Clinical Trials

Date: 2015-03-14

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the American College of Cardiology's 64th Annual Scientific Session

Company: Amgen (USA - CA)

Product: Repatha™ (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: high cardiovascular risk and high cholesterol

Therapeutic area: Cardiovascular diseases

Country: Japan

Trial details:

• YUKAWA-2 (StudY of LDL-Cholesterol Reduction Using a Monoclonal PCSK9 Antibody in Japanese Patients With Advanced Cardiovascular Risk) is a Phase 3, multicenter, double-blind, randomized, placebo-controlled trial designed to evaluate the safety, tolerability and efficacy of evolocumab in 404 Japanese patients with high cardiovascular risk based on the Japan Atherosclerosis Society guidelines9 and with hyperlipidemia or mixed dyslipidemia (LDL-C > 100 mg/dL). Patients were randomized to one of eight treatment groups in a two-step randomization. Eligible patients were initially randomized to one of the following background therapies: atorvastatin 5 mg daily or atorvastatin 20 mg daily. Patients continuing in the study at completion of lipid stabilization were then randomized to one of four treatment arms: evolocumab 140 mg every two weeks, evolocumab 420 mg monthly, subcutaneous placebo every two weeks, or subcutaneous placebo monthly. 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), TC/HDL-C ratio, ApoB/apolipoprotein A1 (ApoA1) ratio, lipoprotein(a), triglycerides, HDL-C and very low-density lipoprotein cholesterol (VLDL-C).
• PROFICIO , which stands for the Program 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 22 clinical trials, with a combined planned enrollment of approximately 30,000 patients. The Phase 3 program includes 16 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; the effects of evolocumab on lipoprotein metabolism (FLOREY); and the administration of evolocumab in statin-treated hyperlipidemic patients (THOMAS-1 and THOMAS-2). Five ongoing studies in the evolocumab Phase 3 program 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; EBBINGHAUS (Evaluating PCSK9 Binding AntiBody Influence oN CoGnitive HeAlth in High CardiovascUlar Risk Subjects), which will evaluate the effect of evolocumab on cognitive function in a subset of patients enrolled in FOURIER; OSLER-2 (Open Label Study of Long TERm Evaluation Against LDL-C Trial-2) in patients with high cholesterol who completed any of the Phase 3 studies; 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; and TAUSSIG (Trial Assessing Long Term USe of PCSK9 Inhibition in Subjects with Genetic LDL Disorders), which will assess the long-term safety and efficacy of evolocumab on LDL-C in patients with severe familial hypercholesterolemia including patients with homozygous familial hypercholesterolemia. The DESCARTES (Durable Effect of PCSK9 Antibody CompARed wiTh PlacEbo Study) study, a long-term safety and efficacy trial in patients with hyperlipidemia at risk for cardiovascular disease, has been completed, presented and published.

Latest news:

• • On March 14, 2015, Amgen announced new detailed data from the Phase 3 YUKAWA-2 study evaluating Repatha™ (evolocumab), in Japanese patients with high cardiovascular risk and high cholesterol. Data from the study showed subcutaneous Repatha 140 mg every two weeks or 420 mg monthly, compared to placebo, in combination with different daily doses of atorvastatin, reduced low-density lipoprotein cholesterol (LDL-C) by 67 to 76 percent from baseline at week 12 and at the mean of weeks 10 and 12. The data were presented at the American College of Cardiology's 64th Annual Scientific Session (ACC.15).
• In the YUKAWA-2 study, the most common adverse events that occurred in greater than 2 percent of the Repatha group were nasopharyngitis (16.8 percent Repatha; 17.8 percent placebo), gastroenteritis (3.0 percent Repatha; 1.0 percent placebo) and pharyngitis (2.5 percent Repatha; 2.5 percent placebo).
• • On August 28, 2014, Amgen announced that the Phase 3 YUKAWA-2 (StudY of LDL-Cholesterol Reduction Using a Monoclonal PCSK9 Antibody in Japanese Patients With Advanced Cardiovascular Risk) study evaluating evolocumab in combination with statin therapy in Japanese patients with high cardiovascular risk and 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 YUKAWA-2 trial evaluated safety, tolerability and efficacy of evolocumab compared to placebo in combination with statin therapy in 404 Japanese patients with high cardiovascular risk and high cholesterol. Patients were randomized to one of eight treatment groups to compare subcutaneous evolocumab (140 mg every two weeks or 420 mg monthly) with subcutaneous placebo (every two weeks or monthly) when added to different daily doses of atorvastatin. The percent reduction in LDL-C, or "bad" cholesterol, was clinically meaningful, statistically significant, and consistent with the results observed for the same doses in the Phase 2 YUKAWA trial for evolocumab compared to placebo. Safety was balanced across treatment groups. The adverse events (AEs) that occurred in > 2 percent of the evolocumab combined group were nasopharyngitis, gastroenteritis and pharyngitis.
• Details of the Phase 3 YUKAWA-2 study results will be submitted to a future medical conference and for publication. Evolocumab is developed in Japan by Amgen Astellas BioPharma K.K., a joint venture between Amgen and Astellas Pharma Inc.

Is general: Yes