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2016年1月28日，美国食品和药品监管局(FDA)批准Zepatier(elbasvir和grazoprevir)有或无利巴韦林[ribavirin]为治疗在成年患者慢性丙型肝炎病毒(HCV)基因型1和4感染。
丙型肝炎是一种病毒病引起肝脏炎症，可导致肝功能减低或肝脏衰竭。大多数受有HCV感染人没有疾病症状直至肝损伤变得明显，这可能几年。有些有HCV感染慢性人历时许多年发生肝硬化，这可能导致并发症例如出血，黄疸(眼或皮肤发黄)，腹腔内积液，感染或肝癌。根据美国疾病控制和预防中心，约3百万美国人被HCV感染，其中基因型1是最常见和基因型4是最少见之一。
FDA的药品评价和研究中心中抗微生物产品室主任Edward Cox，M.D.说：“今天的批准对有基因型1和4 HCV感染没有需要使用干扰素[interferon]的患者提供另一种治疗选择。”
在1,373例有慢性基因型1或4 感染有和无硬化参加者的临床试验中评价Zepatier有或无利巴韦林的安全性和疗效。参加者接受Zepatier有或无利巴韦林每天1次共12或16周。研究被设计成测量在治疗结束后12周时在参加者血中是否再也不能检测到丙型肝炎病毒(持续病毒学反应或SVR)，提示参加者的感染已被治愈。
跨越对被批准治疗方案试验，在基因型1-被感染受试者总体SVR率范围从94-97%和在基因型4-被感染受试者从97-100 %。为了对患者SVR率最大化患者，产品说明书提供关于有或无利巴韦林治疗长度的建议特别地点滴调整至患者和他们的病毒的特征的建议。建议卫生保健专业人员在开始用治疗前筛选基因型1a-感染的患者为确认病毒遗传变异以确定剂量方案和时间。
Zepatier无利巴韦林最常见副作用是疲乏，头痛和恶心。Zepatier有利巴韦林最常见副作用是贫血和头痛。
Zepatier带有一个警告警戒患者和卫生保健提供者在临床试验参加者的约1 %肝酶升高至大于正常上限的5倍一般地在治疗周8时或后。在开始治疗前和治疗期间某些时候应进行肝脏相关血检验。有中度或严重肝受损患者不应给予Zepatier。
Zepatier被授予对在有用透析肾病终末期患者慢性HCV基因型1感染和对慢性HCV基因型4感染的治疗的突破性治疗指定。突破性治疗指定是一种被设计加快意向治疗一种严重情况和初步临床证据表明该药物对临床上重要终点可能显示实质上改善超过可得到治疗药物的开发和审评。
Zepatier是由总部在新泽西州Whitehouse Station的Merck & Co. Inc.上市。
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm483828.htm
New Drugs Online Report for grazoprevir + elbasvir
Information
Generic Name: grazoprevir + elbasvir
Trade Name:
Synonym: MK-5172 + MK-8742
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
Dec 15: The CHMP has advised that the application will now be reviewed on a standard timetable, rather than the accelerated assessment timeline previously announced. A European Commission decision is now anticipated in mid-2016. [26]
21/12/2015 12:09:25
Nov 15: MSD expects a decision in the EU in H1 2016, and the combination is also under a priority review in the US, with an action date of January 28 [24].
16/11/2015 12:52:40
Jul 15: The EMA have agreed to an accelerated assessment process for grazoprevir/elbasvir [22].
24/07/2015 14:31:37
Jun 15: Filed to the FDA for the treatment of adult patients with chronic hepatitis C genotypes (GT) 1, 4 or 6 infection. Within 60 days of submission, the FDA will determine whether it will accept for review Merck´s application as filed. [21]
01/06/2015 16:29:15
Apr 15: Merck plans to file a NDA in the US in H1 2015 [20].
29/04/2015 09:42:53
Apr 15: Merck & Co announced on April 8th that the US FDA had granted two Breakthrough Therapy designations for grazoprevir/elbasvir for the treatment of chronic HCV genotype 1 (GT1). This indicates a change in position for the FDA, because in October 2013, the FDA had initially granted Breakthrough Therapy designation for but rescinded its designation in January 2015 [16].
