MISSISSAUGA, ON (March 17, 2017) – Amgen Canada Inc. today announced results from the 27,564-patient Repatha® (evolocumab) cardiovascular outcomes study, FOURIER, (Further Cardiovascular OUtcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), a Phase 3 trial designed to evaluate whether treatment with Repatha in combination with statin therapy compared to placebo plus statin therapy reduces cardiovascular events. Results demonstrated for the first time that reducing low-density lipoprotein cholesterol (LDL-C) levels with Repatha, beyond what is possible with the current best therapy alone, leads to a further reduction in major cardiovascular events, including heart attacks, strokes and coronary revascularizations.
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 per cent (p<0.001) reduction in these events. The reduction started as early as six months and continued to accrue through the median 2.2 years of the study. In fact, the risk reduction in the hard MACE composite endpoint grew over time, from 16 per cent in the first year to 25 per cent beyond the first year.
The study also found a statistically significant 15 per cent 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.
Patients on Repatha experienced a reduction in the risk of heart attack (27 per cent, nominal p<0.001), stroke (21 per cent, nominal p=0.01) and coronary revascularization (22 per cent, nominal p<0.001). Consistent with recent trials of more intensive LDL lowering, there was no observed effect on cardiovascular mortality.1-5 Similarly, there was no observed effect on hospitalization for unstable angina. In an exploratory analysis, the relative risk reduction for fatal and non-fatal heart attack or stroke was 19 per cent in the first year (p=0.003) and 33 per cent beyond the first year (p<0.00001).
When added to statin therapy, Repatha reduced LDL-C from a median of 2.38 to 0.78 mmol/L, a reduction of 59 per cent at week 48, which was sustained throughout the trial. At 48 weeks, the LDL-C was reduced to at least 0.65 mmol/L in 42 per cent of patients treated with Repatha, as compared with <0.1 per cent in the placebo group (p<0.001). Additionally, treatment with Repatha had effects on other lipid parameters.
“These study results highlight the connection between further lowering of LDL cholesterol with Repatha and reducing the risk of serious cardiovascular events including heart attacks and strokes, even in a population already treated with optimized statin therapy," said Dr. Lawrence A. Leiter, Canadian Lead Investigator of the Repatha Cardiovascular Outcomes Trial (FOURIER) and Director of the Lipid Clinic at St. Michael’s Hospital and Professor of Medicine at the University of Toronto. “The findings are encouraging given recent survey data indicating that about half of Canadian patients with known cardiovascular disease have LDL cholesterol levels above guideline recommended targets, and suggests that patients who have high LDL cholesterol despite optimal statin therapy could benefit from Repatha.”
“We now show for the first time in a dedicated outcomes study that decreasing LDL cholesterol with PCSK9 inhibition results in clinically meaningful cardiovascular benefit,” said Marc S. Sabatine, M.D., M.P.H., chairman of the TIMI Study Group, the Lewis Dexter, MD, Distinguished Chair in Cardiovascular Medicine at Brigham and Women's Hospital, and Professor of Medicine, Harvard Medical School, Boston. “This was achieved with lowering LDL cholesterol down to a median of 0.78 mmol/L, which is well below current targets, and the magnitude of risk reduction increased the longer patients were on therapy. These results suggest the need for long-term, LDL cholesterol reduction in our patients with cardiovascular disease.”
Repatha, a Canadian development,6 was developed from the breakthrough work of Amgen scientists who elucidated the interaction of PCSK9 and the LDL receptor (LDLR), including the site where the LDLR binds to PCSK9, and developed antibodies that bind to PCSK9 at that site and block the interaction of PCSK9 with the LDLR. These scientific advances resulted in the intellectual property to antibodies to PCSK9 that protect Repatha. An extensive set of clinical trials subsequently demonstrated the effectiveness of Repatha in lowering LDL-C, in regressing coronary atherosclerosis and finally now in reducing the risk of major adverse cardiovascular events. From its inception, the program has demonstrated the power of human validation of a drug target based on genetic insights, an approach which is playing an increasingly important role across Amgen’s therapeutic portfolio.
