The GLAGOV study evaluated whether Repatha® (evolocumab), a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor for the treatment of certain patients with high low-density lipoprotein cholesterol (LDL-C), would modify atherosclerotic plaque build-up in the coronary arteries of patients already treated with optimized statin therapy.
A second late-breaking oral presentation will review results of a genome-wide association study (GWAS) exploring whether genetic factors influence statin-associated muscle symptoms. In addition, a new analysis of left atrial size and function from the COSMIC-HF (Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure) study evaluating omecamtiv mecarbil, a novel and investigational cardiac myosin activator for treatment of chronic heart failure, will be presented.
Amgen Webcast Investor Meeting
Live audio of the investor meeting will be simultaneously broadcast over the internet and will be available to members of the news media, investors and the general public.
The webcast, as with other selected presentations regarding developments in
GLAGOV Study Design
GLAGOV (GLobal Assessment of Plaque ReGression with a PCSK9 AntibOdy as Measured by IntraVascular Ultrasound) is a Phase 3, multicenter, double-blind, randomized, placebo-controlled trial designed to evaluate the effect of Repatha on the change in burden of coronary artery disease (CAD) in 968 patients undergoing cardiac catheterization and on optimized background statin therapy. Patients were required to have been treated with a stable statin dose for at least four weeks and to have a LDL-C ≥80 mg/dL or between 60 and 80 mg/dL with one major (defined as non-coronary atherosclerotic vascular disease, myocardial infarction or hospitalization for unstable angina in the preceding two years or type 2 diabetes mellitus) or three minor cardiovascular risk factors (defined as current cigarette smoking, hypertension, low levels of HDL cholesterol, family history of premature coronary heart disease, high sensitivity C-reactive protein (hs-CRP) ≥2mg/dL or age ≥50 years in men and 55 years in women). Patients were randomized 1:1 into two treatment groups to either receive monthly Repatha 420 mg or placebo subcutaneous injections. The primary endpoint was change in percent atheroma volume (PAV) from baseline to week 78 compared to placebo, as determined by intravascular ultrasound (IVUS). IVUS is a high-resolution imaging tool that allows for the quantification of coronary atheroma in the coronary arteries.
Secondary endpoints included PAV regression (any reduction from baseline); change in total atheroma volume (TAV) from baseline to week 78; and regression (any reduction from baseline) in TAV.
COSMIC-HF Trial Design
COSMIC-HF (Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure) was a double-blind, randomized, placebo-controlled, multicenter, Phase 2 trial designed to evaluate an oral formulation of omecamtiv mecarbil in chronic heart failure patients with reduced ejection fraction. The trial consisted of two parts, a dose escalation phase and a larger and longer expansion phase. The dose escalation phase, which completed in 2013, assessed the pharmacokinetics and tolerability of three oral modified-release formulations of omecamtiv mecarbil and was used to select one formulation for further evaluation in the expansion phase. In the dose escalation phase, 96 patients were randomized 1:1:1:1 to placebo or one of three oral modified-release formulations of omecamtiv mecarbil in two cohorts (25 mg twice daily or 50 mg twice daily). Each patient cohort was followed for 35 days.
The expansion phase evaluated 448 chronic heart failure patients with reduced ejection fraction who were dosed with the selected oral formulation of omecamtiv mecarbil for 20 weeks and followed for a total of 24 weeks. Patients were randomized 1:1:1 to receive either placebo or treatment with omecamtiv mecarbil 25 mg twice daily or 25 mg with dose escalation to 50 mg twice daily, depending on plasma concentrations of omecamtiv mecarbil after two weeks of treatment. The pharmacokinetic-based dose titration strategy was designed to maintain patient exposure to omecamtiv mecarbil in a targeted plasma concentration range; approximately 60 percent of patients in the dose titration group were escalated to a dose of 50 mg twice daily.
The primary endpoints for the expansion phase were to assess the maximum and pre-dose plasma concentration of omecamtiv mecarbil. The secondary endpoints were to assess changes from baseline in systolic ejection time, stroke volume, left ventricular end-systolic diameter, left ventricular end-diastolic diameter, heart rate and N-terminal pro-brain natriuretic peptide (a biomarker associated with the severity of heart failure) at week 20, as well as the safety and tolerability of omecamtiv mecarbil including incidence of adverse events from baseline to week 24.
COSMIC-HF was not designed to assess the impact of omecamtiv mecarbil on cardiovascular outcomes in heart failure patients.
