关键词：葛兰素史克,冠心病,darapladib,Lp-PLA2抑制剂

2013年11月13日讯 /生物谷BIOON/ --由葛兰素史克（GSK）开发的一种实验性冠心病（CHD）药物darapladib，在III期项目首个III期试验STABILITY中，未能降低心脏病发作和中风的整体风险，未能达到研究的主要终点。darapladib是GSK最寄予厚望的药物之一，此次试验结果，对GSK而言是一个重大打击。

尽管研究结果令人失望，但也并不令人意外。许多分析师已对darapladib项目表现出低的预期。

STABILITY是darapladib III期项目中的首个III期研究，在冠心病（CHD）成人患者中开展，数据表明，该项研究未能达到主要终点：复合主要心血管不良事件（MACE），评测标准为：首次发生由心肌梗死（心脏病发作）、中风、心血管死亡（相对风险降低6%,p=0.199）所致的任何主要不良心血管事件（MACE）的时间。一些既定次要终点中，严重冠脉事件确实表现出较大幅度的降低（定义为p≤0.05），但需要进一步的分析。STABILITY研究中，活性组和安慰剂组整体安全性未表现出重大不平衡。常见的不良反应包括腹泻及异味（odour），进一步的数据分析正在进行中。

STABILITY研究的完整数据，将提交至2014年的科学会议。III期项目中第2个III期研究SOLID-TIMI52的数据，将在不久后获得。

GSK医药研发部门总裁Patrick Vallance谈及该项研究结果时称：“公司将继续调查Lp-PLA2抑制在冠状动脉疾病和其他疾病中的作用。我们现在的工作是更好地理解STABILITY研究的数据，好医师网，包括亚组患者的数据分析，并等待第2个III期研究SOLID-TIMI52的数据，以决定接下来的开发计划。”

GSK于2012年耗资30亿美元收购人类基因组科学公司（HGS）后，获得了狼疮药物Benlysta，同时获得了darapladib的全部权利。尽管一些业内分析师认为，darapladib如果取得成功，将有望成为一个年销售额达100亿美元的重磅药物。但根据汤姆森路透药业，目前的共识预测指出，darapladib在2018年的年销售额将仅为6.05亿美元。

关于darapladib：

darapladib是一种选择性、口服有效的脂蛋白相关磷脂酶A2（lipoprotein-associated phospholipase A2, Lp-PLA2）抑制剂，目前正调查作为一种潜在的药物，用于降低冠心病（CHD）患者的心血管事件。Lp-PLA2是一种蛋白酶，存在于血液和动脉粥样斑块中。动脉粥样硬化的发生和发展与升高的Lp-PLA2活性相关。

III期STABILITY研究：

STABILITY是darapladib III期项目中的首个III期研究，该研究为随机、双盲安慰剂对照、平行组多中心、事件驱动（event-driven）研究，在慢性冠状动脉心脏疾病（CHD）成人患者中开展。研究中，除标准护理外，医生在线答疑，患者随机接受160mg darapladib或安慰剂。标准护理可能包括一种他汀类药物、阿司匹林、降血压药物。该研究招募患者总数超过1.5万人，主要终点是复合主要心血管不良事件（MACE）：心血管死亡、非致死性心肌梗死、非致死性卒中。关键次要终点包括“主要冠脉事件、总冠脉事件、MACE各个组成部分及全因死亡率。 

2013药品质量控制和工艺优化技术研讨会将于2013年12月5日-6日在杭州召开。专注药品质量控制和工艺优化，期待您一起关注。（生物谷Bioon.com）

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2013药品质量控制和工艺优化技术研讨会

英文原文：GlaxoSmithKline heart drug misses goal in major study

(Reuters) - An experimental GlaxoSmithKline drug, designed to fight heart disease in a new way, failed to meet its main goal in a major late-stage clinical study, dealing a blow to one of the company's biggest new treatment hopes.

Darapladib's inability to reduce the overall risk of heart attacks and strokes in the first of two big Phase III studies is disappointing, but not a huge surprise. Many analysts already had low expectations for the project.

Shares in Britain's biggest drugmaker had fallen 1.2 percent on the news by 1050 GMT on Tuesday, and Deutsche Bank analyst Mark Clark said failure of the drug removed some "blue sky fantasy" about potential multibillion-dollar sales.

GSK obtained full rights to darapladib, along with lupus drug Benlysta, when it bought U.S. biotech firm Human Genome Sciences last year for $3 billion.

The once-daily pill did produce statistically significant reductions in serious coronary events in some of the pre-defined secondary endpoints of the trial, which GSK said required more analysis.

Darapladib is designed to prevent heart attacks and strokes in a completely different way from cholesterol-lowering statin drugs by targeting an enzyme called Lp-PLA2 that is linked to artery-clogging plaques.

While some industry analysts have suggested it could become a $10 billion-a-year seller, if it works, few have pencilled in significant sales forecasts so far, given uncertainty about the product.

Current consensus forecasts point to annual sales of only $605 million in 2018, according to Thomson Reuters Pharma.

Panmure Gordon downgraded GSK shares to "hold" from "buy" on the latest news, which it said was the second big disappointment in the year, following similarly negative results with the company's MAGE-A3 cancer vaccine for melanoma in September.

It also predicted GSK would write down 150 million pounds ($240 million) of its investment in darapladib in the fourth quarter, even though a second Phase III trial is continuing.

"Even if that trial was successful, we believe it will be difficult to gain market registration on one trial alone," said Panmure analyst Savvas Neophytou.

MORE DATA IN 2014

Patrick Vallance, GSK's head of pharmaceuticals R&D, said the group would continue to investigate the role of Lp-PLA2 inhibition in coronary heart disease and other conditions, while also poring over the latest trial results.

"We will now work to better understand the data, including evaluation of the patient sub-groups, and await the outcome of a second Phase III study of darapladib in acute coronary syndrome," he said in a statement.

The first trial, known as STABILITY, enrolled nearly 16,000 patients with chronic coronary heart disease in 39 countries and measured the differences in outcomes between giving them darapladib or a placebo pill, in addition to standard drugs such as statins, aspirin and blood pressure medicines.

A second 13,000-patient study, called SOLID-TIMI 52, is due to complete in March 2014 and is looking at patients who have already suffered an acute coronary event. It will assess if darapladib can prevent a secondary attack.

Some medical experts believe darapladib may have a better chance of success in the second study.

GSK has had some notable successes with its new drugs this year, including approvals of medicines for cancer, lung disease and HIV. But its failure to deliver positive results in more ambitious projects like darapladib and MAGE-A3 may cast doubt over its prowess in the most cutting-edge science.

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