# Efficacy and Safety of Inclisiran in Adolescents With Genetically Confirmed Homozygous Familial Hypercholesterolemia: Results From the Double-Blind, Placebo-Controlled Part of the ORION-13 Randomized Trial

Article · Wiegman A, Peterson AL, Hegele RA, Bruckert E, Schweizer A, Lesogor A, Wang Y, Defesche J

- Archive id: doi:10.1161/circulationaha.124.073233
- Published: 2025-05-20
- Venue: Circulation
- DOI: https://doi.org/10.1161/circulationaha.124.073233
- PMID: 40391436
- PMCID: PMC12180692
- Citations: 13
- Source URL: https://doi.org/10.1161/circulationaha.124.073233
- PDF: https://europepmc.org/articles/PMC12180692/pdf
- Provenance: europepmc

## Abstract

Background Homozygous familial hypercholesterolemia (HoFH) is a genetic disease characterized by high levels of low-density lipoprotein cholesterol (LDL-C) present from birth, leading to early-onset and progressive atherosclerotic cardiovascular disease. Early treatment initiation is crucial for cardiovascular risk reduction; however, many patients do not reach LDL-C treatment goals. Inclisiran, a small interfering RNA targeting hepatic PCSK9 (proprotein convertase subtilisin/kexin type 9), is effective and well tolerated in adult patients with hyperlipidemia; however, it has not yet been studied in pediatric patients. Methods Herein we report results of the 1-year, double-blind, placebo-controlled part of the phase 3 study ORION-13 (Study to Evaluate Efficacy and Safety of Inclisiran in Adolescents With Homozygous Familial Hypercholesterolemia) in adolescents with HoFH. This 2-part multicenter study included 13 patients ≥12 to \<18 years of age with a genetic diagnosis of HoFH (excluding LDL \[low-density lipoprotein\] receptor \[ LDLR \] null/null genotypes) and elevated LDL-C levels (\>130 mg/dL) on maximally tolerated statin treatment, with or without other lipid-lowering therapies. Eligible patients were randomized 2:1 to receive either 300 mg of inclisiran sodium or placebo, administered on days 1, 90, and 270. The primary end point was the mean percentage change in LDL-C from baseline to day 330. Results The mean age of patients was 14.8 years, and mean baseline LDL-C was 272 mg/dL. The placebo-adjusted mean (95% CI) percentage change in LDL-C from baseline to day 330 was -33.3% (-59.2% to -7.3%). Six of 9 (66.7%) inclisiran-treated patients (versus 1 of 4 \[25%\] on placebo) achieved a \>15% reduction in LDL-C, and 5 of 9 (55.6%) inclisiran-treated patients (versus none on placebo) achieved a \>20% reduction. The placebo-adjusted mean (95% CI) percentage change in PCSK9 from baseline to day 330 was -60.2% (-79.8% to -40.7%); corresponding changes in apolipoprotein B, non-high-density lipoprotein cholesterol, and total cholesterol were -23.0%, -32.7%, and -27.8%, respectively. No serious adverse events, treatment discontinuations because of adverse events, or deaths occurred. No new safety findings were reported. Conclusions In a 1-year randomized controlled study (part 1 of ORION-13), inclisiran was effective in lowering LDL-C in adolescents with HoFH and was well tolerated. These results support inclisiran as a potentially useful addition for the treatment of adolescents with HoFH and a minimum of LDLR residual activity. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04659863.

_Abstract reproduced under CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)._

Topics: [Cardiovascular Therapeutics](https://space-kitty.com/topics/cardiovascular-innovation)

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