Amgen recently announced that the Phase 3 LAPLACE-2 (LDL-C Assessment with PCSK9 MonoclonaL Antibody Inhibition Combined with Statin ThErapy-2) trial evaluating evolocumab in combination with statin therapy in patients with high cholesterol met its co-primary endpoints. The mean percent reductions in LDL-C, or “bad” cholesterol, were consistent with the published results observed for the same doses in the Phase 2 LAPLACE-TIMI 57 (LAPLACE-Thrombolysis In Myocardial Infarction-57) trial for evolocumab compared to placebo; and in the Phase 2 MENDEL (Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Patients Currently Not Receiving Drug Therapy For Easing Lipid Levels) study for evolocumab compared to ezetimibe (1-2).
Evolocumab is an investigational fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that reduces the liver’s ability to remove LDL-C from the blood (3).
The LAPLACE-2 trial evaluated safety, tolerability and efficacy of evolocumab in combination with statin therapy compared to placebo and ezetimibe in 1,896 patients with high cholesterol. Patients were randomized to one of 24 treatment groups to compare subcutaneous evolocumab (140 mg every two weeks or 420 mg monthly) with subcutaneous placebo (every two weeks or monthly) or ezetimibe (10 mg daily) when added to different daily doses of statin therapies.
“As statins continue to be an important treatment option in patients with high cholesterol, we are very encouraged by the Phase 3 data from the LAPLACE-2 study,” said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. “Adding evolocumab to statin therapy may help patients control their LDL cholesterol levels when high doses of statins are not sufficient.”
Details of the Phase 3 LAPLACE-2 study results will be submitted to a future medical conference and for publication.
According to the Centers for Disease Control and Prevention, more than 71 million American adults have high LDL-C.4 Elevated LDL-C is recognized as a major risk factor for cardiovascular disease (5-6). A multinational survey of almost 10,000 patients with high cholesterol on statin therapy found approximately one-third of patients did not attain their LDL-C goal (7).
Evolocumab is a fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9)(3). PCSK9 is a protein that targets LDL receptors for degradation and thereby reduces the liver’s ability to remove LDL-C, or “bad” cholesterol, from the blood (8). Evolocumab, being developed by Amgen scientists, is designed to bind to PCSK9 and inhibit PCSK9 from binding to LDL receptors on the liver surface. In the absence of PCSK9, there are more LDL receptors on the surface of the liver to remove LDL-C from the blood (3).
1. Giugliano R, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. The Lancet. 2012;380(9858):2007-2017, Table 2.
2. Koren M, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. The Lancet. 2012;380(9858):1995-2006, Table 2.
3. Amgen Data on File, Investigator Brochure.
4. CDC Morbidity and Mortality Weekly Report. Vital Signs: Prevalence, Treatment, and Control of High Levels of Low-Density Lipoprotein Cholesterol — United States, 1999–2002 and 2005-2008. February 4, 2011. Article Link
5. American Heart Association (2012). Why cholesterol matters. Article Link
6. World Health Organization. Global status report on noncommunicable diseases 2010. Geneva, 2011.
7. Waters D, et al. Lipid Treatment Assessment Project 2: A Multinational Survey to Evaluate the Proportion of Patients Achieving Low-Density Lipoprotein Cholesterol Goals. Circulation. 2009;120:28-34.
8. Abifadel M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet .2003;34:154-156.