Praluent(alirocumab)新类别中第一个的注射降胆固醇药物 2015年7月24日,美国食品药品监督管理局(FDA)批准Praluent(alirocumab)注射液，被批准的在一种新类型药物被称为前蛋白转化酶枯草杆菌蛋白酶Kexin9型(PCSK9)抑制剂中的第一个降胆固醇治疗。 Praluent被批准为使用添加至膳食和最大耐受的他汀类治疗在成年患者有杂合子家族性高胆固醇血症(HeFH)或有临床动脉粥样硬化心血管病患者例如心脏发作或卒中，需要另外LDL胆固醇的降低。 HeFH是一种遗传情况致低密度脂蛋白(LDL)胆固醇的高水平。在血中LDL胆固醇的一个高水平(被称为“坏” 胆固醇)是连接至心血管病. 心脏病对美国人是头号死因，男性和女性都是。按照美国疾病控制和预防中心，在美国每年约610,000人死于心脏病– 等于每四例死亡1例。 药物评价和研究中心新药办公室主任John Jenkins，M.D. 说：“对有HeFH或有已知的心血管病患者用他汀类药物未能足够降低他们的LDL胆固醇Praluent提供另外治疗选择，” “FDA强力支持继续工作以提供新和创新选择为治疗和预防心血管病。” Praluent是一种抗体靶向一种特异性蛋白，称为PCSK9，它作用通过降低肝脏上从血中去除LDL胆固醇受体数量。通过阻断PCSK9的工作能力，被得到更多受体从血中摆脱LDL胆固醇和，其结果，降低LDL胆固醇水平。 在五项安慰剂对照试验，涉及2,476例参加者暴露于Praluent评价Praluent的疗效和安全性。所有参加者有HeFH或否则处于对心脏发作或卒中高危，和曾正在用最大地耐受剂量的一种他汀类，有或无其他脂质修饰治疗。参加者用Praluent与安慰剂比较有在LDL胆固醇中平均减低范围从36至59百分率。 多个临床试验曾显示他汀类药物降低有一个心脏发作或卒中的风险。正在进行一项试验评价添加Praluent 至他汀类药物对减低心血管风险的影响。 Praluent的最常见副作用包括给予注射处的痒，肿胀，疼痛，或瘀血，鼻咽炎，和流感。过敏反应，例如超敏性血管炎(一种皮疹通常地表现为在皮肤上紫色的斑点伴随小血管炎症)和随Praluent的使用曾报道超敏性反应需要住院.患者应停止使用Praluent和得到医疗帮助如他们经历严重过敏反应症状。 Praluent由Sanofi-Aventis 美国，总部在新泽西州Bridgewater，和Regeneron Pharmaceuticals Inc.总部在纽约州Tarrytown上市。 http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455883.htm Praluent, alirocumab(REGN727, SAR236553) Praluent Approval History •FDA approved: Yes (First approved July 24th, 2015) •Brand name: Praluent •Generic name: alirocumab •Company: Sanofi and Regeneron Pharmaceuticals, Inc. •Treatment for: High Cholesterol, High Cholesterol, Familial Heterozygous Praluent (alirocumab) is a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor monoclonal antibody for the treatment of heterozygous familial hypercholesterolemia, or patients with atherosclerotic heart disease who require additional lowering of LDL-cholesterol. New Drugs Online Report for alirocumab Information Generic Name: alirocumab   Trade Name: Praluent  Synonym: REGN-727, SAR236553, Anti-PCSK-9   Entry Type: New molecular entity   Development and Regulatory status UK: Recommended for approval (Positive opinion)  EU: Recommended for approval (Positive opinion)  US: Recommended for approval (Positive opinion)  UK launch Plans: Available only to registered users Actual UK launch date:   Comments Jul 15: EU positive opinion for use in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, 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 effect of Praluent on cardiovascular morbidity and mortality has not yet been determined [28]. 24/07/2015 12:58:03  Jun 15: The FDAs Endocrinologic and Metabolic Drugs Advisory Committee has voted 13-3 in favour of green-lighting alirocumab [27]..  12/06/2015 10:29:05  Jan 15: FDA accepts alirocumab for priority review with a target action date of July 2015 [24].  27/01/2015 10:50:43  Jan 15: Regeneron and Sanofi announce Praluent™ (alirocumab) acceptance of Marketing Authorisation application for review by the EMA. The application is based on data from more than 5,000 patients from the ODYSSEY clinical trial program which is ongoing. A biologics license application (BLA) was submitted to the US FDA in the fourth quarter of 2014 [23]. 13/01/2015 09:56:17  Oct 14: Amgen files a patent-infringement lawsuit to prevent the manufacture, use and sale of Sanofi and Regeneron´s alirocumab [19]. 20/10/2014 10:34:27  Aug 14: Regeneron and Sanofi are expected to file alirocumab in the US in Q4 2014 [17]. 29/08/2014 10:00:31  March 14: No further updates. Over 10 studies in the ODYSSEY phase 3 programme. ODYSSEY OUTCOMES (cardiovascular outcomes study). ODYSSEY FH I, FH II and HIGH FH (heFH, familial hypercholesterolaemia, not adequately controlled with existing lipid-lowering therapy). ODYSSEY COMBO I and COMBO II (non-familial hypercholesterolaemia, add-on therapy). ODYSSEY ALTERNATIVE (non- and familial hypercholesterolaemia, unable to tolerate statins). ODYSSEY OPTIONS I and OPTIONS II (add-on therapy in pts at high cardiovascular risk or with heFH inadequately controlled on statins). ODYSSEY LONG TERM (long-term safety and tolerability). [15] 27/03/2014 11:19:31  Jan 12: PIII study started [1]. 