ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This double-blind, randomized trial, showed that 2 dosing regimens of alirocumab, a human monoclonal antibody to proprotein convertase subtilisin kexin type 9 (PCSK9), reduced LDL-C in children as young as 8 years with heterozygous familial hypercholesterolemia inadequately controlled by statins. Efficacy was sustained over 2 years, and both regimens were generally well tolerated.

Comment: Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant-inherited genetic disorder, with estimated prevalence 1:200–300 individuals. 20-year outcome data demonstrate lower rates of atherosclerotic cardiovascular disease (ASCVD) related events and death in individuals with HeFH treated with statins from childhood, compared to those who initiated statins in adulthood.¹ However, not all children respond to or tolerate statins.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is synthesized primarily in the liver, and enters the circulatory system, where it binds to hepatic LDL receptors, accelerating their degradation.² This process reduces the capacity of the liver to remove LDL-C from the circulation. Individuals with PCSK9 loss-of-function mutations have low levels of LDL-C and low incidence of coronary heart disease. Based on this knowledge, a human monoclonal antibody targeting PCSK9 was developed and was approved by the U.S. FDA in 2015 as a second-line treatment for adults with HeFH or ASCVD whose cholesterol levels are uncontrolled by diet and maximally-tolerated dose of statins. It is now marketed with biweekly dosage of 75 mg (through a self-administered 1 mL pen) which can be up-titrated to 150 mg if necessary.

This study randomized 153 pediatric patients aged 8-17 years to receive injections of Alirocumab either 2-weekly or 4-weekly, while 52 were in the control group. Treatment for 24 weeks reduced LDL-C and other proatherogenic lipid parameters compared to placebo. The difference in % change from baseline was -43% for those treated 2-weekly, and -34% on 4-weekly. After the 24-week trial phase, all patients could receive open-label alirocumab for up to 80 weeks. Improvements in LDL levels were maintained at week 104. Alirocumab was well tolerated with no safety concerns. Based on these results, last year alirocumab use in children received approval in the EU and USA.

References: 1. Peterson AL, McNeal CJ, Wilson DP. Prevention of Atherosclerotic Cardiovascular Disease in Children with Familial Hypercholesterolemia. Curr Atheroscler Rep. 2021 Aug 27;23(10):64. doi:10.1007/s11883-021-00959-8.2. Yadav K, Sharma M, Ferdinand KC. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors: Present perspectives and future horizons. Nutr Metab Cardiovasc Dis. 2016 Oct;26(10):853-62. doi:10.1016/j.numecd.2016.05.006.