COSMIC-HF was conducted by
About Repatha® (evolocumab)
Repatha® (evolocumab) 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.1
The FOURIER outcomes trial is designed to evaluate whether treatment with Repatha or placebo on top of optimized statin therapy, reduces the risk of cardiovascular events in patients with clinically evident atherosclerotic disease. The trial completed patient enrollment in June 2015. The primary endpoint for the FOURIER trial is major cardiovascular events defined as the composite of cardiovascular death, myocardial infarction (MI), stroke, hospitalization for unstable angina or coronary revascularization. The key secondary end point is the composite of cardiovascular death, MI or stroke. The trial is planned to continue until at least 1,630 patients experience the secondary endpoint, thereby providing 90 percent power to detect a relative reduction of 15 percent in this endpoint. Top-line results from the approximately 27,500-patient event-driven FOURIER study are anticipated in the first quarter of 2017.
Repatha is approved in more than 40 countries, including the U.S., Japan, Canada and in all 28 countries that are members of the European Union. Applications in other countries are pending.
Important U.S. Product Information
Repatha® is indicated as an adjunct to diet and:
The effect of Repatha® on cardiovascular morbidity and mortality has not been determined.
The safety and effectiveness of Repatha® have not been established in pediatric patients with HoFH who are younger than 13 years old.
The safety and effectiveness of Repatha® have not been established 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®.
Allergic reactions: Hypersensitivity reactions (e.g. 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 Repatha® -treated patients and more common than placebo) were: nasopharyngitis, upper respiratory tract infection, influenza, back pain, and injection site reactions.
In a 52-week trial, adverse reactions led to discontinuation of treatment in 2.2% of Repatha® -treated patients and 1% of placebo-treated patients. The most common adverse reaction that led to Repatha® treatment discontinuation and occurred at a rate greater than placebo was myalgia (0.3% versus 0% for Repatha® and placebo, respectively).
Adverse 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. The proportions of patients who discontinued treatment due to local injection site reactions in Repatha® -treated patients and placebo-treated patients were 0.1% and 0%, respectively.
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%).
Neurocognitive events were reported in less than or equal to 0.2% in Repatha®-treated and placebo-treated patients.
In a pool of placebo- and active-controlled trials, as well as open-label extension studies that followed them, a total of 1,988 patients treated with Repatha® had at least one LDL-C value <25 mg/dL. Changes to background lipid-altering therapy were not made in response to low LDL-C values, and Repatha® dosing was not modified or interrupted on this basis. Although adverse consequences of very low LDL-C were not identified in these trials, the long-term effects of very low levels of LDL-C induced by Repatha® are unknown.
Musculoskeletal adverse reactions were reported in 14.3% of Repatha® -treated patients and 12.8% of placebo-treated patients. The most common adverse reactions that occurred at a rate greater than placebo were back pain (3.2% versus 2.9% for Repatha® and placebo, respectively), arthralgia (2.3% versus 2.2%), and myalgia (2.0% versus 1.8%).
Homozygous Familial Hypercholesterolemia (HoFH): In 49 patients with homozygous familial hypercholesterolemia studied in a 12-week, double-blind, randomized, placebo-controlled trial, 33 patients received 420 mg of Repatha® subcutaneously once monthly. The adverse reactions that occurred in at least 2 (6.1%) Repatha®-treated patients and more frequently than in placebo-treated patients, included upper respiratory tract infection (9.1% versus 6.3%), influenza (9.1% versus 0%), gastroenteritis (6.1% versus 0%), and nasopharyngitis (6.1% versus 0%).
Immunogenicity: Repatha® is 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 Repatha® availability or find more information, including full Prescribing Information, at www.amgen.com and www.Repatha.com.
About Omecamtiv Mecarbil
Omecamtiv mecarbil is a novel cardiac myosin activator. Cardiac myosin is the cytoskeletal motor protein in the cardiac muscle cell that is directly responsible for converting chemical energy into the mechanical force resulting in cardiac contraction. Cardiac myosin activators are thought to accelerate the rate-limiting step of the myosin enzymatic cycle and shift the enzymatic cycle in favor of the force-producing state. Preclinical research has shown that cardiac myosin activators increase contractility in the absence of changes in intracellular calcium in cardiac myocytes.2-4
Omecamtiv mecarbil is being developed by
About Amgen Cardiovascular
Building on more than three decades of experience in developing biotechnology medicines for patients with serious illnesses,
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