10/03/2012 18:08:48  Trial or other data Jun 15: Results from ODYSSEY OPTIONS I (n=355) published in Journal of Clinical Endocrinology and Metabolism. Adding alirocumab to atorvastatin provided greater LDL-C reductions vs. adding ezetimibe, doubling atorvastatin dose, or switching to rosuvastatin (p<0.001 vs. all compatators), and enabled greater LDL-C goal achievement. Treatment-emergent adverse events occurred in 65.4% of alirocumab patients, vs 64.4% ezetimibe and 63.8% double atorvastatin/switch to rosuvastatin (data pooled) [28].  12/06/2015 11:13:21 Mar 15: ODYSSEY LONG TERM published in NEJM. At week 24, the difference between the alirocumab and placebo groups in the mean percentage change from baseline in calculated LDL cholesterol level was −62 percentage points (P<0.001); the treatment effect remained consistent over a period of 78 weeks. The alirocumab group, as compared with the placebo group, had higher rates of injection-site reactions (5.9% vs. 4.2%), myalgia (5.4% vs. 2.9%), neurocognitive events (1.2% vs. 0.5%), and ophthalmologic events (2.9% vs. 1.9%). In a post hoc analysis, the rate of major adverse cardiovascular events (death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) was lower with alirocumab than with placebo (1.7% vs. 3.3%; hazard ratio, 0.52; 95% confidence interval, 0.31 to 0.90; nominal P=0.02) [26]. 18/03/2015 12:50:58 Feb 15. Results of the ODYSSEY COMBO II trial published in European Heart Journal. This RCT (n=720) reported a 50% reduction in LDL-C from 2.9 to 1.3 mmol/L for patients on alirocumab 75mg sc. every 2 weeks and a 20% reduction from 2.7 to 2.1 mmol/L for those on ezetimibe 10 mg daily (P<0.0001) at week 24 (primary efficacy endpoint). [25] 18/02/2015 14:55:10 Jan 15: The two ODYSSEY PIII trials designed to look at how alirocumab impacted patients with hypercholesterolemia when administered every four weeks met their primary endpoints. ODYSSEY CHOICE I looked at the efficacy and safety of alirocumab in 803 patients at moderate to high cardiovascular risk, while ODYSSEY CHOICE II examined it in patients with the same risk and a history of intolerance to two or more statins. In the monthly dosing trials, the mean percent reduction in LDL-C from baseline was consistent with that seen in previous PIII trials evaluating alirocumab every other week dosing. [22] 12/01/2015 12:42:34 Nov 14: Data from six PIII trials (ODYSSEY LONG TERM, COMBO I, ALTERNATIVE, OPTIONS I, OPTIONS II, and HIGH FH) of alirocumab presented at the American Heart Association (AHA). Pts all had high CV risk, heterozygous familial hypercholesterolemia (HeFH), and/or a history of intolerance to two or more statins. All the PIII trials were reported to have met their primary efficacy endpoints of significantly reduced LDL-C at 24 weeks compared with either active comparator or placebo. In addition, new interim results from ODYSSEY LONG TERM provide further support for alirocumab´s consistent safety profile. The company plans to file for approval by the end of the year [21].  20/11/2014 09:06:56 Nov 14: Data presented at the AHA congress. Among the 360 pts in a PIII study, those in the alirocumab arm reported a 45% LDL cholesterol reduction vs. 14.6% for subjects taking ezetimibe. Alirocumab helped 42% of pts get lower their LDL to target levels vs. 4% in the ezetimibe group [20]. 