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

Feb 02, 2024
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Trial Sponsor:
Novartis Pharma AG
Date Published:
01/29/2024
Date Updated:
02/02/2024
Original Posted Date:
10/23/2023
References

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.

Description:

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).

Interpretation:

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.

References:

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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