New HCV therapies on the horizon

REVIEW

10.1111/j.1469-0691.2010.03430.x

New HCV therapies on the horizon J. Vermehren and C. Sarrazin Medizinische Klinik 1, Klinikum der J. W. Goethe-Universita¨t, Frankfurt am Main, Germany

Abstract Improved understanding of the hepatitis C virus (HCV) life cycle has led to the discovery of numerous potential targets for antiviral therapy. HCV polyprotein processing and replication have been identified as the most promising viral targets. However, viral entry and fusion, RNA translation, virus assembly and release and several host cell factors may provide alternative attractive targets for future anti-HCV therapies. Inhibitors of the HCV NS3/4A protease are currently the most advanced in clinical development. Monotherapy with protease inhibitors has shown high antiviral activity, but is associated with frequent selection of resistant HCV variants, often resulting in viral breakthrough. However, there is encouraging evidence from phase 2/3 trials indicating that the addition of a protease inhibitor (e.g. telaprevir and boceprevir) to pegylated interferon-a/ribavirin substantially improves sustained virological response rates in both treatment-naı¨ve and treatment-experienced patients with HCV genotype 1. Nucleos(t)ide inhibitors of the HCV NS5B polymerase have shown variable antiviral activity against different HCV genotypes, but seem to have a higher genetic barrier to resistance than protease inhibitors. In addition, several allosteric binding sites have been identified for non-nucleoside inhibitors of the NS5B polymerase. However, the development of a substance with high antiviral activity and a high genetic barrier to resistance seems to be difficult. Among the different host cell-targeting compounds in early clinical development, cyclophilin inhibitors have shown the most promising results. Although advances have also been made in improving interferons, combinations of antiviral agents with different mechanisms of action may lead to the eventual possibility of interferon-free regimens. Keywords: Chronic hepatitis C, direct-acting antiviral, protease inhibitor, polymerase inhibitor, NS5A inhibitor, cyclophilin inhibitor, review Article published online: 18 November 2010 Clin Microbiol Infect 2011; 17: 122–134 Corresponding author: C. Sarrazin, Medizinische Klinik 1, Klinikum der J.W. Goethe-Universita¨t, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany E-mail: [email protected]

Introduction Chronic hepatitis C represents a major health burden, affecting approximately 170 million people worldwide [1]. With the current standard of care (SOC), a combination of pegylated interferon (PEG-IFN)-a plus weight-based ribavirin (RBV), viral eradication can be achieved in fewer than half of all patients with hepatitis C virus (HCV) genotype 1 and in approximately 80% of patients with HCV genotype 2 or 3 [2–5]. Treatment may take up to 72 weeks [6], but therapyassociated side effects such as pancytopenia, flu-like symptoms or depression are commonly observed, and may lead to early treatment discontinuation. Improved understanding of the HCV life cycle in recent years has supported the development of direct-acting

antiviral (DAA) agents that specifically target post-translational processing and HCV replication [7–10]. Inhibitors of HCV entry, HCV RNA translation and virus assembly and release are mostly still in preclinical development, whereas several host cell-targeting compounds rate among the more promising therapeutic approaches in recent anti-HCV drug discoveries. Finally, improvements have also been made in the development of new, long-acting interferons with the potential for more favourable safety and efficacy profiles. This review will give an overview of recent developments in the HCV drug pipeline. DAA agents, host cell-targeting compounds and new interferons that have already been evaluated in clinical trials will be discussed. Other treatment approaches, such as toll-like receptor agonists and therapeutic vaccines, are beyond the scope of this article.

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NS3/4A protease inhibitors

The NS3/4A protease has been recognized as an important target for anti-HCV therapy because of its key role within the HCV life cycle (e.g. cleavage of the genome-encoded polyprotein and inactivation of cellular proteins required for innate immunity). NS3/4A protease inhibitors have shown strong antiviral efficacy but a low genetic barrier to resistance in early clinical studies. They can be divided into two chemical classes: macrocyclic inhibitors, and linear, tetrapeptide a-ketoamide derivates (Fig. 1).

Telaprevir

The orally bioavailable, linear, ketoamide protease inhibitor telaprevir was initially investigated in a 14-day randomized, placebo-controlled monotherapy study in patients with HCV genotype 1 [12]. In this study, the greatest reduction in HCV RNA was achieved in patients who received 750 mg of telaprevir every 8 h, with a median viral load decline of

(b)

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123

The clinical proof-of-concept for NS3/4A protease inhibitors was obtained with ciluprevir, a macrocyclic NS3/4A protease inhibitor that showed substantial antiviral activity in patients with HCV genotype 1 [11]. However, the development of ciluprevir was stopped because of serious cardiotoxicity in a monkey model.