19/11/2014 10:10:12 Aug 14: Results from 4 studies announced. FH I and FH II (n=738): At 24 wks (primary outcome), 49% reduction from baseline in LDL-C levels in both studies with alirocumab vs. 9% (FH I) and 3% (FH II) increase with placebo. At 52 weeks, 47% reduction (FH I) and 50% reduction (FH II) in LDL-C with alirocumab vs. 9% and 8% increases with placebo. Pre-specified LDL-C goals achieved by 72% (FH I) and 81% (FH II) of alirocumab treated patients at 24 weeks, vs. 2% and 11% of placebo groups, respectively. [18] 01/09/2014 09:19:12 Aug 14: Results from 4 studies announced. ODYSSEY COMBO II (n=720): At 24 wks (primary outcome), 51% reduction from baseline in LDL-C with alirocumab vs. 21% reduction with ezetimibe. At 52 weeks, 50% reduction from baseline in LDL-C with alirocumab vs. 18% reduction with ezetimibe.[18] 01/09/2014 09:15:56 Aug 14: Results from 4 studies announced. ODYSSEY LONG-TERM (n=2,341): At 24 wks (primary outcome) 61% reduction in LDL-C levels from baseline in alirocumab groups vs. 1% increase in placebo group. At 52 weeks, 57% reduction in LDL-C from baseline with alirocumab vs. 4% increase with placebo. 81% of alirocumab pts achieved pre-specified LDL-C goal [18] . 01/09/2014 09:15:33 Jul 14: Nine PIII ODYSSEY trials of alirocumab in >5000 people with hypercholesterolaemia, met the primary efficacy endpoint of greater reduction from baseline in LDL-C at 24 weeks vs. placebo/active comparator [16]. 01/08/2014 10:07:52 Oct 13: Early PIII data from the ODYSSEY MONO trial have demonstrated that monotherapy with alirocumab reduced levels of LDL-C by 47.2% vs. 15.6% with ezetimibe [14]. 17/10/2013 10:44:26 Aug 13: NCT01926782 (ODySSEY CHOICE 1) is arandomized, double-blind, placebo-controlled PIII study of alirocumab in an every four weeks treatment regimen in 700 patients with primary hypercholesterolemia. The primary outcome is % change in LDL-C with concomitant statins. The study starts Aug 13 and is due to complete May 15 [13]. 22/08/2013 11:57:45 Aug 13: The Company intends to start the PIII study, Odyssey Choice, in which patients would take alirocumab every four weeks, by the end of 2013. Initial results from the PIII ODYSSEY MONO trial are also expected by the end of 2013 [12]. 07/08/2013 09:26:38 Jan 13: In an R&D update Sanofi state that 11 PIII trials are now recruiting hypercholesterolaemic patients not at goal for LDL-C and mainly at high cardiovascular risk [11]. 09/01/2013 17:25:43 Nov 12: Results from a PII study published early online in N Engl J Med (October 31, 2012DOI: 10.1056/NEJMoa1201832). The study enrolled patients with primary hypercholesterolaemia with elevated LDL-C (≥100 mg/dL) who were on a stable 10mg dose of atorvastatin. The mean reduction in LDL-C after 8 weeks in patients who received alirocumab sc once every two weeks + atorvastatin 80mg was 73%, vs 17% in 17% for patients who switched to atorvastatin 80mg alone (p<0.001). 90% vs 17.2% of patients respectively, achieved a pre-specified level of 70mg/dL (p<0.001). In a third arm of the study in which alirocumab was added to the stable 10mg of atorvastatin, 96.6 achieved the pre-specified goal of 70mg/dL. The most common AEs reported in patients on alirocumab were headache, dizziness, and diarrhoea. There was one serious AE in the alirocumab + atorvastatin 80mg group (dehydration) that was deemed not to be treatment-related [10]. 02/11/2012 09:26:44 Aug 12: NCT01663402 (ODYSSEY outcomes) is a PIII study comparing the effect of SAR236553 with placebo on the occurrence of cardiovascular events (composite endpoint of coronary heart disease (CHD) death, non-fatal myocardial infarction, fatal and non-fatal ischaemic stroke, unstable angina requiring hospitalization) in 18,000 patients (aged ≥40 years) who have experienced an acute coronary syndrome) event 4 to 16 weeks prior to randomization and are treated with evidence-based medical and dietary management of dyslipidemia. The maximum study duration will be 70 months, including up to a 4-month run-in period, 64 months randomized treatment period, and 2-month follow-up period. The study will start Oct 12 and is due to complete Mar 18 [9]. 