安进拔得头筹向FDA提交全球首个PCSK9抑制剂evolocumab上市申请

安进拔得头筹向FDA提交全球首个PCSK9抑制剂evolocumab上市申请

                               
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发布日期：2014-08-29  来源：新药汇

立普妥走下神坛，业界掀起PCSK9抑制剂研发狂潮，竞争已趋白热化，近日，安进拔得头筹，率先向FDA提交evolocumab上市申请，代表着全球首个PCSK9抑制剂监管申请，但赛诺菲已耗资6000多万美元入手FDA加速审评券，PCSK9追逐赛究竟鹿死谁手，拭目以待！

                               
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谈到降脂，就不得不提辉瑞（Pfizer）立普妥（Lipitor），该药堪称“药王”，上市15年销售突破1000亿美元，创造了全球药品销售的超级神话。然而，再耀眼的明星也有走下神坛的一天，立普妥自然也逃不过专利悬崖，自2011年底专利到期，市场份额迅速被仿制药瓜分。

掐指一算，至今，立普妥走下神坛已2年有余，而各大制药巨头也正紧锣密鼓地推进与立普妥不同作用机制的非他汀类药物的研发，首当其冲的便是PCSK9抑制剂，这是一类单抗药物，标靶为PCSK9蛋白，该蛋白会增加低密度脂蛋白胆固醇（LDL-C）的生成率，而LDL-C可阻塞血管，是心脏病的罪魁祸首。在PD-1/PD-L1免疫疗法雄霸制药领域之前，PCSK9抑制剂可谓是新药研发中最火爆的项目，被认为是理性药物设计的典范，令所有巨头梦寐以求，因此竞争相当激烈。

PCSK9抑制剂提供了一种全新的治疗模式来对抗LDL-C，该类药物被视为自他汀类药物（如Lipitor和Zocor）之后，在对抗心脏疾病研发领域中所取得的最大进步。

而在这一轮研发狂潮中，安进的evolocumab（又名AMG145）和赛诺菲及合作伙伴Regeneron的alirocumab处于领先地位，双方一度齐头并进，辉瑞bococizumab（RN316）稍微落后，而诺华、罗氏、默沙东则相对落后，正在努力追赶。目前为止，几乎所有公布的III期临床数据都是积极的，疗效也接近，因此，上市次序可能是个决定因素。目前，3家公司（安进、赛诺菲、辉瑞）都在竭尽全力争取率先上市。

其中，安进略微领先，似乎有望在这场PCSK9竞赛中拔得头筹。然而，赛诺菲和Regeneron在7月底发起反击，宣布在高胆固醇血症中开展的一系列（9个）III期研究均达到主要疗效终点，而数个小时后，又公布了惊人之举，史无前例花了6750万美元从BioMarin公司购买了一张FDA的加速审评券。凭借此券，FDA审查alirocumab的时间将从通常的10个月缩短至加速评审的6个月，这样就有望与安进的evolocumab同时上市。赛诺菲和Regeneron已计划在今年第四季度向FDA提交alirocumab的生物制品许可申请（BLA）。

近日，安进又向前迈了一大步，率先向FDA提交了evolocumab的生物制品许可申请（BLA），寻求批准用于高胆固醇血症的治疗。此次BLA提交，也代表着全球首个PCSK9抑制剂监管申请。安进evolocumab BLA数据包囊括了10个III期试验的安全性和疗效数据，该药在他汀不耐受群体、杂合子家族性高胆固醇血症（HeFH）群体和纯合子家族性高胆固醇血症（HoFH）群体中的强大疗效数据令人印象深刻。昨日，安进还公布了在日本开展的III期研究的积极顶线数据。该研究中，evolocumab也达到了降低LDL-C的复合主要终点。

这场PCSK9热潮中，所有巨头都在积极筹划全球部署。然而，美国仍代表着最大的单个市场机会。由于FDA已宣布可以仅根据降低LDL-C疗效数据批准上市，因此就目前情况来看，辉瑞bococizumab已铁定第三个上市，而赛诺菲凭借6000多万美元买进的加速审评券，是否能赶超安进，尚不得而知。这场PCSK9追逐赛，究竟鹿死谁手，让我们拭目以待！

英文原文：Amgen Submits Biologics License Application For Novel Investigational LDL Cholesterol-Lowering Medication Evolocumab To The FDA

Represents First BLA Submission for a PCSK9 Inhibitor

THOUSAND OAKS, Calif., Aug. 28, 2014 /PRNewswire/ -- Amgen (NASDAQ: AMGN) today announced the submission of a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for evolocumab seeking approval for the treatment of high cholesterol. 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 low-density lipoprotein cholesterol (LDL-C), or "bad" cholesterol, from the blood.1 -

The BLA for evolocumab contains data from approximately 6,800 patients, including more than 4,500 patients with high cholesterol in 10 Phase 3 trials. The Phase 3 studies evaluated the safety and efficacy of evolocumab in patients with elevated cholesterol on statins with or without other lipid-lowering therapies; patients who cannot tolerate statins; patients with heterozygous familial hypercholesterolemia (HeFH); and patients with homozygous familial hypercholesterolemia (HoFH), a rare and serious genetic disorder.2

"This BLA submission to the FDA marks the first of several submissions to regulatory authorities around the world for our lipid-lowering program and represents a critical milestone in our overall global development program for evolocumab," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "We look forward to working closely with regulatory authorities to bring this new treatment option to patients with high cholesterol who, despite currently available therapies, are unable to adequately reduce their LDL cholesterol levels."

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,2 and it is estimated that less than one percent of people with FH (heterozygous and homozygous forms) in the U.S. are diagnosed.7

Patients can have either one of two types of FH.1 Heterozygous FH is the more common type of FH and occurs in approximately one in 200 to 500 people.7 It can cause LDL-C levels twice as high as normal (e.g., >190 mg/dL).8 Individuals with HeFH have one altered copy of a cholesterol-regulating gene.8 Homozygous FH is the rare, more severe form, occurring in approximately one in a million individuals.9 It can cause LDL-C levels more than six times as high as normal (e.g., 650-1,000 mg/dL).9 An individual with HoFH has two altered copies of cholesterol-regulating genes (one from each parent).2 In 2013, the FDA granted evolocumab an orphan drug designation for HoFH.

about Evolocumab

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.10 Evolocumab, 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.1

about PROFICIO: The Evolocumab Clinical Trial Program

PROFICIO, which stands for the Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 In Different POpulations, is a large and comprehensive clinical trial program evaluating evolocumab in 22 clinical trials, with a combined planned enrollment of approximately 30,000 patients.

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 22,500 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.

about Amgen's Commitment to Cardiovascular Disease

Amgen is dedicated to addressing important scientific questions in order to advance care and improve the lives of patients with cardiovascular disease. Through its own research and development efforts and innovative partnerships, Amgen has built a robust cardiology pipeline consisting of several investigational molecules in an effort to address a number of today's important unmet patient needs, such as high cholesterol and heart failure.

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