Efficacy and safety of alirocumab in children and adolescents with heterozygous familial hypercholesterolaemia inadequately controlled with statins

Abstract Introduction Alirocumab targets the low-density lipoprotein receptor (LDL-R) regulator proprotein convertase subtilisin/kexin type 9 (PCSK9), preventing LDL-R degradation and reducing LDL-cholesterol (LDL-C) level. Purpose This international Phase 3 trial assessed the efficacy and safety of alirocumab for paediatric patients with heterozygous familial hypercholesterolaemia (HeFH) inadequately controlled with statins. Methods Patients aged 8–17 years with HeFH and LDL-C ≥130 mg/dL who were receiving a stable dose of statin (or non-statin therapy if statin-intolerant) were randomised 2:1 in two consecutive cohorts (dosing every 2 weeks [Q2W] or every 4 weeks [Q4W]) to receive subcutaneous injections of alirocumab or placebo equivalent for 24 weeks (double-blind [DB] treatment period). Dosage was adjusted based on body weight (40 mg Q2W/150 mg Q4W if <50 kg; 75 mg Q2W/300 mg Q4W if ≥50 kg). Dosage was up-titrated from Week 12 if LDL-C was ≥110 mg/dL at Week 8. After completing Week 24, patients could enter an open-label (OL) period during which they received alirocumab treatment for up to 80 weeks. The primary endpoint was difference in LDL-C percentage change from baseline to Week 24 between alirocumab and placebo. Key secondary endpoints assessed the efficacy of alirocumab vs placebo for other lipid parameters. Results Of 153 patients enrolled, 74 were randomised to Q2W treatment (49 alirocumab, 25 placebo) and 79 to Q4W treatment (52 alirocumab, 27 placebo). Baseline characteristics were generally similar between treatment groups. For Q2W and Q4W cohorts, mean (standard deviation [SD]) age was 12.8 (2.6) vs 13.0 (3.0) years, 51% vs 62% were female, mean baseline LDL-C was 171.6 (47.7) vs 176.7 (52.0) mg/dL, and 3/74 vs 8/79 were statin intolerant. At Week 24, least squares (LS) mean difference was −43.3% (97.5% CI: −56.0, −30.7; p<0.0001) for alirocumab Q2W vs placebo Q2W and −33.8% (97.5% CI: −46.4, −21.2; p<0.0001) for alirocumab Q4W vs placebo Q4W (Figure 1). Alirocumab was associated with consistent reduction of LDL-C from baseline to Week 24 vs placebo across dosing cohorts. The first 12 key secondary endpoints in the testing hierarchy (Table 1) showed significant treatment differences in favour of alirocumab at Week 24 for both dosing regimens. Overall, 145 patients entered the OL treatment period; LS mean (SD) change in LDL-C from baseline to Week 104 was similar for alirocumab Q2W (−26.3% [28.0]) and alirocumab Q4W (−23.9% [33.5]). No clinically meaningful differences in AEs (any level) were observed between treatment groups in the DB or OL treatment periods, and no safety concerns were observed in the 4 patients (3 in DB and 1 in OL treatment period) who developed anti-alirocumab antibodies. Conclusions Both dosing regimens of alirocumab were associated with significantly reduced LDL-C and other atherogenic lipid parameters in paediatric patients with HeFH and were well tolerated, with efficacy sustained over time.

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