Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Taichung Veterans General Hospital on 09/01/14 For personal use only.
Drug Profile
Asunaprevir-containing regimens for the treatment of hepatitis C virus infection Expert Rev. Gastroenterol. Hepatol. Early online, 1–12 (2014)
Sheng-Shun Yang1–3 and Jia-Horng Kao*4–6 1 Department of Internal Medicine, Division of Gastroenterology and Hepatology, Taichung Veterans General Hospital, Taichung, Taiwan 2 Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan 3 Department of Nursing, Central Taiwan University of Science and Technology, Taichung, Taiwan 4 Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 7 Chung-Shan South Road, Taipei, Taiwan 5 Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan 6 Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan *Author for correspondence: Tel.: +886 223 123 456/67307 Fax: +886 223 825 962 [email protected]
informahealthcare.com
Chronic hepatitis C virus (HCV) infection has been a tremendous health burden worldwide with an annual mortality of 300,000 people due to decompensated cirrhosis or hepatocellular carcinoma. A combination of interferon (IFN), ribavirin (RBV), and/or direct-acting antivirals (DAAs) can eradicate HCV in a various proportion of infected patients. Unfortunately, IFN-based therapy is associated with significant adverse effects, contraindications, and limited tolerability, leading to lower adherence or even treatment discontinuation. With the rapid evolution of newer DAAs or host-targeting agents, emerging HCV therapy is moving towards an IFN- and RBV-free strategy. To this end, a recently developed NS3 protease inhibitor, asunaprevir (ASV), in combination with other DAAs as IFN/RBV-containing or -free regimen, has shown promising results with fewer adverse effects. In this review, preclinical profiles and clinical proof-of-concept studies of ASV, including viral resistance, host polymorphism, and role of ASV in future HCV therapy are reviewed and discussed. KEYWORDS: asunaprevir • direct-acting antivirals • hepatitis C virus • interferon • NS3 protease inhibitor • ribavirin
Chronic hepatitis C virus (HCV) infection is a global health problem with an estimated prevalence of antibodies against HCV (anti-HCV) ranging from 0.8% to as high as 58% in different countries [1–3]. Approximately 150– 200 million people (~3%) worldwide are chronically infected with HCV, with an estimated 3–4 million newly infected cases each year [2]. More than 80% of subjects with acute HCV infection will become chronic carriers [4]. The incidence of HCV infection declined after the introduction of blood screening for HCV and of disposable syringes, but remaining a non-negligible risk such as intravenous drug use, tattooing, surgery, hemodialysis, sexual intercourse, endoscopy and unsafe therapeutic injections especially in the developing world [2]. According to the statement of WHO, up to 20% of chronic hepatitis C (CHC) patients will develop cirrhosis and of whom up to 25% may progress to hepatocellular carcinoma (HCC) [1]. HCV not only causes liver injury but also leads to many extrahepatic manifestations, including metabolic, hematological, neuropsychiatric, vascular and rheumatological diseases [5–7]. On the basis of genetic differences between HCV isolates, HCV can be
10.1586/17474124.2014.953930
classified into seven major genotypes (GT) and many subtypes within each genotype with a total of 67 subtypes [8]. The distribution of GT 1 and 2 are global, GT 3 predominates in Southeast Asia, GT 4 in Africa and Egypt, GT 5 in South Africa and GT 6 primarily in Hong Kong and Vietnam [9–12]. The distribution, transmission, disease progression and response to interferon (IFN)-based therapy substantially vary among HCV GT. GT 1 is generally associated with a poorer sustained virologic response (SVR) (undetectable serum HCV RNA 12 [SVR12] or 24 weeks [SVR24] after cessation of antiviral therapy) to IFNbased therapy, whereas GT 2 and 3 have more favorable responses [12–16]. GT 4 seems to have an intermediate response [17]. Current standard of care for eradicating HCV GT 1 mainly rely on pegylated IFN-a (PEG-IFN-a), ribavirin (RBV) [12,13,15,16] with or without direct-acting antivirals (DAAs) such as NS3/4A protease inhibitors of boceprevir [18,19], telaprevir [20–23], simeprevir [24–27], and NS5B polymerase nucleotide inhibitor of sofosbuvir [28–37]. With these regimens, a SVR rate of 66–92% can be achieved in HCV GT 1 treatment-naı¨ve patients [18–21,24–28]. Several host and viral
2014 Informa UK Ltd
ISSN 1747-4124
1
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Taichung Veterans General Hospital on 09/01/14 For personal use only.
