Efficacy of alirocumab in 1191 patients with a wide spectrum of mutations in genes causative for familial hypercholesterolemia.

Abstract

BACKGROUND:

Mutation(s) in genes involved in the low-density lipoprotein receptor (LDLR) pathway are typically the underlying cause of familial hypercholesterolemia.

OBJECTIVE:

The objective of the study was to examine the influence of genotype on treatment responses with alirocumab.

METHODS:

Patients from 6 trials (n = 1191, including 758 alirocumab-treated; Clinicaltrials.gov identifiers: NCT01266876; NCT01507831; NCT01623115; NCT01709500; NCT01617655; NCT01709513) were sequenced for mutations in LDLR, apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), LDLR adaptor protein 1, and signal-transducing adaptor protein 1 genes. New mutations were confirmed by Sanger sequencing.

RESULTS:

One or more specific gene mutations were found in 898 patients (75%): 387 and 437 patients had heterozygous LDLR defective and negative mutations, respectively; 46 had a heterozygous APOB-defective mutation; 8 patients had a heterozygous PCSK9 gain-of-function mutation; 293 (25%) had no identifiable mutation in the genes investigated. LDL cholesterol reductions at Week 24 were generally similar across genotypes: 48.3% (n = 131) and 54.3% (n = 89) in LDLR-defective heterozygotes with alirocumab 75 mg Q2W (with possible increase to 150 mg at Week 12) and 150 mg Q2W, respectively; 49.7% (n = 168) and 60.7% (n = 88) in LDLR-negative heterozygotes; 54.1% (n = 20) and 50.1% (n = 6) in APOB-defective heterozygotes; 60.5% (n = 5) and 94.0% (n = 1) in PCSK9 heterozygotes; and 44.9% (n = 85) and 55.4% (n = 69) in patients with no identified mutations. Overall rates of treatment-emergent adverse events were similar for alirocumab vs controls (placebo in 5 trials, ezetimibe control or atorvastatin calibrator arm in 1 trial), with only a higher rate of injection-site reactions with alirocumab.

CONCLUSIONS:

In this large patient cohort, individuals with a wide spectrum of mutations in genes underlying familial hypercholesterolemia responded substantially and similarly to alirocumab treatment.

• Authors: Joep C Defesche, Claudia Stefanutti, Gisle Langslet, Paul N Hopkins, Werner Seiz, Marie T Baccara-Dinet, Sara C Hamon, Poulabi Banerjee, John J P Kastelein
• Journal: Journal of clinical lipidology (J Clin Lipidol) 2017 Nov - Dec Vol. 11 Issue 6 Pg. 1338-1346.e7 ISSN: 1933-2874 [Print] United States
• PMID: 28964736 (Publication Type: Clinical Trial, Journal Article)
• Copyright: Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Chemical References

• APOB protein, human
• Adaptor Proteins, Signal Transducing
• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Apolipoprotein B-100
• Biomarkers, Pharmacological
• Endosomal Sorting Complexes Required for Transport
• LDLR protein, human
• LDLRAP1 protein, human
• Phosphoproteins
• Receptors, LDL
• STAM protein, human
• PCSK9 protein, human
• Proprotein Convertase 9
• alirocumab

Topics

• Adaptor Proteins, Signal Transducing (genetics)
• Adult
• Antibodies, Monoclonal (administration & dosage, adverse effects)
• Antibodies, Monoclonal, Humanized
• Apolipoprotein B-100 (genetics)
• Biomarkers, Pharmacological
• Drug-Related Side Effects and Adverse Reactions (classification, pathology)
• Endosomal Sorting Complexes Required for Transport (genetics)
• Female
• Genotype
• Heterozygote
• Humans
• Hyperlipoproteinemia Type II (drug therapy, genetics, pathology)
• Male
• Middle Aged
• Mutation (genetics)
• Phosphoproteins (genetics)
• Proprotein Convertase 9 (genetics)
• Receptors, LDL (genetics)