The investigational anti-PCSK9 antibody AMG145 significantly lowers LDL cholesterol in high-risk patients unable to tolerate statins, the phase II GAUSS trial showed.
Three subcutaneous injections of AMG145 at varying doses reduced LDL cholesterol by up to 51% when used as monotherapy, and by 63% when combined with ezetimibe (Zetia), compared with an expected 15% reduction with ezetimibe and placebo.
Dr. Evan Stein
These reductions are comparable with those achieved with maximal doses of the most efficacious statins.
If the results are confirmed in larger and longer-term studies, AMG145 could provide a new therapeutic option for high-risk patients who currently have few treatment options, Dr. Evan Stein reported at the annual scientific sessions of the American Heart Association in Los Angeles.
In GAUSS (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects), 84% of all patients were unable to tolerate even low doses of any statin.
Overall, about 10%-20% of people can’t tolerate statins at all or the higher doses needed to achieve recommended LDL cholesterol goals, primarily because of muscle-related side effects. Ezetimibe is frequently used as an alternative for these patients, but without great success.
Evidence and enthusiasm are growing, however, for the use of monoclonal antibodies that block proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine protease that binds to and destroys LDL receptors. It is thought that blocking the destructive capacity of PCSK9 can lead to more LDL receptors on cells and lower cholesterol levels.
Dr. Stein and his associates recently reported that another PCSK9 monoclonal antibody, REGN727 (Regeneron Pharmaceuticals), significantly lowered LDL cholesterol in three early-phase trials involving healthy volunteers and patients with familial or nonfamilial forms of hypercholesterolemia (N. Engl. J. Med. 2012;366:1108-18). GAUSS investigators at 33 sites in North America, Australia, and Europe enrolled patients, aged 18-75 years, with hypercholesterolemia who were considered intolerant to at least one statin because of muscle-related events and had LDL cholesterol levels above risk-based goals set by the National Cholesterol Education Program (NCEP). At baseline, the average LDL cholesterol level was 193 mg/dL, 50% of patients were at high or moderately high cardiovascular risk according to NCEP categories, and 24% had clinical atherosclerotic disease. Their average age was 62.
In all, 160 patients were randomly assigned to AMG145 monotherapy at doses of 280 mg, 350 mg, or 420 mg every 4 weeks, or 450 mg AMG145 every 4 weeks plus daily oral ezetimibe 10 mg, or placebo every 4 weeks plus ezetimibe 10 mg.
At week 12, the mean change from baseline in LDL cholesterol was –41% in the AMG 280-mg group, –43% in the 350-mg group, –51% in the 420-mg group, and –63% in the AMG plus ezetimibe group, compared with –15% in the placebo plus ezetimibe group, all highly significant differences, reported Dr. Stein of the Metabolic and Atherosclerosis Research Center in Cincinnati.
Notably, the reductions in LDL cholesterol levels with AMG145 monotherapy given every 4 weeks are comparable to those obtained with REGN727 given in addition to statins every 2 weeks.
AMG145 produced modest increases in HDL cholesterol that were statistically significant only in the combination group, and nonsignificant reductions in triglycerides.
Myalgia was the most common treatment-related adverse event, reported in five patients in the 280-mg group, one each in the 350-mg and 420-mg groups, six in the AMG145/ezetimibe group, and one in the placebo/ezetimibe group. Fewer than 5% of patients taking AMG145, with or without ezetimibe, reported fatigue, muscle fatigue, or muscle spasm.
There were four serious adverse events reported in patients given AMG 145 – coronary artery disease, acute pancreatitis, hip fracture, and syncope. These patients did not require treatment discontinuation; these adverse events are not known to be linked to the mechanism of action of PCSK9 inhibition, the authors, led by Dr. David Sullivan of Royal Prince Alfred Hospital, Camperdown, Australia, reported in the paper, simultaneously published online (JAMA 2012;308 [doi:10.1001/jama.2012.25790]).
GAUSS was funded by Amgen, which participated in the design and conduct of the study, as well as the collection and management of data. Dr. Stein and Dr. Sullivan reported financial relationships with Amgen and other firms, and four coauthors are employees of Amgen.