2014年10月10日，美国食品和药品监督管理局(FDA)批准Harvoni(ledipasvir和sofosbuvir)片剂治疗慢性丙型肝炎病毒(HCV)基因型1感染，
Harvoni是第一个被批准治疗慢性HCV基因型1 感染二联复方片剂。它也是第一个被批准不需要给予干扰素或利巴韦林[ribavirin]的方案。后两药是被FDA-批准治疗HCV感染的药物。
在Harvoni中的两个药物干扰HCV繁重所需的酶。Sofosbuvir是以前被批准的HCV药物用商品名Sovaldi上市。
Harvoni还含有新药被称为ledipasvir。

注：(以前称为GS-5885) 由Gilead Sciences公司正在开发是为治疗丙肝的一种实验性药物。在完成Phase III期临床试验后，得到ledipasvir/sofosbuvir固定剂量联用片为丙肝基因型1治疗批准。ledipasvir/sofosbuvir联用是直接作用抗病毒药干扰HCV复制和可用于治疗有基因型1a 或1b无 PEG-干扰素患者。Ledipasvir是丙肝病毒NS5A蛋白抑制剂。
http://www.hivandhepatitis.com/hcv-treatment/experimental-hcv-drugs/4005-croi-2013-sofosbuvirledipasvirribavirin-combo-for-hcv-produces-100-sustained-response
FDA药品评价和研究中心抗微生物产品室主任Edward Cox, M.D., M.P.H.说：“随着发展和批准对丙型肝炎病毒新治疗，我们正在改变有此病美国人生活的治疗范式，”“直至去年，对丙型肝炎唯一得到的治疗需要给予干扰素和利巴韦林。现在virin. Now, 患者和卫生保健专业人员有多种治疗选择，包括二联复方药丸有助于简化治疗方案。”
Harvoni是在去年治疗以来被批准治疗男性丙型肝炎的第三个药物。2013年11月FDA批准 Olysio (simeprevir)和2013年12月批准Sovaldi。
丙肝是抑制病毒病，肝脏炎症引起，可能导致肝功能减退或肝衰竭。感染HCV的大多数人在肝损伤变得明显前无疾病症状，可要十年。
患慢性HCV 感染的有些人在经历许多年后发生瘢痕形成和肝功能差(肝硬化)，可能导致并发症例如出血，黄疸(眼或皮肤发黄)，腹腔液体积蓄，感染和肝癌。按照美国疾病控制和预防中心，约3.2百万美国人被HCV 感染，和没有适当治疗，这些人中15-30 %将进行发展肝硬变。
在三项纳入1,518例以前对感染没有接受治疗的参加者(未治疗过)或对以前治疗没有反应(经历治疗)，包括有肝硬化参加者评价Harvoni的疗效。参加者被随机赋予接受Harvoni有或无利巴韦林。试验被设计测量丙肝病毒，在治疗完成后至少12周在血中再也不能检测到丙肝病毒(持续病毒学反应，或SVR)，表明参加者的HCV感染已被治愈。
在第一相试验中，由未治疗过参加者组成，其中94%接受Harvoni共8周和其中96 %接受共 12周实现持续病毒学反应SVR。第二项试验这类参加者显示99 %有和无肝硬化在12周后实现持续病毒学反应SVR。而第三项试验，在经历治疗有和无肝硬化参加者中检查Harvoni疗效，其中94 %接受Harvoni共12周而其中99 %接受Harvoni共24周实现SVR。在所有试验中，利巴韦林不增加参加者中的反应率。
在临床试验中报道参加者的最常见副作用是疲乏和头痛。
Harvoni是第七个接到PDA批准突破性治疗指定的新药。在承办单位请求时，如果初步临床证据表明对有严重或危及生命疾病患者，药物可能证实一种实质上改善超过可得到治疗时，FDA可指定某个药物为一个突破性治疗。Harvoni是在 FDA优先审评程序下审评，它提供治疗严重情况和如批准将提供安全性或有效性重要改进的药物加快审评。
Harvoni和Sovaldi 将由总部设在加州福斯特市的Gilead公司上市。Olysio由总部新泽西州Raritan的Janssen药业上市。

Generic Name: sofosbuvir + ledipasvir  
Trade Name: Harvoni 
Synonym: GS-7977, GS-5855 
Entry Type: New formulation  
Developmental Status
UK: Recommended for approval (Positive opinion) 
EU: Recommended for approval (Positive opinion) 
US: Pre-registration (Filed) 
UK launch Plans: Available only to registered users
Actual UK launch date:  
Comments
Sep 14: EU positive opinion for treatment of chronic hepatitis C infection in adults [16].
29/09/2014 14:24:50 
Apr 14: Granted priority review in the US. A decision on approval is expected by 10 Oct [14]
07/04/2014 19:33:19 
Feb 14: EU CHMP issues an opinion on the use of a fixed-dose combination of ledipasvir and sofosbuvir in the treatment of chronic HCV infection in a compassionate use programme. The assessment report and conditions of use of the combination of ledipasvir and sofosbuvir with or without ribavirin in this setting will be published shortly on the EMA´s website [13].
24/02/2014 11:44:21 
Feb 14: Filed in the EU for treatment of chronic hepatitis C genotype 1 infection in adults [12].
13/02/2014 10:57:02 
Feb 14: Filed in the US as a once-daily fixed-dose combination of ledipasvir 90mg and sofosbuvir 400mg for the treatment of chronic hepatitis C genotype 1 infection in adults [11]
11/02/2014 15:45:52 
Dec 13: Company plans to file in US Q1 2014,where it has been award Breakthrough designation [10]
19/12/2013 21:51:52 
Oct 12: PIII study starts in US, EU & UK [2].