Antivirals Targeting HCV Polyprotein Processing

(a)

New HCV therapies

FIG. 1. Antiviral activity of (a) NS3/4A protease inhibitors, (b) nucleos(t)ide analogue NS5B polymerase inhibitors, (c) non-nucleoside analogue NS5B polymerase inhibitors and (d) NS5A and other inhibitors during monotherapy for 3–14 days in patients with chronic hepatitis C, modified from [9]. No head-to-head studies were conducted. *Alinia was administered at a dose of of 500 mg twice daily for 24 weeks in genotype 4 patients only. BW, body weight; HCV, hepatitis C virus; IV, intravenous. ª2011 The Authors Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 17, 122–134

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4.4 log10 IU/mL HCV RNA from baseline. Viral rebound caused by selected drug-resistant mutants occurred in the majority of patients during treatment [13]. Mutations associated with clinical resistance to telaprevir were identified at four positions of the NS3 catalytic domain — V36A/M/L, T54A, R155K/M/S/T and A156S (all three conferring lowlevel to medium-level resistance) and A156T/V (conferring high-level resistance) [13–16]. In two short-term studies of telaprevir, given in combination with PEG-IFN-a-2a ± RBV for 2–4 weeks, an even more pronounced viral decline, with a reduced frequency of resistance mutations and no viral breakthrough, was observed [17,18]. Subsequently, two large phase 2b placebo-controlled trials of telaprevir in combination with PEG-IFN-a ± RBV were conducted in treatment-naı¨ve patients with HCV genotype 1 in the USA (PROVE 1; n = 250) [19] and in Europe (PROVE 2; n = 323) [20]. Overall, sustained virologic response (SVR) rates of up to 67–69% were achieved in the telaprevir-containing study arms vs. 41–46% in patients who received SOC. In PROVE 1, only patients who achieved an extended rapid virological response (eRVR) (HCV RNA negative at week 4 and thereafter) were eligible for a shortened treatment duration. The exploratory study arms with 12 weeks of telaprevir plus PEG-IFN-a ± RBV were associated with high relapse rates, especially in patients without RBV (up to 48%), indicating that 12 weeks of overall therapy was insufficient to achieve favourable treatment outcomes, and highlighting the importance of adding RBV, because of improved antiviral activity, reduced relapse rates, and a smaller number of patients with selection of resistant variants and viral breakthrough. Rates of treatment discontinuation attributable to adverse events were higher in the telaprevircontaining study arms than in patients treated with SOC alone (12–21% vs. 7–11%). Moreover, discontinuation rates increased to nearly 30% in patients who received telaprevir for 24 weeks. Thus, in subsequent studies, telaprevir dosing was restricted to a maximum of 12 weeks. For more convenient application and to increase treatment adherence, telaprevir every 12 h at a dose of 1125 mg was investigated in a small open-label phase 2 study, conducted in treatment-naı¨ve patients with HCV genotype 1 (study C208). In this study, telaprevir was also given in combination with PEG-IFN-a-2b and RBV. Equally high SVR rates were observed with telaprevir every 12 h vs. every 8 h, and with PEG-IFN-a-2b vs. PEG-IFN-2a [21]. However, differences between the two PEG-IFN formulations may only become visible in a more difficult-to-treat patient population (i.e. patients with high viral load, advanced fibrosis or prior non-response to PEG-IFN-a therapy). Telaprevir was also

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investigated in patients infected with HCV genotypes 2, 3 and 4, with varying success [22,23]. The two pivotal phase 3 studies, known as ADVANCE and ILLUMINATE, were conducted in more than 1500 treatment-naı¨ve patients infected with HCV genotype 1, and showed SVR rates of 75% and 72% following triple therapy for 12 weeks followed by PEG-IFN-a-2a/RBV for an additional 12 or 36 weeks, respectively. Thus, SVR could be increased by approximately 30% as compared with control patients treated with SOC for 48 weeks (44%). Patients who received triple combination therapy for 8 weeks, followed by SOC for 16 or 40 weeks, still achieved an SVR rate of 69% (ADVANCE). Precise plans for the management of adverse events, especially the frequently observed rashes, were developed for the phase 3 studies, and rates of discontinuation attributable to adverse events were somewhat lower than in the PROVE trials (7–8% vs. 4% in patients receiving SOC) [24,25]. In the ADVANCE study, a response-guided therapy approach was applied, with a shortened treatment period of 24 weeks, in patients who achieved an eRVR, whereas all other patients were treated for 48 weeks. In the ILLUMINATE study, no benefit of a longer treatment duration (48 weeks vs. 24 weeks) in eRVR patients could be demonstrated (Fig. 2a). Together, these findings show that an eRVR was achieved in 57–65% of treatment-naı¨ve patients with HCV genotype 1. Thus, the majority of patients were eligible for shortened treatment duration, with equally high SVR rates as those obtained with the standard therapy duration of 48 weeks. Telaprevir in combination with PEG-IFN-a-2a ± RBV was also investigated in treatment-experienced HCV genotype 1 patients (PROVE 3, n = 453; and study 107, n = 117) [26]. Overall, significantly higher SVR rates were achieved in prior relapsers who received triple combination therapy than in those receiving SOC (up to 69–97% vs. 20%). Patients with prior breakthrough or non-response achieved SVR rates in the ranges of 57–86% and 38–39%, respectively, as compared with 20% and 9% when given SOC. Prior non-responders, including partial non-responders (‡2 log10 decline but detectable HCV RNA at treatment week 12) and null-responders (<2 log10 decline in HCV RNA at week 12), experienced the highest rates of viral breakthrough during triple combination therapy. A phase 3 study (REALIZE) of telaprevir evaluated the efficacy of a 12-week triple combination treatment regimen followed by 36 weeks of SOC, or a 4-week lead-in with SOC, followed by 12 weeks of triple combination therapy, followed by 32 weeks of SOC in treatment-experienced genotype 1 patients (partial non-responders, null-responders and relapsers) vs. SOC for 48 weeks. SVR rates for the three

