Evolocumab (AMG 145) for primary hypercholesterolemia

Abstract

Evolocumab is a fully human monoclonal IgG2 antibody that inhibits proprotein convertase subtilisin/kexin type 9, a protein that targets LDL receptors for degradation and thereby reduces the liver's ability to remove LDL-C from the blood. In Phase II and III trials in more than 6000 subjects with primary hypercholesterolemia, evolocumab reduced LDL-C by 50-75% compared with placebo and by 35-45% compared with ezetimibe. Evolocumab reduced the proatherogenic lipid profile, including Lp(a), and modestly increased HDL-C and ApoA1. In subjects with homozygous familial hypercholesterolemia, evolocumab reduced LDL-C by 30%. Safety and tolerability of evolocumab was similar to that of placebo and ezetimibe. The ongoing FOURIER trial, anticipated to report in 2017, will provide definitive evidence on cardiovascular endpoints and additional long-term safety.KEYWORDS: cardiovascular disease . evolocumab . hypercholesterolemia . LDL cholesterol . PCSK9The term primary hypercholesterolemia denotes a heterogeneous group of conditions with elevated LDL-C levels. It comprises both autosomal-dominant familial hypercholesterolemia (ADH) with an estimated frequency of 1 per 200-500, and the more common polygenic non-familial hypercholesterolemia, often in combination with adverse environmental factors, such as a hypercholesterolemic diet and obesity. Epidemiological studies have shown a graded relation between the risk of coronary heart disease (CHD) and cholesterol level [1,2], and clinical trials have demonstrated that LDL-C reduction decreases cardiovascular morbidity and mortality [3][4][5][6]. International treatment guidelines therefore recommend lowering LDL-C in hypercholesterolemic patients, depending on the individual's estimated risk for cardiovascular disease, also taking into account other risk factors [7,8].When added to diet and lifestyle, statins are the current drug of choice for the treatment of hypercholesterolemia. European guidelines from 2011 recommend that LDL-C levels should be below 1.8 mmol/l in highand very high-risk patients and below 2.5 mmol/l in moderate-risk patients [7]. The American Heart Association/American College of Cardiology guidelines from 2013 recommend treating high-risk patients with highintensity statins with the aim of lowering LDL-C by at least 50%, and to treat moderate-risk patients with moderate-intensity statins with the aim of lowering LDL-C by 30-50% [8]. Achieving recommended treatment targets can be difficult with current treatment options, especially in familial hypercholesterolemia [9]. In addition, it is estimated that 5-10% of patients are unable to tolerate any statin or an effective dose of a statin mainly because of statin-associated muscle symptoms [10][11][12][13].Serum levels of LDL-C are determined by several factors, including dietary saturated fats, which upregulate cholesterol synthesis in the liver, and uptake of LDL particles in the liver cells by LDL receptors on the surface of hepatocytes. The LDL receptors are recirculated in the hepatocytes, but are eventu...

The Proprotein Convertase Subtilisin/Kexin Type 9-resistant R410S Low Density Lipoprotein Receptor Mutation

“…The patient was then switched to rosuvastatin (20 and 40 mg) and ezetimibe (10 mg) therapy, leading to a limited ϳ37% reduction in LDLc compared with an expected ϳ70% (27). Additional subcutaneous injections of 140 mg of the PCSK9-mAb Evolocumab every 2 weeks further lowered LDLc by only ϳ15% (expected average 50 -70%) (24,28), suggestive of a resistance to PCSK9 action ( Fig. 2A).…”

ANMCO/ISS/AMD/ANCE/ARCA/FADOI/GICR-IACPR/SICI-GISE/SIBioC/SIC/SICOA/SID/SIF/SIMEU/SIMG/SIMI/SISA Joint Consensus Document on cholesterol and cardiovascular risk: diagnostic–therapeutic pathway in Italy

“…The monoclonal antibodies that inhibit PCSK9 by binding circulating PCSK9 neutralize this protein, inhibit the degradation of LDLR, and increase its expression on the surface of hepatocytes ( Figure 11B ) 172 . Over the past 5 years, many monoclonal antibody PCSK9 inhibitors have been developed including evolocumab, alirocumab, and bococizumab 175 …”

PCSK9 inhibitors – from discovery of a single mutation to a groundbreaking therapy of lipid disorders in one decade

“…The characteristics of the most important studies concerning evolocumab are presented in Table I [70–78]. In summary, in both the phase II and III trials, evolocumab administered at doses of 140 mg every 2 weeks or 420 mg once a month significantly reduced LDL-C levels by approximately 50–75% compared with placebo and 35–45% compared with ezetimibe [78].…”

“…In summary, in both the phase II and III trials, evolocumab administered at doses of 140 mg every 2 weeks or 420 mg once a month significantly reduced LDL-C levels by approximately 50–75% compared with placebo and 35–45% compared with ezetimibe [78]. The important advantage of evolocumab from a practical standpoint is the fact that there is no necessity of dose adjustments for age (18–79 years), gender, race/ethnicity, body weight, or statin therapy [78]. …”