Merel L Hartgers1, Joep C Defesche2, Gisle Langslet3, Paul N Hopkins4, John J P Kastelein1, Marie T Baccara-Dinet5, Werner Seiz6, Sara Hamon7, Poulabi Banerjee7, Claudia Stefanutti8. 1. Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. 2. Department of Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands. 3. Lipid Clinic, Oslo University Hospital, Oslo, Norway. 4. School of Medicine, University of Utah, Salt Lake City, UT, USA. 5. Cardiovascular R&D, Sanofi, Montpellier, France. 6. Translational Medicine and Early Development, Sanofi, Frankfurt, Germany. 7. Translational Medicine, Regeneron Pharmaceuticals, Inc., New York, NY, USA. 8. Department of Molecular Medicine, 'Sapienza' University of Rome, Umberto I Hospital, Rome, Italy. Electronic address: claudia.stefanutti@uniroma1.it.
Abstract
BACKGROUND: Mutations in the genes for the low-density lipoprotein receptor (LDLR), apolipoprotein B, and proprotein convertase subtilisin/kexin type 9 have been reported to cause heterozygous and homozygous familial hypercholesterolemia (FH). OBJECTIVE: The objective is to examine the influence of double heterozygous, compound heterozygous, or homozygous mutations underlying FH on the efficacy of alirocumab. METHODS: Patients from 6 alirocumab trials with elevated low-density lipoprotein cholesterol (LDL-C) and FH diagnosis were sequenced for mutations in the LDLR, apolipoprotein B, proprotein convertase subtilisin/kexin type 9, LDLR adaptor protein 1 (LDLRAP1), and signal-transducing adaptor protein 1 genes. The efficacy of alirocumab was examined in patients who had double heterozygous, compound heterozygous, or homozygous mutations. RESULTS: Of 1191 patients sequenced, 20 patients were double heterozygotes (n = 7), compound heterozygotes (n = 10), or homozygotes (n = 3). Mean baseline LDL-C levels were similar between patients treated with alirocumab (n = 11; 198 mg/dL) vs placebo (n = 9; 189 mg/dL). All patients treated with alirocumab 75/150 or 150 mg every 2 weeks had an LDL-C reduction of ≥15% at either week 12 or 24. At week 12, 1 patient had an increase of 7.1% in LDL-C, whereas in others, LDL-C was reduced by 21.7% to 63.9% (corresponding to 39-114 mg/dL absolute reduction from baseline). At week 24, LDL-C was reduced in all patients by 8.8% to 65.1% (10-165 mg/dL absolute reduction from baseline). Alirocumab was generally well tolerated in the 6 trials. CONCLUSION:Clinically meaningful LDL-C-lowering activity was observed in patients receiving alirocumab who were double heterozygous, compound heterozygous, or homozygous for genes that are causative for FH.
RCT Entities:
BACKGROUND: Mutations in the genes for the low-density lipoprotein receptor (LDLR), apolipoprotein B, and proprotein convertase subtilisin/kexin type 9 have been reported to cause heterozygous and homozygous familial hypercholesterolemia (FH). OBJECTIVE: The objective is to examine the influence of double heterozygous, compound heterozygous, or homozygous mutations underlying FH on the efficacy of alirocumab. METHODS:Patients from 6 alirocumab trials with elevated low-density lipoprotein cholesterol (LDL-C) and FH diagnosis were sequenced for mutations in the LDLR, apolipoprotein B, proprotein convertase subtilisin/kexin type 9, LDLR adaptor protein 1 (LDLRAP1), and signal-transducing adaptor protein 1 genes. The efficacy of alirocumab was examined in patients who had double heterozygous, compound heterozygous, or homozygous mutations. RESULTS: Of 1191 patients sequenced, 20 patients were double heterozygotes (n = 7), compound heterozygotes (n = 10), or homozygotes (n = 3). Mean baseline LDL-C levels were similar between patients treated with alirocumab (n = 11; 198 mg/dL) vs placebo (n = 9; 189 mg/dL). All patients treated with alirocumab 75/150 or 150 mg every 2 weeks had an LDL-C reduction of ≥15% at either week 12 or 24. At week 12, 1 patient had an increase of 7.1% in LDL-C, whereas in others, LDL-C was reduced by 21.7% to 63.9% (corresponding to 39-114 mg/dL absolute reduction from baseline). At week 24, LDL-C was reduced in all patients by 8.8% to 65.1% (10-165 mg/dL absolute reduction from baseline). Alirocumab was generally well tolerated in the 6 trials. CONCLUSION: Clinically meaningful LDL-C-lowering activity was observed in patients receiving alirocumab who were double heterozygous, compound heterozygous, or homozygous for genes that are causative for FH.
Authors: Gerald F Watts; Samuel S Gidding; Pedro Mata; Jing Pang; David R Sullivan; Shizuya Yamashita; Frederick J Raal; Raul D Santos; Kausik K Ray Journal: Nat Rev Cardiol Date: 2020-01-23 Impact factor: 32.419
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