Clinical Trials

Date: 2017-09-15

Type of information: Publication of results in a medical journal

phase: 3

Announcement: publication of results in The Lancet Diabetes & Endocrinology.

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: reduction of recurrent cardiovascular events

Therapeutic area: Cardiovascular diseases - Metabolic diseases

Country: Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hong Kong, Hungary, Iceland, India, Ireland, Israel, Italy, Japan, Republic of Korea, Latvia, Lithuania, Malaysia, Mexico, Netherlands, New Zealand, Norway, Philippines, Poland, Portugal, Romania, Russian Federation, Singapore, Slovakia, South Africa, Spain, Sweden, Switzerland, Taiwan, Turkey, Ukraine, UK, USA

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 ongoing 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. The primary hypothesis is that additional LDL-C lowering with Evolocumab (AMG 145) when used in addition to other treatment for dyslipidemia is well tolerated and decreases the risk of cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, or coronary revascularization in subjects with clinically evident cardiovascular disease. The primary endpoint in the study is the time to cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke or coronary revascularization. Secondary endpoints include time to cardiovascular death, myocardial infarction or stroke; time to death by any cause; time to cardiovascular death or hospitalization for worsening heart failure; and time to ischemic fatal or non-fatal stroke or transient ischemic attack. (NCT01764633)
• This program also include EBBINGHAUS (Evaluating PCSK9 Binding AntiBody Influence oN CoGnitive HeAlth in High CardiovascUlar Risk Subjects - NCT02207634), 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 September 15, 2017, Amgen announced that a new analysis of the cardiovascular outcomes study (FOURIER) demonstrated that lowering low-density lipoprotein cholesterol (LDL-C) levels with Repatha® (evolocumab) significantly and consistently reduced cardiovascular events in patients with and without diabetes at baseline. The analysis showed that diabetes was independently associated with a substantially increased risk of cardiovascular morbidity and mortality in patients with atherosclerotic cardiovascular disease. Patients with diabetes tended to have a greater absolute risk reduction of cardiovascular events with Repatha® treatment because of their heightened baseline risk. Consistent with recent trials of more intensive LDL lowering, Repatha® has not shown an effect on cardiovascular mortality.
• The analysis also showed that Repatha® was not associated with an increased risk of new-onset diabetes or worsening glycemia over a median of 2.2 years of follow-up in patients without diabetes or pre-diabetes. Additionally, no new safety concerns were identified in this analysis. The results were presented at the 53rd Annual Meeting of the European Association for the Study of Diabetes (EASD) in Lisbon, Portugal and simultaneously published in The Lancet Diabetes & Endocrinology.
• As part of a pre-specified analysis of the Repatha® cardiovascular outcomes study, diabetes status was defined on the basis of patient history, clinical events committee review of medical records, or baseline glycated hemoglobin (HbA1c) of 6.5 percent (48 mmol/mol) or greater or fasting plasma glucose (FPG) of 7.0 mmol/L (126 mg/dL) or greater. At study baseline, 40 percent of patients had diabetes (n=11,031) and 60 percent did not have diabetes (n=16,533), of whom 10,344 had pre-diabetes and 6,189 had normoglycemia. In this analysis, compared with placebo, the diabetes subgroup experienced a 57 percent mean reduction in LDL-C levels when treated with Repatha (95 percent confidence interval [CI], 56-58.0; p<0.0001), and in the non-diabetes subgroup, patients treated with Repatha experienced a 60 percent mean reduction at 48 weeks (95 percent CI, 60-61; p<0.0001), down to 0.8 mmol/L (30 mg/dL) in both groups.
