Amgen Presents Long-Term Data Showing Efficacy And Safety Of Investigational Cholesterol-Lowering Medication Evolocumab Across Lipid And LDL-C Levels
Evolocumab 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
"The long-term data analyses from our clinical development program further support that evolocumab is a potential treatment option for patients who, despite current therapies, still need help managing their condition," said
Analysis of pooled data from Phase 2, 3 and open-label extension studies of 3,278 patients with high cholesterol showed that in the year-long extension phase, treatment with subcutaneous evolocumab 140 mg every two weeks or 420 mg monthly plus standard of care (SOC) resulted in mean reductions in Lp(a) from baseline of 22 percent at 24 weeks and 29 percent at 52 weeks. The mean Lp(a) reductions showed consistency with results observed in the 12-week parent studies, indicating treatment with evolocumab resulted in significant and sustained reductions in Lp(a) over a combined period of 64 weeks (p<0.001). Lp(a) is a pro-atherogenic lipoprotein related to LDL and is associated with cardiovascular disease risk.2
"Historically, epidemiologic studies have shown a consistent and independent association between increased lipoprotein(a) and cardiovascular disease risk; however, current therapeutic options to reduce lipoprotein(a) are limited," said evolocumab investigator
Another long-term data analysis from the Phase 2 OSLER-1 and Phase 3 DESCARTES 52-week studies compared the rate of AEs between 1,012 patients with high cholesterol who achieved low LDL-C (<40 mg/dL) and 1,187 patients with higher achieved LDL-C levels (>40 mg/dL). Both groups had comparable rates of at least one AE (78 percent vs. 83 percent [LDL-C <40 mg/dL vs. LDL-C >40 mg/dL]). The overall occurrence of common AEs was balanced between LDL-C groups, and the overall event rates did not appear to be influenced by the use of intensive background statin therapy. The most common AEs across groups achieving low LDL-C and higher LDL-C, respectively, were nasopharyngitis (13.8 percent vs. 13.1 percent), upper respiratory tract infection (8.7 percent vs. 7.3 percent), influenza (5.8 percent vs. 7.2 percent), back pain (7.1 percent vs. 5.3 percent) and arthralgia (5.8 percent vs. 4.7 percent).
"The analysis from the OSLER-1 and DESCARTES studies showed that adverse events were generally balanced between patients with low and higher LDL cholesterol levels," said
Additionally, a dosing regimen analysis presented at the meeting evaluated 248 patients with high cholesterol from the Phase 2 MENDEL and LAPLACE-TIMI 57 trials, and showed the greatest LDL-C reductions were comparable for evolocumab 140 mg every two weeks and 420 mg monthly dosing. Results showed reductions of 72 percent for evolocumab 140 mg every two weeks (measured one week after dosing) and 69 percent for evolocumab 420 mg monthly (measured two weeks after dosing). Similar LDL-C reductions were also observed for the mean of weeks 10 and 12 with evolocumab 140 mg every two weeks (65 percent) and 420 mg monthly (64 percent). Changes in other lipid parameters and unbound PCSK9 showed no clinically significant differences between every two-week and monthly dosing.
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.3,4 Elevated LDL-C is recognized as a major risk factor for cardiovascular disease.5,6 Familial hypercholesterolemia (FH) is an inherited condition caused by genetic mutations which lead to high levels of LDL-C at an early age,7 and it is estimated that less than one percent of people with FH (heterozygous and homozygous forms) in the U.S. are diagnosed.8
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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.9 Evolocumab, being developed by
The Phase 3 program includes 16 trials to evaluate evolocumab 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 evolocumab on lipoprotein metabolism (FLOREY); and the administration of evolocumab in statin-treated hyperlipidemic patients (THOMAS-1 and THOMAS-2).
Five ongoing studies in the evolocumab 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 evolocumab 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 evolocumab 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 evolocumab 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 evolocumab 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, presented and published.
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- Amgen Data on File, Investigator Brochure.
- Raal FJ, Giugliano RP, Sabatine MS, et al. Reduction in Lipoprotein(a) With PCSK9 Monoclonal Antibody Evolocumab (AMG 145). J Am Coll Cardiol. 2014;63:1278–88.
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 October 2014.
- American Heart Association (2012). Why cholesterol matters. http://www.heart.org/HEARTORG/Conditions/Cholesterol/WhyCholesterolMatters/Why-Cholesterol-Matters_UCM_001212_Article.jsp. Accessed October 2014.
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 October 2014.
- 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.
- Abifadel M, Varret M, Rabes JP, et al. Mutations in PCSK9 Cause Autosomal Dominant Hypercholesterolemia.
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