——安进新型降血脂PCSK9抑制剂单抗新药Repatha(evolocumab)获欧盟批准
2015年5月22日，欧洲药品管理局（EMA）人用药品委员会（CHMP）采纳了一项对RepathaTM（evolocumab）上市许可的积极意见，推荐批准该药用于某些高胆固醇血症患者的治疗。Repatha是一种可抑制前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）的试验性全人源化单克隆抗体，PCSK9是一种能够降低肝脏从血液中清除低密度脂蛋白胆固醇（LDL-C）或“坏”胆固醇能力的蛋白。
CHMP推荐授予Repatha上市许可用于：
•作为饮食的一种辅助疗法，用于治疗原发性（杂合子家族性和非家族性[HeFH]）或混合性血脂异常成年患者：
◦联合他汀类药物、或者联合他汀类及其他降脂疗法，用于接受最大耐受剂量的他汀类药物治疗仍无法达到LDL-C目标的患者，或者
◦单独或联合其他降脂疗法，用于不能耐受或者他汀类药物禁忌的患者。
•联合其他降脂疗法，用于成人或12岁及以上年龄的纯合子家族性（HoFH）患者。
Repatha对心血管发病率和死亡率的影响尚未确定
安进研发执行副总裁、医学博士肖恩∙哈珀称，“我们很高兴获得CHMP关于Repatha的积极意见，这意味着我们向着为接受现有治疗仍无法达到LDL胆固醇目标值的欧洲高胆固醇血症患者提供新治疗选择又迈进了重要的一步”。哈珀博士还指出，“无法控制的高胆固醇血症是医疗体系的一项负担，我们期待继续与监管当局合作，将Repatha带给整个欧洲的患者”。
冰岛和挪威的CHMP成员也同意授予Repatha用于上述推荐适应症的上市许可。
欧盟委员会（EC）将审核CHMP的积极意见，EC有权批准药物在欧盟的使用。如果获得批准，Repatha将在欧盟28个成员国获得有统一标签的集中上市许可。作为欧洲经济区（EEA）成员，挪威、冰岛和列支敦斯登将基于EC的决定作出相应决策。
CHMP的意见基于大约6800例患者的数据为基础，其中包括10项3期研究中的超过4500例高胆固醇血症患者。3期研究评价了Repatha用于胆固醇升高患者的安全性和有效性，包括接受他汀类药物，联合或不联合其他降脂疗法的患者；不耐受他汀类药物的患者、HeFH患者、以及HoFH（一种罕见且严重的遗传性疾病）患者。
在欧洲，多达54%的25岁及以上人群总胆固醇水平≥5.0mmol/L（≥190mg/dL）。高胆固醇（尤其是LDL-C升高）是最常见的一类血脂异常（血脂异常是指血液中的胆固醇和/或脂肪异常）。LDL-C升高被认为是心血管疾病的主要危险因素。
关于RepathaTM（evolocumab）
RepathaTM（evolocumab）是一种可抑制前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）的全人源化单克隆抗体1。PCSK9是一种能够降解LDL受体，从而降低肝脏从血液中清除LDL-C或 “坏”胆固醇的能力的蛋白8。Repatha由安进的科学家研发获得，用于结合PCSK9，从而抑制PCSK9与肝脏表面LDL受体的结合。在PCSK9缺失的条件下，肝脏表面的LDL受体水平更高，从而能够更有效地清除血液中的LDL-C1。
关于PROFICIO：RepathaTM（evolocumab）临床研究项目
PROFICIO（不同人群中使用PCSK9抑制剂降低LDL-C以及心血管结局的研究项目）是一项大型全面的临床研究项目，在22项临床研究共计划入选的35,000例患者中评价RepathaTM（evolocumab）。
3期研究项目包括16项临床研究，旨在对每2周一次和每月一次接受Repatha治疗的多种患者人群中进行评价，包括：在高脂血症患者中与他汀类药物联合用药（LAPLACE-2和YUKAWA-2）；在不能耐受他汀类药物的高脂血症患者中（GAUSS-2和GAUSS-3）；在高脂血症患者中单药治疗（MENDEL-2）；在由杂合子（RUTHERFORD-2和TAUSSIG）和纯合子（TESLA和TAUSSIG）家族性等遗传性疾病引起胆固醇水平升高的患者中；以及Repatha对于脂蛋白代谢的作用（FLOREY），和Repatha在接受他汀类治疗的高脂血症患者中的用药管理（THOMAS-1和THOMAS-2）。
Repatha的3期研究项目中有5项正在进行的研究将提供长期的安全性和有效性数据，这些研究包括：FOURIER研究（风险升高的受试者中PCSK9抑制的进一步减少心血管结局研究），该研究在大约27500例心血管疾病患者中评估Repatha合并他汀类治疗相比于安慰剂合并他汀类治疗，是否能够降低再发心血管事件；EBBINGHAUS研究（评估PCSK9结合抗体对于心血管高风险受试者认知健康影响研究），该研究在FOURIER的一个子集患者中评估Repatha对于认知功能的影响；在完成任一3期研究的高胆固醇血症患者中开展的OSLER-2研究（降低LDL-C研究的开放标签长期评估研究-2）；GLAGOV研究（全球利用血管内超声评估PCSK9抗体逆转斑块），该研究将在近950例接受心导管术的患者中评估Repatha对于冠状动脉粥样硬化的疗效；TAUSSIG研究（评价PCSK9抑制剂在遗传性LDL异常受试者中的长期应用该研究在严重家族性患者（包括纯合子家族性患者）中评估Repatha的长期安全性以及降低LDL-C的有效性。DESCARTES研究（PCSK9抗体相比安慰剂的长期疗效研究）是一项在有心血管疾病风险的高脂血症患者中评估Repatha长期安全性和有效性研究，该研究已完成。

http://www.multivu.com/players/English/7414052-amgen-repatha/
EUROPEAN COMMISSION APPROVES AMGEN’S NEW CHOLESTEROL-LOWERING MEDICATION REPATHA™ (EVOLOCUMAB), THE FIRST PCSK9 INHIBITOR TO BE APPROVED IN THE WORLD, FOR TREATMENT OF HIGH CHOLESTEROL
The EC approved Repatha for:
•The treatment of adults with primary hypercholesterolemia (heterozygous familial and non-familial [HeFH]) or mixed dyslipidemia, as an adjunct to diet:
◦in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin, or
◦alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated.
•The treatment of adults and adolescents aged 12 years and over with homozygous familial hypercholesterolemia (HoFH) in combination with other lipid-lowering therapies.
New Drugs Online Report for evolocumab
Information
Generic Name: evolocumab  
Trade Name: Repatha 
Synonym: AMG 145 
Entry Type: New molecular entity  
Development and Regulatory status
UK: Approved (Licensed) 
