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新类丙肝组合药物Epclusa（sof/vel）获欧盟批准即将上市

2016-06-29 10:24:58 作者：新特药房来源：互联网浏览次数：9 文字大小：【大】【中】【小】

简介： 2016年5月31日，欧洲药品管理局 (EMA) 批准两个新组合药物用于慢性丙型肝炎病毒感染：Epclusa(sofosbuvir/velpatasvir)用于全部6种基因型丙肝患者和Zepatier (grazoprevir/elbasvir)用于基因型1/4丙肝患者 ...

关键字：sofosbuvir/velpatasvir 商标名Epclusa 新组合药物用于全基因型丙肝1/4丙肝新药

2016年5月31日，欧洲药品管理局 (EMA) 批准两个新组合药物用于慢性丙型肝炎病毒感染：Epclusa(sofosbuvir/velpatasvir)用于全部6种基因型丙肝患者和Zepatier (grazoprevir/elbasvir)用于基因型1/4丙肝患者。
欧洲药品管理局 (EMA) 新闻发布会上指出，Sofosbuvir/velpatasvir和elbasvir/grazoprevir 通过阻断病毒复制所需的蛋白来治疗丙肝。Zepatier(grazoprevir/elbasvir)靶向 NS3/4A 和 NS5A蛋白，而Epclusa(sofosbuvir/velpatasvir)靶向NS5A 和 NS5B蛋白。
Epclusa（sof/vel，400mg/100mg）是一种日服一次的泛基因型丙肝鸡尾酒疗法，用于全部6种基因型丙肝患者的治疗。该鸡尾酒由Sovaldi（sofosbuvir）和另一种抗病毒药物velpatasvir组成。其中，sofosbuvir是一种核苷类似物聚合酶抑制剂，velpatasvir则是一种泛基因型NS5A抑制剂。
Epclusa（sof/vel）的有效性和安全性监管文件的提交基于纳入了2,000例患者的临床研究，这些研究评估了SOF/VEL联合或不联合利巴韦林治疗丙肝患者的疗效和安全性。数据显示，治疗12周后，患者血液中检测不到病毒，提示该药物针对所有6种基因型丙肝全部有效，包括伴有代偿性和失代偿性肝硬化患者群体。研究中，1035例泛基因型丙肝患者用药12周后，治愈率达到了98%。然而，基因型3丙肝患者的SVR率仍较低，在90%左右。药物安全性相对良好，与SOF相似；临床试验中报告的最常见不良事件为头痛、疲劳和恶心。
Zepatier是一种每日口服一次的固定剂量组合片剂，由两种新型HCV蛋白抑制剂组成：一种HCV NS5A抑制剂elbasvir（50mg）和一种HCV NS3/4A蛋白酶抑制剂grazoprevir（100mg）。欧洲药品管理局（EMA）人用医药产品委员会（CHMP）支持批准Zepatier，联用或不联用利巴韦林（RBV）用于基因型1和4慢性丙型肝炎病毒（HCV）成人感染者的治疗。
Zepatier(elbasvir/grazoprevir)的安全性和有效性监管文件的提交基于纳入了大约2000例患者的临床试验。研究显示，Zepatier 治疗结束后12周，患者血液内未检测到病毒，90%以上的患者获得SVR，甚至针对预后不良的慢性肾脏病患者亦有效。药物安全性相对良好；临床试验中报告的最常见不良事件为疲劳、头痛和恶心。在美国，Zepatier于今年1月底获FDA批准用于基因型1/4HCV感染患者的治疗
New Drugs Online Report for sofosbuvir + velpatasvir
Information
Generic Name: sofosbuvir + velpatasvir
Trade Name: Epclusa
Synonym: GS-7977 + GS-5816
Entry Type: New formulation
Development and Regulatory status
UK: Recommended for approval (Positive opinion)
EU: Recommended for approval (Positive opinion)
US: Pre-registration (Filed)
UK launch Plans: Available only to registered users
Actual UK launch date:
Comments
May 16: EU positive opinion for treatment of chronic hepatitis C virus (HCV) infection in adults [15].
27/05/2016 14:42:16
Jan 16: The FDA will make its final decision by June 28, 2016 [14].
13/01/2016 18:00:44
Jan 16. Assigned priority review by FDA [13].
06/01/2016 13:44:09
Dec 15: Filed in EU via centralised procedure [12].
18/12/2015 10:14:35
Oct 15: Filed in the US [6].
30/10/2015 09:36:44
Jul 14: PII in the US [1].
04/08/2014 14:26:20
Trial or other data
Nov 15: Results of ASTRAL 2 (NCT0220998) and ASTRAL-3 (NCT02201953) published in the NEJM. These two RCTs in people with HCV genotype 2 or 3 with or without previous treatment, found that 12 weeks of sofosbuvir-velpatasvir resulted in rates of sustained virologic response that were more superior to those with standard treatment with sofosbuvir-ribavirin (95-99% vs. 80-94%)[11].