• The hazard ratio (HR) of Repatha treatment for the composite primary endpoint, which included hospitalization for unstable angina, coronary revascularization, heart attack, stroke or cardiovascular death, was 0.83 (95 percent CI, 0.75-0.93; p=0.0008) for those with diabetes, and 0.87 (95 percent CI, 0.79-0.96; p=0.0052) for patients without diabetes. Because of their greater baseline risk of cardiovascular events, patients with diabetes tended to have a greater absolute risk reduction with Repatha treatment than patients without diabetes (2.7 percent [95 percent CI, 0.7-4.8] versus 1.6 percent [95 percent CI, 0.1-3.2]), driven largely by a greater absolute risk reduction in coronary revascularisation (2.7 percent [95 percent CI, 1.1-4.2] versus 1.8 percent [95 percent CI, 0.6-3.1]). The HR of Repatha treatment for the secondary composite endpoint of heart attack, stroke or cardiovascular death was 0.82 (95 percent CI, 0.72-0.93; p=0.0021) for those with diabetes and 0.78 (95 percent CI, 0.69-0.89; p=0.0002) for those without diabetes. As was seen in the overall trial results, the magnitude of risk reduction in both the primary and secondary endpoints tended to increase over time beyond the first year in patients with and without diabetes.
• Repatha, compared to placebo, did not increase the risk of new-onset diabetes in patients without diabetes at baseline (8.0 percent [663/8,256] versus 7.6 percent [631/8,254], respectively; HR 1.05, 95 percent CI, 0.94-1.17), including those with pre-diabetes (HR 1.00, 95 percent CI, 0.89-1.13). Levels of HbA1c and FPG were similar between the Repatha and placebo groups over time in patients with diabetes, pre-diabetes or normoglycemia.
• The overall rates of adverse events and serious adverse events were similar between Repatha and placebo in patients with and without diabetes. Among patients with diabetes at baseline, the proportions of patients with adverse events were 78.5 percent (4,327 of 5,513 patients) in the Repatha group and 78.3 percent (4,307 of 5,502 patients) in the placebo group. Among patients without diabetes at baseline, the proportions with adverse events were 76.8 percent (6,337 of 8,256 patients) in the Repatha group and 76.8 percent (6,337 of 8,254 patients) in the placebo group.
• The primary analysis included 27,564 patients with established cardiovascular disease. The study was statistically powered around the hard major adverse cardiovascular event (MACE) composite endpoint of first heart attack, stroke or cardiovascular death (key secondary composite endpoint) and found that adding Repatha to optimized statin therapy resulted in a statistically significant 20 percent (p<0.001) reduction in these events. The study also found a statistically significant 15 percent reduction (p<0.001) in the risk of the extended MACE composite (primary) endpoint, which included hospitalization for unstable angina, coronary revascularization, heart attack, stroke or cardiovascular death.6
• No new safety concerns were identified in this large clinical trial with roughly 60,000 patient-years of follow-up; this included the assessment of patients who achieved very low levels of LDL-C.
• • On May 20, 2017, Amgen announced new data from the Repatha® (evolocumab) cardiovascular outcomes trial (FOURIER), which showed that Repatha® consistently and safely reduced cardiovascular events in patients with established cardiovascular disease regardless of baseline low-density lipoprotein cholesterol (LDL-C) level below or above 70 mg/dL. A separate analysis also demonstrated Repatha® reduced cardiovascular events in patients being treated with maximum-intensity statin therapy. These results were presented during a late-breaker session at the 2017 National Lipid Association Scientific Sessions.
• The two analyses compared clinical outcomes in patients stratified by baseline LDL-C above and below 70 mg/dL and in patients on maximum-intensity statin therapy, defined as atorvastatin 80 mg or rosuvastatin 40 mg daily, versus patients on less intense statin therapy. Baseline LDL-C Analysis: In patients with a baseline LDL-C below 70 mg/dL (n=2,034), Repatha® reduced the median baseline LDL-C from 65.5 mg/dL to 21.0 mg/dL. Repatha® consistently reduced the risk of the composite primary endpoint, which included hospitalization for unstable angina, coronary revascularization, heart attack, stroke or cardiovascular death, regardless of whether baseline LDL-C was below or above 70 mg/dL (20 percent in patients with baseline <70 mg/dL; 14 percent in patients with baseline =70 mg/dL, P-interaction=0.65). The results were also consistent for the more robust, secondary composite endpoint of heart attack, stroke or cardiovascular death where patients with a baseline LDL-C less than 70 mg/dL experienced a 30 percent reduction in cardiovascular events and patients with a baseline LDL-C greater than or equal to 70 mg/dL experienced a 19 percent reduction in cardiovascular events (P-interaction=0.44). Background Statin Analysis: In patients on maximum-intensity statins (n=7,533), Repatha® reduced the median baseline LDL-C from 93 mg/dL to 32 mg/dL. Additionally, Repatha® consistently reduced the risk of major cardiovascular events in patients on maximum-intensity and less intense statin therapy in both the composite primary endpoint (14 percent in patients on maximum-intensity statin therapy; 15 percent in patients on less intense statin therapy, P-interaction=0.88) and the composite secondary endpoint (22 percent in patients on maximum-intensity statin therapy; 19 percent in patients on less intense statin therapy, P-interaction=0.71).