EU: Approved (Licensed) 
US: Recommended for approval (Positive opinion) 
UK launch Plans: Available only to registered users
Actual UK launch date:  
Comments
Jul 15: Approved in EU [12].
22/07/2015 09:36:41 
Jun 15: FDA panel vote 11-4 in favour of approval. The group´s recommendation now goes to the FDA, which is not required to obey its panels´ recommendations but typically does so. The agency has promised to rule on evolocumab by Aug 27 [11].
12/06/2015 12:09:36 
May 15: EU positive opinion for use in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet: (a) in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin, or (b) alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contra-indicated. Also positive opinion for adults and adolescents aged 12 years and over with homozygous familial hypercholesterolaemia in combination with other lipid-lowering therapies [10].
22/05/2015 13:43:01 
Nov 14: FDA has accepted the BLA application and will issue a decision by Aug 27, 2015 [7].
10/11/2014 17:45:00 
Oct 14: Amgen files a patent-infringement lawsuit to prevent the manufacture, use and sale of Sanofi and Regeneron´s PCSK9 antibody, alirocumab [6].
20/10/2014 10:36:38 
Sep 14: Filed to the EMA seeking approval for the treatment of high cholesterol. [5]
03/09/2014 15:03:26 
Aug 14: Biologics License Application (BLA) submitted to US FDA for evolocumab, seeking approval for the treatment of high cholesterol. The BLA contains data from approximately 6,800 patients, including>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.[4]
29/08/2014 09:09:49 
Trial or other data
Mar 15: Two reports published in NEJM describe results of three long-term studies. One trial, entitled Long-term Safety and Tolerability of Alirocumab in High Cardiovascular Risk Patients with Hypercholesterolemia Not Adequately Controlled with Their Lipid Modifying Therapy (ODYSSEY LONG TERM), was a double-blind, randomized, controlled trial of alirocumab (150 mg administered subcutaneously every 2 weeks) versus placebo for 78 weeks in 2341 patients at high risk for cardiovascular events who were already receiving the maximum tolerated doses of statins. Two other trials, entitled Open-Label Study of Long-Term Evaluation against LDL Cholesterol 1 (OSLER-1) and OSLER-2, used a randomized, open-label design in a total of 4465 patients with various degrees of cardiovascular risk. Evolocumab, administered subcutaneously at a dose of 140 mg every 2 weeks or 420 mg monthly, was added to standard therapy and compared with standard therapy alone over a period of approximately 1 year; the two OSLER trials were analysed together. Both the ODYSSEY LONG TERM trial and the OSLER trials included a mix of patients with cardiovascular disease, cardiovascular risk factors, or heterozygous familial hypercholesterolemia, and both included patients with elevated LDL cholesterol values despite statin use. As compared with placebo or standard therapy, the intervention reduced LDL cholesterol levels by an average of 61 to 62%. As with statins, levels of apolipoprotein B, non–high-density lipoprotein (HDL) cholesterol, and triglycerides were lowered by treatment, and levels of apolipoprotein A1 and HDL cholesterol were increased. However, unlike with statins, significant reductions in lipoprotein(a) were also observed [8].
