HCV New Drugs: Current Prospects for Interferon-free Treatment of Hepatitis C in 2012

Updated Article - 2017
Novel emerging treatments for hepatitis C infection: a fast-moving pipeline

2013
Journal of Gastroenterology and Hepatology

Current Prospects for Interferon-free Treatment of Hepatitis C in 2012

Catherine AM Stedman

J Gastroenterol Hepatol. 2013;28(1):38-45.

Source - Medscape

Abstract and Introduction
Abstract
Present interferon-based therapy for chronic hepatitis C is limited by both efficacy and tolerability. Telaprevir and boceprevir are the first two direct-acting antiviral drugs (DAAs) that inhibit hepatitis C virus replication to be licensed for use in conjunction with pegylated interferon and ribavirin. Numerous other DAAs are in clinical development, and phases 2 and 3 trials are evaluating interferon-free combination DAA therapy. Interferon-free sustained virologic responses have now been achieved with combinations of asunaprevir and daclatasvir; sofosbuvir and ribavirin; sofosbuvir and daclatasvir; faldaprevir and BI207127; ABT-450, ritonovir and ABT-333; ABT-450, ritonovir and ABT-072; miracitabine, danoprevir and ritonavir; and alisporivir and ribavirin. Some drugs are genotype-specific in their activity, whereas others are pan-genotypic, and differential responses for the genotype 1 subtypes 1a and 1b have emerged with many DAA combinations. Viral breakthrough and resistance are important considerations for future trial design. The prospect of interferon-free combination DAA therapy for hepatitis C virus is now finally becoming a reality.

Introduction
Interferon has been the mainstay of chronic hepatitis C (CHC) treatment for the past two decades. Combination therapy with pegylated interferon alpha (PEG-IFN) and ribavirin (RBV) has resulted in sustained virologic response (SVR) of up to 40–50% for genotype 1 and up to 70–80% in genotypes 2 and 3 in clinical trials.[1,2] However, interferon is often poorly tolerated, and recent "real-life" studies have found SVR rates approximately 20% lower than those reported in clinical trials among patients who initiated treatment for CHC.[3] Interferon-based treatment therefore has both limited tolerability and efficacy.

Over the last decade, advances in the understanding of the hepatitis C virus (HCV) life cycle have led to the development of many direct-acting antiviral (DAA) agents. Telaprevir and boceprevir, linear inhibitors of nonstructural protein 3/4A (NS3/4A) serine protease, were approved for HCV treatment in the United States and Europe in 2011. When combined with PEG-IFN and RBV, these drugs are effective in treatment of genotype 1 HCV, with SVR rates of 73% and 67%, respectively, in treatment-naïve genotype 1 patients.[4,5] These drugs are not able to be used as monotherapy because of the rapid development of virologic breakthrough.[6,7] Their dosing regimens require 8-h dosing, specific dietary requirements and care regarding drug interactions, and they also confer additional toxicity, particularly cytopenias and rashes, so the tolerability from the patient perspective is challenging when combined with PEG-IFN and RBV.[4,5]

It is important to remember that phase 3 trial results reflect highly selected subsets of patients. Emerging data from expanded access programs indicate that the "real-life" experience of treating compensated cirrhotics with protease inhibitor-based triple therapy is of a high rate of serious adverse events (38–48%), including severe anemia, liver decompensation and sepsis.[8] Although telaprevir and boceprevir represent a major therapeutic advance, there remains a large unmet medical need for interferon-free therapy, and this future lies in the DAA drugs. This review will focus on the major prospects for interferon-free therapy over the next few years.

