GAUSS-2, RUTHERFORD-2, LAPLACE-2, DESCARTES, and TESLA Part B: PCSK9 inhibitors gain momentum

Lowering of low density lipoprotein (LDL) cholesterol (LDL-C) has been shown to be associated with significant reduction of adverse cardiovascular (CV) events.1 The 2013 ACC/AHA guidelines recommend high-intensity statin therapy - to lower LDL-C levels by ≥  50% with no specific target goal - for adults at high risk for atherosclerotic CV diseases, and moderate-intensity statin therapy - to lower LDL-C levels by 30% - < 50% - if a high-intensity statin is not tolerated.2 Furthermore, European and Canadian guidelines recommend LDL-C goal of less than 70 mg/dL (1.8 mmol/L) in patients at very high CV risk.3,4 Despite intensive statin therapy, many patients are unable to achieve the recommended target levels of LDL-C. In addition, statin-related adverse events have been reported in up to 10% to 20% of patients,5 and stains may be not tolerated by certain subgroups of patients. This highlights the need for additional LDL-C lowering drugs. Unfortunately and up till recently, currently available non-statin LDL-C lowering therapies are either weak (ezetimibe) or poorly tolerated (niacin, and bile acid sequestrants). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a novel serine protease protein (Fig. 1) produced predominantly in the liver, and plays a central role in regulating LDL-C concentrations. PCSK9 binds to hepatic LDL receptors, promotes their degradation, and reduces the ability of the liver to clear LDL-C from the blood (Fig. 2).6,7 Statin use also upregulates PCSK9 levels, therefore PCSK9 inhibiton may additionally or synergistically lower LDL-C with statins. Figure 1. Structure of the PCSK9 protein: Ribbons diagram of PCSK9 structure with the prodomain in magenta, the catalytic domain in wheat, and the V domain in blue. Thr61 marks the first observed residue, and Gln152 marks the C terminus of the prodomain. Ser153 ... Figure 2. PCSK9 mediated degradation of LDL receptors (From Lambert G et al. The PCSK9 decade. J. Lipid Res. 2012;53:2515-2524)6 Evolocumab (AMG145) – manufactured by Amgen - is a fully human monoclonal antibody that binds to PCSK9 and inhibits its interaction with LDL receptors (Fig. 2). Evolocumab has taken the lead in the race with other PCSK9 inhibitors to be the first in a new class of LDL-C lowering drugs close to the market (Table 1). Many phase II trials9–11 have evaluated the efficacy of evolocumab -including the longer term (52 weeks) OSLER study-12 and yielded robust reduction of circulating LDL-C concentration. Table 1 Therapeutic Approaches Targeting PCSK9. Adapted from Urban et al. Targeting the Proprotein Convertase Subtilisin/Kexin Type 9 for the Treatment of Dyslipidemia and Atherosclerosis. J Am Coll Cardiol 2013;62:1401–8.13 Data from several phase III studies have been recently released - as a part of the PROFICIO (Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 In Different POpulation) comprehensive program (Table 2). These trials serve to clarify the efficacy of evolocumab in different groups of patients, and are critically reviewed here with particular reference to their clinical utility, and their place in future clinical practice. Table 2 PROFICIO program GAUSS-2 study The Goal Achievement after Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects (GAUSS-2) study was a randomized, double-blind, phase III clinical trial that has been recently published in the Journal of the American College of Cardiology in June 2014.14 This study was designed to evaluate the efficacy and safety of subcutaneous (SC) evolocumab injection, compared to ezetemibe, in statin-intolerant (to at least 2 statins) hypercholesterolemic patients. A total of 307 patients, 18-80 years old, were randomized 2:2:1:1 to SC evolocumab 140 mg every two weeks (Q2W) or evolocumab 420 mg once monthly (QM) “both with daily oral placebo” or SC placebo Q2W or QM “both with daily oral ezetimibe 10 mg”. Co-primary endpoints were percent change from baseline in LDL-C concentration at the mean of weeks 10 and 12 and at week 12. Co-secondary efficacy endpoints at the same time points included absolute change in LDL-C from baseline, percent of patients achieved LDL-C < 70 mg/dl, and percent change of other lipoproteins. Safety endpoints included treatment emergent and serious adverse events, creatine kinase (CK) and hepatic enzyme elevations, and anti-evolocumab antibodies. At a mean of weeks 10 and 12, evolocumab achieved mean percent reductions of LDL-C of 56.1% (Q2W dose) and 55.3% (QM dose), compared to 36.9-38.7% in ezetemibe-treated patients (p < 0.001). Furthermore, 87.5% of evolocumab treated patients achieved LCL-C <  70 mg/dl compared to only 2% in ezetemibe-treated patients. Evolocumab reduced lipoprotein(a) levels by 27% (Q2W dose) and 22% (QM dose) at week 12 compared to 1.7 - 5.8% in ezetemibe-treated patients. Evolocumab was discontinued due to adverse events in 8% of patients compared to 13% in ezetemibe treated patients. Myalgia occurred in 8% of evolocumab-treated patients and 18% of ezetimibe-treated patients. No binding or neutralizing antibodies to evolocumab were detected.