ª2011 The Authors Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 17, 122–134

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(b)

66

59

38

48 PR

PR ±

B3 2

PR

4/

PR

PR 4/

12

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*SVR data are shown for patients with eRVR only

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PR T1 2

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SVR (%)

64

66

PR

REALIZE

ILLUMINATE*

69

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Boceprevir

100 90 80 70 60 50 40 30 20 10 0

±

92

B2 4

Telaprevir

100 90 80 70 60 50 40 30 20 10 0

PR

SVR (%)

(a)

New HCV therapies

PR

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FIG. 2. Sustained viral response (SVR) results of recent telaprevir (ADVANCE, ILLUMINATE and REALIZE) and boceprevir (SPRINT-2 and RESPOND-2) trials. No head-to-head studies were conducted. (a) ADVANCE and ILLUMINATE were conducted in treatment-naı¨ve patients with hepatitis C virus (HCV) genotype 1. The ADVANCE treatment arms were as follows: (i) 12 weeks of telaprevir (T) plus PEG-IFN-a-2a and ribavirin (PR) followed by PR for 12 or 36 weeks, based on treatment response at weeks 4 and 12; (ii) 8 weeks of T plus PR followed by PR for 16 or 40 weeks, based on treatment response at weeks 4 and 12; and (iii) PR alone for 48 weeks. In the ILLUMINATE trial, patients who achieved an extended rapid virological response (eRVR) were randomized to receive 12 weeks of T plus PR followed by PR for (i) 12 weeks or (ii) 24 weeks. Treatment-experienced patients with HCV genotype 1 (REALIZE) received: (i) 12 weeks of T plus PR followed by PR for 36 weeks; (ii) a 4-week PR lead-in followed by T plus PR for 12 weeks, followed by PR alone for 32 weeks; or (iii) PR alone for 48 weeks. In the REALIZE study, relapsers and non-responder (null-responder and partial non-responder) patients were enrolled. (b) The SPRINT-2 treatment arms in treatment-naı¨ve patients with HCV genotype 1 were as follows: (i) 4-week lead-in with PEG-IFN-a-2b plus ribavirin (PR) followed by 44 weeks of PR plus boceprevir (B); (ii) 4-week lead-in with PR followed by PR plus B for 24 weeks or followed by PR plus B for 24 weeks and PR for an additional 20 weeks, based on treatment response at weeks 8 and 12; and (iii) PR alone for 48 weeks. A similar treatment schedule was used in treatment-experienced genotype 1 patients (RESPOND-2): (i) 4-week lead-in with PR followed by PR plus B for 44 weeks; (ii) 4-week lead in with PR followed by PR plus B for 32 weeks or followed by PR plus B for 32 weeks and PR for an additional 12 weeks, based on treatment response at weeks 8 and 12; and (iii) PR alone for 48 weeks.

treatment arms were 64%, 66% and 17%, respectively. Prior relapsers achieved SVR rates of 83–88%, whereas prior nullresponders achieved SVR rates in the range of 29–33%. Discontinuation because of adverse events occurred in 4% of the combined telaprevir study arms and in 3% of the control group. [27]. During triple therapy with telaprevir plus PEG-IFN-a/RBV, viral breakthrough associated with the selection of resistant variants was observed in 1–5% of treatment-naı¨ve patients and in up to 25% of previous non-responders. Moreover, variants conferring resistance to NS3 protease inhibitors were also detected in patients with viral relapse after the end of treatment. The long-term significance of these resistant variants is unknown but, generally, a decline in frequency over time was observed. However, in single patients, low to medium levels of the V36 and A156 variants were observed for up to 4 years after telaprevir therapy [28]. Boceprevir

In a phase 1 study, administration of boceprevir (200 or 400 mg every 8 h), a peptidomimetic orally bioavailable

a-ketoamide HCV protease inhibitor, with or without PEGIFN-a-2b, resulted in mean maximum reductions of HCV RNA of up to 1.61 log10 and 2.88 log10 IU/mL, respectively, in treatment-experienced patients infected with HCV genotype 1 [29]. Subsequently, a number of mutations conferring boceprevir resistance at low to medium levels were discovered in vivo: V36M/A, T54A/S, V55A, R155K/T, A156S and V170A [30–33]. As for telaprevir, reduced antiviral activities of boceprevir in HCV genotype 2/3-infected patients were reported. In a phase 2 clinical trial (SPRINT-1), boceprevir (800 mg every 8 h) in combination with PEG-IFN-a-2b and RBV was investigated in treatment-naı¨ve patients with HCV genotype 1 (n = 595) [34]. Patients received either all three drugs in combination for 28 or 48 weeks or for 24 or 44 weeks after a previous 4-week lead-in phase of PEG-IFN-a-2b/RBV, or SOC for 48 weeks. SVR rates ranged from 54% for 28 weeks of triple therapy to 75% after a 4-week lead-in with PEG-IFN-a-2b/RBV followed by 44 weeks of triple therapy, as compared with 38% in the control group. Treatment discontinuations attributable to adverse events occurred in