Classes of HCV DAA Drugs in Clinical Development
DAA drugs are directed at multiple targets in the HCV life cycle. The major targets are listed in Table 1, and some of the DAAs currently in phases II or III clinical trials are listed in Table 2. Briefly, the major HCV targets include the following: the NS3/4A protease, which is involved in post-translation processing of HCV polyproteins; the NS5B RNA-dependent RNA polymerase that is required for copying the HCV-RNA genome and transcribing messenger RNA; and the NS5A enzyme that is also involved in HCV viral replication, although its functions are somewhat less clear. In addition to DAAs that target the HCV replication directly, there are also molecules that target host cell proteins that are involved in the HCV life cycle, including cyclophilin inhibitors.^[9,10]

The major challenge to development of an all-oral, interferon-free treatment for hepatitis C is drug resistance. HCV circulates as quasispecies, a mixture of viruses with heterogeneous virus sequences. It has been estimated that pre-existing drug resistance variants with one, two, three and even four mutations may be present in most HCV-infected patients and account for the rapid development of drug resistance on exposure to DAAs. The emergence of clinically relevant, drug-resistant variants depends on several factors, such as the potency of the drug, the genetic barrier to resistance and the replication fitness of the resistant virus.^[11,12] It has been suggested that for successful interferon-free treatment, it is necessary to use several DAAs concurrently, and each of these should have potent antiviral activity, possess nonoverlapping resistance profiles, and have limited or manageable drug interactions and minimal adverse effects.^[11,13]

**Table 1. Classes of drugs in development for hepatitis C**
Drug class	Mechanism of action	Advantages	Disadvantages
NS3/4A protease inhibitors		—	—
First generation	NS3/4A protease involved in post-translation processing of HCV polyproteins	Potent inhibitors of HCV genotype 1	Low genetic barrier to resistance Cross-resistance is extensive between different compounds in class Drug interactions (CYP)
Second generation	NS3/4A protease involved in post-translation processing of HCV polyproteins	Pan-genotypic antiviral activity	Higher genetic barrier to resistance than first-generation PIs; activity against many substitutions that cause resistance in first-generation PIs
NS5B polymerase inhibitors	NS5B RdRp is required for copying HCV-RNA genome and transcribing mRNA	—	—
Nucleoside inhibitors	Analogs of natural substances; bind active site of RdRp; terminate viral RNA chain generation	High barrier for resistance Pan-genotypic	Fewer in pipeline
Non-nucleoside inhibitors	Bind various allosteric sites, inducing conformational change in polymerase	Multiple target sites identified Low/medium antiviral efficacy Active against genotype 1	Low genetic barrier HCV genotype-/subtype-dependent
NS5A inhibitors	Bind domain I of NS5A protein, exact role in viral replication is unclear	High potency Potential activity against multiple genotypes	Low genetic barrier to resistance
Cyclophilin Inhibitors	Target host cyclophilin enzyme; functional regulator of HCV replication	Good potency Pan-genotypic High barrier to resistance	Drug interactions

CYP, cytochrome P450; HCV, hepatitis C virus; mRNA, messenger RNA; PI, protease inhibitor; NS, nonstructural protein; RdRp, RNA-dependent RNA polymerase; —, no drugs in this class in this phase of development.

**Table 2. Hepatitis C virus direct-acting antiviral therapy agents in clinical development in phases II/III clinical trials**
	Phase 2	Phase 3	Licensed
NS3/NS4A protease inhibitors
First generation	Danoprevir/r* (RG7227) Sovaprevir (ACH-1625) GS-9256 GS-9451 ABT-450/r* Vaniprevir (MK7009)	Simeprevir (TMC435) Faldaprevir (BI201335) Asunaprevir (BMS-650032)	Boceprevir Telaprevir
Second generation	MK-5172
NS5B polymerase inhibitors
Nucleos(t)ide analogs	Mericitabine (RG7128); IDX-184 PSI-7851	Sofosbuvir (GS-7977)	—
Non-nucleos(t)ide analogs	VX-222 BMS-791325 ABT-333 ABT-072 Setrobuvir(ANA598) BI207127 Filibuvir IDX375 VCH-916 [tegobuvir (GS-9190)]	—	—
NS5A inhibitors	ABT-267 GSK2336805 GS-5885	Daclatasvir (BMS-790052)	—
Cyclophilin	NIM-811; SCY-635	[Alisporivir]	—

NS, nonstructural protein; —, no drugs of this class in this phase of development; /r*, ritonavir-boosted.

