ESPE Yearbook of Paediatric Endocrinology

Circulation. 2025 Jun 24;151(25):1758-1766. doi: 10.1161/CIRCULATIONAHA.124.073233

Brief Summary: This 1-year, double-blind, placebo-controlled phase 3 study assessed the efficacy and safety of inclisiran in adolescents (12 to <18 years of age) with homozygous familial hypercholesterolemia.

Comment: RNA interference (RNAi) is a natural biological process in which double-stranded RNA molecules mediate sequence-specific gene silencing, either by degrading messenger RNA (mRNA) or by inhibiting its translation. This mechanism plays a critical role in regulating gene expression. The discovery of RNAi, for which Andrew Fire and Craig Mello were awarded the 2006 Nobel Prize in Physiology or Medicine, was a major breakthrough in molecular biology.A key component of the RNAi pathway is small interfering RNA (siRNA), also known as short interfering RNA or silencing RNA. siRNAs are double-stranded, non-coding RNA molecules typically 20–24 base pairs in length. They guide the RNA-induced silencing complex to complementary mRNA targets, leading to mRNA degradation and, consequently, inhibition of protein translation.

Inclisiran is a small interfering RNA that targets hepatic PCSK9 synthesis. By reducing intrahepatic PCSK9 levels, inclisiran upregulates LDL receptors (LDLRs), thereby increasing LDL-C uptake and lowering circulating LDL-C levels, except in individuals with null variants in both LDLR alleles. A recent meta-analysis demonstrated that among adults, inclisiran treatment led to a pooled mean LDL-C reduction of −48.6% in individuals with heterozygous familial hypercholesterolemia (HeFH). However, the reduction was much smaller in those with homozygous FH (HoFH: −9.1%). The current study assessed inclisiran treatment in adolescents with HoFH. At day 330, the mean±SD percentage change in LDL-C from baseline was −21.6±13.4% in the inclisiran group, compared to an increase of +11.7±30.5% in the placebo group. Among adolescents receiving inclisiran, 56% (5/9) achieved an LDL-C reduction greater than 15%, 33% (3/9) had reductions over 20%, and 33% had reductions exceeding 30%. Subgroup analysis by genotype demonstrated that inclisiran lowered LDL-C consistently, regardless of the specific causal genetic variant associated with HoFH.

Inclisiran was well tolerated, with a safety profile comparable to that observed in adults. No new safety concerns emerged; there were no serious adverse events, deaths, or treatment discontinuations related to adverse effects.

The results in adolescents are consistent with those observed in adults. On one hand, there is a meaningful reduction in cholesterol levels and a significant difference compared to placebo. In addition, the convenience of treatment, administration once every six months, should not be overlooked. On the other hand, individuals with homozygous mutations are more severely affected and tend to have extremely higher LDL-C levels. Thus, even a 20% reduction may still leave their LDL-C levels well above target.

Reference: 1. Khan Z, Singh A, Haseeb Ur Rasool M, Qasim N, Yafaa Naveed Chaudhary M, Syed S, Riaz M, Rehman W, Rehman I, Islam R, Islam H, Muhammad A, Devi R, Wei CR, Naaz F, Akilimali A. Efficacy and outcomes of inclisiran in the management of homozygous and heterozygous familial hypercholesterolemia: a systematic review and meta-analysis. Ann Med Surg (Lond). 2025 Feb 6;87(3):1599-1608. doi: 10.1097/MS9.0000000000002982. PMID: 40213236; PMCID: PMC11981386.