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

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.