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2016年2月3日,美国食品和药品监督管理局(FDA)批准Zepatier (elbasvir/grazoprevir)联合或不联合利巴韦林用于治疗成人基因1型、4型慢性丙型肝炎病毒(HCV)感染。
丙肝是一种病毒引起的肝脏炎症，可导致肝功能受损或肝衰竭。大多数HCV感染患者在肝功能明显受损前(可长达数年)多无临床症状。部分慢性HCV感染患者数年后发展为肝硬化，可出现诸如出血、黄疸、腹水、感染或肝癌等并发症。根据美国疾病控制和预防中心数据，约3百万美国人感染HCV，其中基因1型最常见，基因4型少见。
FDA药物评价与研究中心中抗菌产品办公室主任Edward Cox博士说道：“Zepatier的批准为基因1型、4型 HCV感染患者提供另一种治疗选择，且无需使用干扰素。”
一项纳入1,373例基因1或4型慢性HCV感染、伴或不伴肝硬化患者的临床试验，充分评价了Zepatier单药或联合利巴韦林的安全性及有效性。受试者每日服药1次，持续12或16周。旨在探究是否治疗结束后12周，受试者血样中将无法检测到HCV病毒(持续病毒学反应或SVR)，提示感染已治愈。
在不同试验中，基因1型组总体SVR率为94-97%，基因4型组为97-100 %。为使患者SVR率最大化，产品说明书建议，无论是否联合利巴韦林治疗，均根据患者与其病毒特征调整疗程。并建议医疗人员在治疗开始前筛选基因1a型感染患者，确认病毒遗传变异，以制定具体剂量与疗程。
Zepatie单药组最常见的副作用是疲乏，头痛和恶心。而Zepatier联合利巴韦林组则是贫血与头痛。
患者与医疗人员需警惕，一般在Zepatier治疗8周或以后，约1%受试者出现肝酶升高至大于正常上限5倍。在治疗开始前及治疗期间固定时间，应行肝功能抽血检测。中、重度肝功能损害患者不应予Zepatier治疗。
Zepatier被FDA授予突破性疗法资格(BTD)，用于治疗基因型1型慢性HCV感染合并终末期肾病的血透患者与基因型4型慢性HCV感染患者。
BTD旨在加速开发及审查治疗严重疾病的新药，需初步临床证据表明，该药对临床主要终点事件起到实质改善作用，药效超过现有药品。
ZEPATIER (ELBASVIR; GRAZOPREVIR，50mg/100mg)TABLET
ZEPATIER Rx
Pharmacological Class:
HCV NS5A inhibitor + HCV NS3/4A protease inhibitor.
Active Ingredient(s):
Elbasvir, grazoprevir 50mg/100mg; tablets.
Company
Merck & Co., Inc.
Indication(s):
Chronic HCV genotypes 1 or 4 infection with or without ribavirin (RBV).
Pharmacology:
Zepatier combines two direct-acting antivirals with distinct mechanisms of action. Elbasvir is an inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly.
Grazoprevir is an inhibitor of the HCV NS3/4A protease which is necessary for the proteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication.
Clinical Trials:
The efficacy of Zepatier was assessed in 2 placebo-controlled trials and 4 uncontrolled Phase 2 and 3 clinical trials in 1,401 subjects with genotype (GT) 1, 4, or 6 chronic hepatitis C virus infection with compensated liver disease (with or without cirrhosis).
The 6 clinical studies (C-EDGE TN, C-EDGE COINFECTION, C-SURFER, C-SCAPE, C-EDGE TE, and C-SALVAGE), which enrolled a total of 1,373 patients, contributed to the assessment of efficacy in genotype 1 or 4.
The primary endpoint in all trials was sustained virologic response defined as HCV RNA
For more clinical trial data, see full labeling.
Legal Classification:
Rx
Adults:
≥18 years: 1 tablet once daily. Genotype 1a: treatment-naive or PegIFN/RBV-experienced without baseline NS5A polymorphisms: treat for 12 weeks; with baseline NS5A polymorphisms: take with RBV for 16 weeks. Genotype 1b: treatment-naive or PegIFN/RBV-experienced: treat for 12 weeks. Genotype 1a or 1b: PegIFN/RBV/HCV NS3/4A protease inhibitor (PI)-experienced: take with RBV for 12 weeks. Genotype 4: treatment-naive: treat for 12 weeks; if PegIFN/RBV-experienced: take with RBV for 16 weeks. HCV/HIV-1 co-infected with or without cirrhosis, renal impairment including hemodialysis: follow same dosage regimen. See full labeling.
Children:
<18 years: not established.
Contraindication(s):
Moderate or severe hepatic impairment. Concomitant atazanavir, carbamazepine, cyclosporine, darunavir, efavirenz, lopinavir, phenytoin, rifampin, saquinavir, St. John’s wort, tipranavir. When coadministered with ribavirin, its contraindications also apply to this combination regimen (eg, Pregnancy Category X).
