Clinical Trials

Date: 2015-03-15

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 (ACC.15)

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: patients with high cholesterol

Therapeutic area: Cardiovascular diseases

Country:

Trial details:

• 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 Repatha™ (evolocumab) in 22 clinical trials, with a combined planned enrollment of approximately 35,000 patients. The Phase 3 program includes 16 trials to evaluate Repatha 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 Repatha on lipoprotein metabolism (FLOREY); and the administration of Repatha in statin-treated hyperlipidemic patients (THOMAS-1 and THOMAS-2).
• Five studies in the Repatha 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 Repatha in combination with statin therapy compared to placebo and statin therapy reduces recurrent cardiovascular events in approximately 27,500 patients with cardiovascular disease; EBBINGHAUS (Evaluating PCSK9 Binding AntiBody Influence oN CoGnitive HeAlth in High CardiovascUlar Risk Subjects), which will evaluate the effect of Repatha 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 Repatha 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 Repatha 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 completed.

Latest news:

• • On March 15, 2015, Amgen announced one-year data from prespecified exploratory endpoints of adjudicated cardiovascular events in the Phase 2 (OSLER-1) and Phase 3 (OSLER-2) open-label extension studies of Repatha™ (evolocumab). These data were presented at a Late-Breaking Clinical Trial session at the American College of Cardiology's 64th Annual Scientific Session (ACC.15) and published in the New England Journal of Medicine. A two-year analysis of Repatha® safety and tolerability data from the longest proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor trial to date (OSLER-1) was also presented.
• Data from prespecified exploratory endpoints in the ongoing open-label OSLER-1 and OSLER-2 studies showed Repatha plus standard of care (SOC) treatment reduced adjudicated cardiovascular events (0.95 percent Repatha plus SOC; 2.18 percent SOC) over a one-year analysis period. Adverse events (AEs) (?1 percent in the Repatha plus SOC group and more frequent in the Repatha plus SOC group by at least 1 percent) included arthralgia, headache, pain in extremity and fatigue. The cardiovascular events analysis comprises exploratory findings from the ongoing open-label OSLER studies. Repatha plus SOC treatment reduced LDL-C by 61 percent compared to SOC.
• Effect of Repatha on Adjudicated Cardiovascular Events: The OSLER-1 and OSLER-2 trials are ongoing open-label extension studies designed to characterize long-term effects of Repatha. The trials enrolled 4,465 patients who had completed one of 12 Phase 2 and 3 Repatha studies, 2,976 of whom were randomized to subcutaneous Repatha 140 mg every two weeks or 420 mg monthly plus SOC therapy and 1,489 were randomized to SOC alone over one year. The median LDL-C was 120 mg/dL at parent study baseline; approximately 70 percent of patients were on a statin at the start of the extension studies. Compared to SOC alone, Repatha plus SOC reduced adjudicated cardiovascular events (death, myocardial infarction, unstable angina requiring hospitalization, coronary revascularization, stroke and transient ischemic attack or heart failure requiring hospitalization) compared to SOC alone (0.95 percent Repatha plus SOC vs. 2.18 percent SOC over one year), with a consistent effect on death, coronary and cerebrovascular events as well as by subgroups (e.g., age, sex, baseline LDL-C, statin use, National Cholesterol Education Program [NCEP] risk).
• Adverse events with a frequency of at least 1 percent in the Repatha plus SOC arm and that were more frequent with Repatha plus SOC by at least 1 percent included arthralgia (4.6 percent Repatha plus SOC; 3.2 percent SOC), headache (3.6 percent Repatha plus SOC; 2.1 percent SOC), pain in extremity (3.3 percent Repatha plus SOC; 2.1 percent SOC) and fatigue (2.8 percent Repatha plus SOC; 1.0 percent SOC). Adverse events of interest included muscle-related AEs (6.4 percent Repatha plus SOC; 6.0 percent SOC), injection site reactions (4.3 percent Repatha plus SOC; N/A SOC) and neurocognitive events (0.9 percent Repatha plus SOC; 0.3 percent SOC). Compared to SOC alone, Repatha plus SOC reduced LDL-C by 61 percent to a median of 48 mg/dL. In this analysis, median study exposure for the first year of the extension studies was 11.1 months.
• Two-Year Safety and Tolerability Analysis: Data from the OSLER-1 study showed Repatha maintained its efficacy over a two-year period and no safety risk was identified. The study, which began in October 2011, randomized 1,104 patients who completed short-term, double-blind, controlled Repatha studies to receive SOC (n=370) or SOC plus open-label Repatha 420 mg monthly (n=734) for one year. After the first year, all patients received monthly Repatha plus SOC. At the end of year two, 590 patients were still receiving Repatha, showing a persistence rate of 80 percent. Of the patients on Repatha over the entire two-year period, 33 patients (4.5 percent) discontinued use due to an AE. Safety and tolerability were comparable regardless of achieved LDL-C level. Low-density lipoprotein cholesterol-lowering was sustained for more than two years, with a reduction of 54 percent at week 52 and 52 percent at week 124.

Is general: Yes