09/04/2015 09:16:08
Feb 15: FDA withdraws breakthrough therapy status citing the availability of other recently approved treatments for genotype 1 patients. Merck will discuss this matter with the FDA and does not expect it will impact its ability to file an NDA for this combination regimen or the timing of that filing [15].
09/02/2015 10:42:06
Nov 14: Merck will not proceed with further testing of a four-week regimen of grazoprevir + elbasvir (with sofosbuvir) after the C-SWIFT study failed to meet its primary endpoint. Longer durations of this combination (6 and 8 weeks) have shown efficacy [12].
12/11/2014 09:36:44
Mar 14: Merck plans to start the PIII programme, C-EDGE, in the next few weeks, which will evaluate MK-5172 and MK-8742 across genotypes and in different HCV subpopulations, including patients with chronic kidney disease, HIV/HCV co-infection and cirrhosis [5].
30/03/2014 17:32:25
Oct 13: Awarded breakthrough therapy status in the US [1].
23/10/2013 19:29:37
Trial or other data
Nov 15: Results presented from the C-EDGE CO-STAR, PIII randomised, double-blind, placebo-controlled trial (n=301) which evaluated treatment with elbasvir/grazoprevir in pts with chronic HCV GT1, 4 or 6 infection who are on OAT (e.g., methadone, buprenorphine). Pts received immediate treatment with elbasvir/grazoprevir (blinded) for 12 weeks (n=201) or deferred treatment of 12 weeks of placebo (control arm) followed by a 4-week follow-up period and then elbasvir/grazoprevir (open-label) for 12 weeks (n=100). Overall, 95% (189/198) of pts treated with elbasvir/grazoprevir for 12 weeks achieved SVR12 after the completion of treatment. Discontinuation due to adverse events occurred in 1% of pts, including 2 pts (1%) in the immediate treatment grp (ITG) and two (2%) in the delayed treatment grp (DTG). Two pts (1% across both groups) reported a serious drug-related AE. The most common AEs in the ITG versus the DTG, respectively, were fatigue (16% vs. 20%), headache (13% vs. 14%), nausea (11% vs. 9%) and diarrhoea (10% vs. 9%). One pt receiving placebo died for reasons unrelated to the study drug [25].
17/11/2015 10:45:52
Nov 15; Patients whose chronic hepatitis C virus infection is complicated by cirrhosis are at a more advanced stage of the disease, and have historically been harder to treat because they are less responsive to antiviral therapy. With current levels of treatment the number of patients with HCV-related cirrhosis in England is expected to increase by 20% over the next decade [24].
16/11/2015 12:53:34
Nov 15: Data from six PII and III trials show that treatment-naive patients who received elbasvir/grazoprevir with or without ribavirin (RBV) achieved virologic cure at rates of 90% (28/31) and 98% (135/138), respectively. Treatment-experienced patients who receiving the pill with or without RBV for 12 weeks achieved virologic cure rates of 91% (74/81) and 89% (48/54), respectively, while those in the 16 or 18 weeks treatment groups showed cure rates of 100% (49/49) and 94% (46/49), respectively [24].
16/11/2015 12:51:29
Oct 15: Data from the PIII trial of grazoprevir/elbasvir in patients with advanced kidney disease, including those on dialysis, has been published online in the Lancet [23].
13/10/2015 11:27:33
Apr 15: Results of PIII (NCT02105467) study have been published in Annals of Internal Medicine. Grazoprevir and elbasvir achieved high SVR12 rates in treatment-naïve cirrhotic and noncirrhotic patients with genotype 1,4 or 6 infections; 299 patients out of 316 receiving immediate treatment with once daily, oral grazoprevir 100mg/ elbasvir 50mg for 12 weeks achieved SVR12. Virological failure occurred in 13 patients, including 1 case of breakthrough infection and 12 relapses. Serious adverse events occurred in 9 patients in the treatment group vs. 3 patients in placebo group, none were considered drug related. The most common adverse events in the active group were headache (17%), fatigue (16%), nausea (9%) [19].
