Amgen Publishes Safety Analysis Of Investigational Cholesterol-Lowering Medication Repatha™ (evolocumab) In The New England Journal of Medicine
Data from prespecified exploratory endpoints in the ongoing open-label OSLER-1 and OSLER-2 studies showed Repatha plus standard of care (SOC) treatment reduced adjudicated cardiovascular events (0.95 percent Repatha plus SOC; 2.18 percent SOC) over a one-year analysis period. Adverse events (AEs) (≥1 percent in the Repatha plus SOC group and more frequent in the Repatha plus SOC group by at least 1 percent) included arthralgia, headache, pain in extremity and fatigue. The cardiovascular events analysis comprises exploratory findings from the ongoing open-label OSLER studies. Repatha plus SOC treatment reduced LDL-C by 61 percent compared to SOC.
"We are excited to present several data analyses at ACC.15 from the Repatha clinical trial program, including an analysis of cardiovascular events and safety data from the longest PCSK9 inhibitor trial to date," said
Effect of Repatha on Adjudicated Cardiovascular Events
The OSLER-1 and OSLER-2 trials are ongoing open-label extension studies designed to characterize long-term effects of Repatha. The trials enrolled 4,465 patients who had completed one of 12 Phase 2 and 3 Repatha studies, 2,976 of whom were randomized to subcutaneous Repatha 140 mg every two weeks or 420 mg monthly plus SOC therapy and 1,489 were randomized to SOC alone over one year. The median LDL-C was 120 mg/dL at parent study baseline; approximately 70 percent of patients were on a statin at the start of the extension studies. Compared to SOC alone, Repatha plus SOC reduced adjudicated cardiovascular events (death, myocardial infarction, unstable angina requiring hospitalization, coronary revascularization, stroke and transient ischemic attack or heart failure requiring hospitalization) compared to SOC alone (0.95 percent Repatha plus SOC vs. 2.18 percent SOC over one year), with a consistent effect on death, coronary and cerebrovascular events as well as by subgroups (e.g., age, sex, baseline LDL-C, statin use, National Cholesterol Education Program [NCEP] risk).
Adverse events with a frequency of at least 1 percent in the Repatha plus SOC arm and that were more frequent with Repatha plus SOC by at least 1 percent included arthralgia (4.6 percent Repatha plus SOC; 3.2 percent SOC), headache (3.6 percent Repatha plus SOC; 2.1 percent SOC), pain in extremity (3.3 percent Repatha plus SOC; 2.1 percent SOC) and fatigue (2.8 percent Repatha plus SOC; 1.0 percent SOC). Adverse events of interest included muscle-related AEs (6.4 percent Repatha plus SOC; 6.0 percent SOC), injection site reactions (4.3 percent Repatha plus SOC; N/A SOC) and neurocognitive events (0.9 percent Repatha plus SOC; 0.3 percent SOC). Compared to SOC alone, Repatha plus SOC reduced LDL-C by 61 percent to a median of 48 mg/dL. In this analysis, median study exposure for the first year of the extension studies was 11.1 months.
"Data analysis from the OSLER studies show that evolocumab consistently reduced LDL cholesterol over the one-year period and reduced the rate of cardiovascular events when added to standard of care," said
Two-Year Safety and Tolerability Analysis
Data from the OSLER-1 study showed Repatha maintained its efficacy over a two-year period and no safety risk was identified. The study, which began in
"We are pleased to see that over two years, evolocumab showed a safety and efficacy profile in hypercholesterolemic patients consistent with what we've seen in previous studies," said
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High cholesterol, particularly elevated LDL-C, is the most common form of dyslipidemia, which is an abnormality of cholesterol and/or fats in the blood.1,2 Elevated LDL-C is recognized as a major risk factor for cardiovascular disease.3,4 Familial hypercholesterolemia (FH) is an inherited condition caused by genetic mutations which lead to high levels of LDL-C at an early age,5 and it is estimated that less than one percent of people with FH (heterozygous and homozygous forms) in the U.S. are diagnosed.6
About Repatha™ (evolocumab)
Repatha™ (evolocumab) is a fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9).7 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.8 Repatha, being developed by
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; EBBINGHAUS (Evaluating PCSK9 Binding AntiBody Influence oN CoGnitive HeAlth in High CardiovascUlar Risk Subjects), 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.
This news release contains forward-looking statements that are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and assumptions that could cause actual results to differ materially from those described. All statements, other than statements of historical fact, are statements that could be deemed forward-looking statements, including estimates of revenues, operating margins, capital expenditures, cash, other financial metrics, expected legal, arbitration, political, regulatory or clinical results or practices, customer and prescriber patterns or practices, reimbursement activities and outcomes and other such estimates and results. Forward-looking statements involve significant risks and uncertainties, including those discussed below and more fully described in the
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World Health Organization. Quantifying Selected Major Risks to Health. In: The World Health Report 2002 - Reducing Risks, Promoting Healthy Life. Geneva. 2002:49-97.
- Merck Manuals website. http://www.merckmanuals.com/professional/endocrine_and_metabolic_disorders/lipid_disorders/dyslipidemia.html. Accessed February 2015.
- American Heart Association (2012). Why cholesterol matters. http://www.heart.org/HEARTORG/Conditions/Cholesterol/WhyCholesterolMatters/Why-Cholesterol-Matters_UCM_001212_Article.jsp. Accessed February 2015.
World Health Organization. Global status report on noncommunicable diseases 2010. Geneva, 2011. National Human Genome Research Institute. Learning About Familial Hypercholesterolemia. http://www.genome.gov/25520184. Accessed February 2015.
- Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial Hypercholesterolaemia is Underdiagnosed and Undertreated in the General Population: Guidance for Clinicians to Prevent Coronary Heart Disease. Eur Heart J. 2013;34:3478-3490.
- Amgen Data on File, Investigator Brochure.
- Abifadel M, Varret M, Rabes JP, et al. Mutations in PCSK9 Cause Autosomal Dominant Hypercholesterolemia.
Nat Genet. 2003;34:154-156.
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