2015年7月8日，瑞士制药巨头诺华（Novartis）的慢性心衰药物Entresto（前称LCZ696）近日提前6周获得FDA批准，用于射血分数降低的心力衰竭（heart failure）患者，降低心血管死亡和心衰住院风险。Entresto是一种首创新药，以多种方式作用于心脏的神经内分泌系统，该药是过去25年内心衰治疗领域的一个伟大突破，有望成功动摇过去10年未被修改的心衰治疗整体框架。 Entresto（sacubitril/valsartan）是一种万众瞩目的心衰药物，是首个也是唯一一个在临床试验中疗效显著超越标准治疗药物依那普利（enalapril）的药物，而且表现出更高的安全性。Entresto的杰出表现，使该药成为过去10年中心脏病学领域最重要的进展之一 Entresto是一种首创的双效血管紧张素受体-脑啡肽酶抑制剂（ARNI），具有独特的作用模式，能够增强心脏的保护性神经内分泌系统（NP系统，钠尿肽系统），同时抑制有害系统（RAAS系统，肾素-血管紧张素-醛固酮系统），被认为能够减少衰竭心脏的应变。LCZ696结合了诺华的高血压药物代文（Diovan，通用名：valsartan，缬沙坦）和实验性药物AHU-377。AHU377是一种脑啡肽酶抑制剂，可阻断威胁负责降血压的2种多肽的作用机制，valsartan是一种血管紧张素II受体拮抗剂，可改善血管舒张，刺激身体排泄钠和水。 Entresto适用人群为心功能分级为II-IV（NYHA class II-IV）的中度至重度心衰患者，该药通常是与其他心衰药物联用，以取代血管紧张素转化酶（ACE）抑制剂或其他血管紧张素受体阻断剂（ARB）。心力衰竭是一种危机生命的心脏疾病，患者心脏无法泵出足够的血液，因而面临着高风险死亡、反复住院治疗及其他症状（如呼吸困难，疲劳，体液潴留），该病会严重影响患者寿命及生活质量。据估计，在美国有近600万心衰患者，约一半伴有射血分数降低，其中约有220万患者归类为NYHA分级 II-IV。 Entresto的获批，是基于里程碑III期PARADIGM-HF研究的积极顶线数据，这是在心衰患者群体中开展的有史以来规模最大的研究。数据显示，在多个关键终点，Entresto均显著优越于心衰标准治疗药物ACE抑制剂依那普利（enalapril），数据具有高度统计学显著差异和临床重要性。 横跨各治疗组，Entresto从治疗早期便表现出了可持续的治疗利益： （1）心血管疾病死亡风险降低20%（p=0.00004）； （2）心脏衰竭住院率降低21%（p=0.00004）； （3）全因死亡风险降低16%（p=0.0005）； （4）总体而言，综合衡量心血管死亡或心脏衰竭住院主要终点，风险降低20%（p=0.0000002）。安全性方面，Entresto表现出了超越常规药物的更高安全性。 本品包装规格 24mg/26mg/片*60片/瓶 49mg/51mg/片*60片/瓶 97mg/103mg/片*60片/瓶 Novartis’ new heart failure medicine LCZ696 approved by FDA to reduce risk of cardiovascular death and heart failure hospitalization; now called Entresto™ (sacubitril/valsartan) FDA approved: Yes (First approved July 7th, 2015) Brand name: Entresto Generic name: sacubitril and valsartan Previous name: LCZ696 Company: Novartis Pharmaceuticals Corporation Treatment for: Heart Failure Entresto (sacubitril and valsartan) is a neprilysin inhibitor and angiotensin II receptor blocker combination indicated to reduce the risk of death and hospitalization in patients with chronic heart failure. Heart failure is serious disease in which the heart cannot pump enough blood and oxygen around the body. Breathlessness, fatigue and fluid retention can occur. Entresto works by reducing strain on the failing heart. Entresto contains a combination of sacubitril, a first-in-class neprilysin inhibitor, and valsartan, an angiotensin II antagonist already FDA approved as Diovan. In the PARADIGM-HF Phase III study, Entresto was superior to ACE inhibitor enalapril on key endpoints in the largest heart failure study ever done. Entresto reduced the risk of death from cardiovascular causes and heart failure hospitalization by 20% and 21%, respectively, and reduced the risk of all-cause mortality by 16%. Entresto tablets are taken twice daily, usually in conjunction with other heart failure medicines. Angioedema has been reported as a serious side effect of Entresto, and patients are advised to seek emergency medical assistance if they experience symptoms such as trouble breathing. Common side effects include hypotension, hyperkalemia, renal impairment. New Drugs Online Report for sacubitril + valsartan Information Generic Name: sacubitril + valsartan   Trade Name: Entresto  Synonym: LCZ 696  Entry Type: New molecular entity   Development and Regulatory status UK: Pre-registration (Filed)  EU: Pre-registration (Filed)  US: Pre-registration (Filed)  UK launch Plans: Available only to registered users Actual UK launch date:   Comments Apr 15: PIM (Promising Innovative Medicine) status granted. If quality, safety and efficacy data are found to be sufficient to support a positive benefit/risk balance and added clinical value, the MHRA will issue a EAMS (Early Access to Medicines Scheme) Scientific Opinion for the drug [20]. 24/04/2015 10:15:14  Apr 15: In Nov 2014, the EMA granted accelerated assessment for sacubitril/valsartan. The designation allows the CHMP to grant an opinion at day 150 compared with the standard 210 day procedure. A decision on EU approval is expected in 2015 [19] 17/04/2015 16:23:08  Feb 15: Filed in the EU via the centralised procedure [18]. 24/02/2015 14:31:57  Feb15. FDA has accepted for priority review, an application for approval of LCZ696 (sacubitril combination with valsartan) for chronic NYHA II-IV heart failure with LVEF<40%. [15] 17/02/2015 09:40:46  Oct 14: Novartis plans to file an FDA application by end of 2014. EU submission still scheduled for early 2015 [13]. 30/10/2014 10:42:30  Sep 14: LCZ696 has been granted fast-track status by the US FDA which allows for rolling submission in the USA, which Novartis expects to complete by the end of 2014 [12]. 03/09/2014 11:51:24  Jul 14: In view of positive PARADIGM-HF study results, Novartis will now file in the EU Q1 2015 [10]. 15/07/2014 11:17:50  Jan 14: Novartis plan to file LCZ696 for heart failure (with preserved ejection fraction) in 2018 or beyond [8]. 