Drug Profile
Yang & Kao
factors such as low viral load, mild hepatic fibrosis stage, favorable genotype of IL-28B gene, low ferritin or homocysteine levels, achievement of rapid virologic response (undetectable HCV RNA at week 4 of therapy) are known to predict a SVR to IFN-based therapies [38,39]. Accumulating lines of evidence demonstrate that CHC patients can benefit from achieving SVR in terms of improving quality of life, decreasing liver-related and all-cause mortality, even in those after curative HCC treatment [40–43]. Although these regimens are efficacious in GT 1 patients, complicated dosing schedules (twice or three-times daily with multiple pills) and significant adverse effects (AEs), for example, anemia, dysgeusia and skin reaction, add further limitations to IFN-based regimens and leading to dose reductions or high discontinuation rates [18–23]. These drawbacks highlight the unmet medical needs and more effective, bettertolerated therapeutic agents for HCV infection are urgently warranted. To this end, several antivirals with different mechanisms of action to directly inhibit HCV replication have been approved or under active clinical development aiming at strategies of more robust antiviral potency, less or no viral resistance, IFN and/or RBV-free, less or no AEs, less pill burden and easy to use, as well as shorter treatment period [44–53]. In this review, the relevant preclinical and clinical data regarding a second-wave HCV protease inhibitor of asunaprevir (ASV) and its potential role in future HCV treatment regimens will be discussed. Lifecycle of HCV
HCV is a member of the genus Hepacivirus in the family Flaviviridae, which comprises small (55–65 nm in size), enveloped, single-stranded, positive-sense RNA viruses with genome size 9.6-kb. HCV RNA genome consists of one large openreading frame flanked on the 5´ and 3´ ends by untranslated regions essential for replication and translation of the polyprotein. The viral genome exposed within the cytoplasm of hepatocyte after its uptake by receptor-mediated endocytosis. RNA replication requires the presence of an RNA-dependent RNA polymerase and proceeds via a negative-strand RNA intermediate, which provides a template for the production of new positive-strand viral genomes. The genomes then translated and either further replicated or packaged within new viral particles and encodes a single polypeptide of about 3000 amino acids that is cleaved by viral and host proteases into three structural proteins (the nucleocapsid and envelope glycoproteins: core, E1, and E2) and seven nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, NS5B and protein p7, derived from E2 cleavage). The HCV polyprotein is processed into proteins that are essential for the virus replication cycle. The bifunctional NS3 protein consists of an N-terminal catalytic subunit that, when complexed with its activating cofactor NS4A, is required for cleavage of the polyprotein and subsequent viral replication [54]. The NS2 cysteine autoprotease and the NS3/ 4A serine protease are responsible for the cleavage of downstream, nonstructural proteins, including NS5A. NS5B is an RNA-dependent RNA polymerase [55]. New viral particles are assembled by the Golgi apparatus and subsequently released doi: 10.1586/17474124.2014.953930
from the hepatocytes. Viral replication also requires the intervention of host factors, such as proteins involved in lipid metabolism, miR-122 and cyclophilin A [56–58]. Role of NS3/4A in HCV replication cycle
The NS3 protein is a bifunctional or probably multifunctional protein, with a serine protease domain in its N-terminal onethird and a helicase domain in the C-terminal two-third [59,60]. The NS3/4A serine protease is a noncovalent, heterodimer complex formed by two HCV-encoded proteins, the N-terminal serine protease domain of NS3 function as catalytic subunit and the NS4A cofactor as its activation subunit [60]. The NS3/4A serine protease is responsible for the proteolytic cleavage at four junctions of the HCV polyprotein precursor: NS3/NS4A (self cleavage), NS4A/NS4B, NS4B/NS5A and NS5A/NS5B [59]. The development of NS3/4A serine protease inhibitor
