PCSK9i reduces LDL-c in pediatric patients with inadequately controlled HeFH


In a phase 3 RCT, biweekly or monthly alirocumab, in addition to stable lipid-lowering therapy, reduced LDL-c and other proatherogenic lipids in pediatric patients with familial hypercholesterolemia (HeFH) at 24 weeks compared with placebo.

This summary is based on the publication of Santos RD, Wiegman A, Caprio S, et al. - Alirocumab in Pediatric Patients With Heterozygous Familial Hypercholesterolemia: A Randomized Clinical Trial. JAMA Pediatr. 2024 Mar 1;178(3):283-293. doi: 10.1001/jamapediatrics.2023.6477

Introduction and methods


For some pediatric patients with heterozygous familial hypercholesterolemia (HeFH), high-dose statins or other lipid-lowering therapies (LLTs), such as ezetimibe and bile acid sequestrants, are not sufficient to achieve LDL-c targets. The PCSK9 inhibitor alirocumab reduced LDL-c up to 46% in pediatric patients with HeFH inadequately controlled with statins, as shown by the phase 2 trial ODYSSEY KIDS (8-Week Open-Label, Sequential, Repeated Dose-Finding Study to Evaluate the Efficacy and Safety of Alirocumab in Children and Adolescents With Heterozygous Familial Hypercholesterolemia Followed by an Extension Phase) [1].

Aim of the study

The authors assessed the efficacy and safety of alirocumab in pediatric patients with inadequately controlled HeFH.


This was an international, multicenter, double-blind, placebo-controlled, phase 3 RCT in which 153 pediatric patients aged 8–17 years with HeFH and LDL-c ≥130 mg/dL who were receiving statins and/or other LLTs were included. After a 4-week run-in period and a 2-week screening period, participants were randomized 2:1 to subcutaneous alirocumab or placebo for 24 weeks, in addition to stable LLT, in 2 consecutive dosing cohorts (Q2W and Q4W). Alirocumab dosage in each cohort was based on the participant’s body weight: (1) biweekly dosing (Q2W): 40 mg if <50 kg and 75 mg if ≥50 kg; and (2) monthly dosing (Q4W): 150 mg if <50 kg and 300 mg if ≥50 kg. If LDL-c was ≥110 mg/dL at 8 weeks, the alirocumab dose was adjusted at 12 weeks to 75 mg Q2W for patients with a body weight <50 kg and 150 mg Q2W for those weighing ≥50 kg, regardless of cohort. After completion of the 24-week double-blind period, all patients could enter an open-label treatment period to receive alirocumab for up to 80 weeks.


The primary efficacy endpoint was the percent change in LDL-c from baseline to 24 weeks in each cohort. Key secondary efficacy endpoints were percent change in LDL-c at 12 weeks and other lipid parameters, including apoB, non–HDL-c, total cholesterol, HDL-c, Lp(a), triglycerides, and apoA-1, at 12 and 24 weeks. Additional secondary endpoints were safety, tolerability, and development of antialirocumab antibodies after 24 weeks.

Main results


  • At 24 weeks, the least-squares (LS) mean difference in the primary efficacy endpoint (i.e., percent change in LDL-c from baseline) for alirocumab versus placebo was –43.3% (97.5%CI: –56.0% to –30.7%; P<0.001) in the Q2W cohort and –33.8% (97.5%CI: –46.4% to –21.2%; P<0.001) in the Q4W cohort. The LDL-c reductions with alirocumab were already present at 8 weeks.
  • Hierarchical analysis of the first 12 key secondary efficacy endpoints showed significant reductions in apoB, non–HDL-c, and total cholesterol with alirocumab versus placebo in both dosing cohorts at 12 and 24 weeks (all P<0.001), as well as significant reductions in Lp(a) in both cohorts at 24 weeks (both P≤0.02).
  • At 24 weeks, 38 patients (77.3%) receiving alirocumab in the Q2W cohort and 39 (76.3%) in the Q4W cohort achieved LDL-c <130 mg/dL.
  • LDL-c reduction ≥50% at 24 weeks was observed in 10 patients (21.6%) in the Q2W cohort (vs. 0% in placebo group) and 17 (32.4%) in the Q4W cohort (vs. 9.1% in placebo group).
  • During the open-label period, LDL-c reductions were well maintained in patients who had received alirocumab in the double-blind period, whereas those who switched from placebo to alirocumab showed LDL-c reductions at 32 weeks, which were maintained through 104 weeks. The LS mean change in LDL-c from baseline to 104 weeks was −26.3% (SD: 28.0) in the Q2W cohort and −23.9% (SD: 33.5) in the Q4W cohort.


  • The frequency of any adverse event during the double-blind period was 53.1% in patients receiving alirocumab and 52.0% those receiving placebo in the Q2W cohort and 50.0% and 59.3%, respectively, in the Q4W cohort.
  • Most adverse events were mild or moderate, and no significant difference in adverse event rate was observed between the treatment groups.
  • Serious adverse events occurred in 8.2% of the patients receiving alirocumab and 4.0% of those receiving placebo in the Q2W cohort and in 3.8% and 3.7%, respectively, in the Q4W cohort. Most serious adverse events were resolved or recovered by the end of the double-blind period.
  • Two patients in the Q4W cohort experienced adverse events leading to discontinuation of alirocumab (syncope, and nonserious disturbance in attention and memory).


This international phase 3 RCT showed that biweekly or monthly dosing of alirocumab, in addition to stable LLT, was associated with reductions in LDL-c and other proatherogenic lipid parameters in pediatric HeFH patients at 24 weeks compared with placebo. The LDL-c reductions were present as early as 8 weeks and were maintained through 104 weeks. Alirocumab was well tolerated, and there were no safety concerns. The authors point out that “[t]he efficacy of alirocumab reported here in pediatric patients with HeFH is generally consistent with that in adult patients, although the LDL-c reduction in the current study appeared to be lower than reductions previously reported in adults [2].” However, they do warn that “comparisons across clinical trials should be considered cautiously given differences in study design and patient populations, particularly given the differences in treatment targets and uptitration thresholds between adult and pediatric patients.”


1. Daniels S, Caprio S, Chaudhari U, et al. PCSK9 inhibition with alirocumab in pediatric patients with heterozygous familial hypercholesterolemia: the ODYSSEY KIDS study. J Clin Lipidol. 2020;14(3):322-330.e5. doi:10.1016/j.jacl.2020.03.001

2. Kastelein JJ, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015;36(43):2996-3003. doi:10.1093/eurheartj/ehv370

Find this article online at JAMA Pediatr.

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