08/10/2012 17:57:03 
Trial or other data
Apr 14: NHS England commissioned. Patients eligible for treatment are those with significant risk of death or irreversible damage within the next 12 months, irrespective of genotype [15]
22/04/2014 09:17:03
Apr 14: Results from three PIII studies published early on-line in the NEJM: ION-1 (http://www.nejm.org/doi/full/10.1056/NEJMoa1402454), ION-2 (http://www.nejm.org/doi/full/10.1056/NEJMoa1316366) and ION-3 (http://www.nejm.org/doi/full/10.1056/NEJMoa1402355)
14/04/2014 08:37:45
Feb 14: Results of the PII LONESTAR study (n=100) published in the Lancet Feb 8 2014: 383: 515-23. The study found that the fixed dose-combination of sofosbuvir-ledipasvir alone or with ribavirin has the potential to cure most patients with genotype-1 HCV irrespective of treatment history or presence of compensated cirrhosis.
11/02/2014 15:10:32
Dec 13: Topline results announced from three PIII clinical trials (ION-1, ION-2 and ION-3) of the once-daily fixed-dose combination of sofosbuvir 400mg ledipasvir 90mg, with and without ribavirin, for the treatment of genotype 1 chronic HCV infection. 1,952 patients were enrolled across the 3 studies; of these, 1,512 were treatment-naïve, 440 were treatment experienced and 224 had compensated cirrhosis. Of the 1,518 patients randomized to the 12-week arms of ION-1 and to all arms of ION-2 and ION-3, 1,456 patients (95.9%) achieved the primary efficacy endpoint of SVR12. Of the 62 patients (4.1%) who failed to achieve SVR12, 36 patients (2.4%) experienced virologic failure: 35 due to relapse and only one patient due to on-treatment breakthrough (with documented noncompliance). Twenty-six patients (1.7%) were lost to follow-up or withdrew consent [10].
19/12/2013 21:49:46
May 13: NCT01851330 (ION-3) starts May 13 and is due to complete Dec 14 [9].
13/05/2013 09:13:20
May 13: Company is to start a 3rd PIII trial (ION-3) of the once daily fixed-dose combination tablet of sofosbuvir and ledipasvir in 600 non-cirrhotic, treatment-naïve genotype 1 HCV-infected patients. The design of ION-3 is based on interim results from the PII LONESTAR study, which evaluated 8- and 12-week courses of therapy in 60 treatment-naïve, non-cirrhotic patients. In this study, 19/19 patients in the 12-week arm had a sustained virologic response four weeks after completing therapy (SVR4) and 40/41 in the 8-week arms had a SVR8, with one relapse occurring in the arm receiving sofosbuvir/ledipasvir without RBV. In ION-3, participants will be randomized to receive sofosbuvir and ledipasvir for 8 weeks (n=200), sofosbuvir and ledipasvir + RBV for 8 weeks (n=200), or sofosbuvir and ledipasvir for 12 weeks (n=200). The primary endpoint is SVR12, defined as maintaining undetectable HCV RNA 12 weeks post-treatment and considered a cure for HCV infection. The study is designed to assess non-inferiority of the 8-week treatment duration arms to the 12-week treatment duration arm [8].
03/05/2013 08:43:40
Mar 13: A planned review by the study´s Data and Safety Monitoring Board (DSMB) of safety data from 200 pts in all four arms and of SVR4 rates (sustained virologic response four weeks after completion of therapy) from 100 pts in the two 12-week duration arms concluded that the ION-1 trial should continue without modification [7]. 
05/04/2013 09:35:12
Jan 13: NCT01768286 (ION-2) is a PIII, multicentre, randomized, open-label study to investigate the efficacy and safety of sofosbuvir/GS-5885 fixed-dose combination (400/90 mg) ± ribavirin for 12 and 24 weeks in 400 treatment-experienced subjects with chronic Genotype 1 HCV Infection. The primary outcomes are SVR12 and safety and tolerability. The study starts Jan 13 and is due to complete Nov 14 [4].
24/01/2013 17:22:13
Oct 12: NCT01701401 is a PIII, multicentre, randomized, open-label study to investigate the efficacy and safety of sofosbuvir/GS-5885 fixed-dose combination (400/90 mg) +/- ribavirin for 12 and 24 weeks in 800 treatment-naive subjects with chronic genotype 1 HCV Infection. The primary outcome is sustained virologic response (SVR) 12 weeks after discontinuing therapy. The study starts Oct 12 and is due to complete Dec 14 [2].
08/10/2012 17:56:34
Jul 12: Gilead is planning to start a PIII study of the combination of GS-7977 + GS-5855 in a single pill to treat hepatitis C in a trial of 800 patients by Q4 2012. If the combination is effective, the company could apply for regulatory approval in the middle of 2014 [1].
31/07/2012 08:41:11 
Evidence Based Evaluations
NHSC/NIHR  http://www.hsc.nihr.ac.uk/topics/sofosbuvir-with-ledipasvir-for-hepatitis-c-genotyp/   
References  
Available only to registered users
 Category
BNF Category: Viral hepatitis (05.03.03)
Pharmacology:  
Epidemiology: ~200,000 to 500,000 people are infected with HCV in England and Wales [5], and around 45% of these are of genotype 1 [6]  
Indication: Hepatitis C infection 
Additional Details: in adults 
Method(s) of Administration  
Oral 
Company Information
Name: Gilead Sciences 
US Name: Gilead Sciences 
NICE Information
In timetable: No  
When:   
PBR Likely specified high cost drug.
Service
Implications Available only to registered users
Prescribing
Outlook: Available only to registered users