16/03/2015 18:00:14
March 14: Data from LAPLACE-2 presented at ACC 14. LAPLACE-2 is a P3 RCT designed to evaluate safety, tolerability and efficacy of evolocumab in 1,896 patients with primary hypercholesterolemia and mixed dyslipidemia when added to statin therapy. Pts were randomised to 1 of 24 treatment groups depending on their initial statin dose allocation (atorvastatin, rosuvastatin or simvastatin). Evolocumab was given either as 140mg every 2 weeks or 420mg monthly. Treatment with SC evolocumab in combination with different daily doses of statin therapy significantly reduced mean LDL-C by 55-76% from baseline compared to placebo and 38-47% from baseline compared to ezetimibe (p<0.001). Mean reduction in LDL-C from baseline to weeks 10 and 12 was 66-75% with evolocumab 140mg vs. placebo and 38-45% vs. ezetimibe. For evolocumab 420mg, the mean reductions were 63-75% and 44% respectively. [3]
01/04/2014 09:37:28
March 14: Data from GAUSS-2 study presented at the American College of Cardiology´s 63rd Annual Scientific Session (ACC.14). Mean reduction from baseline in LDL-C at weeks 10 and 12 were 37% for evolocumab 140mg every 2 weeks and for 420mg monthly vs. ezetimibe (p<0.001). The most common AEs (>5% in evolocumab combined group) were headache (7.8% evolocumab; 8.8% ezetimibe), myalgia (7.8% evolocumab; 17.6% ezetimibe), pain in extremity (6.8% evolocumab; 1.0% ezetimibe) and muscle spasms (6.3% evolocumab; 3.9% ezetimibe). [3] 
01/04/2014 09:30:35
Jan 14: Rreliminary results reported from the PIII GAUSS-2 study (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-2) trial. The randomized, multicentre, double-blind, placebo- and ezetimibe-controlled trial enrolled 307 patients with high cholesterol levels who could not tolerate effective doses of at least two different statins due to muscle-related side effects. Patients were randomized to one of four treatment groups: subcutaneous evolocumab 140mg every two weeks or 420mg monthly; ezetimibe 10mg daily with either oral or subcutaneous placebo. The study met its co-primary endpoints: % reduction from baseline in LDL-C at week 12 and the mean % reduction from baseline in LDL-C at weeks 10 and 12. The mean % reductions in LDL-C vs ezetimibe were consistent with results observed in the PII GAUSS study. Safety was generally balanced across treatment groups. The most common adverse events (> 5 % in evolocumab combined group) were headache (7.8% evolocumab; 8.8% ezetimibe), myalgia (7.8 vs 17.6%), pain in extremity (6.8 vs 1%), and muscle spasms (6.3 vs 3.9%) [2].
24/01/2014 08:33:06
Nov 13: NCT01984424 is a double-blind, randomized, multicentre study of evolocumab, vs ezetimibe in 500 hypercholesterolaemic subjects unable to tolerate an effective dose of statin due to muscle related side effects. The primary outcome is change from baseline in LDL-C to 24 weeks. The study starts Nov 13 and is due to complete Apr 18 [1]
18/11/2013 11:25:23
Evidence Based Evaluations
NICE scope  http://www.nice.org.uk/guidance/indevelopment/gid-tag498/documents 
References  
Available only to registered users
 Category
BNF Category: Lipid-regulating drugs (02.12)
Pharmacology: Fully human monoclonal antibody to Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9), a negative regulator of the LDL receptor.  
Epidemiology: It is estimated that 6 in 10 adults in England have cholesterol levels >5 mmol/litre, and more than half of CV disease-associated events are attributed to high cholesterol. For familial hypercholesterolaemia, NICE recommends a bile acid sequestrant, nicotinic acid or a fibrate for people with intolerance or contraindications to statins or ezetimibe. For heterozygous familial monotherapy, NICE recommends ezetimibe alone when statins are contraindicated or not tolerated [9].  
Indication: Hypercholesterolaemia 
Additional Details: primary (heterozygous familial and non‑familial) or mixed dyslipidaemia alone or in combination with other lipid-lowering therapies in adults who are statin-intolerant, or for whom a statin is contra-indicated 
Method(s) of Administration  
Subcutaneous 
Company Information
Name: Amgen 
US Name: Amgen 
Further Information
Anticipated commissioning route (England) CCG 
High cost drug list? Awaiting Update
In NICE timetable: Yes 
When: Apr / 2016 
Note: www.nice.org.uk/guidance/indevelopment/gid-tag498 
Implications Available only to registered users