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9–19% of patients receiving boceprevir as compared with 8% in the control group. In patients with prior non-response to SOC therapy, the addition of boceprevir to PEG-IFN-a and RBV gave only slightly increased SVR rates as compared with standard therapy in a phase 2b study with suboptimal boceprevir/RBV dosing (14% vs. 2%) [35]. The 4-week lead-in phase with PEG-IFN-a/RBV was introduced into boceprevir phase 2 trials to decrease the probability of resistance development. During the lead-in, a viral decline of >2 log10 IU/mL was induced in the majority of treatment-naive patients, resulting in undetectable HCV RNA levels in 60–64% of patients after an additional 4 weeks of triple therapy (week 8 of overall treatment), whereas only 37–39% of patients without lead-in therapy achieved undetectable HCV RNA levels after 4 weeks of triple therapy. Numerically, lower breakthrough rates and higher SVR rates were observed in patients with a lead-in period than in those without induction therapy. The lead-in period may help in the selection of the optimal triple-therapy duration for both treatment-naı¨ve and treatment-experienced patients. However, in virological non-sustained responders treated with telaprevir-based triple therapy, no benefit of a lead-in-phase was observed [27]. In subsequent phase 3 studies, a larger number of treatment-naı¨ve (SPRINT-2; n = 1097) and treatment-experienced (RESPOND-2; n = 403; partial non-responders and relapsers only) patients with HCV genotype 1 infection were enrolled to receive a 4-week lead-in treatment with PEG-IFN-a-2b/ RBV alone, followed by either 44 weeks of triple combination therapy or a response-guided schedule with the possibility of stopping therapy at week 28 or week 36 of overall treatment duration, respectively. SVR rates were 63–66% in treatment-naı¨ve patients and 59–66% in treatment-experienced patients, as compared with 38% and 21% in the respective control groups (Fig. 2b). Treatment discontinuations attributable to adverse events occurred in 12–16% of treatment-naı¨ve patients and in 8–12% of treatment-experienced patients, as compared with 16% and 3% in the respective control groups [36,37]. Other protease inhibitors

A large number of NS3/4A protease active site inhibitors are currently in early clinical development (Table 1a): danoprevir (RG 7227/ITMN191), TMC435, vaniprevir (MK-7009), BI 201335, narlaprevir (SCH900518), BMS-650032, PHX 1766, ACH-1625, IDX320, ABT-450, MK-5172, GS9256 and GS-9451 have all been tested in phase 1 and/or phase 2 clinical trials [38–52]. Overall, these compounds exhibit high antiviral activity in HCV genotype 1 patients, and

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recently reported phase 2 results showed SVR rates comparable to those achieved with telaprevir and boceprevir [48– 50]. Potential advantages of the newer antiviral compounds include improved pharmacokinetics (once-daily to twice-daily dosing), broader genotypic activity and better tolerability. In addition, ritonavir boosting is being investigated for a number of protease inhibitors, including narlaprevir and danoprevir, to reduce side effects and to enhance patient exposure to the latter agents, thereby potentially overcoming resistance and allowing less frequent dosing. The resistance profiles of all NS3 protease inhibitors currently in clinical development overlap (Table 2) [9].

Antivirals Targeting HCV Replication NS5B polymerase inhibitors

Two classes of NS5B polymerase inhibitors can be distinguished: nucleoside or nucleotide analogue inhibitors, which mimic the natural substrates of the RNA-dependent RNA polymerase and are incorporated into the elongated RNA, where they act as chain terminators; and non-nucleoside analogue inhibitors, representing a heterogeneous group of compounds that bind to different allosteric enzyme sites, resulting in a conformational protein change before the elongation complex is formed. Nucleos(t)ide inhibitors

Nucleos(t)ide inhibitors potentially show similar efficacies against all HCV genotypes, because the active centre of NS5B is a highly conserved region. The first nucleoside analogue in development was valopicitabine (NM283, 2¢-C-methylcytidine/NM107). However, valopicitabine showed only weak antiviral activity, and further drug development was stopped because of gastrointestinal side effects [53]. The nucleoside analogue R1626 (4¢-azidocytidine/PSI-6130) showed marked antiviral activity when given at high doses alone or in combination with PEG-IFN-a-2a/RBV. No viral breakthrough was reported for either monotherapy or combination therapy. However, further development was stopped because of severe adverse events, including severe lymphocytopenia with lethal outcomes [54,55]. Among the nucleos(t)ide analogues still in development, RG 7128 is the most advanced. Week 12 interim results of a phase 2 trial of RG 7128 in combination with PEG-IFN-a-2a/ RBV in treatment-naı¨ve genotype 1 or 4 patients have shown early virological response rates of >80% and no resistancerelated viral breakthrough [56]. SVR rates have to be awaited. Other nucleotide analogue inhibitors that are

