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Editor's Note: Commentary based on Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol 2014;63:2541-8.

The proprotein convertase subtilisin/kexin type 9 (PCSK9) protein regulates the activity of low-density lipoprotein (LDL) receptors. Inhibition of PCSK9 with a monoclonal antibody results in increased cycling of LDL receptors and increased clearance of LDL cholesterol (LDL-C). The objective of the present study was to test the efficacy and safety of the monoclonal antibody evolocumab (AMG145) for cholesterol lowering in patients who are intolerant to statins.

Goal Achievement After Utilizing an anti-PCSK9 Antibody in Statin-Intolerant Subjects 2 (GAUSS-2) is a phase 3 study that enrolled patients between the ages of 18 to 80 years who were intolerant of at least two different statins because of muscle side effects.¹ The study was sponsored by AMGEN, the manufacturer of evolocumab. Eligible patients had LDL-C greater than the recommended goal based on the National Cholesterol Education Program/Adult Treatment Panel (NCEP/ATP) III guidelines. Patients were randomly assigned 2:2:1:1 to subcutaneous (SQ) evolocumab 140 mg every two weeks (Q2W) or 420 mg once monthly (QM) both with daily oral placebo, or SQ placebo Q2W or QM and both with daily oral ezetimibe. The co-primary endpoints were the percent change from baseline in LDL-C at the mean of weeks 10 and 12 and at week 12. Pre-specified secondary endpoints included changes in other lipids including high-density lipoprotein cholesterol (HDL-C), non-HDL-C, and lipoprotein(a).

A total of 307 patients (mean age = 62 ± 10 years, mean LDL-C 193 ± 59 mg/dl) were randomized to evolocumab (N = 205) or placebo (N = 102) and the duration of follow-up was 12 weeks. The mean percent LDL-C reduction at weeks 10 and 12 with evolocumab was 56.1% with 140 mg Q2W and 55.3% with 420 mg QM. Compared with ezetimibe, treatment with evolocumab resulted in a 38-42% reduction in LDL-C. Evolocumab also resulted in a 27% reduction in lipoprotein(a). Adverse events leading to drug discontinuation occurred in 8% of patients allocated to evolocumab and 13% of patients allocated to ezetimibe. Myalgias occurred in 8% of evolocumab-treated patients and in 18% of ezetimibe-treated patients; the cumulative incidence of muscle adverse events was 12% with evolocumab and 23% with ezetimibe.

In patients with elevated LDL-C and statin intolerance due to muscle adverse events, evolocumab has greater efficacy in cholesterol lowering compared with ezetimibe. Compared with ezetimibe, evolocumab had a similar safety profile with a trend towards a reduced incidence of musculoskeletal side effects. The most important study limitation is a relatively brief duration of follow-up and the absence of data on clinical outcomes.

The GAUSS-2 study is a phase 3 clinical trial that demonstrates the safety and effectiveness of the PCSK9 inhibitor evolocumab for the lowering of LDL-C in statin-intolerant patients. Evolocumab was superior to ezetimibe in LDL reduction and with fewer adverse muscle events. Other phase 3 trials of evolocumab, including Durable Effect of PCSK9 Antibody Compared with Placebo Study (DESCARTES)² and LDL-C Assessment w/ PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy-2 (LAPLACE-2)³ have demonstrated that LDL reduction is sustained out to one year with monthly or semiweekly administration of SQ evolocumab, alone or in combination with statin therapy. The side effect profile also appears to be tolerable. PCSK9 inhibitors may have a particularly important role in select subgroups of patients, including familial hypercholesterolemia and statin-intolerant patients.

Clinical trials to determine the effect PCSK9 inhibitors on clinical outcomes are ongoing. However, the FDA is expected to consider approval of PCSK9 inhibitors prior to publication of clinical trial data on hard clinical outcomes. Thus, PCSK9 inhibitors may soon provide an additional therapeutic option for the treatment of hyperlipidemia.

References

1. Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol 2014;63:2541-8.
2. Blom DJ, Hala T, Bolognese M, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med 2014;370:1809-19.
3. Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA 2014;311:1870-82.

Keywords: Adenosine Triphosphate, Antibodies, Azetidines, Cholesterol, Cholesterol, LDL, Cholesterol, HDL, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipoproteinemia Type II, Immunoconjugates, Lipids, Lipoprotein(a), Lipoproteins, HDL, Lipoproteins, LDL, Myalgia, Proprotein Convertases, Receptors, LDL, Subtilisins

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