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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
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
Details of the Phase 3 LAPLACE-2 study results will be submitted to a future medical conference and for publication.
According to the
LAPLACE-2 Study Design
LAPLACE-2 (LDL-C Assessment with P
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.
The Phase 3 program includes 13 trials, with a combined planned enrollment of more than 28,000 patients. The Phase 3 studies will evaluate evolocumab administered every two weeks and monthly in multiple patient populations, including in combination with statins in patients with hyperlipidemia (LAPLACE-2), in patients with hyperlipidemia who cannot tolerate statins (GAUSS-2), as a stand-alone treatment in patients with hyperlipidemia (MENDEL-2), and in patients whose elevated cholesterol is caused by genetic disorders called heterozygous (RUTHERFORD-2) and homozygous (TESLA and TAUSSIG) familial hypercholesterolemia.
Five studies of evolocumab will provide long-term safety and efficacy data. These include FOURIER (Further Cardiovascular OUtcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), which will assess whether treatment with evolocumab in combination with statin therapy compared to placebo and statin therapy reduces recurrent cardiovascular events in approximately 22,500 patients with cardiovascular disease, DESCARTES (Durable Effect of PCSK9 Antibody CompARed wiTh PlacEbo Study) in patients with hyperlipidemia at risk for cardiovascular disease, and GLAGOV (GLobal Assessment of Plaque ReGression with a PCSK9 AntibOdy as Measured by IntraVascular Ultrasound), which will determine the effect of evolocumab on coronary atherosclerosis in approximately 950 patients undergoing cardiac catheterization.
Additional information about clinical trials of evolocumab can be found at www.clinicaltrials.gov.
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
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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.
7. Waters D, et al.
8. Abifadel M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.