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

J Clin Lipidol. 2017 Nov-Dec;11(6):1338-1346.e7. doi: 10.1016/j.jacl.2017.08.016. Epub 2017 Sep 4.

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.

Keywords: APOB; Cardiovascular; Clinical trial; Genetics; Hypercholesterolemia; LDLR; PCSK9.

Publication types

  • Clinical Trial

MeSH terms

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

Substances

  • 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

Associated data

  • ClinicalTrials.gov/NCT01709513
  • ClinicalTrials.gov/NCT01507831
  • ClinicalTrials.gov/NCT01709500
  • ClinicalTrials.gov/NCT01623115
  • ClinicalTrials.gov/NCT01617655
  • ClinicalTrials.gov/NCT01266876