The success of developing HIV protease inhibitors highlights viral proteases such as the HCV NS3/4A protease can be a potential target for a structure-based drug development. However, the shallow substrate-binding groove of the HCV NS3/4A serine protease observed in an X-ray crystal structure suggested that discovery of a potent, small-molecule and orally available drug would be very challenging [61]. Although a robust and consistent HCV infection cell culture was not available at that time, a subgenomic replicon system developed by Lohmann et al. years later became the mainstay as the standard assay of antiviral activity of the HCV NS3/4A protease inhibitors [62]. In addition, the dearth of a robust HCV infection small animal model has driven scientists to investigate anti-HCV activity on cell culture systems and animal pharmacokinetics prior to human clinical trials [63]. Significant progress in identifying potent smallmolecule inhibitors against the HCV protease has been achieved over the past years. Proof-of-concept HCV NS3/4A protease inhibitors have been obtained with BILN 2061 (ciluprevir, a NS2-3 macrocyclic protease inhibitor manufactured by Boehringer Ingelheim) and VX-950 (telaprevir, a linear protease inhibitor marketed by Vertex Pharmaceuticals and Johnson & Johnson) reported in 2004 and 2005, respectively [64,65]. Viral load in CHC patients was reduced by 2–3 log10 after a treatment with BILN 2061 or VX-950 for 2–3 days, and up to a 4-log10 reduction in HCV viral load was observed at the end of a 14-day VX-950 treatment [64,65]. Some patients even achieved unquantifiable HCV RNA (
Drug Profile
Asunaprevir-containing regimens for the treatment of hepatitis C virus infection Expert Rev. Gastroenterol. Hepatol. Early online, 1–12 (2014)
Sheng-Shun Yang1–3 and Jia-Horng Kao*4–6 1 Department of Internal Medicine, Division of Gastroenterology and Hepatology, Taichung Veterans General Hospital, Taichung, Taiwan 2 Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan 3 Department of Nursing, Central Taiwan University of Science and Technology, Taichung, Taiwan 4 Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 7 Chung-Shan South Road, Taipei, Taiwan 5 Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan 6 Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan *Author for correspondence: Tel.: +886 223 123 456/67307 Fax: +886 223 825 962 [email protected]
informahealthcare.com
Chronic hepatitis C virus (HCV) infection has been a tremendous health burden worldwide with an annual mortality of 300,000 people due to decompensated cirrhosis or hepatocellular carcinoma. A combination of interferon (IFN), ribavirin (RBV), and/or direct-acting antivirals (DAAs) can eradicate HCV in a various proportion of infected patients. Unfortunately, IFN-based therapy is associated with significant adverse effects, contraindications, and limited tolerability, leading to lower adherence or even treatment discontinuation. With the rapid evolution of newer DAAs or host-targeting agents, emerging HCV therapy is moving towards an IFN- and RBV-free strategy. To this end, a recently developed NS3 protease inhibitor, asunaprevir (ASV), in combination with other DAAs as IFN/RBV-containing or -free regimen, has shown promising results with fewer adverse effects. In this review, preclinical profiles and clinical proof-of-concept studies of ASV, including viral resistance, host polymorphism, and role of ASV in future HCV therapy are reviewed and discussed. KEYWORDS: asunaprevir • direct-acting antivirals • hepatitis C virus • interferon • NS3 protease inhibitor • ribavirin