Clinical Trials of DAA Combinations
Initial DAA combinations

Table 3 summarizes the key clinical trials of interferon-free DAA therapy for HCV. The first proof of concept study of combination DAAs was the INFORM-1 study undertaken in Australia and New Zealand, which demonstrated that mericitabine (NS5B nucleoside polymerase inhibitor) and danoprevir (NS3/4 protease inhibitor) in combination produced potent viral suppression in patients with genotype 1 CHC with 13–63% of treatment-naïve and 25% of null responders having, undetectable HCV-RNA by day 14. No viral breakthrough was found during the study, suggesting that mericitabine, which has a high genetic barrier to resistance, may have prevented the emergence of resistance to danoprevir.^[14] Patients in this study were subsequently treated with PEG-IFN and RBV.

Several studies subsequently evaluated short-term combinations of macrocyclic NS3/4A protease inhibitors with non-nucleoside NS5B polymerase inhibitors, also with follow-on PEG-IFN/RBV treatment. The combination of BI207127 with faldaprevir (BI201335) and RBV resulted in a week 4 rapid viral response (RVR) of 73–100%, with viral breakthrough only in the arm with low-dose NS5B inhibitor.^[15] In contrast, low rates of RVR were seen when tegobuvir was combined with GS-9256 in the absence of RBV, with high rates of virologic breakthrough, highlighting the importance of RBV in this DAA regimen. High RVR rates of 100% were seen, without virologic breakthrough, when PEG-IFN and RBV were added to this drug combination in a quadruple therapy regimen.^[16]

Asunaprevir/Daclatasvir Combination Therapy
The first successful reports of SVR using interferon-free dual DAA therapy were with asunaprevir (NS3/4A protease inhibitor) and daclatasvir (NS5A inhibitor).^[17,18] Both included patients with genotype 1 CHC and prior null response to PEG-IFN/RBV. The first study compared a dual therapy regimen with a quadruple therapy regimen (dual + PEG-IFN + RBV) for 24 weeks. While the 90% SVR 24 weeks post-treatment (SVR24) rates in the quadruple arm are impressive, the 36% SVR rate in the dual therapy arm was proof of concept that combination DAA therapy can successfully treat HCV without PEG-IFN/RBV.^[17] The second study of dual therapy in Japanese patients with genotype 1b HCV resulted in a 100% SVR rate in all 10 patients, including one patient who discontinued treatment at week 2.^[18] Preliminary data from another study of this regimen in genotype 1b patients resulted in SVR 12 weeks post-treatment (SVR12) rates of 90% in prior null responders and 64% in interferon ineligible/intolerant patients.^[19] The latter two studies were exclusively in genotype 1b, and in the first paper, both genotype 1b patients were cured compared with only two of nine genotype 1a patients.^[17] This suggests that this regimen has promise for treatment of genotype 1b CHC but may have less efficacy in patients with genotype 1a HCV.

Sofosbuvir/RBV
The ELECTRON study evaluated sofosbuvir, a NS5B pyrimidine nucleotide inhibitor, in combination with RBV initially in treatment-naïve patients with genotypes 2 and 3 CHC. In the first four cohorts, all patients received sofosbuvir 400 mg once daily, plus RBV twice daily for 12 weeks. Groups 1–3 received PEG-IFN for 4, 8, and 12 weeks, respectively. Among the 40 patients randomized, SVR24 was achieved by 100% of patients, irrespective of whether they received PEG-IFN or not. Two additional cohorts of genotypes 2 and 3 patients received sofosbuvir monotherapy for 12 weeks or sofosbuvir plus PEG-IFN and RBV for 8 weeks, with SVR24 rates of 60% and 100%, respectively, suggesting that RBV is important in preventing relapse after treatment.^[20] These data suggest that genotypes 2 and 3 CHC can be successfully treated with a 12-week all-oral regimen of sofosbuvir and RBV; however, these are small numbers of patients, and phase 3 results are awaited.

