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二联复方Harvoni获得FDA批准,抗丙肝新金标
Harvoni是首款获批用于治疗慢性HCV基因型1感染的复方药物。它也是首个获批的不需要干扰素或利巴韦林的治疗方案，干扰素和利巴韦林也是FDA批准的用于治疗慢性HCV感染的药物。
Harvoni中的两款药物可干扰HCV增殖所需要的酶。Sofosbuvir是一款之前被批准的HCV药物，以Sovaldi为商品名上市销售。Harvoni中还包含了一款新的药物Ledipasvir。
“随着丙型肝炎治疗药物的开发与批准，我们正在改变美国丙型肝炎患者的治疗范式，”FDA药物评价与研究中心抗微生物产品办公室主任、医学博士、公共卫生学硕士Cox表示称。“直到去年，仅有的可供使用的丙型肝炎治疗药物需要使用干扰素和利巴韦林。目前，患者与卫生保健专业人员有多种治疗选择，包括一款帮助简化治疗方案的复方药物。”
Harvoni是过去一年FDA批准的第三款慢性HCV感染治疗药物。FDA于2013年11年批准Simeprevir，于2013年12月批准Sovaldi。丙型肝炎是一种病毒性疾病，可引起肝脏炎症，导致肝功能下降或肝功能衰竭。大多数HCV感染患者直到肝脏损伤变得明显时才出现疾病症状，这可能需要几十年。
一些慢性HCV感染患者多年之后会发生疤痕和肝硬化，可导致并发症，如出血、黄疸(黄色眼睛或皮肤)、肝腹水、感染和肝癌。据美国疾病控制与预防中心提供的信息，大约有320万美国人感染有HCV，这些人没有正常的治疗，其中15%-30%的人将继续发展成肝硬化。
Harvoni的有效性在3项临床试验中得到评价，试验受试者为1518名之前未接受过感染治疗或对之前治疗没有响应的患者，包括肝硬化患者。受试者在试验中被随机配给Harvoni，添加或不添加利巴韦林。试验旨在完成12周治疗（持续病毒学响应，或SVR)后，丙型肝炎病毒是否还能在血液中被检测到，结果显示受试者的HCV感染得到治愈。
第一项试验的受试者为之前未曾治疗过的患者，在治疗8周时，94%的Harvoni治疗患者获得SVR，在治疗12周时，96%的患者获得SVR。第二项试验中，同样为之前未曾治疗过的有或没有肝硬化的受试者，受试者在12周治疗后获得SVR。
第三项试验是在之前治疗过的有或没有肝硬化受试者身上检测Harvoni的有效性，在治疗12周时，94%的Harvoni治疗患者获得SVR，在治疗24周时，99%的Harvoni治疗患者获得SVR。在所有三项试验中，利巴韦林未增加患者的响应率。临床试验中，受试者最常报道的副作用是疲劳和头疼。
Harvoni是第7款以突破性治疗药物资格获得FDA批准的药物。如果临床前证据显示一款药物与现有治疗药物相比，证明对严重或危及生命疾病患者有实质性的改善，那么FDA可以根据申请者的请求指定这款药物为突破性治疗药物。Harvoni在FDA优先审评计划下完成审评，优先审评为治疗严重疾病及如果获得批准将在安全性及有效性上提供明显改善的药物提供一个加快的审评。
Harvoni和Sovaldi由位于加州福斯特城的吉利德上市销售。Olysio由位于新泽西州力登的杨森制药上市销售。
Harvoni获得FDA“优先评审”资格，也是第7个获得“突破性药物”资质的药物。虽然Sovaldi是抗丙肝药物的头号明星，上市后前两个个季度的销售额分别高达23和35亿美元，但Harvoni凭借以上的诱人数据，相信一旦开始销售很快会取代Sovaldi的霸主地位，成为抗丙肝新的标准疗法。甚至部分医生建议一些早期患者等待Harvoni进入药房。
当然吉利德也不会永远高枕无忧。艾伯维的全口服抗丙肝三联复方预计在今年12月份能获得美国FDA的批准，而且在披露的几个临床实验中平均持续病毒学应答率更高。默克的MK-5172/MK-8742二联复方的二期临床结果也引人注目，甚至部分分析师认为能直追吉利德。无论如何，短期内Harvoni将必定红极一时，年销售峰值有望超过100亿美元。
本周，百时美施贵宝（BMS）爆出惊人消息，宣布放弃寻求FDA批准其二合一丙肝疗法的上市申请，而专注于开发疗程更短的丙肝治疗方案。这也意味着，在丙肝领域的激烈竞争中，吉利德可以腾出更多的时间。
此外，在研发方面，制药巨头们已开始关注丙肝治疗的下一个前沿阵地。百时美施贵宝（BMS）已经启动一项研究，调查daclatasvir/asunaprevir/Sovaldi鸡尾酒疗法是否能在短短4周内治愈患者。而默沙东在今年6月耗资39亿美元收购Idenix制药获得相关丙肝资产，也正在积极开发4周丙肝鸡尾酒疗法。强生（JNJ）上月耗资17.5亿美元收购Alios Biopharma公司，也有开发4周丙肝鸡尾酒疗法的计划。而同时，吉利德为了捍卫其丙肝领域的领先优势，也已启动一项临床项目，评估4周丙肝鸡尾酒疗法。
另外，今年9月底，Harvoni在欧盟方面也获得了好消息，欧洲药品管理局（EMA）人用医药产品委员会（CHMP）已建议批准Harvoni。预计将在年底上市欧盟。
Harvoni is a recently approved drug to treat patients with hepatitis C (HCV) – which is common among HIV-positive individuals who injected drugs.
