the other genetic types group (−22.5%; n = 22; p = 0.40), but LDL-C level increased in the homozygous LDLR group (+26.6%; n = 19; p = 0.18).


The results of this trial indicate that inclisiran is not superior to placebo in reducing LDL-C between baseline and day 150 among patients with HoFH who are already on maximal doses of statins and other lipid-lowering therapy. Inclisiran is a long-acting, small interfering dsRNA agent that affects the production of PCSK9 in the liver. As evidence of the effect of inclisiran on its biological target, placebo-corrected changes in PCSK9 levels from baseline to day 150 were observed with inclisiran treatment and were sustained throughout the study. There was substantial variability in the LDL-C–lowering response to inclisiran treatment, possibly because of the different genotype subgroups with varying treatment effects; the reduction in LDL-C level was of greater magnitude in patients with higher residual LDLR function, although the small sample size precluded meaningful inferences.


Highlighted text has been updated as of February 2, 2024.

Raal F, Durst R, Bi R, et al., on behalf of the ORION-5 Study Investigators. Efficacy, Safety, and Tolerability of Inclisiran in Patients With Homozygous Familial Hypercholesterolemia: Results From the ORION-5 Randomized Clinical Trial. Circulation 2024;149:354-62.

Editorial: Santos RD, Cuchel M. LDL-C–Lowering Therapies for Adults and Children With Homozygous Familial Hypercholesterolemia: Challenges and Successes. Circulation 2024;149:363-6.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins

Keywords: Cholesterol, LDL, Dyslipidemias, Hypercholesterolemia

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