• In the two analyses, there were no differences in the rates of adverse events leading to discontinuation between treatment groups in patients who had a baseline LDL-C below 70 mg/dL (4.4 percent Repatha®; 4.6 percent placebo) or in patients on maximum-intensity statin therapy (3.9 percent Repatha®; 3.7 percent placebo). Primary Analysis: Results from the primary analysis of the 27,564-patient Repatha® cardiovascular outcomes study were also presented at the meeting. The study was statistically powered around the hard major adverse cardiovascular event (MACE) composite endpoint of first heart attack, stroke or cardiovascular death (key secondary composite endpoint) and found that adding Repatha to optimized statin therapy resulted in a statistically significant 20 percent (p<0.001) reduction in these events. The study also found a statistically significant 15 percent reduction (p<0.001) in the risk of the extended MACE composite (primary) endpoint, which included hospitalization for unstable angina, coronary revascularization, heart attack, stroke or cardiovascular death. No new safety concerns were identified in this large clinical trial with roughly 60,000 patient-years of follow-up; this included the assessment of patients who achieved very low levels of LDL-C. The detailed results from the Repatha® cardiovascular outcomes study were initially presented during a Late-Breaking Clinical Trials Session at the American College of Cardiology 66th Annual Scientific Session (ACC.17) and simultaneously published in the New England Journal of Medicine .
• • On February 2, 2017, Amgen announced that the FOURIER trial evaluating whether Repatha® (evolocumab) reduces the risk of cardiovascular events in patients with clinically evident atherosclerotic cardiovascular disease (ASCVD) met its primary composite endpoint (cardiovascular death, non-fatal myocardial infarction (MI), non-fatal stroke, hospitalization for unstable angina or coronary revascularization) and the key secondary composite endpoint (cardiovascular death, non-fatal MI or non-fatal stroke). No new safety issues were observed. The EBBINGHAUS cognitive function trial conducted in FOURIER patients also achieved its primary endpoint, demonstrating that Repatha was non-inferior to placebo for the effect on cognitive function. Detailed results from the Repatha FOURIER outcomes trial and from the Repatha EBBINGHAUS cognitive function trial will be presented at the American College of Cardiology (ACC) 66th Annual Scientific Session in Washington, on Friday, March 17 and on Saturday, March 18.
• • On June 5, 2015, Amgen announced the completion of patient enrollment in the FOURIER outcomes trial designed to evaluate whether treatment with Repatha™ (evolocumab) in combination with statin therapy compared to placebo plus statin therapy reduces the risk of recurrent cardiovascular events in patients with high cholesterol and clinically evident cardiovascular disease. Results from the approximately 27,500-patient FOURIER study are expected no later than 2017.
• FOURIER, a Phase 3 randomized, multicenter, double-blind, placebo-controlled trial, is designed to evaluate whether treatment with Repatha™ in combination with statin therapy compared to placebo plus statin therapy reduces recurrent cardiovascular events. Eligible patients with high cholesterol (LDL-C =70 mg/dL or non-high-density lipoprotein cholesterol [non-HDL-C] =100 mg/dL) and clinically evident cardiovascular disease at more than 1,200 study locations around the world were randomized to receive subcutaneous Repatha 140 mg every two weeks or 420 mg monthly plus effective statin dose; or subcutaneous placebo every two weeks or monthly plus effective statin dose. Effective statin dose is defined as greater than or equal to atorvastatin 20 mg or an equivalent statin.

Is general: Yes