ESC 2013：安进AMG 145显著降低LDL-C水平

在8月31日荷兰阿姆斯特丹举行的2013年欧洲心脏病学会年会（ESC 2013）上，安进（Amgen）公布了有关实验性单抗药物AMG 145的4项II期研究的汇总数据。

这些为期12周的II期研究，在高胆固醇患者中开展，评价了AMG 145的疗效、安全性、耐受性。汇总数据的疗效分析结果表明，AMG 145显着降低了低密度脂蛋白胆固醇（LDL-C）或“坏”胆固醇的水平，降低幅度高达59%。

AMG 145是一种实验性全人源化单克隆抗体，靶向PCSK9，这是一种蛋白质，能够降低肝脏从血液中清除LDL-C的能力。

LDL-C水平的升高，被认为是心血管（CV）疾病的一个主要危险因素。尽管目前有各种药物能够降低LDL-C的水平，但据估计，在三分之二经治疗的高危患者中，LDL-C并没有得到良好的控制。

目前，安进正在开展一项大型而全面的III期临床项目，利用2种给药方案，在多个患者群体中评价AMG 145，来推进不受控制的LDL-C高水平患者的临床护理，并改善他们的生活质量。

疗效分析结果表明，以超速离心衡量，治疗12周时，AMG 145各剂量组LDL-C水平平均从基线下降幅度从40-59%不等，安慰剂组LDL-C水平从基线下降幅度从0.1-0.5不等（p=0.001）。AMG 145治疗也与其他脂质参数的改善相关，包括高密度脂蛋白胆固醇（HDL-C）、甘油三酯、载脂蛋白B、脂蛋白a和载脂蛋白A1。

安全性分析结果表明，AMG 145治疗组不良事件比安慰剂组更频繁（57% vs 49%），最常见的不良事件为鼻咽炎（8.3% vs 7.5%）、上呼吸道感染（4.1% vs 3.3%）。AMG 145治疗组严重不良事件率为2.0%，安慰剂组为1.2%。注射部位反应率AMG 145和安慰剂组相似（4.1% vs 3.3%），而肌肉相关不良事件和抗药性结合抗体发生率AMG 145治疗组和对照组分别为6.0% vs 3.9%和0.1% vs 0.3%。

关于汇总分析：

既定的汇总数据，来自于在各种高脂血症患者群体中开展的4项II期、安慰剂对照、随机试验。每项试验的治疗时长为12周，以超速离心衡量，主要终点是LDL-C水平从基线的下降幅度。试验中，患者每2周或4周接受一次各种剂量的AMG 145皮下注射，其中3个试验中，允许患者接受稳定的背景他汀类药物治疗。

MENDEL研究：在未接受他汀类药物治疗的高脂血症患者（100mg/dL＜LDL-C水平≤190mg/dL）中开展，评价了每2周和每4周皮下注射AMG 145的疗效、安全性、耐受性。

LAPLACE-TIMI 57研究：在具有心血管（CV）疾病风险的高血脂症患者（LDL-C水平＞85mg/dL）中开展，评价了每2周和每4周皮下注射AMG 145结合稳定剂量他汀类药物治疗的疗效、安全性、耐受性。

RUTHERFORD研究：在正在接受稳定剂量他汀类药物治疗的杂合子家族性高胆固醇血症患者（LDL-C＞100mg/dL）中开展，评价了每4周皮下注射AMG 145的疗效、安全性、耐受性。

GAUSS研究：在那些因肌肉相关副作用而无法耐受有效的他汀类剂量的高血脂症患者中开展，评价了每4周注射AMG 145的疗效、安全性、耐受性。（生物谷Bioon.com）

英文原文：Amgen Presents Pooled Analysis Showing AMG 145 Significantly Reduced LDL Cholesterol In Over 1,200 Patients

Pooled Data from Four Phase 2 Studies Demonstrated Consistent Reductions in LDL Cholesterol of Up to 59 Percent

Results of Analyses Presented at ESC Congress 2013

THOUSAND OAKS, Calif., Aug. 31, 2013 /PRNewswire/ -- Amgen (NASDAQ: AMGN) today announced treatment with AMG 145 resulted in significant reductions in low-density lipoprotein cholesterol (LDL-C), or "bad" cholesterol, of up to 59 percent in an efficacy analysis of pooled data from four 12-week Phase 2 studies evaluating AMG 145 in patient populations with high cholesterol. AMG 145 is an investigational human monoclonal antibody that inhibits PCSK9, a protein that reduces the liver's ability to remove LDL-C from the blood. Amgen presented the data at the ESC Congress 2013, organized by the European Society of Cardiology, in Amsterdam.

