Background: Homozygous familial hypercholesterolemia, a genetic disease causing very high levels of LDL-C present from birth, leads to premature atherosclerotic CV disease. Early treatment initiation is crucial, but LDL-C goals aren’t reached. We present two recently published trials: one in adolescents with little residual activity of LDL Receptors (LDLR), and one in children with no or only a few LDLR left. 

Method 1: Inclisiran (siRNA targeting PCSK9) is evaluated in a 1-year RCT in 13 adolescents (12-17 years) with HoFH (excluding LDLR null/null variants), with LDL-C >130 mg/dL on max. tolerated statins, randomized 2:1 to 300 mg inclisiran-Na+ or placebo, on days 1, 90 and 270. The primary endpoint was the mean % change in LDL-C from baseline to day 330. 

Results 1: Placebo-adjusted mean % change in LDL-C from baseline to day 330 was -33.3%, change in PCSK9 from baseline to day 330 was -60.2%. Corresponding changes in ApoB, non-HDL-C and TC were -23.0%, -32.7% and -27.8%, respectively. Six of 9 inclisiran-treated patients (versus 1 of 4 on placebo) achieved a >15% reduction in LDL-C, and 5 of 9 (none on placebo) achieved a >20% reduction. No serious adverse events, treatment discontinuations or deaths occurred. 

Conclusions 1: In a 1-year RCT (ORION-13), inclisiran was effective in lowering LDL-C in adolescents with HoFH and well tolerated, supporting inclisiran as potentially useful in adolescents with HoFH and little LDLR residual activity.

Method 2: Evinacumab (mAb inhibiting ANGPTL3), acting independently of LDLR, is evaluated in a phase 3 open-label study in 14 children (5-11 years) with HoFH, with LDL-C >130 mg/dL, despite lipid-lowering therapy (LLT) (including apheresis and lomitapide). They were treated with IV evinacumab 15 mg/kg every 4 weeks. The primary endpoint was the mean % change in LDL-C from baseline to week 24. Evinacumab was administered within 1 day of completing apheresis. 

Results 2: Evinacumab decreased LDL-C by 48.3% from baseline to week 24. Corresponding changes in ApoB, non-HDL-C and TC were -41.3%, -48.9% and -49.1%, respectively. Treatment-related adverse events were reported in 2 (14.3%) patients (nausea and abdominal pain). One serious adverse event occurred (tonsillitis), not considered treatment-related. 

Conclusions 2: Evinacumab constitutes a new treatment for children with HoFH and inadequate LDL-C levels despite LLT, lowering LDL-C by nearly half in these high-risk and difficult-to-treat children. 

Albert Wiegman is an Associate Professor and Principal Investigator at Amsterdam UMC, the Netherlands, with internationally recognized expertise in pediatric lipid disorders, cardiovascular prevention, and inherited metabolic diseases. He is affiliated with the Departments of Pediatrics and Pediatric Metabolic Diseases and conducts research within the Amsterdam Gastroenterology Endocrinology & Metabolism (AGEM) and Amsterdam Cardiovascular Sciences research institutes. His work focuses on the early diagnosis, prevention, and treatment of familial hypercholesterolemia and other inherited lipid disorders in children, aiming to reduce lifelong cardiovascular risk through early intervention.

Over the course of his academic career, Professor Wiegman has authored more than 150 peer-reviewed publications and has contributed to numerous international clinical guidelines and landmark studies in pediatric lipidology and preventive cardiology. His research has advanced the understanding and management of familial hypercholesterolemia, novel lipid-lowering therapies, and cardiovascular risk assessment in children. Through his leadership in clinical research, education, and international collaborations, he continues to play a significant role in improving evidence-based care for children and adolescents with inherited metabolic and cardiovascular disorders worldwide.