28/04/2015 08:59:51
Apr 15: Merck announced the first data from the company’s Phase II/III C-SURFER phase II/III study (NCT02092350) which was initiated in March 2014, to evaluate efficacy and tolerability of elbasvir and grazoprevir in 220 pts with chronic hepatitis C virus (HCV) genotype 1 (GT1) infection and chronic kidney disease (CKD). Pts were randomised to immediate or deferred treatment study arms, or to an open-label immediate treatment arm for intensive pharmacokinetic testing. The C-SURFER trial demonstrated a cure rate of 99% for the 12-week regimen of grazoprevir and elbasvir [18].
27/04/2015 09:36:46
Apr 15: Results of PII/III C-SURFER study (NCT02092350) announced by Merck & Co. Following 12 weeks treatment with grazoprevir (100mg) and elbasvir (50mg) once daily, 99% (115/116) patients with HCV GT1 and advanced CKD with or without liver cirrhosis achieved a sustained virologic response 12 weeks after completion with treatment [17].
27/04/2015 09:30:19
Nov 14: Part B of the C-WORTHY (NCT01717326) published in The Lancet. In patients with HCV genotype 1 infection and characteristics of poor response, the combination of grazoprevir and elbasvir ± ribavirin, for both 12 and 18 weeks’ duration, was associated with high rates of sustained virological response at 12 weeks (90-100%) [13].
13/11/2014 11:52:36
Nov 14: Part A of the C-WORTHY (NCT01717326) published in The Lancet. In previously untreated patients with HCV genotype 1 infection without cirrhosis with mono-infection or HIV/HCV co-infection, the combination of grazoprevir and elbasvir ± ribavirin for 12 weeks achieved rates of sustained virological response at 12 weeks of 87-98% [14].
13/11/2014 11:52:19
Nov 14: Merck announces data at the meeting of the American Association for the Study of Liver Diseases. Grazoprevir + elbasvir, in combination with sofosbuvir, produced a 94.7% cure rate for treatment naïve cirrhotic patients at 8 weeks. But at 4 weeks cure rate was 38.7%. At 6 weeks the combination produced an 80% cure rate in the treatment-naïve group of cirrhotic patients and 86.7% in the non-cirrhotic cohort. All patients were genotype 1 [11].
10/11/2014 17:35:27
Apr 14: NCT02115321 A PII/III study of MK-5172 + MK-8742 in 170 subjects with chronic hepatitis C (CHC) genotype (GT) 1, 4-6 infection and who have cirrhosis and Child-Pugh (CP) score 7-9 moderate hepatic insufficiency. The primary endpoint is SVR12. Additionally, ten non-cirrhotic HCV-infected GT1 participants will be given MK-5172 + MK-8742 at the beginning of the study for the purpose of collecting plasma pharmacokinetic data in HCV GT1-infected participants who do not have hepatic insufficiency. The study starts May 14 and is due to complete Feb 16 [10]
22/04/2014 10:11:51
Apr 14: NCT02105688 (C-EDGE RECOVERY - MK-5172-062) is a PIII open-label clinical trial of a 12 week combination regimen of MK-5172/MK-8742 in 200 treatment-naïve subjects with chronic HCV GT1, GT4, GT5, and GT6 infection who are on opiate substitution therapy. . The primary efficacy outcome is the percentage of participants achieving SVR12. The study starts Jun 14 and is due to complete May 15 [9]
15/04/2014 09:29:38
Apr 14: NCT02105662 (C-EDGE COINFECTION - MK-5172-061) is a PIII open-label clinical trial of a 12 week combination regimen of MK-5172/MK-8742 in 200 treatment-naïve subjects with chronic HCV GT1, GT4, GT5, and GT6 infection who are co-infected with HIV. The primary efficacy outcome is the percentage of participants achieving SVR12. The study starts Jun 14 and is due to complete May 15 [8].
