First Large-Scale Registry to Evaluate Real-World Lipid Management and Effectiveness of PCSK9 Inhibitors Announced – Cath Lab Digest

New Registry, cvMOBIUS, Will Assess Lipid Therapies and Five-Year Cardiovascular Outcomes in 8,500 High-Risk Patients With a Recent Atherosclerotic Cardiovascular Disease Event

THOUSAND OAKS, Calif. (Nov. 15, 2019) Amgen in collaboration with the Duke Clinical Research Institute (DCRI) today announced plans to initiate theCardiovascularMulti-dimensionalObservationalInvestigation of theUse of PCSK9 inhibitors (cvMOBIUS) studythe first large-scale real-world study to assess lipid management and the impact of PCSK9 inhibitors on cardiovascular (CV) outcomes in clinical practice. While there is strong evidence demonstrating the efficacy of PCSK9 inhibitors from various randomized clinical trial studies, there is less information on the effectiveness of these medicines on cardiovascular outcomes in real-world practice.

The cvMOBIUS study will be conducted across the U.S. and Canada and will begin patient enrollment this month. A prospective observational registry of 8,500 adults eligible for treatment with a PCSK9 inhibitor will be followed for five years. In parallel, an electronic health record (EHR)-based registry will follow a broader population of adults hospitalized with atherosclerotic cardiovascular disease (ASCVD) at participating sites.

Cardiovascular disease is one of the most significant public health issues facing our country today. Gathering robust, large-scale data from diverse patients will better inform lipid management and help decrease the burden of cardiovascular disease in these high-risk patients, said Ann Marie Navar, M.D., Ph.D., assistant professor of medicine at the Duke University School of Medicine and member of the DCRI. The clinical evidence supporting the efficacy and safety of PCSK9 inhibitors in patients with cardiovascular disease is well established, but we still have a lot to learn about the benefits of these medicines in the real world.

Patients who have experienced a recent ASCVD event, including a myocardial infarction (MI), are at higher risk of experiencing another CV event, especially within the first year after.1,2Lipid lowering is one of the key approaches for reducing a patients risk for secondary events.1Based on large randomized trials, major professional cardiology societies, including the American Heart Association and the American College of Cardiology, acknowledge that lower is better when it comes to low density lipoprotein cholesterol (LDL-C) management in patients who have experienced an MI and other ASCVD events.3

LDL-C is one of the most important modifiable risk factors for cardiovascular disease, so lipid management is an essential element in reducing future CV events and improving clinical outcomes for high-risk patients, said Eric D. Peterson, M.D., MPH, distinguished professor of medicine at the Duke University School of Medicine and member of the DCRI. This large registry will examine how care is being delivered in clinical practice to patientswhether we are using the right medicines, whether we are reaching guideline-based LDL-C targets, and the degree to which achieving these goals impacts outcomes in real-world practice.

The cvMOBIUS study is important because it is one of the few instances that researchers will utilize data pulled directly from hospitals EHR systems for research. This should help set the stage for future big data analyses and pragmatic clinical trials, said Dr. Peterson.

Two large randomized outcomes trials, including the Repatha(evolocumab) cardiovascular outcomes (FOURIER) study, have demonstrated that innovative therapies like PCSK9 inhibitors lower LDL-C levels and can reduce the risk of heart attacks in high-risk patients with established cardiovascular disease. Additionally, the VESALIUS-CV trial, initiated in March 2019, is an ongoing randomized outcomes trial, designed to evaluate the long-term effects of Repatha in high-risk cardiovascular disease (CVD) patients without a prior heart attack or stroke. The study will be the first to investigate long-term outcomes in this population with Repatha for a minimum of four years.

Amgen is committed to building a vast body of evidence for Repathaclinical trial and real-world effectiveness data setsto advance the knowledge and treatment of cardiovascular disease, saidDavid M. Reese, M.D.,executive vice president of Research and Development at Amgen. This study will generate valuable real-world evidence to help us demonstrate that PCSK9 inhibitors, like Repatha, are an important treatment option for very high-risk patients and can help prevent recurrent cardiovascular events in the real world.

Drs. Navar and Peterson are co-primary investigators of the study.

About cvMOBIUS

cvMOBIUS is a multicenter prospective observational registry in the U.S. and Canada. The study will be comprised of two parallel arms: a multicenter, prospective observational arm that will include 8,500 patients who experienced an ASCVD event within 12 months, from 250 sites; and a parallel EHR-based registry of a larger cohort of patients hospitalized with an ASCVD event treated at participating centers. The primary endpoint includes time to death, any non-fatal MI and any non-fatal ischemic stroke (IS).

About the Duke Clinical Research Institute

The DCRI, part of the Duke University School of Medicine, is the largest academic research organization in the world. It delivers on its mission to develop and share knowledge that improves the care of patients through innovative clinical research by conducting groundbreaking multinational clinical trials, managing major national patient registries, and performing landmark outcomes research. DCRI research spans multiple disciplines, from pediatrics to geriatrics, primary care to subspecialty medicine, and genomics to proteomics. The DCRI also is home to the Duke Databank for Cardiovascular Diseases, the largest and oldest institutional cardiovascular database in the world, which continues to inform clinical decision-making 40 years after its founding.

About Repatha(evolocumab)

Repatha is a human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9). Repatha binds to PCSK9 and inhibits circulating PCSK9 from binding to the low-density lipoprotein (LDL) receptor (LDLR), preventing PCSK9-mediated LDLR degradation and permitting LDLR to recycle back to the liver cell surface. By inhibiting the binding of PCSK9 to LDLR, Repatha increases the number of LDLRs available to clear LDL from the blood, thereby lowering LDL-C levels.4

Repatha is approved in more than 70 countries, including the U.S.,Japan,Canadaand in all 28 countries that are members of theEuropean Union. Applications in other countries are pending.

