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
Bibliographic record
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: ] 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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.003 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".