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TABLE 1. New hepatitis C virus therapies in the pipeline (a) Drug name NS3/4A protease inhibitors Ciluprevir (BILN 2061) Boceprevir (SCH503034) Telaprevir (VX-950) Danoprevir (RG 7227) TMC435 Vaniprevir (MK-7009) BI 201335 BMS-650032 GS-9256 ABT-450 Narlaprevir (SCH900518) PHX 1766 ACH-1625 IDX320 MK-5172 VX-985 GS-9451 Nucleos(t)ide NS5B polymerase inhibitors Valopicitabine (NM283) RG 7128 IDX184 R1626 PSI-7977 Non-nucleoside NS5B polymerase inhibitors BILB 1941 BI 207127 MK-3281 Filibuvir (PF-00868554) VX-916 VX-222 VX-759 ANA598 ABT-333 ABT-072 Nesbuvir (HCV-796) Tegobuvir (GS-9190) IDX375 NS5A inhibitors BMS-790052 BMS-824393 PPI-461 AZD7295

Company

Target/active drug

Study phase

Boehringer Ingelheim Merck Vertex InterMune/Roche Tibotec/Medivir Merck Boehringer Ingelheim Bristol-Myers Squibb Gilead Abbott/Enanta Merck Phenomix Achillion Idenix Merck Vertex Gilead

Active Active Active Active Active Active Active Active Active Active Active Active Active Active Active Active Active

site/macrocyclic site/linear site/linear site/macrocyclic site/macrocyclic site/macrocyclic site/linear site site site site/linear site site site/macrocyclic site/macrocyclic site site

Stopped Phase 3 Phase 3 Phase 2 Phase 2 Phase 2 Phase 2 Phase 2 Phase 2 Phase 2 On hold Phase 1 Phase 1 On hold Phase 1 Phase 1 Phase 1

Idenix/Novartis Roche/Pharmasset Idenix Roche Pharmasset

Active Active Active Active Active

site/NM107 site/PSI-6130 site site/R1479 site

Stopped Phase 2 On hold Stopped Phase 2

Boehringer Ingelheim Boehringer Ingelheim Merck Pfizer Vertex Vertex Vertex Anadys Abbott Abbott ViroPharma/Wyeth Gilead Idenix

NNI NNI NNI NNI NNI NNI NNI NNI NNI NNI NNI NNI NNI

Bristol-Myers Squibb Bristol-Myers Squibb Presidio AstraZeneca

NS5A NS5A NS5A NS5A

Novartis Scynexis Debiopharm/Novartis Romark Migenix

Cyclophilin inhibitor Cyclophilin inhibitor Cyclophilin inhibitor PKR induction? a-Glucosidase inhibitor

Stopped Phase 1 Phase 2 Phase 2 Phase 2

Biolex ZymoGenetics/BMS HGS/Novartis

Interferon receptor type 1 Interferon receptor type 3 Interferon receptor type 1

Phase 2 Phase 2 Stopped

site site site site site site site site site site site site site

1/thumb 1 1/thumb 1 1/thumb 1 2/thumb 2 2/thumb 2 2/thumb 2 2/thumb 2 3/palm 1 3/palm 1 3/palm 1 4/palm 2 4/palm 2 4/palm 2

Stopped Phase 2 Stopped Phase 2 On hold Phase 2 Phase 1 Phase 2 Phase 2 Phase 2 Stopped Phase 2 Phase 1

domain 1 inhibitor inhibitor inhibitor inhibitor

Phase Phase Phase Phase

2 1 1 1

(b) Indirect inhibitors/unknown mechanism of action NIM811 SCY-635 Alisporivir (Debio 025) Nitazoxanide Celgosivir New interferons Locteron (BLX-883) PEG-rIL-29 (pegylated interferon-k) Joulferon (albinterferon-a-2b) Double-stranded-RNA-activated protein kinase. PKR.

TABLE 2. Mutations conferring resistance to hepatitis C virus NS3 protease inhibitors; modified from [9] V36A/M Telaprevir (linear)

T54S/A

V55A

Q80R/K

R155K/T/Q

A156S

A156T/V

D168A/V/T/H

V170A/T a

a

Boceprevir (linear)

a

Narlaprevir (linear) Ciluprevir (macrocyclic) Danoprevir (macrocyclic)

a

a

Vaniprevir (macrocyclic) TMC435 (macrocyclic) BI-201335 (linear) aMutations

associated with resistance in vitro but not described in patients

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currently in clinical development include PSI-7977 (a chirally pure isomer form of PSI-7851) and IDX184 [57,58].

inhibitors include ABT-072 and ABT-333, both of which have entered phase 2 clinical trials [70].

