Effect of a Monoclonal Antibody to PCSK9 on Low-Density Lipoprotein Cholesterol Levels in Statin-Intolerant Patients: The GAUSS Randomized Trial

Study Questions:

What is the efficacy and tolerability of AMG145, a human monoclonal antibody to plasma protein convertase subtilisin/kexin type 9 (PCSK9), in statin-intolerant patients with a documented history of muscle-related adverse effects?


GAUSS (Goal Achievement after Utilizing an anti-PCSK9 antibody in Statin Intolerant Subjects) was a short-term (12-week) international multicenter, phase 2, randomized, double-blind, placebo- and ezetimibe-controlled, and dose-ranging study. The assignment to ezetimibe was not blinded. AMG145 or placebo was administered subcutaneously every 4 weeks. The primary endpoint was the percentage change from baseline in low-density lipoprotein cholesterol (LDL-C) following 12 weeks of therapy.


A total of 160 patients who had had intolerance to one or more statins because of muscle-related adverse events were randomized (mean baseline LDL-C, 193 mg/dl). At week 12, mean changes in LDL-C levels were −67 mg/dl (−41%; 95% confidence interval [CI], −49% to −33%) for the AMG145, 280 mg group; −70 mg/dl (−43%; 95% CI, −51% to −35%) for the 350 mg group; −91 mg/dl (−51%; 95% CI, −59% to −43%) for the 420 mg group; and −110 mg/dl (−63%; 95% CI, −71% to −55%) for the 420 mg/ezetimibe group compared with −14 mg/dl (−15%; 95% CI, −23% to −7.0%) for the placebo/ezetimibe group (p < 0.001). The overall incidence of all adverse effects was similar among patients receiving AMG145 without ezetimibe (58%), those receiving AMG145/ezetimibe (67%), and those receiving placebo/ezetimibe (59%).


Short-term therapy with a human monoclonal antibody to PCSK9 is associated with significant reductions in LDL-C and at least short-term tolerability.


Although limited by a short 12-week study duration and small sample sizes, the results of this phase 2 trial offer hope for statin-intolerant patients. Should larger-scale and longer-term studies continue to demonstrate such favorable outcomes, there would be important implications for the 10-20% of patients treated with statin medications who are not able to tolerate any therapy or enough therapy to achieve standardized LDL-C targets.

Keywords: Proprotein Convertases, Cholesterol, Azetidines, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cardiovascular Diseases, Saccharomyces cerevisiae Proteins, Lipoproteins, Confidence Intervals, Subtilisin

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