Context:
An estimated 10% to 20% of patients cannot tolerate statins or adequate doses to achieve treatment goals. plasma proprotein convertase subtilisin/kexin type 9 (pcsk9) binds to low-density lipoprotein (ldl) receptors, promoting their degradation and increasing ldl cholesterol levels. in phase 1 studies, a human monoclonal antibody to pcsk9, amg145, was well tolerated and reduced ldl cholesterol levels.
Objective:
To assess the efficacy and tolerability of amg145 in patients with statin intolerance due to muscle-related side effects.
Design, setting, and patients:
A 12-week, randomized, double-blind, placebo- and ezetimibe-controlled, dose-ranging study conducted between july 2011 and may 2012 in statin-intolerant adult patients at 33 international sites.
Intervention:
Patients were randomized 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.
Main outcome measures:
The primary end point was percentage change from baseline to week 12 in ultracentrifugation-measured ldl cholesterol. other end points included measures of safety and tolerability of different doses of amg145 and amg145 plus ezetimibe.
Results:
Of 236 patients screened, 160 were randomized (mean age, 62 years; 64% female; mean baseline ldl cholesterol, 193 mg/dl); all patients had intolerance to 1 or more statins because of muscle-related events. at week 12, mean changes in ldl cholesterol levels were -67 mg/dl (-41%; 95% 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 < .001). four serious adverse events were reported with amg145 (coronary artery disease, acute pancreatitis, hip fracture, syncope). myalgia was the most common treatment-emergent adverse event 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.
Conclusion:
In this phase 2 study in statin-intolerant patients, subcutaneous administration of a monoclonal antibody to pcsk9 significantly reduced ldl cholesterol levels and was associated with short-term tolerability. trial registration clinicaltrials.gov identifier: nct01375764.