15/04/2014 09:29:22
Apr 14: NCT02105467 is a PIII randomized study of a 12 week combination regimen of MK-5172/MK-8742 in 400 treatment-naïve subjects with chronic HCV GT1, GT4, GT5, and GT6 infection. Participants will be randomly assigned (3:1 ratio) to immediate treatment or deferred treatment (placebo control). The primary efficacy outcome is the percentage of participants in the Immediate Treatment Arm achieving SVR12. The study starts Jun 14 and is due to complete May 15 [7].
15/04/2014 09:28:56
Apr 14: NCT02105701 is a PIII study of the combination regimen of MK-5172/MK-8742 in 400 subjects who have failed prior treatment with pegylated interferon and ribavirin (P/R) with chronic HCV GT1, GT4, GT5, and GT6 infection. Subjects will receive MK-5172 100mg/MK-8742 50mg fixed-dose combination tablets orally, once daily for 12 weeks or for 16 weeks, or the combination + RBV twice daily for 12 weeks or for 16 weeks. The primary outcome is SVR12. Safety outcomes include the number of subjects with an AE and the number of subjects who discontinue because of an AE. The study starts Jun 14 and is due to complete Jun 15 [6].
15/04/2014 09:10:44
Mar 14: Data from the C-Worthy study in HIV co-infected patients reported. After 12 weeks of treatment, all 29 patients who received MK-5172 + MK-8742 + ribavirin had undetectable levels of the HCV. Among the 29 treated with MK-5172 + MK-8742, 26 (90%) achieved SRV12. No co-infected patients discontinued treatment due to either an adverse side effect or study medication intolerance [4]
06/03/2014 21:48:29
Nov 13: Interim data from the ongoing PII C-WORTHY study reported. 65 patients with genotype 1a or 1b infection were enrolled in one of three 12-week treatment arms (MK-5172 + MK-8742 (100/20mg) + ribavirin (RBV), and MK-5172 + MK-8742 (100/50mg) +/- RBV). The RBV-free arm included only genotype 1b-infected patients. The primary efficacy endpoint was SVR12. Cure rates ranged from 96% to 100% in the per protocol population (n=58). The most frequently reported AEs were fatigue (26%), headache (22%), nausea (18%), diarrhea (12%), dizziness (11%) and rash (11%). The incidence of anemia (<10 mg/dL Hb) and total bilirubin levels 2x ULN was 19% and 4%, respectively, in the RBV-containing arms and 0%, in the RBV-free arm. The C-WORTHY trial has been expanded by an additional 400 patients to include difficult-to-cure HCV genotype 1-infected populations including those with cirrhosis, co-infected with HIV or prior interferon + RBV treatment failures [2].
04/11/2013 18:18:39
Oct 13: MK-5172 / MK-8742 is in a PIIb trial with interim data due out early next month [1]
23/10/2013 19:30:38
Evidence Based Evaluations
NHSC/NIHR http://www.hsc.nihr.ac.uk/topics/mk-5172-and-mk-8742-fixed-dose-combination-for-chr/
References
Available only to registered users
Category
BNF Category: Viral hepatitis (05.03.03)
Pharmacology: All-oral combination regimen: MK-5172 is a NS3/4A protease inhibitor, and MK-8742 a NS5A replication complex inhibitor
Epidemiology: In the UK, ~215,000 subjects are chronically infected with hepatitis C; the majority (90%) are of genotype 1 and 3 . In 2012, 124 registrations for liver transplants were made which had ‘post-hepatitis C cirrhosis’ as the primary code [3]
Indication: Hepatitis C infection
Additional Details: genotypes 1,4,5 & 6; including HIV co-infection
Method(s) of Administration
Oral
Company Information
Name: Merck Sharp & Dohme (MSD)
US Name: Merck (or Merck KGaA)
Further Information
Anticipated commissioning route (England) NHSE
High cost drug list? Awaiting Update
Tariff Likely specified high cost drug
Implications Available only to registered users
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