Approximately 10-20% of patients are unable to tolerate statins or the higher doses needed to achieve LDL cholesterol goals. Perprotein convertase subtilisin/kexin type 9 (PCSK9) mediates the binding and trafficking of LDL receptors, and in phase 1 studies a human monoclonal antibody to to PCSK9 (AMG145)lowered LDL levels. The Goal Achievement after Utilizing an anti-PCSK9 antibody in Statin Intolerant Subjects (GAUSS) trial aimed to assess the efficacy and safety of AMG145 in patients with a documented history of muscle-related adverse effects with statins.

In this 12-week, randomized, double-blind, placebo and ezetimibe-controlled study, 160 patients from 33 international sites were randomised equally to 1 of 5 groups: AMG145 alone at doses of 280 mg, 350 mg, or 420 mg; AMG145 at 420 mg plus 10 mg of ezetimibe; or 10 mg of ezetimibe plus placebo. AMG145 or placebo was administered subcutaneously every 4 weeks. All patients had intolerance to one or more statins because of muscle-related events. The primary endpoint was the percentage change from baseline to week 12 in ultracentrifugation-measured LDL cholesterol.

After 12 weeks of treatment, mean changes in LDL cholesterol levels were −67 mg/dL (−41%) for the AMG145, 280-mg, group; −70 mg/dL (−43%) for the 350-mg group; −91 mg/dL (−51%) for the 420-mg group; and −110 mg/dL (−63%) for the AMG145 420-mg/ezetimibe group compared with −14 mg/dL (−15%) for the placebo/ezetimibe group (P < .001). Myalgia was the most common adverse event related to treatment seen during the study, occurring in 5 patients (15.6%) in the 280-mg group (n = 32); 1 patient (3.2%) in the 350-mg group (n = 31), 1 patient (3.1%) in the 420-mg group (n = 32), 6 patients (20.0%) receiving 420-mg AMG145/ ezetimibe, and 1 patient (3.1%) receiving placebo/ezetimibe.

Conclusions:

Subcutaneous administration of a monoclonal antibody to PCSK9 – one of several in production – led to significant reductions in LDL cholesterol levels, and was tolerated well in the short-term.

• Sullivan D, Olsson AG, Scott R et al. Effect of a Monoclonal Antibody to PCSK9 on Low-Density Lipoprotein Cholesterol Levels in Statin-Intolerant Patients. The GAUSS Randomized Trial. JAMA 2012;308:2497-2506.