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HARVONI(ledipasvir 90mg/sofosbuvir 400mg)tablets
Harvoni® Patient Information Leaflet By Gilead
Gilead has published both U.S. Prescribing Information and Patient Information, on their support website. In addition check out HCV Advocates new factsheet; Genotype 1 Treatment: Harvoni (Sofosbuvir & Ledipasvir).
The FDA approved Gilead’s much anticipated drug Harvoni (ledipasvir/sofosbuvir), our first combination pill approved for the treatment of chronic HCV genotype 1 infection, without interferon or ribavirin.
The new drug also appears to be a bit less expensive for some patients than Gilead’s existing blockbuster hepatitis C drug, Sovaldi, which has become the poster child for those complaining that the cost of medicines is out of control.
Ledipasvir-sofosbuvir (Harvoni)
sofosbuvir (Harvoni) was approved by the FDA for the treatment of chronic hepatitis C genotype 1 infection in adults.
Indications: The fixed dose combination ledipasvir-sofosbuvir (90 mg/400 mg) is FDA-approved for the treatment of chronic hepatitis C genotype 1 in both treatment-naive and treatment-experienced patients. The treatment duration depending on prior treatment experience and the presence or absence of cirrhosis. Treatment experience is defined as patients who have failed treatment with either peginterferon plus ribavirin or peginterferon plus ribavirin plus a HCV protease inhibitor.
•Genotype 1 treatment-naïve patients with or without cirrhosis: 12 weeks
•Genotype 1 treatment-experienced patients without cirrhosis: 12 weeks
•Genotype 1 treatment-experienced patients with cirrhosis: 24 weeks
•Treatment experience is defined as patients who have failed treatment with either peginterferon plus ribavirin or peginterferon plus ribavirin plus a HCV protease inhibitor.
•Note: a treatment duration of 8 weeks can be considered in treatment-naive patients without cirrhosis who have a baseline HCV RNA level less than 6 million IU/mL.
Dosing: Ledipasvir/sofosbuvir (90 mg/400 mg) is a fixed-dose combination tablet (Figure 2). The recommended dosage is one tablet once daily, with or without food
•For patients with mild to moderate renal impairment, no dosage adjustment of ledipasvir/sofosbuvir is recommended. There are insufficient data regarding the safety and effiacy of ledipasvir/sofosbuvir in patients with severe renal impairment (eGFR less than 30 ml/min/1.73m2) or end-stage renal disease requiring dialysis. Thus, no dosage recommendation has been given for patients with severe renal impairment or end-stage renal disease requiring dialysis.
•For patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C), no dosage adjustment is recommended, but the safety and efficacy of ledipasvir/sofosbuvir in patients with decompensated cirrhosis has not been established.
Clinical Use: The combination of ledipasvir-sofosbuvir has primarily been studied as an all-oral (interferon-free) combination regimen in treatment-naive and treatment-experienced patients with genotype 1 chronic HCV infection. Phase 3 studies (ION-1, ION-2, and ION-3) have consistently shown SVR12 rates greater than 90% with a 12-week course of ledipasvir-sofosbuvir in patients with genotype 1 chronic HCV. For treatment-experienced patients with cirrhosis, the SVR12 rates were significantly better with 24 weeks of therapy than with 12 weeks. A subanalysis of the ION-3 trial showed that treatment-naive patients without cirrhosis had excellent SVR12 rates with only 8 weeks of ledipasvir-sofosbuvir if their pre-treatment HCV RNA level was less than 6 million IU/mL. For the treatment of patients with genotype 1 infection, the addition of ribavirin to ledipasvir-sofosbuvir did not provide significant benefit. The approved clinical use for ledipasvir-sofosbuvir is only for genotype 1 chronic HCV-infected adults. Ledipasvir-sofosbuvir does not have a specific indication for HIV-infected persons.
Gilead has an active ledipasvir-sofosbuvir patient assistance program for eligible patients with hepatitis C who do not have insurance, are underinsured, or who otherwise need financial assistance to pay for or obtain access to ledipasvir-sofosbuvir. Information regarding the Gilead sofosbuvir patient assistance program can be obtained at the Support Path for Solvaldi and Harvoni web site and by contacting them directly by phone at 1-855-769-7284 (hours of operation Monday through Friday between 9:00 am and 8:00 pm Eastern Time).
Adverse Effects: Available data from clinical trials has demonstrated the combination of ledipasvir and sofosbuvir has been very well tolerated. The most common reported adverse effects are fatigue and headache.
Major Drug Interactions: Ledipasvir-sofosbuvir has significant drug-drug interactions with P-gp inducers (e.g., St. John's wort and rifampin). The concomitant use of ledipasvir-sofosbuvir with P-gp inducers is not recommended. Additional drug-drug interactions may occur with ledipasvir-sofosbuvir and other medications and these are detailed in the Ledipasvir-sofosbuvir (Harvoni) Full Prescribing Information.
Resistance: In vitro, ledipasvir can select for the primary NS5A mutations Q30E and Y93H with genotype 1a and Y93H with genotype 1b; these mutations confer high-level reduced susceptibility to ledipasvir. In phase 3 trials, the most common mutations detected at failure for genotype 1a were Q30R, Y93H or N, and L31M; with genotype 1b, the most common mutation was Y93H. In vitro, the substitution S282T is associated with a 2- to 18-fold reduced susceptibility to sofosbuvir. The S282T mutation was not detected in any of the lepidasvir-sofosbuvir phase 3 trials. Ledipasvir has excellent in vitro activity against the NS5B S282T mutants. Similarly, sofosbuvir retains full activity against the NS5A ledipasvir-associated mutations.
