Efficacy and Safety of Alirocumab in Children and Adolescents With Homozygous Familial Hypercholesterolemia: Phase 3, Multinational Open-Label Study

Eric Bruckert, Sonia Caprio, Albert Wiegman, Min-Ji Charng, Cézar A Zárate-Morales, Marie T Baccara-Dinet, Garen Manvelian, Anne Ourliac, Michel Scemama, Stephen R Daniels, Eric Bruckert, Sonia Caprio, Albert Wiegman, Min-Ji Charng, Cézar A Zárate-Morales, Marie T Baccara-Dinet, Garen Manvelian, Anne Ourliac, Michel Scemama, Stephen R Daniels

Abstract

Background: Despite progress in treating homozygous familial hypercholesterolemia, most patients do not achieve low-density lipoprotein cholesterol (LDL-C) targets. This study examined efficacy and safety of the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, alirocumab, in pediatric patients (aged 8-17 years) with inadequately controlled homozygous familial hypercholesterolemia.

Methods: In this open-label, single-arm, multinational, Phase 3 study, patients (n=18) received alirocumab 75 mg or 150 mg (bodyweight <50 kg/≥50 kg) every 2 weeks as an adjunct to background treatment. The primary endpoint was percent change in LDL-C from baseline to Week 12. Secondary endpoints included changes in LDL-C and other lipid parameters up to 48 weeks, safety/tolerability, and alirocumab pharmacokinetics.

Results: The mean age of patients was 12.4 years; 16/18 (89%) had mutations in the low-density lipoprotein receptor gene (LDLR) and 2/18 (11%) had mutations in the LDLR adapter protein 1 gene (LDLRAP1). At baseline, mean LDL-C (standard deviation) was 373.0 (193.5) mg/dL, which decreased by 4.1% at Week 12 (primary endpoint) and 11.4%, 13.2%, and 0.4% at Weeks 4, 24, and 48, respectively. At Week 12, 9/18 (50%) patients achieved LDL-C reductions ≥15%. Mean absolute LDL-C decreases ranged from 25 to 52 mg/dL over follow-up. A post hoc analysis demonstrated heterogeneity of responses according to genotype. There were no unexpected safety/tolerability findings. Free PCSK9 was reduced to near zero for all patients at Weeks 12 and 24.

Conclusions: The study supports the efficacy and safety of alirocumab as a potential adjunct to treatment for some pediatric patients with homozygous familial hypercholesterolemia.

Registration: URL: https://www.

Clinicaltrials: gov; NCT03510715.

Figures

Figure 1.
Figure 1.
Individual percent change from baseline in low-density lipoprotein cholesterol (LDL-C) from baseline over the study period, by genotype. Each line represents absolute LDL-C change from baseline for 1 individual patient. *Patient death recorded following treatment discontinuation. LDLR indicates LDL receptor; and LDLRAP1, LDLR adapter protein 1.
Figure 2.
Figure 2.
Low-density lipoprotein cholesterol (LDL-C) change for the whole cohort at Weeks 12, 24, and 48. N=17 from Week 24 onward. CH indicates compound homozygote; LDLR, LDL receptor; TH, true homozygote; and W, Week.
Figure 3.
Figure 3.
Low-density lipoprotein cholesterol (LDL-C) absolute values (mg/dL) and percent (%) change from baseline to Week 48 according to assigned low-density lipoprotein receptor (LDLR) functional status. *n=5 from Week 24 onward. Measurements were performed pre-apheresis where applicable. Error bars indicate SD. LDLRAP1 indicates low-density lipoprotein receptor adapter protein 1.
Figure 4.
Figure 4.
Percent change in low-density lipoprotein cholesterol (LDL-C) from baseline (pre-apheresis if applicable) according to assigned functional status at Week 12, Week 24, and Week 48.*Patient on apheresis; †patient deceased. Measurements were performed pre-apheresis where applicable. LDLR indicates LDL receptor; and LDLRAP1, low-density lipoprotein receptor adapter protein 1.

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Source: PubMed

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