Amgen 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 per cent, compared to ezetimibe in patients with high cholesterol who cannot tolerate statins (GAUSS-2) and between 55-76 per cent compared to placebo when used in combination with statin therapy in patients with high cholesterol (LAPLACE-2).
Results from the two separate 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). Positive results from the GAUSS-2 study were simultaneously published in the Journal of the American College of Cardiology.
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.
In the GAUSS-2 study, the most common adverse events (AEs) (=5 per cent in the combined evolocumab group) were headache, myalgia, pain in extremity and muscle spasms. In the LAPLACE-2 study, no AEs occurred in 2 per cent of the evolocumab combined group. The most common AEs in the evolocumab combined group (>1.5 per cent) were back pain, arthralgia, headache, muscle spasms and pain in extremity.
"As treatment with statins continues to be an important tool in the management of high cholesterol, we are encouraged by the positive data from the Phase 3 studies of evolocumab in patients with statin intolerance and in patients already on statin therapy," said Sean E. Harper, managing director., executive vice president of Research and Development at Amgen. "We hope that evolocumab will be able to help patients who are on a moderate or high-intensity statin and not adequately controlled, as well as patients who cannot tolerate statins and are in need of an alternate treatment option to help lower their LDL cholesterol levels."
"Results from the five phase 3 pivotal studies that we presented at ACC span more than 4,000 patients and provide us with important insights on the potential of evolocumab as a treatment for a range of patients at-risk for cardiovascular disease," Harper added. "We are working closely with regulatory authorities on our global filing plan in hopes of bringing this new treatment option to patients with dyslipidemia."
The GAUSS-2 study showed that in 307 patients with high cholesterol who could not tolerate effective doses of at least two different statins due to muscle-related side effects, treatment with subcutaneous evolocumab (140 mg every two weeks or 420 mg monthly), significantly reduced mean LDL-C by 37-39 per cent from baseline compared to ezetimibe (p<0.001).
Results of the study showed the mean per cent reduction from baseline in LDL-C at weeks 10 and 12 were 37 per cent for evolocumab 140 mg every two weeks and 39 per cent for evolocumab 420 mg monthly compared to ezetimibe.
At week 12, the per cent reduction from baseline in LDL-C was 38 per cent for evolocumab 140 mg every two weeks and 38 percent for evolocumab 420 mg monthly compared to ezetimibe.
The most common AEs (>5 per cent in evolocumab combined group) were headache (7.8 per cent evolocumab; 8.8 per cent ezetimibe), myalgia (7.8 per cent evolocumab; 17.6 per cent ezetimibe), pain in extremity (6.8 per cent evolocumab; 1.0 per cent ezetimibe) and muscle spasms (6.3 per cent evolocumab; 3.9 per cent ezetimibe).
"Data from the GAUSS-2 study suggest evolocumab could be a promising lipid-lowering treatment for patients with high cholesterol who cannot tolerate effective doses of statins," said GAUSS-2 lead investigator Erik S.G. Stroes, managing directors, chair and professor of the Department of Vascular Medicine at the Academic Medical Centre (AMC), Amsterdam. "The GAUSS-2 results are encouraging for these patients who are in need of effective lipid-lowering treatment options."
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 per cent from baseline compared to placebo and 38-47 per cent 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 per cent for evolocumab 140 mg every two weeks versus placebo and between 38-45 per cent versus ezetimibe, for all statin cohorts.
Results of the study also showed the mean per cent reduction in LDL-C from baseline at weeks 10 and 12 was between 63-75 per cent for evolocumab 420 mg monthly versus placebo and 44 per cent versus ezetimibe, for all statin cohorts.
At week 12, the per cent reduction from baseline in LDL-C was between 68-76 per cent for evolocumab 140 mg every two weeks and between 55-71 per cent for evolocumab 420 mg monthly, compared to placebo, for all statin cohorts. Compared with ezetimibe, evolocumab reduced LDL-C from baseline between 40-47 per cent when dosed every two weeks and between 39-41 per cent 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 per cent evolocumab; 3.2 per cent ezetimibe; 2.5 percent placebo), arthralgia (1.7 per cent evolocumab; 1.8 per cent ezetimibe; 1.6 per cent placebo), headache (1.7 per cent evolocumab; 2.3 per cent ezetimibe; 2.7 per cent placebo), muscle spasms (1.5 percent evolocumab; 2.7 per cent ezetimibe; 1.1 per cent placebo) and pain in extremity (1.5 per cent evolocumab;1.4 per cent ezetimibe; 1.3 per cent placebo).
"The positive results from the LAPLACE-2 study show that adding evolocumab to statin therapy additionally lowers LDL cholesterol levels when added to moderate or high doses of statins," said LAPLACE-2 lead investigator Jennifer G. Robinson, managing director, M.P.H., director of the Prevention Intervention Centre, professor of the Departments of Epidemiology & Medicine, College of Public Health at the University of Iowa. "While statins are effective in reducing LDL cholesterol levels and the risk of heart attack and stroke, some patients still need more LDL- lowering treatment options."
High cholesterol is the most common form of dyslipidemia, which is an abnormality of lipids in the blood. There are approximately 300 million cases of dyslipidemia in the US., Japan and Western Europe. According to the Centres for Disease Control and Prevention, more than 71 million American adults have high LDL-C5, or "bad" cholesterol, and elevated LDL-C is recognised as a major risk factor for cardiovascular disease.
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.
PROFICIO, which stands for the Programme to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 In Different Populations, is a large and comprehensive clinical trial program evaluating evolocumab in 20 clinical trials, with a combined planned enrollment of nearly 30,000 patients.
The phase 3 programme includes 14 trials to evaluate evolocumab administered every two weeks and monthly in multiple patient populations, including in combination with statins in patients with hyperlipidemia (LAPLACE-2 and YUKAWA-2); in patients with hyperlipidemia who cannot tolerate statins (GAUSS-2 and GAUSS-3); as a stand-alone treatment in patients with hyperlipidemia (MENDEL-2) in patients whose elevated cholesterol is caused by genetic disorders called heterozygous (RUTHERFORD-2 and TAUSSIG) and homozygous (TESLA and TAUSSIG) familial hypercholesterolemia; as well as the administration of evolocumab (THOMAS-1 and THOMAS-2).