10/03/2014 17:21:32  Mar 2013: No new information available, company pipeline still indicates planned filing in 2014 [6] 28/03/2013 11:12:48  Filing planned 2014 [2] 24/03/2011 11:23:45  PIII Dec 09 [1]. 24/12/2009 12:13:30  Trial or other data Feb 15: Priority review based on results from the PARADIGM-HF trial, which showed that LCZ696 reduced risk of either cardiovascular death or heart failure hospitalisation by 20% compared to enalapril. The trial was stopped early, according to pre-specified rules, after a median follow-up of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed [16,17]. 17/02/2015 09:54:02 Feb 15: A study published in the European Heart Journal looked at one of the components of LCZ696, sacubitril, which inhibits the action of neprilysin. Neprilysin has two conflicting roles; it leads to increased levels of neuropeptides and vasodilators which are beneficial to the cardiology system but in the brain, however, it also plays a role in degrading the beta amyloid plaques linked to Alzheimer’s disease. Hence it has been speculated that it could speed the progression of Alzheimer’s disease, especially in people at high risk. It is important to note that it is unknown whether LCZ696 can pass the blood brain barrier [14,15].  10/02/2015 09:26:04 Aug 14: Results from PARADIGM-HF study. Significantly more pts on LCZ696 were alive and had fewer hospitalisations than those taking enalapril. LCZ696 reduced the risk of death from cardiovascular (CV) causes by 20% (p=0.00004); reduced heart failure hospitalisations by 21% (p=0.00004) and reduced the risk of all-cause mortality by 16% (p=0.0005). Overall there was a 20% risk reduction on the primary endpoint, a composite measure of CV death or heart failure hospitalisation (p=0.0000002). [11] 01/09/2014 09:05:44 Mar 14: Novartis announce that the data monitoring committee for the PARADIGM-HF study has recommended an early close due to interim data showing LCZ696 is associated with delays in CV deaths and fewer hospitalisations resulting from heart failure in comparison to enalapril [9]. 01/04/2014 10:07:24 Aug 13: NCT01920711 (PARAGON-HF) is a multicentre, randomized, double-blind study to evaluate the efficacy and safety of LCZ696 vs. valsartan, on morbidity and mortality in 4300 heart failure patients (NYHA Class II-IV) with preserved ejection fraction (LVEF ≥45% prior to study entry). The primary outcome is cumulative number of primary composite events of cardiovascular death and total (first and recurrent) HF hospitalizations. The study starts Nov 13 and is due to complete Aug 18 [7]. 13/08/2013 09:29:57 Aug 12: PII PARAMOUNT study published early online in the Lancet. 301 pts with NYHA class II—III heart failure were randomised to LCZ696 (200 mg twice daily) or valsartan (160 mg twice daily) and treated for 36 weeks. The primary endpoint was change in NT-proBNP, a marker of left ventricular wall stress, from baseline to 12 weeks and was significantly reduced in the LCZ696 group (LCZ696: baseline, 783 pg/mL [95% CI 670—914], 12 weeks, 605 pg/mL [512—714]; valsartan: baseline, 862 pg/mL [733—1012], 12 weeks, 835 [710—981]; ratio LCZ696/valsartan, 0.77, 95% CI 0.64—0.92, p=0.005). The reduction in NT-proBNP in pts receiving LCZ696 became evident at 4 weeks and appeared to be sustained to 36 weeks, although the between-group difference was no longer significant. LCZ696 had adverse effects similar to those of valsartan; 22 pts (15%) on LCZ696 and 30 (20%) on valsartan had one or more serious adverse event [3]. 30/08/2012 10:07:52 NCT01035255 (PARADIGM-HF): this study, which started in Dec 09 will compare LCZ696 (200mg twice daily) vs enalapril (10mg twice daily) on morbidity and mortality in 7980 patients with chronic heart failure (NYHA Class II - IV and EF< 40%). The primary endpoint is time to first occurrence of the composite of CV death or HF hospitalization. The study is expected to complete Jul13 [1]. 24/12/2009 12:15:55 Evidence Based Evaluations NHSC/NIHR  http://www.hsc.nihr.ac.uk/topics/lcz696-for-chronic-heart-failure-andndash-first-li/  References   Available only to registered users  Category BNF Category: Drugs affecting the renin-angiotensin system (02.05.05) Pharmacology: Fixed dose combination preparation containing first-in-class neprilysin inhibitor (sacubitril) with an angiotensin receptor antagonist (valsartan). Sacubitril augments natriuretic peptides.   Epidemiology: The unadjusted prevalence of heart failure is 0.7% of all patients registered with a GP in England and there were 61,130 admissions for heart failure (ICD10 I50) in 2011-12 [4,5].   Indication: Heart failure  Additional Details: chronic, NYHA II-IV and LVEF<40%  Method(s) of Administration   Oral  Company Information Name: Novartis  US Name: Novartis  Further Information Anticipated commissioning route (England) CCG  High cost drug list? Awaiting Update Implications Available only to registered users