19/11/2015 12:34:33
Nov 15: Results of ASTRAL-1 (NCT02201940) published in NEJM. Of 624 patients who received treatment with sofosbuvir–velpatasvir, 34% had HCV genotype 1a, 19% genotype 1b, 17% genotype 2, 19% genotype 4, 6% genotype 5, and 7% genotype 6. A total of 8% of patients were black, 19% had cirrhosis, and 32% had been previously treated for HCV. Rate of sustained virologic response among patients receiving sofosbuvir–velpatasvir was 99% (95% confidence interval, 98 to >99). Two patients receiving sofosbuvir–velpatasvir, both with HCV genotype 1, had a virologic relapse. None of the 116 patients receiving placebo had a sustained virologic response. Serious adverse events were reported in 15 patients (2%) in the sofosbuvir–velpatasvir group and none in the placebo group [10].
19/11/2015 12:31:43
Nov 15: Results of ASTRAL-4 (NCT02201901) published in the NEJM. Of 267 patients who received treatment, 78% had HCV genotype 1, 4% genotype 2, 15% genotype 3, 3% genotype 4, and less than 1% genotype 6; no patients had genotype 5. Overall rates of sustained virologic response were 83% (95% confidence interval [CI], 74 to 90) among patients who received 12 weeks of sofosbuvir–velpatasvir, 94% (95% CI, 87 to 98) among those who received 12 weeks of sofosbuvir–velpatasvir plus ribavirin, and 86% (95% CI, 77 to 92) among those who received 24 weeks of sofosbuvir–velpatasvir. Post hoc analysis did not detect any significant differences in rates of sustained virologic response among the three study groups. Serious adverse events occurred in 19% of patients who received 12 weeks of sofosbuvir–velpatasvir, 16% of those who received 12 weeks of sofosbuvir–velpatasvir plus ribavirin, and 18% of those who received 24 weeks of sofosbuvir–velpatasvir. The most common adverse events were fatigue (29%), nausea (23%), and headache (22%) in all patients and anemia (31%) in the patients receiving ribavirin [9].
19/11/2015 11:45:04
Nov 15: Results of PII (NCT01909804 & NCT01858766) trials published in the Annals of Internal Medicine [7,8].
11/11/2015 21:28:16
Not routinely commissioned by NHSE - IFR approval [4]
05/10/2015 15:37:52
Sep 15: Gilead announces topline results from four international PIII studies. In the ASTRAL-1, ASTRAL-2, and ASTRAL-3 studies, 1,035 patients with genotype 1-6 HCV infection received 12 weeks of SOF/VEL. Among these patients, 21% had compensated cirrhosis and 28% had failed prior treatments. The ASTRAL-4 study randomized 267 patients with decompensated cirrhosis (Child-Pugh class B) to receive 12 weeks of SOF/VEL with or without ribavirin (RBV), or 24 weeks of SOF/VEL. The primary endpoint for all studies was SVR12. Of the 1,035 patients treated with SOF/VEL for 12 weeks in the ASTRAL-1, ASTRAL-2 and ASTRAL-3 studies, 1,015 (98%) achieved the primary efficacy endpoint. Of the 20 patients who did not achieve SVR12, 13 patients (1.3%) experienced virologic failure and seven did not complete an SVR12 visit (e.g., lost to follow-up). Twelve of the 13 virologic failure patients relapsed (two genotype 1 HCV-infected patients and 10 genotype 3 HCV-infected patients). There was one patient with documented reinfection. No patients with genotype 2, 4, 5 or 6 HCV infection had virologic failure. Patients treated with SOF/VEL for 12 weeks in these three studies had similar adverse events compared with placebo-treated patients in ASTRAL-1. Two patients (0.2%) treated with SOF/VEL for 12 weeks, one each in ASTRAL-1 and ASTRAL-2, discontinued treatment due to adverse events. The most common adverse events were headache, fatigue and nausea. In ASTRAL-4, patients with Child-Pugh class B cirrhosis receiving SOF/VEL+RBV achieved higher SVR12 rates than patients receiving SOF/VEL for 12 or 24 weeks. Among genotype 1 and 3 patients treated with SOF/VEL+RBV for 12 weeks, the SVR12 rates were 96% and 85%, respectively [5].
22/09/2015 10:44:31
Nov 14: Positive data from three PII open-label studies evaluating safety and efficacy of oral sofosbuvir + GS-5816 in pts with chronic hepatitis C virus (HCV) infection across genotypes. Three studies evaluated SOF 400 mg + GS-5816 dosed at 25 or 100 mg, with and without ribavirin (RBV) for 8 or 12 weeks; GS-US-342-0109, (n=160 pts with treatment-experienced genotype 1 and 3 pts +/- cirrhosis); ELECTRON 2 (n=53 pts with non-cirrhotic, treatment-naïve genotype 3) and GS-US-342-0102 (pts with non-cirrhotic treatment-naïve HCV). Rates of sustained virologic response (defined as SVR12 which is considered a cure) ranged from 88% to 100%. Sofosbuvir + GS-5816 at 100 mg for 12 weeks was the regimen selected for PIII studies and well tolerated in PII studies with low incidence of serious ADRs and few discontinuations. Common ADR’s (>10%) were fatigue, headache, nausea, insomnia. Decrease in haemoglobin concentration was seen in the RBV-containing gps. The company looks forward to providing PIII data on this combination across all six genotypes [3].