Repatha Cardiovascular Outcomes (FOURIER) Study Design

FOURIER (Further cardiovascularOUtcomesResearch with PCSK9Inhibition in Subjects withElevatedRisk), a multinational Phase 3 randomized, double-blind, placebo-controlled trial, was designed to evaluate whether treatment with Repatha in combination with statin therapy compared to placebo plus statin therapy reduces cardiovascular events. The primary endpoint was the time to cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary endpoint was the time to cardiovascular death, MI or stroke.

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 ASCVD at more than 1,300 study locations around the world were randomized to receive Repatha subcutaneous 140 mg every two weeks or 420 mg monthly plus effective statin dose; or placebo subcutaneous every two weeks or monthly plus effective statin dose. Optimized 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.

Important U.S. Product Information

Repatha is a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor antibody indicated:

to reduce the risk of myocardial infarction, stroke, and coronary revascularization in adults with established cardiovascular disease.

as an adjunct to diet, alone or in combination with other lipid-lowering therapies (e.g., statins, ezetimibe), for treatment of adults with primaryhyperlipidemia (including heterozygous familial hypercholesterolemia [HeFH]) to reduce low-density lipoprotein cholesterol (LDL-C).

as an adjunct to diet and other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) in patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C.

The safety and effectiveness of Repathahave not been established in pediatric patients with HoFH who are younger than 13 years old or in pediatric patients with primary hyperlipidemia or HeFH.

Important U.S. Safety Information

Contraindication:Repatha is contraindicated in patients with a history of a serious hypersensitivity reaction to Repatha. Serious hypersensitivity reactions including angioedema have occurred in patients treated with Repatha.

Allergic reactions:Hypersensitivity reactions (e.g. angioedema, rash, urticaria) have been reported in patients treated with Repatha, including some that led to discontinuation of therapy. If signs or symptoms of serious allergic reactions occur, discontinue treatment with Repatha, treat according to the standard of care, and monitor until signs and symptoms resolve.

Adverse reactions:The most common adverse reactions (>5% of patients treated with Repatha and occurring more frequently than placebo) were: nasopharyngitis, upper respiratory tract infection, influenza, back pain, and injection site reactions.

From a pool of the 52-week trial and seven 12-week trials: Local injection site reactions occurred in 3.2% and 3.0% of Repatha-treated and placebo-treated patients, respectively. The most common injection site reactions were erythema, pain, and bruising.

Allergic reactions occurred in 5.1% and 4.7% of Repatha-treated and placebo-treated patients, respectively. The most common allergic reactions were rash (1.0% versus 0.5% for Repatha and placebo, respectively), eczema (0.4% versus 0.2%), erythema (0.4% versus 0.2%), and urticaria (0.4% versus 0.1%).

The most common adverse reactions in the Cardiovascular Outcomes Trial (>5% of patients treated with Repatha and occurring more frequently than placebo) were: diabetes mellitus (8.8% Repatha, 8.2% placebo), nasopharyngitis (7.8% Repatha, 7.4% placebo), and upper respiratory tract infection (5.1% Repatha, 4.8% placebo).

Among the 16,676 patients without diabetes mellitus at baseline, the incidence of new-onset diabetes mellitus during the trial was 8.1% in patients assigned to Repatha compared with 7.7% in those assigned to placebo.

Homozygous Familial Hypercholesterolemia (HoFH):The adverse reactions that occurred in at least two patients treated with Repatha and more frequently than placebo were: upper respiratory tract infection, influenza, gastroenteritis, and nasopharyngitis.

Immunogenicity:Repathais a human monoclonal antibody. As with all therapeutic proteins, there is a potential for immunogenicity with Repatha.

Please contact Amgen Medinfo at 800-77-AMGEN(800-772-6436) or 844-REPATHA (844-737-2842) regarding Repathaavailability or find more information, including fullPrescribing Information, atwww.amgen.comandwww.Repatha.com.

AboutAmgenin the Cardiovascular Therapeutic Area

Building on more than three decades of experience in developing biotechnology medicines for patients with serious illnesses,Amgenis 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.5Amgen'sresearch into cardiovascular disease, and potential treatment options, is part of a growing competency atAmgenthat utilizes human genetics to identify and validate certain drug targets. Through its own research and development efforts, as well as partnerships,Amgenis 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.

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 biologics manufacturing expertise to strive for solutions that improve health outcomes and dramatically improve peoples lives. A biotechnology pioneer since 1980, Amgen has grown to be the worlds largest independent biotechnology company, has reached millions of patients around the world and is developing a pipeline of medicines with breakaway potential.

For more information, visitwww.amgen.comand follow us onwww.twitter.com/amgen.

References

1.Yusuf S, et al. Lancet. 2004;364:937-952. 5. Ference BA, et al. EHJ. 2017;38:2459-2472.

2.Kuklina, EV. Centers for Disease Control and Prevention. Vital signs: prevalence, treatment, and control of high levels of low-density lipoprotein cholesterol. United States, 19992002 and 20052008. MMWR. 2011;60(4):10914.

3.Grundy SM, et al. JACC. 2018; 1-80.

4.Repatha Prescribing Information; Amgen, Thousand Oaks, CA, 2018.

5.World Health Organization. Cardiovascular diseases (CVDs) fact sheet.http://www.who.int/mediacentre/factsheets/fs317/en/.

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First Large-Scale Registry to Evaluate Real-World Lipid Management and Effectiveness of PCSK9 Inhibitors Announced - Cath Lab Digest