Elsevier

The Lancet

Volume 385, Issue 9965, 24–30 January 2015, Pages 331-340
The Lancet

Articles
PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(14)61399-4Get rights and content

Summary

Background

Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of LDL cholesterol, increased plasma LDL cholesterol concentrations, and premature cardiovascular disease. Despite intensive statin therapy, with or without ezetimibe, many patients are unable to achieve recommended target levels of LDL cholesterol. We investigated the effect of PCSK9 inhibition with evolocumab (AMG 145) on LDL cholesterol in patients with this disorder.

Methods

This multicentre, randomised, double-blind, placebo-controlled trial was undertaken at 39 sites (most of which were specialised lipid clinics, mainly attached to academic institutions) in Australia, Asia, Europe, New Zealand, North America, and South Africa between Feb 7 and Dec 19, 2013. 331 eligible patients (18–80 years of age), who met clinical criteria for heterozygous familial hypercholesterolaemia and were on stable lipid-lowering therapy for at least 4 weeks, with a fasting LDL cholesterol concentration of 2·6 mmol/L or higher, were randomly allocated in a 2:2:1:1 ratio to receive subcutaneous evolocumab 140 mg every 2 weeks, evolocumab 420 mg monthly, or subcutaneous placebo every 2 weeks or monthly for 12 weeks. Randomisation was computer generated by the study sponsor, implemented by a computerised voice interactive system, and stratified by LDL cholesterol concentration at screening (higher or lower than 4·1 mmol/L) and by baseline ezetimibe use (yes/no). Patients, study personnel, investigators, and Amgen study staff were masked to treatment assignments within dosing frequency groups. The coprimary endpoints were percentage change from baseline in LDL cholesterol at week 12 and at the mean of weeks 10 and 12, analysed by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01763918.

Findings

Of 415 screened patients, 331 were eligible and were randomly assigned to the four treatment groups: evolocumab 140 mg every 2 weeks (n=111), evolocumab 420 mg monthly (n=110), placebo every 2 weeks (n=55), or placebo monthly (n=55). 329 patients received at least one dose of study drug. Compared with placebo, evolocumab at both dosing schedules led to a significant reduction in mean LDL cholesterol at week 12 (every-2-weeks dose: 59·2% reduction [95% CI 53·4–65·1], monthly dose: 61·3% reduction [53·6–69·0]; both p<0·0001) and at the mean of weeks 10 and 12 (60·2% reduction [95% CI 54·5–65·8] and 65·6% reduction [59·8–71·3]; both p<0·0001). Evolocumab was well tolerated, with rates of adverse events similar to placebo. The most common adverse events occurring more frequently in the evolocumab-treated patients than in the placebo groups were nasopharyngitis (in 19 patients [9%] vs five [5%] in the placebo group) and muscle-related adverse events (ten patients [5%] vs 1 [1%]).

Interpretation

In patients with heterozygous familial hypercholesterolaemia, evolocumab administered either 140 mg every 2 weeks or 420 mg monthly was well tolerated and yielded similar and rapid 60% reductions in LDL cholesterol compared with placebo.

Funding

Amgen Inc.

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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  • Cited by (0)

    The RUTHERFORD-2 study investigators are listed in the appendix

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