Sofosbuvir has pan-genotypic activity against the HCV virus, and two groups of patients with genotype 1 HCV were also treated with the sofosbuvir/RBV 12-week regimen, 10 with null response to prior treatment and 25 treatment-naïve patients. Eighty-four percent of genotype 1 treatment-naïve and 10% of null responders achieved SVR12. Of those with genotype 1 infection, 89% had genotype1a HCV, which is associated with lower response rates to telaprevir or boceprevir-based triple therapy than genotype 1b infection. Additionally, 63% of patients carried the non-CC interleukin-28B (IL28B) genotypes (CT or TT) that also correlate with poor response to PEG-IFN/RBV treatment. These data suggest that sofosbuvir and RBV are also likely to form the backbone of next generation of treatment for genotype 1 HCV.^[20]

Preliminary results have also been reported from a phase 2a study evaluating sofosbuvir and daclatasvir +/− RBV for 24 weeks in treatment-naïve patients with HCV genotypes 1–3. SVR4 rates ranged from 88% to 100% in genotypes 2 and 3, and 83% to 100% in genotype 1, and SVR4 of 95% was reported for a 12-week regimen.^[21] Sofosbuvir data show high levels of concordance between SVR4 and SVR24 results,^[22] so it is likely that this also represents a promising combination.

NS3/4A Protease Inhibitor and NS5B Polymerase Inhibitor Combinations
Several studies have examined the efficacy of dual therapy combinations of NS3/4A inhibitors with non-nucleoside polymerase inhibitors, with or without RBV. Two curative-intent studies including a study arm of dual therapy without RBV have presented preliminary data, showing high rates of viral breakthrough or relapse in arms without RBV. The Vertex ZENITH study originally had two dual therapy arms (Vx222 + telaprevir without RBV); these arms were both terminated early because of high rates of viral breakthrough up to 31% in arm B. However, in the quadruple therapy arms (including PEG-IFN/RBV), SVR12 rates greater than 80% were obtained using a response-guided therapy approach.^[23,24]

In the SOUND-C2 study, patients in the RBV-free arm achieved markedly lower SVR12 rates of 39% overall, and no patients achieved SVR in the genotype 1a/IL28B non-CC group without RBV. SVR rates in the arms with faldaprevir + BI207127 + RBV ranged from 56% to 68%. In a pooled analysis, the genotype 1a/IL28B CC/all genotype 1b HCV patient group (with favorable characteristics) demonstrated SVR rates of 62–82%, whereas those with unfavorable features (1a IL28B non-CC HCV patient group) achieved SVR rates of only 32–42%.^[25]

Two studies of ABT-450 (NS3/4A protease inhibitor) boosted with ritonavir have shown promising results when combined with non-nucleoside polymerase inhibitors and RBV. When ABT-450 + ABT-333 + RBV were combined in genotype 1 treatment-naïve patients (88% G1a), the SVR12 were 93–94% and 47% in a third group who were treatment-experienced.^[26] In a smaller study restricted to G1, treatment-naïve patients with IL28B-CC genotype ABT-450 + ritonavir + ABT-072 + RBV resulted in SVR24 of 91%, although there was one additional late relapse by week 36.^[27]

These results demonstrate that inclusion of RBV in these regimens is essential to reduce the risk of viral breakthrough. Even when RBV is used, viral breakthrough and resistance are a significant issue with some drug combinations, particularly in HCV genotype 1a, and it is also apparent that there are marked differences in therapeutic outcomes between different drugs within the same class.

