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HARVONITM(ledipasvir/sofosbuvir)片为一天一次的抗慢性丙型肝炎毒(HCV)基因型1感染的二联复方上市新药.
Harvoni是第一个被批准治疗慢性HCV基因型1 感染二联复方药丸。第一个被批准不需要干扰素或利巴韦林的方案。
FDA药品评价和研究中心抗微生物产品室主任说：“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；第七个接到PDA批准突破性治疗指定的新药。
HARVONITM(ledipasvir和sofosbuvir)片为新一代治疗丙肝的口服药
美国初次批准：2014
适应证和用途
HARVONI是一个ledipasvir，一种丙肝病毒(HCV)NS5A抑制剂，和sofosbuvir，一种HCV核苷酸类似物NS5B聚合酶抑制剂的固定剂量组合复方，和适用在成年中为慢性丙肝(CHC)基因型1感染的治疗。
剂量和给药方法
⑴ 推荐剂量：1片(90mg ledipasvir和400 mg sofosbuvir)口服每天1次有或无食物。
⑵ 推荐治疗时间：
⒈未治疗过有或无肝硬化：12周
⒉经历治疗无肝硬化：12周
⒊经历治疗有肝硬化：24周
⑶ 对有严重肾受损或肾病终末期患者不能做推荐剂量。
剂型和规格
片：90mg ledipasvir和400mg sofosbuvir。
禁忌证
无
警告和注意事项
不建议与其他含sofosbuvir其他药物使用，包括SOVALDI。
不良反应
用HARVONI治疗共8，12，或24周观察到最常见不良反应(发生率大于或等于10%，所有级别)是疲乏和头痛。
药物相互作用
⑴ P-gp诱导剂(如，利福平[rifampin]，圣约翰草[St. John’s wort])：可能改变ledipasvir和sofosbuvir的浓度。不建议HARVONI与P-gp诱导剂使用。
⑵ 使用前为药物相互作用潜在咨询完整处方资料
Harvoni (ledipasvir/sofosbuvir) for Treatment of Chronic Hepatitis C Virus Genotype 1 Infection, United States of America
Developed by Gilead Sciences, Harvoni (ledipasvir/sofosbuvir) is the first combination pill approved for the treatment of adult patients with chronic hepatitis C genotype 1 infection. Harvoni is the first approved medicine that does not require administration with interferon or ribavirin, which are also indicated to treat the same infection.
Gilead Sciences submitted a new drug application (NDA) for Harvoni to US Food and Drug Administration (FDA) in February 2014. The FDA granted Harvoni a priority review and breakthrough therapy designation. The drug was approved for the treatment of chronic hepatitis C genotype 1 infection by the FDA in October 2014.
The marketing authorisation application (MAA) for Harvoni was submitted to the European Medicines Agency (EMA) in March 2014. Harvoni received a positive response from the Committee for Medicinal Products for Human Use (CHMP) of the EMA, following an accelerated review procedure in September 2014.
The company also submitted an NDA for Harvoni to Pharmaceutical and Medical Devices Agency (PMDA) in Japan in September 2014. It is currently under review.
Hepatitis C disease details
Hepatitis C is a disease caused by the hepatitis C virus (HCV) and results in an inflamed liver. HCV is a blood-borne virus, which can cause both acute and chronic infection. The disease transmits through unsafe injection practices using unsterilised medical equipment and the transfusion of unscreened blood.
The complications of the disease include developing liver cirrhosis or liver cancer, and people infected with HCV in most cases show no symptoms until liver damage becomes apparent.
According to the World Health Organisation's (WHO) statistics, up to 150 million people in the world including 3.2 million people in the US and nine million in Europe are infected with HCV.
Harvoni's mechanism of action
Harvoni is a combination of two antiviral drugs, ledipasvir and sofosbuvir. It contains 90mg of ledipasvir and 400mg sofosbuvir, which act as a HCV NS5A inhibitor and nucleotide analogue inhibitor of HCV NS5B polymerase respectively. Harvoni is available in the form of a film-coated tablet in orange colour and diamond shape for oral administration
Clinical trials on Harvoni
The FDA approval for Harvoni was based on the results from three Phase III clinical trials known as ION-1, ION-2 and ION-3, which were conducted to evaluate the drug's efficacy with or without ribavirin. The studies enrolled 1,518 participants with chronic HCV genotype 1 infection and compensated liver disease, who previously had not received any prior treatment or not responded to the previous treatment.
The first Phase III clinical study ION-1 included cirrhotic and non-cirrhotic treatment-naive subjects. The second clinical study ION-2 had cirrhotic and non-cirrhotic subjects who failed in earlier therapies including regimens containing an HCV protease inhibitor. The third clinical study ION-3 included non-cirrhotic treatment-naive subjects.
The participants in the three clinical studies randomly received Harvoni with or without ribavirin. The treatment was conducted for a period of eight, 12 or 24 weeks based on factors including prior treatment history, history of cirrhosis and baseline viral load. The primary endpoint for each study was sustained virologic response (SVR) after completing therapy at week 12 (SVR12).
The results demonstrated that in the first study ION-1, 94% of the participants treated with Harvoni for eight weeks and 96% of those treated with Harvoni for 12 weeks achieved SVR. In ION-2, 99% of participants achieved SVR while in ION-3, 94% subjects treated with Harvoni for 12 weeks and 99% of those who received Harvoni for 24 weeks achieved SVR. Those who achieved SVR 12 were considered free from HCV.
Use of ribavirin showed no increase in response rates. The ribavirin-free treatment arms achieved between 94%-99% SVR12 rates.
The most commonly reported adverse reactions in patients treated with Harvoni included fatigue, headache, nausea, diarrhoea, and insomnia.
New Drugs Online Report for sofosbuvir + ledipasvir
Information
Generic Name: sofosbuvir + ledipasvir
Trade Name: Harvoni
Synonym: GS-7977, GS-5855
Entry Type: New formulation
Developmental 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
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) evaluating 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) evaluated 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) evaluated 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 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
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:
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:
Method(s) of Administration
Oral
Company Information
Name: Gilead Sciences
US Name: Gilead Sciences
NICE Information
Anticipated Commissioning route (England) -
In timetable: Yes
When: Jun / 2015
Note: www.nice.org.uk/guidance/indevelopment/gid-tag484
PBR Likely specified high cost drug.
Implications Available only to registered users
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产地国家: 美国
原产地英文商品名:
HARVONI 90mg; 400mg 28tablets
原产地英文药品名:
LEDIPASVIR; SOFOSBUVIR
中文参考商品译名:
HARVONI 90毫克;400毫克 28片/盒
中文参考药品译名:
LEDIPASVIR; SOFOSBUVIR
生产厂家英文名:
Gilead
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产地国家: 加拿大
原产地英文商品名:
HARVONI 90mg; 400mg 28tablets
原产地英文药品名:
LEDIPASVIR; SOFOSBUVIR
中文参考商品译名:
HARVONI 90毫克;400毫克 28片/盒
中文参考药品译名:
LEDIPASVIR; SOFOSBUVIR
生产厂家英文名:
Gilead
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