Elevated LDL-C is recognized as a major risk factor for cardiovascular (CV) disease.1,2 Despite the availability of various treatments to lower LDL-C, it is estimated that in two-thirds of treated, high-risk patients, LDL-C is not well-controlled.3,4

"Millions of people around the world are unable to control their LDL cholesterol with currently available treatment options," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "The data that we have accumulated in our Phase 2 clinical program is evidence that AMG 145 has the potential to help patients reach their cholesterol goals. We are conducting a large and comprehensive Phase 3 clinical program evaluating AMG 145 in multiple patient populations and utilizing two dosing schedules, with the hopes of advancing care and improving the lives of patients with uncontrolled high LDL cholesterol."

Results from the efficacy analysis showed mean reductions in LDL-C from baseline to week 12, as measured by preparative ultracentrifugation, ranged from 40 to 59 percent across AMG 145 doses in comparison to 0.1 to 0.5 percent for placebo (p=0.001). AMG 145 treatment was also associated with improvements in other lipid parameters, including high-density lipoprotein cholesterol (HDL-C), triglycerides, apolipoprotein B, lipoprotein(a) and apolipoprotein A1, within each targeted dose frequency of AMG 145.

In the safety analysis, adverse events (AEs) were observed more frequently with AMG 145 than placebo (57 percent vs. 49 percent) with the most frequent AEs being nasopharyngitis (8.3 percent vs. 7.5 percent) and upper respiratory tract infection (4.1 percent vs. 3.3 percent). Serious AEs were 2.0 percent with AMG 145 and 1.2 percent with placebo. The rates of injection-site reactions were similar between patients treated with AMG 145 and those treated with placebo (4.1 percent vs. 3.3 percent) while muscle-related AEs and anti-drug binding antibodies were 6.0 percent vs. 3.9 percent and 0.1 percent vs. 0.3 percent, respectively. 

About the Pooled Analyses

The pre-specified, pooled analyses of data were from four Phase 2, placebo-controlled, randomized trials of AMG 145 in various patient populations with hyperlipidemia. In each trial, treatment duration was 12 weeks and the primary endpoint was percentage change in LDL-C from baseline, as measured by ultracentrifugation. Patients enrolled in the trials received various doses of AMG 145 subcutaneously every two weeks or monthly. Three of the four trials permitted stable background statin therapy. The trials included:

– MENDEL (Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Patients Currently Not Receiving Drug Therapy for Easing Lipid Levels) evaluated the efficacy, safety and tolerability of AMG 145 administered subcutaneously every two weeks and every four weeks in hyperlipidemic patients (LDL-C 3 100 mg/dL and < 190 mg/dL) who were not receiving statin therapy.

– LAPLACE-TIMI 57 (LDL-C Assessment with PCSK9 MonoclonaL Antibody Inhibition Combined With Statin ThErapy – Thrombolysis In Myocardial Infarction-57) evaluated the efficacy, safety and tolerability of AMG 145 administered subcutaneously every two weeks and every four weeks in hyperlipidemic patients at risk for CV disease (LDL-C > 85 mg/dL) when added to a stable dose of statin, with or without ezetimibe.

– RUTHERFORD (RedUction of LDL-C With PCSK9 InhibiTion in HEteRozygous Familial HyperchOlesteRolemia Disorder Study) evaluated AMG 145 administered subcutaneously every month, in heterozygous familial hypercholesterolemic patients with an LDL-C >100 mg/dL who were on a stable dose of statin, with or without ezetimibe.

– GAUSS (Goal Achievement After Utilizing an anti-PCSK9 Antibody in Statin Intolerant Subjects) evaluated the efficacy, safety and tolerability of AMG 145 dosed subcutaneously every month, in hyperlipidemic patients who could not tolerate effective statin doses due to muscle-related side effects.

About AMG 145

AMG 145 is a human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9). 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.5 AMG 145, being developed by Amgen scientists, is designed to bind to PCSK9 and inhibit PCSK9 from binding to LDL receptors on the liver surface. In the absence of PCSK9, there are more LDL receptors on the surface of the liver to remove LDL-C from the blood.6

About the AMG 145 Clinical Trial Program

PROFICIO, which stands for the Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 In Different POpulations, is the large and comprehensive clinical trial program evaluating AMG 145.

The Phase 3 clinical trial program for AMG 145 builds upon the successful Phase 2 studies and includes 12 trials, with a combined planned enrollment of more than 27,000 patients. The Phase 3 studies will evaluate AMG 145 administered every two weeks and monthly in multiple patient populations, including in combination with statins in patients with hyperlipidemia (LAPLACE-2), in patients with hyperlipidemia who cannot tolerate statins (GAUSS-2), as a stand-alone treatment in patients with hyperlipidemia (MENDEL-2), and in patients whose elevated cholesterol is caused by genetic disorders called heterozygous (RUTHERFORD-2) and homozygous (TESLA and TAUSSIG) familial hypercholesterolemia.

Five studies of AMG 145 will provide long-term safety and efficacy data, including the FOURIER (Further Cardiovascular OUtcomes Research with PCSK9 Inhibition in

Subjects with Elevated Risk) study, which will assess whether treatment with AMG 145 compared to placebo reduces recurrent cardiovascular events in approximately 22,500 patients with cardiovascular disease.