New Detailed Data From Phase 3 Study Show Amgen's Repatha™ (Evolocumab) In Combination With Statins Reduced LDL-C By 67-76 Percent Compared To Placebo In Japanese Patients With High Cardiovascular Risk And High Cholesterol
In the YUKAWA-2 study, the most common adverse events that occurred in greater than 2 percent of the Repatha group were nasopharyngitis (16.8 percent Repatha; 17.8 percent placebo), gastroenteritis (3.0 percent Repatha; 1.0 percent placebo) and pharyngitis (2.5 percent Repatha; 2.5 percent placebo).
"The positive results from this study in
Repatha is an investigational fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that reduces the liver's ability to remove LDL-C, or "bad" cholesterol, from the blood.1 In Japan, LDL-C levels are not adequately controlled for many high-risk patients taking statins, nearly half of whom have not reached their LDL-C goal.2,3
"Statins are a cornerstone of treatment for people with high cholesterol who are unable to lower their LDL cholesterol to appropriate levels despite efforts to improve diet and exercise," said Arihiro Kiyosue,
High cholesterol is the most common form of dyslipidemia, which is an abnormality of cholesterol and/or fats in the blood.4,5 There are approximately 300 million cases of dyslipidemia in the U.S., Japan and
YUKAWA-2 Study Design
YUKAWA-2 (StudY of LDL-Cholesterol Reduction Using a Monoclonal PCSK9 Antibody in Japanese Patients With Advanced Cardiovascular Risk) is a Phase 3, multicenter, double-blind, randomized, placebo-controlled trial designed to evaluate the safety, tolerability and efficacy of Repatha™ (evolocumab) in 404 Japanese patients with high cardiovascular risk based on the Japan Atherosclerosis Society guidelines2 and with hyperlipidemia or mixed dyslipidemia (LDL-C >100 mg/dL). Patients were randomized to one of eight treatment groups in a two-step randomization. Eligible patients were initially randomized to one of the following background therapies: atorvastatin 5 mg daily or atorvastatin 20 mg daily and entered a four-week lipid stabilization period. At completion of lipid stabilization, patients were then randomized to one of four treatment arms: Repatha 140 mg every two weeks, Repatha 420 mg monthly, subcutaneous placebo every two weeks or subcutaneous placebo monthly. The co-primary endpoints were the percent reduction from baseline in LDL-C at week 12 and the mean percent reduction from baseline in LDL-C at weeks 10 and 12. Co-secondary efficacy endpoints included means at weeks 10 and 12 and at week 12 for the following: LDL-C <70 mg/dL; absolute change from baseline in LDL-C; and the percentage change from baseline in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), total cholesterol (TC), TC/HDL-C ratio, ApoB/apolipoprotein A1 (ApoA1) ratio, lipoprotein(a), triglycerides, HDL-C and very low-density lipoprotein cholesterol (VLDL-C).
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About Repatha™ (Evolocumab)
Repatha™ (evolocumab) is a fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9).1 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.7 Repatha, being developed by
Repatha is developed in Japan by Amgen Astellas BioPharma K.K., a joint venture between Amgen and
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 been completed.
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- Amgen Data on File, Investigator Brochure.
- Teramoto T, Sasaki J, Ishibashi S, et al. Executive Summary of the Japan Atherosclerosis Society (JAS) Guidelines for the Diagnosis and Prevention of Atherosclerotic Cardiovascular Diseases in Japan – 2012 version. J Atheroscler Thromb. 2013;20(6):517-523.
- Teramoto T, Kashiwagi A, Ishibashi S,
Daida H. Cross-Sectional Surveyto Assess the Status of Lipid Management in High-Risk Patients With Dyslipidemia: Clinical Impact of Combination Therapy With Ezetimibe. Current Therapeutic Research. 2013;73(1-2). World Health Organization. Quantifying Selected Major Risks to Health. In: The World Health Report 2002 - Reducing Risks, Promoting Healthy Life. Chapter 4: Geneva: World.
- Merck Manuals website. http://www.merckmanuals.com/professional/endocrine_and_metabolic_disorders/lipid_disorders/dyslipidemia.html. Accessed February 2015.
National Instituteof Health (2009). Federal Register Volume 74 (250). Washington, DC: U.S. Government Printing Office. http://www.gpo.gov/fdsys/pkg/FR-2009-12-31/html/E9-31072.htm. Accessed February 2015.
- Abifadel M et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.
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