12/11/2014 12:11:01
Jul 14: PIII ASTRAL-3 (NCT02201953) study begins. The This study will evaluate the safety, tolerability, and efficacy of treatment with sofosbuvir (SOF)/GS-5816 fixed dose combination (FDC) for 12 weeks compared to treatment with SOF plus ribavirin (RBV) for 24 weeks in participants with chronic genotype 3 hepatitis C virus (HCV) infection. 500 pts will be recruited from sites globally including the US & EU (+ UK). The primary outcomes are proportion of participants with sustained virologic response 12 weeks after discontinuation of therapy, and adverse effects. Collection of primary outcome data should be complete Dec 15 [2].
24/09/2014 16:33:02
Jul 14: PIII ASTRAL-2 (NCT02220998) study begins. The study will evaluate safety, tolerability, and efficacy of treatment with sofosbuvir (SOF)/GS-5816 fixed dose combination (FDC) for 12 weeks compared to treatment with SOF plus ribavirin (RBV) for 12 weeks in participants with chronic genotype 2 hepatitis C virus (HCV) infection. 240 pts will be recruited from sites in the US & Puerto Rico. The primary outcomes are proportion of participants with sustained virologic response 12 weeks after discontinuation of therapy, and adverse effects. Collection of primary outcome data should be complete Nov 15 [2].
24/09/2014 16:31:26
Jul 14: PIII ASTRAL-4 (NCT02201901) study begins. The study will evaluate the efficacy, safety, and tolerability of sofosbuvir (SOF)/GS-5816 fixed dose combination (FDC) with and without ribavirin (RBV) for 12 weeks and SOF/GS-5816 FDC for 24 weeks in adults with hepatitis C virus (HCV) infection and Child-Pugh (CPT) class B cirrhosis. 225 pts will be recruited in the US. The primary outcomes are proportion of participants with sustained virologic response 12 weeks after discontinuation of therapy, and adverse effects. Collection of primary outcome data should be complete Nov 15 [2].
24/09/2014 16:29:53
Jul 14: PIII ASTRAL-1 (NCT02201940) study begins. The study will evaluate the efficacy, safety, and tolerability of sofosbuvir (SOF)/GS-5816 fixed dose combination (FDC) for 12 weeks in adults with chronic genotype 1, 2, 4, 5, or 6 hepatitis C virus (HCV) infection. 600 pts will be recruited from sites globally including the US & EU (+ UK). The primary outcomes are proportion of participants with sustained virologic response 12 weeks after discontinuation of therapy, and adverse effects. Collection of primary outcome data should be complete Oct 15 [2].
24/09/2014 16:27:28
Apr 14: Gilead is planning to conduct PIII studies evaluating the safety and efficacy of GS 5816 in combination with sofosbuvir, pending full results from two PII trials - Study GS-US-342-0109 in treatment-experienced patients (NCT01909804) and Study GS-US-342-0102 in treatment-naive patients (NCT01858766) [1].
04/08/2014 14:28:36
Apr 14: Positive interim results reported from a PII study investigating the efficacy, safety and tolerability of sofosbuvir in combination with GS 5816 (25 and 100 mg/day), with or without RBV, in treatment-experienced patients with chronic HCV genotype 1 or 3 infection (NCT01909804). The drug combination comparison trial is intended to enrol approximately 300 patients from sites in the US, Australia, New Zealand and Puerto Rico [1].
04/08/2014 14:27:57
May 13: Gilead initiates a 12-week PII trial to assess the safety and efficacy of GS 5816 (25mg or 100mg once-daily) in combination with sofosbuvir in treatment-naive, non-cirrhotic patients with chronic genotypes 1-6 hepatitis C virus infections (NCT01858766; GS-US-342-0102). The primary endpoints are the proportion of patients with a sustained virologic response at 12 weeks after completion of dosing, and safety and tolerability. The trial has completed enrolment of approximately 140 patients in the US and Puerto Rico. Positive results were released in April 2014 [1].
04/08/2014 14:27:15
Evidence Based Evaluations
NICE scope https://www.nice.org.uk/guidance/indevelopment/gid-ta10064/documents
NIHR HSRIC http://www.hsric.nihr.ac.uk/topics/sofosbuvir-sovaldi-with-gs-5816-for-chronic-hepatitis-c/
References
Available only to registered users
http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208341s000lbl.pdf