Allosteric, non-nucleoside inhibitors

Non-nucleoside site 4 inhibitors (palm 2/benzofuran site)

The structure of the NS5B polymerase resembles a characteristic ‘right-hand motif’, consisting of finger, palm and thumb domains. At least four different allosteric binding sites have been identified for the inhibition of the NS5B polymerase by non-nucleoside inhibitors: a benzimidazole (thumb 1)-binding site, a thiophene (thumb 2)-binding site, a benzothiadiazine (palm 1)-binding site, and a benzofuran (palm 2)-binding site [59,60]. As non-nucleoside inhibitors bind more distantly to the active site of NS5B, resistant mutations occur more frequently than for nucleos(t)ide analogues.

Monotherapy with HCV-796 (nesbuvir) showed low antiviral activity in HCV genotype 1-infected patients, and resulted in selection of resistant variants and viral breakthrough in several patients. Further drug development was suspended because of abnormal liver enzyme elevations in a subsequent phase 2 study [71]. GS-9190 (tegobuvir) displayed low antiviral activity in a phase 1 clinical study, and drug-resistant variants were observed [72]. However, GS-9190 has entered phase 2 clinical trials, both in combination with SOC and with the protease inhibitor GS-9256 ± RBV. Finally, IDX375 also binds to the palm pocket, and is currently in phase 1 clinical trials [73].

Non-nucleoside site 1 inhibitors (thumb 1/benzimidazole site)

BI 207127, BILB 1941 and MK-3281 are non-nucleoside site 1 inhibitors that have been shown to exhibit low to medium antiviral activity in phase 1 clinical trials [61–63]. Four weeks of BI 207127 (600 mg three times daily) in combination with PEG-IFN-a-2a/RBV resulted in a median reduction of 5.6 log10 HCV RNA in treatment-naı¨ve genotype 1 patients, and no viral breakthrough was observed [64]. Results of further studies have to be awaited. The further development of BILB 1941 and MK-3281 was halted because of gastrointestinal adverse events. Non-nucleoside site 2 inhibitors (thumb 2/thiophene site)

The non-nucleoside site 2 inhibitor filibuvir (PF-00868554) has shown medium antiviral activity in phase 1 clinical trials. Interim results from a phase 1 trial investigating different doses of filibuvir in combination with PEG-IFN-a-2a/RBV for 4 weeks followed by SOC for 44 weeks have shown similar SVR (at 12 weeks of follow-up) results for the different filibuvir groups and for the SOC group, indicating that longer dosing with filibuvir is needed [65]. Other site 2 inhibitors include VX-759, VX-916 and VX-222 [66–68]. However, only VX-222 has progressed to phase 2 development. Non-nucleoside site 3 inhibitors (palm 1/benzothiadiazine site)

A phase 2 trial of ANA598 in combination with PEG-IFN-a2a/RBV in treatment-naı¨ve patients with HCV genotype 1 is currently ongoing. It was recently reported that 75% of patients who received 400 mg of ANA598 twice daily achieved undetectable HCV RNA levels at treatment week 12 (complete early virological response (cEVR)) [69]. However, SVR rates have to be awaited. Other site 3 palm 1

NS5A inhibitors

Inhibitors of NS5A are potentially active against all HCV genotypes. BMS-790052 binds to domain I of the NS5A protein, which is crucial for the regulation of HCV replication, assembly and release. Following promising results from a phase 1 study, BMS-790052 is currently under investigation in a number of phase 2 clinical trials. Recently, interim data were released from a phase 2 study investigating different doses of BMS-790052 in combination with SOC. Rapid virological response rates were 83% and 92% in patients who received 10 and 60 mg BMS-790052 once daily, respectively. In addition, undetectable HCV RNA levels at week 12 (cEVR) were observed in 83% of patients [74]. Other NS5A inhibitors that are in early clinical development include BMS-824393, AZD7295 and PPI-461 [75–77].

DAA Combination Therapies Interferon-associated side effects may limit treatment success in a large number of patients. Therefore, one of the primary future goals of DAA therapy is to control viral replication or even to achieve SVR in interferon-free regimens. In the INFORM-1 study, combinations of different doses of a polymerase inhibitor (RG 7128) and the NS3/4A protease inhibitor danoprevir (RG 7227/ITMN191) were tested in both treatment-naı¨ve and treatment-experienced patients with HCV genotype 1 for up to 2 weeks. Up to 63% of treatment-naı¨ve patients achieved undetectable HCV RNA levels after 2 weeks of combination therapy, and only one patient experienced viral rebound without exhibiting resistance mutations [78]. HCV RNA negativity rates were somewhat lower in treatment-experienced patients (25%).

