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Long-Term Study Identified No New Safety Concerns
THOUSAND OAKS, Calif. (March 14, 2017) – Amgen (NASDAQ:AMGN) today announced that four-year follow-up results from the Repatha® (evolocumab) OSLER-1 study, the longest PCSK9 inhibitor clinical trial to date, were published in JAMA Cardiology. Repatha, when added to standard of care (SOC), achieved median low-density lipoprotein cholesterol (LDL-C) reductions of 57 percent at four years, with no new safety concerns identified and no neutralizing antibodies observed with cumulative exposure.1
“For patients with cardiovascular disease, persistent LDL-C reduction is an important component of managing this chronic disease,” said Michael J. Koren, M.D., Jacksonville Center for Clinical Research. “These results reinforce that adding Repatha to the cardiovascular standard of care can achieve additional sustained LDL-C reductions over several years with no increased risk of safety concerns for patients who continue to struggle with elevated cholesterol levels.”
The OSLER-1 open-label extension (OLE) study enrolled 1,324 of the 1,650 (80.2 percent) eligible patients who completed a Phase 2 parent study. OSLER-1 evaluated the durability of LDL-C reduction and incidence of adverse events (AE) with long-term therapy with Repatha. Once therapy was initiated, 79 percent of patients persisted with Repatha treatment with average exposure duration of 44 months. Patients who reached four years of follow-up achieved a median LDL-C of 60 mg/dL1.
“Safely reducing LDL-C over the long term is an important treatment objective given that many patients with elevated cholesterol will experience one or more cardiovascular events in their lifetime,” said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. “These long-term follow-up data reaffirm our conviction that Repatha is a valuable tool in the management of cardiovascular disease.”
The analysis found no new safety concerns with prolonged observation and reported that AEs occurred in 52.6 percent of patients treated with Repatha and SOC during year four compared to 79.3 percent during year one. The annualized AE rates in the Repatha and SOC group versus SOC alone were 2.8 percent versus 4.0 percent for new onset diabetes, 0.4 percent versus 0 percent for neurocognitive events, and 4.7 percent versus 8.5 percent for muscle related events. The patients who discontinued Repatha due to AEs was 0.5 percent in year four and 2.8 percent in year one. Additionally, no neutralizing antibodies and only four transient binding antibody cases were observed.1
Cardiovascular disease is the leading cause of death worldwide.2 In the U.S., there are approximately 11 million people with atherosclerotic cardiovascular disease (ASCVD) and/or familial hypercholesterolemia (FH) who have uncontrolled levels of LDL-C over 70 mg/dL, despite treatment with statins or other cholesterol-lowering therapies.3,4
OSLER-1 Study Design
Open Label Study of Long TERm Evaluation Against LDL-C 1 (OSLER-1) is an open-label extension study (OLE) with Repatha, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. The study is being conducted across 192 sites in 18 countries.
Subjects were eligible to enroll in OSLER-1 study after completing one of the double-blind Phase 2 parent studies without experiencing a serious AE requiring treatment discontinuation. During the first year patients were randomized 2:1 to Repatha 420 mg monthly in addition to SOC or SOC alone. After year one, all patients continuing in the study received Repatha 420 mg monthly in addition to SOC. Lipid parameters, safety and tolerability were assessed every 12 weeks.
The primary objective of this analysis is to evaluate whether LDL-C reductions with Repatha persist across different populations during an extended period of time. The secondary objective included the assessment of AEs, anti-drug antibodies (ADAs), and factors contributing to treatment discontinuation.
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.5
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 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.2 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.
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. A biotechnology pioneer since 1980, Amgen has grown to be one of the world's leading independent biotechnology companies, has reached millions of patients around the world and is developing a pipeline of medicines with breakaway potential.
For more information, visit www.amgen.com and follow us on www.twitter.com/amgen.
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