22/08/2012 13:51:41 Jul 12: The ODYSSEY global PIII programme of SAR236553/REGN727 administered as a single injection every two weeks in multiple treatment strategies and patient types will comprise over ten clinical trials and include more than 22,000 patients. The programme includes: ODYSSEY FH I, FH II and HIGH FH - add-on therapy in heFH not adequately controlled with their lipid-modifying therapy; ODYSSEY COMBO I and COMBO II: add-on therapy in primary hypercholesterolemia with high cardiovascular risk not adequately controlled with lipid-modifying therapy; ODYSSEY MONO - monotherapy vs ezetimibe primary hypercholesterolemia; ODYSSEY ALTERNATIVE: - vs ezetimibe in patients with primary hypercholesterolemia (heFH and non-familial hypercholesterolemia) who are unable to tolerate statins; ODYSSEY OPTIONS I and OPTIONS II- add-on therapy in patients with primary hypercholesterolemia at high cardiovascular risk or with heFH who are not adequately controlled on statins, in comparison to several second line lipid lowering strategies; ODYSSEY LONG TERM - safety and tolerability 7 in patients with hypercholesterolemia at high cardiovascular risk or patients with heFH inadequately controlled with their current lipid-modifying therapy. In addition, ODYSSEY OUTCOMES will enroll about 18,000 patients and evaluate the effect of SAR236553/REGN727 on the occurrence of cardiovascular events [8]. 24/07/2012 08:58:17 Jul 12: NCT01644175 is a PIII randomized, double-blind study of SAR236553/REG727 vs placebo in 306 high cardiovascular risk patients with hypercholesterolaemia not adequately controlled on stable maximally tolerated daily statin therapy with or without other lipid-modifying therapy. The primary outcome is % change in LDL-C after 24 weeks. The study will run for 62 weeks including a 52 week randomised treatment period. The study will start Jul 12 and is due to complete Mar 14 [7]. 20/07/2012 09:57:39 Jul 12: NCT01644474 is a PIII randomized, double-blind, active-controlled, study of SAR236553/REGN727 vs ezetimibe over 24 weeks in 100 patients with hypercholesterolaemia. The primary outcome is % change in LDL-C after 24 weeks. The study will run for 34 weeks: including a 24 week randomised treatment period. The study will start Jul 12 and is due to complete Nov 13 [7]. 20/07/2012 09:57:12 Jul 12: NCT01644188 is a PIII randomized, double-blind study of SAR236553/REGN727 vs ezetimibe in 660 high cardiovascular risk patients with hypercholesterolemia not adequately controlled on stable maximally tolerated daily statin therapy. The primary outcome is % change in LDL-C after 24 weeks. The study will run for 114 weeks comprising 2 weeks screening, 104 randomised treatment and 8 weeks follow-up periods. The study will start Jul 12 and is due to complete Mar 15 [7]. 20/07/2012 09:57:04 Jun 12: NCT01623115 is a PIII, double-blind, placebo-controlled RCT to 471 in patients with heterozygous familial hypercholesterolemia not adequately controlled with their lipid-modifying therapy. The primary outcome is % change in LDL-C at week 24. The study will start Jul 12 and is due to complete Sep 14 [6]  25/06/2012 13:56:04 Jun 12: NCT01617655 is a PIII double-blind, placebo-controlled RCT to of SAR236553 in 105 patients with heterozygous familial hypercholesterolemia and ≥LDL-C 160mg/dL despite lipid-modifying therapy. The primary outcome is % change in LDL-C from week 0 to 24. The study will start Jun 12 and is due to complete Sep 14. The maximum study duration will be 88 weeks per patient, including a 78-week randomized treatment period [5]. 