Date: 2014-05-13
Type of
information: Publication of results in a medical journal
phase: 3
Announcement: publication of results in the Journal of the American Medical Association (JAMA)
Company: Amgen (USA - CA)
Product: evolocumab
Action
mechanism:
- monoclonal antibody/RNAi/PCSK9 inhibitor. Evolocumab is a fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9).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. 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.
Disease: patients with high cholesterol
Therapeutic
area: Cardiovascular diseases
Country:
Trial
details:
- LAPLACE-2 (LDL-C Assessment with P CSK9 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.Evolocumab phase III program, PROFICIO (Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 In Different POpulations), 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.
Latest
news:
- • On May 13, 2014, Amgen announced the publication of data from the Phase 3 LAPLACE-2 (LDL-C Assessment with PCSK9 MonoclonaL Antibody Inhibition Combined with Statin ThErapy-2) study in the Journal of the American Medical Association (JAMA). Results from the 12-week study, which evaluated 1,896 patients with high cholesterol, showed treatment with subcutaneous evolocumab (140 mg every two weeks or 420 mg monthly) in combination with different daily doses of statin therapy significantly reduced mean low-density lipoprotein cholesterol (LDL-C) regardless of statin dose. These findings were initially presented at the American College of Cardiology's 63rd Annual Scientific Session (ACC.14) in March 2014 (See below).
Evolocumab reduced mean LDL-C by 55-76 percent from baseline compared to placebo and 38-47 percent from baseline compared to ezetimibe (p<0.001). 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.
- • On March 30, 2014, Amgen has announced new detailed data from two Phase 3 pivotal studies that showed treatment with its novel investigational cholesterol-lowering medication, evolocumab (AMG 145), resulted in a statistically significant reduction in low-density lipoprotein cholesterol (LDL-C) between 37-39 percent, compared to ezetimibe in patients with high cholesterol who cannot tolerate statins (GAUSS-2) and between 55-76 percent compared to placebo when used in combination with statin therapy in patients with high cholesterol (LAPLACE-2). Results from the Phase 3 studies, GAUSS-2 and LAPLACE-2, were presented as Late-Breaking Clinical Trials and complement the three Phase 3 studies presented yesterday as Featured Clinical Research at the American College of Cardiology's 63rd Annual Scientific Session (ACC.14).
- The LAPLACE-2 study showed that in 1,896 patients with high cholesterol (LDL-C >80 mg/dL), treatment with subcutaneous evolocumab (140 mg every two weeks or 420 mg monthly) in combination with different daily doses of statin therapy significantly reduced mean LDL-C by 55-76 percent from baseline compared to placebo and 38-47 percent from baseline compared to ezetimibe (p<0.001).
- Results of the study showed the mean reduction in LDL-C from baseline at weeks 10 and 12 was between 66-75 percent for evolocumab 140 mg every two weeks versus placebo and between 38-45 percent versus ezetimibe, for all statin cohorts.
- Results of the study also showed the mean percent reduction in LDL-C from baseline at weeks 10 and 12 was between 63-75 percent for evolocumab 420 mg monthly versus placebo and 44 percent versus ezetimibe, for all statin cohorts. At week 12, the percent reduction from baseline in LDL-C was between 68-76 percent for evolocumab 140 mg every two weeks and between 55-71 percent for evolocumab 420 mg monthly, compared to placebo, for all statin cohorts. Compared with ezetimibe, evolocumab reduced LDL-C from baseline between 40-47 percent when dosed every two weeks and between 39-41 percent when dosed monthly, for all statin cohorts.No AEs occurred in =2 percent of the evolocumab combined group. The most common AEs in the evolocumab combined group were back pain (1.8 percent evolocumab; 3.2 percent ezetimibe; 2.5 percent placebo), arthralgia (1.7 percent evolocumab; 1.8 percent ezetimibe; 1.6 percent placebo), headache (1.7 percent evolocumab; 2.3 percent ezetimibe; 2.7 percent placebo), muscle spasms (1.5 percent evolocumab; 2.7 percent ezetimibe; 1.1 percent placebo) and pain in extremity (1.5 percent evolocumab; 1.4 percent ezetimibe; 1.3 percent placebo).
- • On January 28, 2014, Amgen has announced that the Phase 3 LAPLACE-2 (LDL-C Assessment with P CSK9 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. 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.
Is
general: Yes