Prescribing Information: Ledipasvir-sofosbuvir (Harvoni) Full Prescribing Information.
Summary: The fixed dose combination of ledipasvir-sofosbuvir provides a very attractive and effective one pill once a day option for treatment of genotype 1 chronic hepatitis C infection. This regimen is the first FDA-approved interferon- and ribavirin-free regimen to treat hepatitis C. Three phase 3 trials (ION-1, ION-2, and ION-3) have demonstrated SVR rates consistently above 90%. For treatment-naive, non-cirrhotic patients who have a pretreatment HCV RNA level less than 6 million IU/ml, use of the shorter 8-week regimen is justified and will provide a major cost savings over the 12-week regimen (and it is less expensive than a 12-week regimen of sofosbuvir plus ribavirin). The 24-week regimen for treatment-experienced cirrhotic patients is prohibitively expensive. Insufficient data exist to recommend the use ledipasvir-sofosbuvir in genotypes other than genotype 1. Although ledipasvir-sofosbuvir is not specifically FDA-approved for HIV-infected patients, it will likely generate significant interest for use in this arena.
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Drug Name(s) |
HARVONI |
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FDA Application No. |
(NDA) 205834 |
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Active Ingredient(s) |
LEDIPASVIR; SOFOSBUVIR |
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Company |
GILEAD SCIENCES INC |
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Original Approval or Tentative Approval Date |
October 10, 2014 |
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Chemical Type |
1 New molecular entity (NME) |
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Review Classification |
P Priority review drug |
View the label approved on 10/10/2014 (PDF) for HARVONI, NDA no. 205834
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) 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
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:
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 Harvoni是NS5A抑制剂ledipasvir（LDV）和核苷酸类似物聚合酶抑制剂sofosbuvir（SOF）的组合药物，可以用于治疗成人的慢性丙型肝炎病毒（HCV）。
上市许可主要基于三个3期临床试验，ION-1，ION-2和ION-3，在这些实验评估了Harvoni与利巴韦林联用或单独使用Harvoni治疗近2000个基因型1丙型肝炎病毒感染的并有失代偿性肝病的患者，疗程为8周，12周或24周。
2014年1月，Harvoni被欧洲委员会批准以商品名Sovaldi销售。
建议未曾治疗过或有过治疗的肝硬化和非肝硬化性基因1型和4型患者使用Harvoni。根据既往治疗史及肝硬化的状态确定疗程为12或24周。
该公司表示，对于没有被治疗过的非肝硬化基因1型患者，建议Harvoni的疗程为8周。
对于有失代偿性肝硬化的基因型1和4型患者，有肝硬化和/或先前治疗失败的基因3型患者，Harvoni应结合利巴韦林使用并治疗24周。
伦敦大学玛丽皇后学院的肝病教授Foster表示：“在欧洲，基因1型丙肝患者，以及治疗他们的医生已经期待这样的一款药物几十年了。
“随着Harvoni的出现，我们要改变我们对欧洲的常见类型丙肝患者的治疗方式。
“现在，我们可以期望非常高的体循环血管阻力（SVR），而对于许多患者而言，我们可以不再需要干扰素注射剂和利巴韦林，并且每天只需服用一次片剂。”
欧盟的批准基于SOLAR-1试验的数据，试验中涉及的患者有难以治疗的失代偿性肝硬化或是接受过肝移植，另一个是ERADICATE试验，评估了患有基因1型丙型肝炎，并且初步数据证明感染HIV的患者。
Harvoni将超过Sovaldi
Harvoni预计将超过丙肝明星药Sovaldi的创记录表现，这反映在2014财年第三季度Sovaldi销售季度环比下降20%。然而，吉利德其实也没有什么可担忧的，该公司只会从Harvoni上市中获益，尽管该药将与Sovaldi自相残杀。据彭博社数据，Harvoni上市第一周的处方量达503例，是Sovaldi上市第一周处方量248例的2倍还多。
此外，Harvoni上市第5周的处方量达到3606例，其中3004例为新写处方（New Written Prescriptions，NWP），处方量每周环比增长37%。花旗集团（Citigroup）预计，根据上周1.02亿美元的销售额，Harvoni的年销售额将达到53亿美元。对于第四季度，业界的共识是14亿美元销售额，花旗集团预期为19亿美元。
治疗周期缩短——容量游戏
击败Sovaldi及其他竞争药物，对于Harvoni而言将是一个容量游戏。Sovaldi售价1000美元一片，通常治疗周期为12周，该药通常处方联合干扰素，12周治疗成本为94500美元。
然而，由于Harvoni更有效，对于最常见的基因型1丙肝患者（约占丙肝病例的45%），该药仅需治疗8周。因此，8周的治疗周期意味着成本将低至63000美元，比任何其他竞争对手的药物治疗成本要低，如强生Olysio，该药与Sovaldi的联合治疗成本为130000美元。因此，尽管Harvoni价格便宜对患者更实惠，但这一优势也将为吉利德带来更大的目标市场。 |
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