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A number of other drug combinations are currently being investigated. Dual, triple and quadruple therapy with GS9256 and GS-9190 alone or in combination with RBV or PEG-IFN-a/RBV for up to 28 days revealed the importance of RBV for the enhancement of antiviral activity and reduction of viral breakthrough [79]. Interferon-sparing triple combination therapy with BI 201335 and BI 207127 (400 or 600 mg three times daily) plus RBV resulted in undetectable HCV RNA after 4 weeks in all patients treated with the higher dose of BI 207127 [80]. Finally, in an ongoing trial of HCV genotype 1 null-responders treated with BMS-790052 plus BMS-650032 alone or in combination with PEG-IFN-a/ RBV for 24 weeks, 14/21 patients achieved cEVR, whereas all patients with viral breakthrough (n = 6) were genotype 1a patients, indicating that not all DAAs may be equally effective in both HCV genotype 1a and 1b patients [81]. Overcoming drug resistance will be the primary challenge in DAA combination therapy, and drug combinations that have a genetic barrier of four or more mutations may be required [82]. Future trials need to address the tolerability and safety of long-term DAA administration, and whether SVR can be achieved without the addition of PEG-IFN-a/ RBV.

Emerging Mechanisms Emerging potential drug candidates in future anti-HCV therapies include inhibitors of HCV entry, internal ribosome entry site inhibitors, inhibitors of HCV assembly and release, and a-glucosidase inhibitors. However, potential compounds are currently still in preclinical or very early clinical development. Host cells may provide additional targets for antiviral therapies, and several host cell-targeting inhibitors have entered clinical development, with promising results. Cyclophilin inhibitors

Cyclophilins are ubiquitous proteins in human cells, and are involved in protein folding. Moreover, cyclophilins participate in HCV replication as functional regulators of the HCV NS5B polymerase. The cyclophilin inhibitor Debio 025 (alisporivir) showed antiviral activity in patients infected with different HCV genotypes (1–4) during monotherapy and in combination studies with PEG-IFN-a. Maximum log10 changes in HCV RNA of up to 4.75 were observed in HCV genotype 1 or 4 patients who received 1000 mg of Debio 025 in combination with PEG-IFN-a-2a/RBV for 4 weeks [83]. There is one case report of a genotype 3a patient who achieved SVR following

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4 weeks of Debio 025 1000 mg/day as monotherapy [84]. No viral breakthrough has been observed in clinical studies so far. However, selection of HCV variants resistant to Debio 025 with mutations clustering in the NS5A gene was observed in the HCV replicon system [85,86]. SCY-635 is another non-immunosuppressive analogue of cyclosporin A that exhibits potent suppression of HCV. Different doses of SCY-635 were investigated in patients infected with HCV genotype 1, and a mean maximum decline of 2.3 log10 IU/mL in viral load was observed after 15 days of 900-mg SCY-635 monotherapy [87]. No viral rebound was observed during SCY-635 therapy. However, minimal evidence of resistance selection was observed within NS5B [88]. Silibinin

Silymarin, an extract of milk thistle (Silybum marianum) with antioxidant activity, has been used as self-medication for liver diseases for centuries [89]. Silibinin is one of the six major flavonolignans in silymarin. Although its mechanism of action and treatment efficacy are not yet fully understood, it was recently reported that silibinin inhibited HCV RNA-dependent RNA polymerase activity [90]. However, its antiviral action includes blocking of virus entry and transmission, possibly by targeting the host cell [91]. Intravenous silibinin was investigated in non-responders to prior IFN-based antiviral therapy, and led to a significant decline in HCV RNA of between 0.55 and 3.02 log10 IU/mL after 7 days, and a further decrease after an additional 7 days in combination with PEG-IFN-a-2a/RBV, in the range of 1.63–4.85 log10 IU/mL [92]. Studies in larger patient cohorts, including resistance analyses, are underway. Nitazoxanide

Nitazoxanide (alinia) is a thiazolide that has been shown in vitro to have activity against both hepatitis B virus and HCV. The antiviral method of action of nitazoxanide is still unknown, but it is believed that it inhibits viral glycoproteins at the post-translational level (i.e. PKR induction). A phase 2 study of 500 mg of nitazoxanide twice daily for 12 weeks, followed by nitazoxanide, PEG-IFN-a-2a ± RBV for 36 weeks, yielded an SVR rate of 79% in treatment-naı¨ve genotype 4 patients [93]. However, a similar regimen in treatment-naı¨ve genotype 1 patients yielded a week 12 SVR rate of only 44% [94]. Further studies are warranted.

New Interferons Albinterferon-a-2b (Joulferon) is a recombinant protein consisting of interferon-a-2b fused to human albumin that can