Warnings/Precautions:
HCV genotype 1a: test for presence of virus with NS5A resistance-associated polymorphisms prior to initiation. Monitor hepatic function prior to initiation, at Week 8, and as clinically indicated; perform additional testing at Week 12 for patients receiving 16 weeks of therapy. Consider discontinuing if ALT persistently >10XULN. Discontinue if ALT elevation is accompanied with liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR. Pregnancy. Nursing mothers.
Interaction(s)
See Contraindications. Concomitant moderate CYP3A inducers or certain strong CYP3A inhibitors: not recommended. May be antagonized by nafcillin, bosentan, etravirine, modafinil. May be potentiated by ketoconazole, elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or tenofovir alafenamide. Potentiates tacrolimus (monitor tacrolimus levels, changes in renal function), atorvastatin (limit maximum 20mg/day), rosuvastatin (limit maximum 10mg/day). May potentiate fluvastatin, lovastatin, simvastatin; use lowest effective dose of these drugs.
Adverse Reaction(s)
Fatigue, headache, nausea, diarrhea, anemia.
Notes:
For ribavirin specific dosing and safety information, refer to the full prescribing label.
How Supplied:
Carton—2 x 14 dose packs
LAST UPDATED:
3/4/2016
Zepatier for the Treatment of Chronic Hepatitis C Genotype 1 and 4 Infection
Zepatier (elbasvir and grazoprevir) is a once-daily oral selective NS5A replication complex inhibitor (elbasvir-50mg) and NS3/4A protease inhibitor (grazoprevir-100mg) for the treatment of patients with chronic hepatitis C virus (HCV) GT1 with end-stage renal disease and patients with chronic HCV GT4.
The new drug application (NDA) for Zepatier was submitted by Merck to US Food and Drug Administration (FDA) on 28 May 2015.
The FDA granted breakthrough therapy designation status for the drug in April 2015 and approved it for the treatment of patients with chronic HCV GT1 and GT4 infections on 28 January 2016.
Hepatitis C virus GT1 and GT4 infection
Hepatitis C infection is a liver disease caused by hepatitis C, a blood borne virus. The infection may range from an acute mild illness to a chronic lifelong illness.
HCV is a small enveloped, single-stranded, positive-sense RNA virus, which occurs in seven major genotypes classified as one to seven. It causes inflammation of the liver, leading to decreased liver function or liver failure.
The infection is an asymptomatic until the liver damage becomes evident in patients, which takes several years. The chronic viral infection is characterised by cirrhosis, associated with complications such as bleeding, jaundice, fluid accumulation in the abdomen, infections or liver cancer.
Approximately three million Americans are estimated to have HCV, of which genotype one is most common and genotype four is the least common.
Zepatier's (elbasvir and grazoprevir) mechanism of action
Zepatier is a combination of NS5A replication complex inhibitor and NS3 / 4A protease inhibitor, which functions by inhibiting the activity of NS5A protein and NS3 / 4A protease of the viral cells.
The NS5A replication complex inhibitor prevents replication of viral cells by interacting with NS5A protein on HCV replicon cells, which are responsible for reducing human interferon antiviral activity.
The NS3/4A protease inhibitor stops viral replication by binding to the NS3/4A protease, a serine protease domain that is essential for viral poly-protein maturation and neutralisation of the host's innate antiviral immunity for HCV.
Clinical trials
The FDA approved Zepatier (elbasvir and grazoprevir) based on results obtained from the Phase II, Phase IIb / III and Phase III clinical trials namely C-SCAPE (Phase II), C-SALVAGE (Phase-II), C-SUFFER (Phase IIb / III), C-EDGE (Phase III), C-EDGE TN (Phase III), C-EDGE CO-INXFN (Phase III) and C-EDGE TE (Phase III).
The open-label, randomised, double-blind, placebo-controlled clinical trials enrolled 1,373 patients with chronic HCV GT1 or GT4 infection to demonstrate the safety and efficacy of Zepatier (elbasvir and grazoprevir) by assessing the rate of sustained virologic response 12 weeks after completion of treatment (SVR12).
The trials conducted on HCV genotype one infected patients were C-EDGE TN (double-blind, placebo-controlled), C-EDGE CO-INFXN (open-label, single arm), C-SUFFER (double blind, placebo-controlled) C-EDGE TE (open-label, comparative) and C-SALVAGE (open label, single arm).
The trials conducted on HCV genotype 4 infected patients were C-SCAPE (open label), C-EDGE TN, C-EDGE CO-INFXN and C-EDGE TE.
Merck also conducted three more Phase II trials namely C-CREAST 1, C-CREAST 2 and C-WORTHY on HCV GT1, GT2 and GT3 infected patients respectively.
The drug's safety and efficacy with or without ribavirin were evaluated in clinical trials on 1,373 chronic HCV genotype one or four infected patients with and without cirrhosis.
Subjects were administered Zepatier with or without ribavirin once daily for either 12 or 16 weeks. Overall SVR rates were observed to be from 94% to 97% in genotype one infected subjects, while the range in genotype four infected subjects was from 97% to 100%.
Fatigue, headache and nausea were the most common side effects of Zepatier without ribavirin, while those in Zepatier with ribavirin were anaemia and headache
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