THE FDA HAS approved Harvoni, a new drug that is up to 99% effective in treating chronic hepatitis C virus (HCV) genotype 1 infection, providing a major improvement in treatment for people living with the disease.
In clinical trials, 94% of those who received Harvoni for 12 weeks and 99% of those who received the drug for 24 weeks achieved “sustained virologic response,” according to reports, which indicates that a person’s HCV infection has been cured.
The Centers for Disease Control estimates that a quarter of HIV-infected individuals in the U.S. also are infected with HCV. Infection with HCV is common (50%- 90%) among HIV-positive individuals who inject drugs.
A blood-borne virus, HCV is one of the most common causes of chronic liver disease in the U.S.
New Drugs Online Report for sofosbuvir + ledipasvir
Information
Generic Name: sofosbuvir + ledipasvir
Trade Name: Harvoni
Synonym: GS-7977, GS-5855
Entry Type: New formulation
Development and Regulatory status
UK: Launched
EU: Launched
US: Approved (Licensed)
UK launch Plans: Available only to registered users
Actual UK launch date: November 2014
Comments
Nov 14: Launched in the UK. NHS list price of 28 tabs of Harvoni (90mg ledipasvir/400mg sofosbuvir) is £12,993.33 [20].
27/11/2014 15:43:43
Nov 14: Marketed authorisation granted by European Commission allowing for marketing of Harvoni in all 28 countries of the EU [19].
19/11/2014 08:40:11
Oct 14: Approved in the US for HCV genotype 1 infection. Approval is based on three PIII studies which showed that Harvoni achieved cure rates (SVR 12) of 94%-99% [17].
13/10/2014 11:15:54
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
Mar 15: NICE issues draft guidelines recommending Harvonia as a treatment option for some adults with genotype 1 or 4 chronic hepatitis C (HCV), but not for those with genotype 3 [21].
04/03/2015 11:33:01
Nov 14: Gilead announce results from several PII & PIII studies. In a pooled analysis of PII & PIII open-label studies (Oral #82) in more than 500 genotype 1 HCV infected pts with compensated cirrhosis who received Harvoni alone or with ribavirin (RBV) for 12 or 24 weeks, 96% of pts achieved SVR12. Pts who achieve SVR12 are considered cured of HCV infection. Two prospective analyses from a PII open-label study (Study GS-US-337-0123) eva luating pts with decompensated cirrhosis and those with HCV recurrence following liver transplantation also are being presented. In the first subgroup (Oral #239), 108 genotype 1 and 4 infected pts with decompensated cirrhosis, including those with moderate hepatic impairment (Child-Pugh-Turcotte (CPT) Class B) and severe hepatic impairment (CPT Class C), received Harvoni plus RBV for 12 or 24 weeks. Overall, SVR12 rates were 87% in the 12-week arm and 89% in the 24-week arm. The second subgroup (Oral #8) eva luated 12 or 24 weeks of Harvoni plus RBV among 223 genotype 1 and 4 pts who developed HCV recurrence following liver transplantation. Among non-cirrhotic pts, SVR12 rates were 96% & 98% following 12 and 24 weeks of treatment, respectively. For pts with compensated cirrhosis, SVR12 rates were 96% for both 12 weeks & 24 weeks of therapy. SVR12 rates among pts with decompensated cirrhosis were 81% for both 12 weeks & 24 weeks of therapy. Study GS-US-337-0121 (Late Breaker Oral #LB-6) eva luated 155 genotype 1 pts with compensated cirrhosis who had failed prior treatment with pegylated interferon (PegIFN)/RBV and subsequently PegIFN/RBV plus a protease inhibitor. In this study, pts were randomized (1:1) to receive Harvoni plus RBV for 12 weeks or Harvoni alone for 24 weeks. 96% of those receiving Harvoni plus RBV for 12 weeks and 97% of those receiving Harvoni for 24 weeks achieved SVR12. In a second study (Oral #235), 51 genotype 1 pts who previously failed SOF/PegIFN/RBV, SOF/RBV or a SOF placebo/PegIFN/RBV treatment regimen received Harvoni plus RBV for 12 weeks. 29% of pts had cirrhosis. 98% achieved SVR12 following 12 weeks of treatment with Harvoni plus RBV. In all of these studies, Harvoni was well tolerated and its safety profile was generally consistent with that observed in clinical trials of Harvoni. Adverse events included fatigue, headache, nausea and anemia, which was more common among patients taking RBV. Grade 3/4 laboratory abnormalities were infrequent and included decreases in hemoglobin, which is consistent with RBV-associated anaemia [18].
14/11/2014 12:03:55
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 eva luated 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 eva luations
SMC http://www.scottishmedicines.org.uk/SMC_Advice/Advice/1030_15_ledipasvir_sofosbuvir_Harvoni/ledipasvir_
sofosbuvir_Harvoni
EPAR http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003850/WC500177996.pdf
NICE scope http://www.nice.org.uk/guidance/indevelopment/gid-tag484/documents
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: A fixed-dose combination product. Sofosbuvir is a second generation uridine nucleoside analogue which inhibits the NS5B protein of HCV. Ledipasvir is a direct-acting macrocyclic antiviral agent & NS5A serine protease inhibitor.
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
Further Information
Anticipated commissioning route (England) NHSE
High cost drug list? Yes
Tariff Not routinely commissioned by NHSE - IFR approval [22]
In NICE timetable: Yes
When: Jun / 2015
Note: www.nice.org.uk/guidance/indevelopment/gid-tag484
Implications Available only to registered users |
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