Amgen announces positive top-line results from Phase 3 LAPLACE-2 trial of Evolocumab (AMG 145) in combination with statins in patients with high cholesterol

Amgen (NASDAQ:AMGN) today 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 percent reduction from baseline in low-density lipoprotein cholesterol (LDL-C) at week 12 and the mean percent reduction from baseline in LDL-C at weeks 10 and 12. 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.

Safety was balanced across treatment groups. No adverse events (AEs) occurred in ≥ 2 percent of the evolocumab combined group. The most common AEs in the evolocumab combined group were back pain, arthralgia, headache, muscle spasms and pain in extremity.

“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

LAPLACE-2 Study Design

LAPLACE-2 (LDL-C Assessment with PCSK9 MonoclonaL Antibody Inhibition Combined with Statin ThErapy-2) is a Phase 3 randomized, multicenter, double-blind, placebo- and ezetimibe-controlled study designed to evaluate safety, tolerability and efficacy of evolocumab in 1,896 patients with primary hypercholesterolemia and mixed dyslipidemia (LDL-C > 80 mg/dL) when added to statin therapy. Patients were randomized to one of 24 treatment groups in a two-step randomization. Eligible patients were initially randomized to one of five open label background statin treatments: atorvastatin 10 mg, atorvastatin 80 mg, rosuvastatin 5 mg, rosuvastatin 40 mg or simvastatin 40 mg daily. Patients randomized to atorvastatin were then randomized to one of six treatment groups: evolocumab every two weeks and oral placebo, evolocumab every month and oral placebo, subcutaneous placebo every two weeks and oral placebo, subcutaneous placebo every month and oral placebo, subcutaneous placebo every two weeks and ezetimibe 10 mg, or subcutaneous placebo every month and ezetimibe 10 mg. Patients randomized to rosuvastatin or simvastatin were then randomized to one of four treatment groups: evolocumab every two weeks, evolocumab every month, subcutaneous placebo every two weeks, or subcutaneous placebo every month.

The co-primary endpoints were the mean percent change from baseline in LDL-C at weeks 10 and 12 and the percent change in LDL-C reduction at week 12. Co-secondary efficacy endpoints included means at weeks 10 and 12 and at week 12 for the following: LDL-C < 70 mg/dL; absolute change from baseline in LDL-C; and the percentage change from baseline in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), total cholesterol (TC)/HDL-C ratio, ApoB/apolipoprotein A1 (ApoA1) ratio, lipoprotein(a), triglycerides, HDL-C and very low-density lipoprotein cholesterol (VLDL-C).

Reference above to the published Phase 2 MENDEL study results for evolocumab compared to ezetimibe is made because the Phase 2 MENDEL study included a randomized comparison to ezetimibe and the Phase 2 LAPLACE-TIMI 57 study did not.

References

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. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61770-X/abstract
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. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61771-1/abstract
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. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6004a5.htm?s_cid=mm6004a5_w. Accessed January 2014.
5. American Heart Association (2012). Why cholesterol matters. http://www.heart.org/HEARTORG/Conditions/Cholesterol/WhyCholesterolMatters/Why-Cholesterol-Matters_UCM_001212_Article.jsp. Accessed January 2014.
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.