14/06/2012 08:52:22 May 12: Results from the PII trial, Study 1003 (NTC01266876) in 77 patients with heterozygous familial hypercholesterolemia (heFH) were reported at the European Atherosclerosis Society Congress and published online in The Lancet. Patients enrolled had LDL-C levels uncontrolled on statin therapy with or without ezetimibe. Across the four different dosing regimens tested, patients receiving SAR236553 / REGN727 for 12 weeks achieved a mean LDL-C reduction from baseline of 28.9% to 67.9%, vs 10.7% in patients receiving placebo (p<0.05). In the most intense dose regimen tested (150mg every two weeks), 93.8% of patients achieved LDL-C levels <2.59 mmol/L vs 13.3% of patients on placebo, and 81.3% reached LDL-C levels <1.81 mmol/L vs none on placebo. There were no serious adverse events on active treatment. No elevations in liver function tests >3 times the upper limit of normal and no cases of elevated creatinine kinase were reported. The most common adverse event reported was injection-site reaction [4]. 29/05/2012 22:10:23 Mar 12: PII data presented at the American College of Cardiology´s 61st Annual Scientific Meeting in Chicago. The dose-finding study enrolled 183 pts with elevated LDL-C (greater than or equal to 100 mg/dL) despite being on a stable dose of atorvastatin. Across the five different dose regimens tested, pts receiving twice monthly SC injections of SAR236553 for 12 wks achieved & sustained a mean LDL-C reduction from baseline of 40% to 72%, vs. 5% in pts receiving placebo (p<0.0001). Pts in the study were followed for a total of 20 wks for safety. Most common adverse events (AEs) were injection site reactions. Serious AEs occurred in one pt receiving placebo & three pts in the active treatment arms, including a pt on active treatment who experienced a skin rash diagnosed as leukocytoclastic vasculitis. Six pts, all on active treatment, prematurely discontinued therapy due to AEs. Muscle complaints were infrequent & similar across all treatment gps. There were no significant elevations in liver enzymes or other lab values in pts on active treatment [2]. 27/03/2012 10:31:45 Mar 12: NCT01507831A PIII double blind, placebo controlled long-term safety study of SAR236553 (REGN727 – given subcutaneously every 2 weeks over 18 months) in 2,100 high cardiovascular risk patients with hypercholesterolaemia not adequately controlled with their lipid modifying therapy. Inclusion criteria include patients with heterozygous familial hypercholesterolaemia (heFH) with or without established coronary heart disease (CHD) or CHD risk equivalents OR patients with hypercholesteroleamia together with established CHD or CHD risk equivalents. The study started Jan 12 and is due to complete Sep 14 [1]. 10/03/2012 18:09:39 Evidence Based Evaluations NHSC   References   Available only to registered users  Category BNF Category: Lipid-regulating drugs (02.12) Pharmacology: PCSK9 inhibitor - PCSK9 is a naturally occurring molecule involved in the regulation of cholesterol levels by modulating low-density lipoprotein cholesterol receptors   Epidemiology: 2/3 of UK population have a total cholesterol >5.2mmol/L. [3]   Indication: Primary hypercholesterolemia  Additional Details: in patients not at goal with standard of care LDLc-lowering  Method(s) of Administration   Subcutaneous injection  Company Information Name: Sanofi   US Name: Sanofi   Further Information Anticipated commissioning route (England) CCG  High cost drug list? Yes - Likely Implications Available only to registered users