Chronic hepatitis C virus (HCV) infection is a global health problem with an estimated prevalence of antibodies against HCV (anti-HCV) ranging from 0.8% to as high as 58% in different countries [1–3]. Approximately 150– 200 million people (~3%) worldwide are chronically infected with HCV, with an estimated 3–4 million newly infected cases each year [2]. More than 80% of subjects with acute HCV infection will become chronic carriers [4]. The incidence of HCV infection declined after the introduction of blood screening for HCV and of disposable syringes, but remaining a non-negligible risk such as intravenous drug use, tattooing, surgery, hemodialysis, sexual intercourse, endoscopy and unsafe therapeutic injections especially in the developing world [2]. According to the statement of WHO, up to 20% of chronic hepatitis C (CHC) patients will develop cirrhosis and of whom up to 25% may progress to hepatocellular carcinoma (HCC) [1]. HCV not only causes liver injury but also leads to many extrahepatic manifestations, including metabolic, hematological, neuropsychiatric, vascular and rheumatological diseases [5–7]. On the basis of genetic differences between HCV isolates, HCV can be
10.1586/17474124.2014.953930
classified into seven major genotypes (GT) and many subtypes within each genotype with a total of 67 subtypes [8]. The distribution of GT 1 and 2 are global, GT 3 predominates in Southeast Asia, GT 4 in Africa and Egypt, GT 5 in South Africa and GT 6 primarily in Hong Kong and Vietnam [9–12]. The distribution, transmission, disease progression and response to interferon (IFN)-based therapy substantially vary among HCV GT. GT 1 is generally associated with a poorer sustained virologic response (SVR) (undetectable serum HCV RNA 12 [SVR12] or 24 weeks [SVR24] after cessation of antiviral therapy) to IFNbased therapy, whereas GT 2 and 3 have more favorable responses [12–16]. GT 4 seems to have an intermediate response [17]. Current standard of care for eradicating HCV GT 1 mainly rely on pegylated IFN-a (PEG-IFN-a), ribavirin (RBV) [12,13,15,16] with or without direct-acting antivirals (DAAs) such as NS3/4A protease inhibitors of boceprevir [18,19], telaprevir [20–23], simeprevir [24–27], and NS5B polymerase nucleotide inhibitor of sofosbuvir [28–37]. With these regimens, a SVR rate of 66–92% can be achieved in HCV GT 1 treatment-naı¨ve patients [18–21,24–28]. Several host and viral
2014 Informa UK Ltd
ISSN 1747-4124
1
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Taichung Veterans General Hospital on 09/01/14 For personal use only.
Drug Profile
Yang & Kao
factors such as low viral load, mild hepatic fibrosis stage, favorable genotype of IL-28B gene, low ferritin or homocysteine levels, achievement of rapid virologic response (undetectable HCV RNA at week 4 of therapy) are known to predict a SVR to IFN-based therapies [38,39]. Accumulating lines of evidence demonstrate that CHC patients can benefit from achieving SVR in terms of improving quality of life, decreasing liver-related and all-cause mortality, even in those after curative HCC treatment [40–43]. Although these regimens are efficacious in GT 1 patients, complicated dosing schedules (twice or three-times daily with multiple pills) and significant adverse effects (AEs), for example, anemia, dysgeusia and skin reaction, add further limitations to IFN-based regimens and leading to dose reductions or high discontinuation rates [18–23]. These drawbacks highlight the unmet medical needs and more effective, bettertolerated therapeutic agents for HCV infection are urgently warranted. To this end, several antivirals with different mechanisms of action to directly inhibit HCV replication have been approved or under active clinical development aiming at strategies of more robust antiviral potency, less or no viral resistance, IFN and/or RBV-free, less or no AEs, less pill burden and easy to use, as well as shorter treatment period [44–53]. In this review, the relevant preclinical and clinical data regarding a second-wave HCV protease inhibitor of asunaprevir (ASV) and its potential role in future HCV treatment regimens will be discussed. Lifecycle of HCV