Interim results from the INFORM-SVR study, using mericitabine (nucleoside polymerase inhibitor) and ritonavir boosted danoprevir in G1 HCV have proved disappointing. Randomization to the 12-week treatment arm was stopped prematurely because of unacceptable relapse rates, and patients assigned to 24 weeks of treatment in arm B were offered follow-on PEG-IFN and RBV. SVR12 rates of 41% have been reported for arm A, with a large differential between genotypes 1a and 1b. This combination only appears to have a promise in genotype 1b.^[28]

Cyclophilin Inhibitors
Alisporivir is a host-targeting antiviral with pangenotypic anti-HCV activity. Interim results have been presented from a phase 2b trial of genotypes 2 and 3 patients with 46–49% RVR in those receiving dual therapy (alisporivir + RBV); patients with RVR continued with interferon-free therapy, and patients with detectable week 4 HCV-RNA continued with alisporovir + PEG-IFN + RBV. Overall SVR rates of 77–83% are reported.^[29] However, the clinical trial was halted by the Food and Drug Administration (FDA) after three cases of pancreatitis.

Significance of Il28B Genotype
IL28B genotype influences response to PEG-IFN and RBV combination therapy,^[30,31] but the impact on treatment outcomes in the DAA era is less clear. In the INFORM-1 study, IL28B genotype did influence early viral kinetics, and patients with the CC genotype had slightly greater reduction in HCV viral load during 14 days of interferon-free treatment.^[32] In both curative studies of prior null responders treated with asunaprevir and daclatasvir, 80–90% of patients carried IL28B CT or TT genotypes, but these did not appear to impact outcomes.^[17,18] Several other studies have shown no significant difference in outcomes based on IL28B genotype,^[20,26] although the SOUND-C2 study has shown some difference in subgroup analysis results when stratified by IL28B.^[33] Overall, IL28B genotype appears to have less impact on SVR rates relative to differences observed between HCV G1a and G1b patients.

Resistance
It is well established that monotherapy with NS3/4A protease inhibitors results in rapid development of viral breakthrough and resistance. Additionally, some second-generation NS3/4 protease inhibitors will have cross-resistance with some of the most common mutations associated with resistance seen with telaprevir and boceprevir. These are specifically the R155K and D168A mutations that have now shown cross-resistance to faldaprevir, simeprevir, asunaprevir, GS9451 and ABT-450.^[34]

This means that telaprevir and boceprevir need to be used with care because of the risk of cross-resistance.

DAAs are often used in combination in order to increase antiviral activity and also to attempt to reduce the risk of viral breakthrough. The activity of the DAA does have an impact on the development of resistance as resistance is less likely if the viral load rapidly drops down to undetectable. However, the genetic barrier to resistance of the individual DAA drugs appears to be more important in terms of the risk of resistance developing. When two drugs with a low barrier to resistance are combined in curative-intent trials (e.g. NS3/4A protease inhibitors and non-nucleoside polymerase inhibitors), the combination of two does not result in a higher barrier to resistance than each drug used alone, and breakthrough occurs rapidly.^[10,16,25] Strategies to overcome this can include addition of other drugs such as PEG-IFN or RBV, or combination with a drug that has a high barrier to resistance, such as the nucleoside analogues that in general have a high barrier to resistance.^[35]

Emerging data show that RBV continues to have an important role in interferon-free DAA regimens. When two agents with a low barrier to resistance are combined, the addition of RBV accelerates the HCV-RNA level decline, delays emergence/selection of resistance and results in a greater proportion of patients achieving an RVR, as well as reducing the incidence of relapse after therapy and thereby improving SVR.^[11,18,20] The exact mechanism by which RBV prevents relapse when added to interferon or DAA agents remains uncertain. The role of RBV has not been studied in all new DAA combinations, for example, whether RBV would also be synergistic in the daclatasvir/asunaprevir combination has not yet been established.