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. In particular, there were no notable differences seen between treatment arms in the overall rate of adverse events, serious adverse events or adverse events leading to study drug discontinuation. Likewise, rates of adjudicated new onset diabetes (8.1 per cent Repatha; 7.7 per cent placebo), muscle-related side effects (5.0 per cent Repatha; 4.8 per cent placebo), cataract (1.7 per cent Repatha; 1.8 per cent placebo), neurocognitive adverse events (1.6 per cent Repatha; 1.5 per cent placebo) and allergic reactions (3.1 per cent Repatha; 2.9 per cent placebo) were similar between the two arms. Injection site reactions were more common with Repatha than with placebo (2.1 per cent Repatha; 1.6 per cent placebo). In the Repatha arm, post-baseline new binding antibodies were detected in 43 patients (0.3 per cent) and neutralizing antibodies in none. Detailed results from the Repatha cognitive function study (EBBINGHAUS) will be presented in a separate Late-Breaking Clinical Trial Session on Saturday, March 18 at 9:00 a.m. ET.
Repatha Cardiovascular Outcomes (FOURIER) Study Design
FOURIER (Further Cardiovascular OUtcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), a multinational Phase 3 randomized, 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 cardiovascular events. The primary endpoint is the time to cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary endpoint is the time to cardiovascular death, myocardial infarction or stroke.
Eligible patients with high cholesterol (LDL-C ≥1.8 mmol/L or non-high-density lipoprotein cholesterol [non-HDL-C] ≥2.6 mmol/L) and clinically evident atherosclerotic cardiovascular disease at more than 1,200 study locations around the world, including Canada, were randomized to receive Repatha subcutaneous 140 mg every two weeks or 420 mg monthly plus optimized statin dose; or placebo subcutaneous every two weeks or monthly plus effective statin dose. Effective statin therapy was defined as at least atorvastatin 20 mg or equivalent daily with a recommendation for at least atorvastatin 40 mg or equivalent daily where approved. The study was event driven and continued until at least 1,630 patients experienced a key secondary endpoint.
About Repatha® (evolocumab)7
Repatha (evolocumab) is a fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9). Repatha binds selectively and with high affinity to PCSK9, and inhibits circulating PCSK9 from binding to the LDLR on the liver cell surface, thus preventing PCSK9-mediated LDLR degradation therefore increasing the number of LDLR available to clear LDL, thereby lowering serum LDL-C levels.
Repatha is indicated as an adjunct to diet and maximally tolerated statin therapy in adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (CVD), who require additional lowering of LDL-C; and as an adjunct to diet and other LDL-lowering therapies in adults and adolescent patients aged 12 years and over with homozygous familial hypercholesterolemia (HoFH), who require additional lowering of LDL-C. The effect of Repatha on cardiovascular morbidity and mortality has not been determined.
Health Canada recently approved the Repatha automated mini doser (AMD) delivery system (on-body infusor with prefilled cartridge), a monthly single-dose administration option. The AMD delivery system is a hands-free device designed to provide 420 mg of Repatha in a single dose.
About Amgen in the Cardiovascular Therapeutic Area
Building on more than three decades of experience in developing biotechnology medicines for patients with serious illnesses, Amgen is dedicated to addressing important scientific questions to advance care and improve the lives of patients with cardiovascular disease, the leading cause of morbidity and mortality worldwide.8 Amgen's research into cardiovascular disease, and potential treatment options, is part of a growing competency at Amgen that utilizes human genetics to identify and validate certain drug targets. Through its own research and development efforts, as well as partnerships, Amgen is building a robust cardiovascular portfolio consisting of several approved and investigational molecules in an effort to address a number of today's important unmet patient needs, such as high cholesterol and heart failure.
About Amgen Canada Inc.
With main operations located in Mississauga, Ont.’s vibrant biomedical cluster, and its research facility in Burnaby, B.C., Amgen Canada has been an important contributor to advancements in science and innovation in Canada since 1991. Amgen is committed to unlocking the potential of biology for patients suffering from serious illnesses by discovering, developing, manufacturing and delivering innovative human therapeutics. This approach begins by using tools like advanced human genetics to unravel the complexities of disease and understand the fundamentals of human biology. Amgen focuses on areas of high unmet medical need and leverages its expertise to strive for solutions that improve health outcomes and dramatically improve people’s lives. To learn more about Amgen Canada, visit www.amgen.ca.
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