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be administered every 2 weeks, owing to a longer half-life than that of the currently marketed pegylated interferons. The efficacy and safety of albinterferon-a-2b administered every 2 weeks in combination with RBV for 48 weeks in patients infected with HCV genotype 1, and for 24 weeks in patients infected with HCV genotype 2/3, were recently studied in two large phase 3 clinical trials (ACHIEVE 1 and ACHIEVE 2/3) that were designed to demonstrate the noninferiority of these regimens as compared with SOC [95,96]. Both studies achieved the primary objective. In patients with HCV genotype 1, intention-to-treat SVR rates of 51%, 48.2% and 47.3% were achieved for PEG-IFN-a-2a, albinterferon-a2b (900 lg) and albinterferon-a-2b (1200 lg), respectively. For genotype 2/3-infected patients, intention-to-treat SVR rates were 84.8%, 79.8% and 80%, respectively. The safety profile was similar between the different treatment regimens, indicating that albinterferon-a-2b was not better tolerated than PEG-IFN-a-2a. Owing to concerns expressed by the regulatory authorities regarding the benefit/risk ratio, further development of albinterferon was recently suspended. Locteron is a controlled-release formulation of interferona-2b that can be administered every 2 weeks. Week 12 interim results from a phase 2b study have shown a similar reduction in HCV RNA and a reduction of flu-like symptoms by 57% for locteron at a dose of 480 lg as compared with PEG-IFN-a-2b in treatment-naı¨ve patient with HCV genotype 1 [97]. SVR results have to be awaited. PEG-IFN-k (PEG-rIL-29) is a type III interferon that binds to a unique receptor with a more limited distribution than the type I interferon receptor used by interferon-a. In a phase 1b trial, 56 treatment-naı¨ve and SOC relapser patients were enrolled to receive different doses of PEG-IFN-k (ranging from 0.5 to 3.0 lg/kg) administered every 2 weeks or weekly with or without daily RBV for 4 weeks. Antiviral activity was seen at all dose levels, with a mean maximum change of HCV RNA from baseline of 3.27 log10 IU/mL in treatment-naı¨ve patients treated with weekly PEG-IFN-k (1.5 lg/kg) plus RBV [98]. Phase 2 trials are currently ongoing.

Conclusions A number of advances have been made in the development of new therapeutic options for the treatment of chronic hepatitis C. In particular, the challenges of treating patients with HCV genotype 1 who achieve SVR rates in the range of 40– 50% with the current SOC have been met by the development of DAA agents. Although monotherapy with DAAs may not be suitable, owing to the selection of drug-resistant

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HCV variants followed by viral breakthrough, convincing results have been achieved for the combination of new antiviral agents with SOC. Results from phase 2 clinical studies of the currently most advanced compounds, telaprevir and boceprevir, have indicated that the addition of an HCV protease inhibitor to PEG-IFN-a/RBV significantly improves SVR rates in both treatment-naı¨ve and treatment-experienced patients. In addition, response-guided treatment schedules have been successfully applied [19,20,26]. Thus, two of the major goals of anti-HCV therapy, i.e. higher SVR rates and shorter treatment duration based on RVR results, can be achieved. The pivotal phase 3 trials of telaprevir and boceprevir in treatment-naı¨ve patients infected with HCV genotype 1 recently confirmed these promising results, showing SVR rates ranging from 72% to 75% in telaprevir-treated patients and from 63% to 66% in boceprevir-treated patients [24,25,37]. Most HCV polymerase inhibitors have shown low to medium antiviral activities during monotherapy studies. Therefore, the future role of HCV polymerase inhibitors has yet to be determined, and SVR data from larger studies with triple combination therapies have to be awaited. Unlike protease inhibitors, which are mostly active in patients with HCV genotype 1 only, polymerase inhibitors bind to the highly conserved centre of the HCV polymerase, with the possible advantage of being equally effective for different HCV genotypes. With the addition of new antiviral compounds to standard therapy, a number of additional side effects unrelated to SOC have been observed, and increased treatment discontinuation rates have been reported. In addition, frequent dosing intervals (i.e. three times daily) may lead to increased non-adherence outside of clinical trials, and more patientfriendly formulations need to be developed. One of the major challenges of future anti-HCV treatment regimens will be the emerging field of DAA drug resistance. Relatively low genetic barriers to resistance have been reported for HCV protease inhibitors and non-nucleoside polymerase inhibitors as compared with nucleos(t)ide HCV polymerase inhibitors, which appear to have a high genetic barrier to resistance [9]. However, HCV eradication may not be achieved by monotherapy with either substance group, and drug combinations with non-cross-resistance patterns have to be further evaluated. In addition, pre-existing resistant variants and their potential long-term persistence have to be taken into account for the selection of optimal treatment and retreatment strategies. Although the addition of PEG-IFN-a and RBV substantially reduces the frequency of viral breakthrough caused by resistance development,

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combinations of different classes of DAA agents may eventually replace interferon-based regimens. Several trials addressing this issue are currently underway. In addition, the future of hepatitis C therapy will probably involve individually tailored treatment durations, based on viral kinetics, IL28B polymorphisms and other parameters. Besides compounds that target HCV polyprotein processing or HCV replication, inhibitors of HCV entry and host cell-targeting inhibitors (e.g. cyclophilin inhibitors) represent further interesting strategies for future anti-HCV therapies. Indeed, the cyclophilin inhibitor alisporivir (Debio 025) has exhibited substantial antiviral efficacy with and without SOC in early clinical trials. As interferon and RBV are likely to remain the backbone of anti-HCV therapy in the near future, the development of new interferon formulations is also underway, and preliminary study results have shown that these may facilitate antiviral therapy without providing additional antiviral efficacy.

Transparency Declaration C. Sarrazin has served as a clinical investigator, consultant and/or member of speakers’ bureaus for Abbott, BMS, Boehringer Ingelheim, Gilead, Merck, Novartis, Roche, Tibotec, and Vertex. J. Vermehren has nothing to disclose.

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