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FDA取消丙肝药物grazoprevir/elbasvir 突破性药物（BTD）地位
FDA将取消其丙肝药物grazoprevir/elbasvir (MK-5172/MK-8742）突破性药物（BTD）地位的消息。由于吉利德科学的Harvoni和艾伯维的V Pak已经上市并且在疗效上基本没有什么改进空间，再把默克的组合叫做突破性药物有点自相矛盾。据默克讲FDA这个意向尚未最后定死，默克在未来几周还会和FDA就此事沟通。
FDA突破性药物被誉为近年来药监政策的最大创新，为制药工业的研发方向起到非常有效的导航作用，有人甚至呼吁厂家只开发BTD药物。获得BTD药物的产品在开发和评审过程中会得到FDA的全力支持，这样一可以避免走不必要的弯路，二也可以更高效完成所有规定动作。
这应该是第一个被撤销BTD地位的案例，但显然这不会是最后一个。历来热门项目都不会只有一个厂家自己做，除非靶点未知而只有单个厂家有未被公开的先导物，但这种情况现在非常少。有竞争就必然有胜负。虽然这次FDA并未公开其理由，但这个决定似乎也符合常理。如果以后FDA按这个逻辑行事，落后首创药物2年以上的同类产品估计即使得到BTD称号在上市前被取消的可能性也非常大。
当然这样的决定对厂家影响不一定很大，因为厂家主要是在开发阶段受益于这个地位。默克在2013年获得BTD地位到现在已经从中受到很多关照，三期临床已经招募完毕，估计今年就可以报批。另外作为第三个上市的药物如果没有特殊疗效和前两个药物的竞争本来就处于很大劣势。Grazoprevir/elbasvir组合最大的希望是能缩短疗程但去年的二期临床显示无法在四周有效治愈丙肝，所以晚几个月上市对销售不会有太大影响。默克本来就没准备参与丙肝的早期竞争，而是要主攻中盘和收官阶段。如何竞争全球1.7亿丙肝病人的后2/3和竞争最富有的第一波病人可能需要不同的策略
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: Phase III Clinical Trials
EU: Pre-registration (Filed)
US: Pre-registration (Filed)
UK launch Plans: Available only to registered users
Actual UK launch date:
Comments
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position for the FDA, because in October 2013, the FDA had initially granted Breakthrough Therapy designation for but rescinded its designation in January 2015 [16].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 eva luate 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
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 eva luate 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 eva luations
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
US Name: Merck Pharmaceuticals
Further Information
Anticipated commissioning route (England) -
High cost drug list? Awaiting Update
Implications Available only to registered users |
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