Genotypes 1a and 1b subtypes do result in differential responses to DAA combinations that include an NS3/4A protease inhibitor, with SVR rates for genotype 1b typically at least double those of genotype 1a.^[17,25,28] The barrier to resistance for protease inhibitors is relatively low, and lower for genotype 1a as opposed to genotype 1b because the 1a virus only requires one mutation to generate resistance to protease inhibitors, whereas the 1b virus requires two mutations in order to generate a significant resistance variant. Viral breakthroughs because of the selection of NS5A inhibitor-resistant variants have also been described more commonly in genotype 1a than 1b, and differential antiviral effects have also been described for some non-nucleoside polymerase inhibitors.^[10]
In general, the nucleoside/nucleotide analogs have a high barrier to resistance^[35] and are very potent. In the ELECTRON study of sofosbuvir, no differential was observed between genotypes 1a and 1b, and no resistance was seen despite 89% of subjects being the unfavorable genotype 1a population in the study.^[20] However, viral breakthrough has been described with mericitabine in the INFORM-SVR study,^[14] demonstrating that there are clearly differences between drugs of this class.

Cirrhosis
There is a paucity of data regarding the effectiveness of DAA combination therapy in patients with established cirrhosis, as these patients tend to be excluded from early clinical trials. Treatment with interferon-based therapy is associated with reduced response rates and also a risk of decompensation during treatment. The SOUND-C2 study offers the first glimpse of DAA safety and efficacy in people with compensated cirrhosis.^[33] A group of 37 SOUND-C2 participants (or 10%) had cirrhosis; more than half (n = 25) had HCV genotype 1b. Overall, the SVR-12 was 54–57%, with higher SVR-12 in HCV genotype 1b than HCV genotype 1a in some treatment arms. The Gilead Phase 2 SPARE study of sofosbuvir and RBV includes some patients with cirrhosis, and interim data suggest a higher relapse rate (especially in the low dose RBV group) than seen in the ELECTRON study, but final data is pending.^[36] Phase 3 data should provide further information on efficacy in patients with cirrhosis.

Toxicity
Ideally, interferon-free DAA combination therapy will reduce toxicity associated with HCV treatment as well improving efficacy. It is clear that protease inhibitor-based triple therapy with PEG-IFN and RBV increases overall toxicity, particularly skin rashes and cytopenias.^[4,5] Transient bilirubin elevations are frequently observed in patients taking NS3 serine protease inhibitors associated with a class effects on bilirubin transporters,^[16] and bilirubin elevations have also been reported with alisporivir.^[29] Gastrointestinal side effects, jaundice and anemia have been reported with some DAA combinations.^[18,25] The ongoing requirement for RBV in many of these regimens will continue to cause some anemia and rashes, although it appears that the severity of anemia is less severe when RBV is not used in conjunction with PEG-IFN.^[20]

Although the nucleotide polymerase inhibitors and other classes of new DAAs have great potential, it should be noted that a significant number of drugs have been developed but had their development halted because of toxicity. Some recent examples include discontinuation of development of BMS-986094 (cardiac and renal toxicity), GS −938 (liver test abnormalities); the non-nucleoside polymerase inhibitor tegobuvir (serious adverse events) and trials of the cyclophilin inhibitor alisporivir have been halted because of pancreatitis.

Long-term Durability
Late viral relapse (recurrence of HCV-RNA in serum after week 24 of follow-up) has been reported in one study to date, occurring at week 36 after treatment.^[27] One patient in another study had detectable HCV-RNA transiently at week 48 but was again undetectable 43 days later.^[17] The FDA have required that all patients in DAA trials be followed up for 3 years after therapy because the long-term durability of SVR after DAA combination therapy has not yet been established.

Conclusions
This is a very exciting time for the field of CHC. There are many potential therapeutic options for treatment, and it is not yet clear whether there will be a single major treatment option used for all genotypes of HCV (perhaps a single DAA combined with RBV), or whether there will be an individualized therapeutic approach that considers viral genotype, IL28B genotype, resistance mutations and other factors in planning a treatment for each patient. Many phase 3 trial results are pending. Key challenges include fully evaluating optimal combinations of drugs for different genotypes further elucidating the role of RBV, optimizing durations of treatment and also careful development of new treatments in order to minimize the risk of development of drug resistance. If these things are done well, then there may be a truly realizable goal of providing curative management for the majority of patients with HCV who are treated.

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