|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。
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。
New Drugs Online Report for sofosbuvir + velpatasvir
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:
May 16: EU positive opinion for treatment of chronic hepatitis C virus (HCV) infection in adults .
Jan 16: The FDA will make its final decision by June 28, 2016 .
Jan 16. Assigned priority review by FDA .
Dec 15: Filed in EU via centralised procedure .
Oct 15: Filed in the US .
Jul 14: PII in the US .
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%).
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 .
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 .
Nov 15: Results of PII (NCT01909804 & NCT01858766) trials published in the Annals of Internal Medicine [7,8].
Not routinely commissioned by NHSE - IFR approval 
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 .
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 .
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 .
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 .
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 .
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 .
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) .
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 .
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 .
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/
Available only to registered users
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 ...