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LAPLACE-2 and GAUSS-2 Explore Different Aspects of PCSK9 Use

March 30, 2014

The monoclonal antibody evolocumab produced significant reductions in LDL as an add-on to statins in all treatment groups, according to results of the LAPLACE-2 trial presented March 30 as part of ACC.14 in Washington, DC.

LAPLACE-2: Combining PCSK9 Monoclonal Antibody Inhibition and Statins to Assess LDL-C
GAUSS-2: Use of an Anti-PCSK9 Antibody in Statin-Intolerant Patients

The 12-week study was conducted between January and December of 2013, and looked at patients with primary hypercholesterolemia (HeFH) and mixed dyslipidemia who were randomized to a daily, moderate-intensity statin (atorvastatin 10 mg, simvastatin 40 mg, or rosuvastatin 5 mg), or high-intensity statin (atorvastatin 80 mg, rosuvastatin 40 mg). Following a four-week lipid-stabilization period, 1,899 patients were randomized to one of 24 treatment arms to compare subcutaneous evolocumab (140 mg every two weeks or 420 mg monthly) with subcutaneous placebo (every two weeks or monthly) or ezetimibe (10 mg daily; atorvastatin patients only) when added to statin therapies.

All evolocumab-treated groups showed highly significant reductions in LDL cholesterol versus placebo: 66 percent to 75 percent on a schedule of evolocumab injections every two weeks, or 63 percent to 75 percent on a four-week schedule. Patients achieved an LDL cholesterol level of less than 70 mg/dL in 86 percent to 94 percent in the moderate-intensity statin groups and 93 percent to 95 percent in the high-intensity groups. Ezetimibe reduced LDL cholesterol by 17 percent to 20 percent in moderate-intensity statin groups and 51 percent to 62 percent in high-intensity groups. Adding evolocumab reduced LDL cholesterol levels to 39 mg/dL to 49 mg/dL with moderate-intensity statin regimens and 33 mg/dL to 39 mg/dL with high-intensity regimens. Evolocumab also significantly reduced non-HDL cholesterol, apolipoprotein B and lipoprotein (a) levels. There were no notable differences in safety and tolerability in evolocumab-, placebo-, and ezetimibe-treated patients.

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"Many patients can’t tolerate high-intensity statins and cannot achieve desired LDL reductions with moderate- or low-intensity statins, and those with high cholesterol levels often need more than high-intensity statins to lower LDL levels adequately," said Jennifer G. Robinson, MD, MPH, director of the Prevention Intervention Center at the University of Iowa College of Public Health. Robinson notes that evolocumab may be useful for these patients.

Meanwhile, in the GAUSS-2 trial External Link , the monoclonal antibody administered over three months yielded a significant reduction in LDL-C in patients unable to tolerate effective doses of at least two statins.

The trial looked at 307 patients (mean [SD] age 62 [10], LDL-C 193 [59] mg/dL) randomized 2:2:1:1 to evolucumab (140 mg every two weeks or 420 mg monthly), both with daily oral placebo; or, subcutaneous placebo (every two weeks or monthly), both with daily oral ezetimibe (10 mg). Evolocumab reduced LDL-C from baseline by 53 percent to 56 percent, corresponding to treatment differences, versus ezetimibe of 37 percent to 39 percent (p < 0.001). Of evolocumab-treated patients at high risk, over 75 percent achieved LDL-C <100 mg/dL compared with less than 10 percent ezetimibe-treated patients.

"Robust efficacy combined with favorable tolerability makes evolocumab a promising therapy for addressing the large unmet clinical need in high-risk patients with elevated cholesterol who are statin intolerant," said Erik Stroes, MD, PhD, Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.

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