HCV is a member of the genus Hepacivirus in the family Flaviviridae, which comprises small (55–65 nm in size), enveloped, single-stranded, positive-sense RNA viruses with genome size 9.6-kb. HCV RNA genome consists of one large openreading frame flanked on the 5´ and 3´ ends by untranslated regions essential for replication and translation of the polyprotein. The viral genome exposed within the cytoplasm of hepatocyte after its uptake by receptor-mediated endocytosis. RNA replication requires the presence of an RNA-dependent RNA polymerase and proceeds via a negative-strand RNA intermediate, which provides a template for the production of new positive-strand viral genomes. The genomes then translated and either further replicated or packaged within new viral particles and encodes a single polypeptide of about 3000 amino acids that is cleaved by viral and host proteases into three structural proteins (the nucleocapsid and envelope glycoproteins: core, E1, and E2) and seven nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, NS5B and protein p7, derived from E2 cleavage). The HCV polyprotein is processed into proteins that are essential for the virus replication cycle. The bifunctional NS3 protein consists of an N-terminal catalytic subunit that, when complexed with its activating cofactor NS4A, is required for cleavage of the polyprotein and subsequent viral replication [54]. The NS2 cysteine autoprotease and the NS3/ 4A serine protease are responsible for the cleavage of downstream, nonstructural proteins, including NS5A. NS5B is an RNA-dependent RNA polymerase [55]. New viral particles are assembled by the Golgi apparatus and subsequently released doi: 10.1586/17474124.2014.953930
from the hepatocytes. Viral replication also requires the intervention of host factors, such as proteins involved in lipid metabolism, miR-122 and cyclophilin A [56–58]. Role of NS3/4A in HCV replication cycle
The NS3 protein is a bifunctional or probably multifunctional protein, with a serine protease domain in its N-terminal onethird and a helicase domain in the C-terminal two-third [59,60]. The NS3/4A serine protease is a noncovalent, heterodimer complex formed by two HCV-encoded proteins, the N-terminal serine protease domain of NS3 function as catalytic subunit and the NS4A cofactor as its activation subunit [60]. The NS3/4A serine protease is responsible for the proteolytic cleavage at four junctions of the HCV polyprotein precursor: NS3/NS4A (self cleavage), NS4A/NS4B, NS4B/NS5A and NS5A/NS5B [59]. The development of NS3/4A serine protease inhibitor
The success of developing HIV protease inhibitors highlights viral proteases such as the HCV NS3/4A protease can be a potential target for a structure-based drug development. However, the shallow substrate-binding groove of the HCV NS3/4A serine protease observed in an X-ray crystal structure suggested that discovery of a potent, small-molecule and orally available drug would be very challenging [61]. Although a robust and consistent HCV infection cell culture was not available at that time, a subgenomic replicon system developed by Lohmann et al. years later became the mainstay as the standard assay of antiviral activity of the HCV NS3/4A protease inhibitors [62]. In addition, the dearth of a robust HCV infection small animal model has driven scientists to investigate anti-HCV activity on cell culture systems and animal pharmacokinetics prior to human clinical trials [63]. Significant progress in identifying potent smallmolecule inhibitors against the HCV protease has been achieved over the past years. Proof-of-concept HCV NS3/4A protease inhibitors have been obtained with BILN 2061 (ciluprevir, a NS2-3 macrocyclic protease inhibitor manufactured by Boehringer Ingelheim) and VX-950 (telaprevir, a linear protease inhibitor marketed by Vertex Pharmaceuticals and Johnson & Johnson) reported in 2004 and 2005, respectively [64,65]. Viral load in CHC patients was reduced by 2–3 log10 after a treatment with BILN 2061 or VX-950 for 2–3 days, and up to a 4-log10 reduction in HCV viral load was observed at the end of a 14-day VX-950 treatment [64,65]. Some patients even achieved unquantifiable HCV RNA (
