ArticlesPCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial
Introduction
Heterozygous familial hypercholesterolaemia is the most common dominantly inherited disorder in human beings worldwide,1 and recent extensive screening in several countries suggests that it affects between one in 250 and one in 300 people worldwide.2, 3 Thus, more than 3 million people probably have the disorder in the USA and Europe alone. Familial hypercholesterolaemia is caused by mutations in genes encoding key proteins involved in LDL cholesterol metabolism, which leads to reduced cellular uptake of LDL cholesterol, increased plasma LDL cholesterol concentrations, and premature development of cardiovascular disease.2 More than 90% of affected patients have mutations in the LDL receptor gene, and more than 1700 such mutations have been described.4 On fibroblast culture, most of these mutations are shown to be associated with residual receptor function (receptor defective) or absence of function (receptor negative).5, 6 LDL receptor-negative alleles tend to be associated with higher LDL cholesterol concentrations and earlier onset of coronary artery disease than receptor-defective alleles.7 Mutations in the apolipoprotein B gene account for a further 5% of familial hypercholesterolaemia cases,8 and proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations are present in less than 1% of cases.9 However, in most studies, despite next-generation sequencing, no mutation can be identified in up to 20% of patients with a clinical diagnosis of definite heterozygous familial hypercholesterolaemia.10
Statin therapy has significantly improved the treatment of familial hypercholesterolaemia, with apparent reductions in cardiovascular morbidity and mortality reported in registry and longitudinal cohort studies.11, 12 However, many patients do not achieve desirable LDL cholesterol concentrations despite intensive statin therapy, even if treatment is combined with other lipid-modifying drugs such as ezetimibe.13, 14 Phase 1 and 2 trials have shown that further LDL cholesterol reductions of 55–60% can be achieved when PCSK9 inhibitors are added to existing lipid-lowering treatments. These reductions in LDL cholesterol are similar to those reported in patients without familial hypercholesterolaemia.15, 16, 17, 18
The aims of this phase 3 trial were to assess the safety and efficacy of evolocumab (AMG 145) administered subcutaneously every 2 weeks or every month in a large and diverse cohort of patients with heterozygous familial hypercholesterolaemia with LDL cholesterol concentrations of 2·6 mmol/L or higher despite intense lipid-lowering therapy.
Section snippets
Study design and participants
RUTHERFORD-2 was a multicentre, randomised, double-blind, placebo-controlled study undertaken at 39 sites (mostly specialised lipid clinics, mainly attached to academic centres) in Australia, Asia, Europe, New Zealand, North America, and South Africa between Feb 7 and Dec 19, 2013. Patients 18–80 years of age with a clinical diagnosis of heterozygous familial hypercholesterolaemia according to Simon Broome criteria19 at screening and on a stable dose of a statin with or without other approved
Results
Of the 415 patients initially screened, 84 were excluded, either because they did not meet the inclusion criteria (the most common reasons were their LDL cholesterol concentration at screening was <2·6 mmol/L or they had hyperthyroidism or hypothyroidism) or because they did not want to enrol in the trial (figure 1). 331 eligible patients were enrolled and randomly assigned to evolocumab 140 mg every 2 weeks (n=111), evolocumab 420 mg monthly (n=110), placebo every 2 weeks (n=55), or placebo
Discussion
This study, the largest reported global trial of patients with heterozygous familial hypercholesterolaemia with a monoclonal antibody to PCSK9, showed that the addition of evolocumab 140 mg every 2 weeks or 420 mg monthly to existing lipid-lowering therapy achieved similar LDL cholesterol reductions of roughly 60%. Additionally, more than 60% of patients who were given evolocumab at either dosing frequency achieved LDL cholesterol levels lower than 1·8 mmol/L. These results support and expand
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