AMG 145 Lowers LDL-C in Statin-Intolerant Patients

Los Angeles—Patients with high cholesterol who cannot tolerate statins achieved reductions in low-density lipoprotein cholesterol (LDL-C) after taking AMG 145, an investigational drug, according to a global, phase 2, randomized, double-blind, controlled study. AMG 145 was also well tolerated: <5% of patients had fatigue, muscle fatigue, or muscle spasm, and none had liver function abnormalities.

AMG 145, a fully human monoclonal antibody, blocks plasma proprotein convertase subtilsin/kexin type 9 (PCSK9) from binding to the LDL-C receptor and lowers plasma LDL.

Evan A. Stein, MD, the study’s lead author and director of the Metabolic and Atherosclerosis Research Center in Cincinnati, Ohio, presented the findings in a late-breaking abstract session at the AHA meeting. Results were simultaneously published online in the Journal of the American Medical Association [2012;308(23):doi:10.1011/jama.2012.25790].

Amgen Inc., the manufacturer of AMG 145, funded the study.

Dr. Stein said although statins are the most effective drugs to reduce LDL-C and cardiovascular risk, approximately 10% to 20% of patients cannot tolerate them. For these patients, the most common alternative is ezetimibe, but they do not typically achieve LDL-C goals if they take ezetimibe alone or in combination with a low-dose statin.

Phase 1 trials had shown that AMG 145 was well tolerated and effective, reducing LDL-C by up to 64% in healthy patients and 81% in those that had hypercholesterolemia.

The GAUSS (Goal Achievement after Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects) study enrolled 160 patients between 18 and 75 years of age who did not tolerate statins because of muscle-related side effects and were at increased risk of cardiovascular diseases. Patients were allowed to receive stable doses of statins, bile-acid sequestering resins, or plant stanols/sterols.

After a screening and placebo run-in period, patients were randomized in a 1:1:1:1:1 ratio to receive 280 mg, 350 mg, or 420 mg of AMG 145 subcutaneously every 4 weeks, 420 mg of AMG 145 and 10 mg of ezetimibe every 4 weeks, or placebo and 10 mg of ezetimibe every 4 weeks. Patients knew if they were taking ezetimibe, but they did not know if they received AMG 145 or placebo, according to Dr. Stein.

Approximately 20% of patients were females, average age was approximately 62 years, and average LDL-C level was between 183 and 204 mg/dL. Every patient failed at least 1 previous statin, 70% to 80% had failed at least 2 previous statins, and approximately 33% had failed at least 3 previous statins.

Patients who took AMG 145 had a 41% to 63% reduction in LDL-C from baseline to week 12, with all of the differences being statistically significant compared with the group that took placebo plus ezetimibe (P<.001).

Ninety percent of patients in the combination AMG 145/ezetimibe group achieved a LDL-C <100 mg/dL at week 12 compared with 61% of patients in the 420-mg AMG 145 group, 53% of patients in the 350-mg AMG 145 group, 47% of patients in the 280-mg AMG 145 group, and 7% of patients who took placebo plus ezetimibe. Meanwhile, 62%, 29%, 17%, 9%, and 0% of the patients in the groups, respectively, achieved a LDL-C <70 mg/dL after 12 weeks of therapy.

Dr. Stein indicated AMG 145 was well tolerated. Only 4 of the 157 patients had a serious adverse event: 2 in the 280-mg AMG 145 group, 1 in the 350-mg AMG 145 group, and 1 in the 420-mg AMG 145 group. The serious adverse events were acute pancreatitis, coronary artery disease, hip fracture, and syncope, and none were treatment related.