Interferon-free Regimen for Hepatitis C Advances-ABT-450/ABT-333/ABT-267/ribavirin

Medscape Medical News > Conference News

Interferon-free Regimen for Hepatitis C Advances

Neil Canavan

Jul 11, 2013

KUALA LUMPUR, Malaysia — A new interferon-free drug regimen for the treatment of hepatitis C is safe and effective in treatment-naïve patients and in those who previously had a poor response to treatment, according to the phase 2b AVIATOR trial.

The direct-acting antiviral combination, manufactured by AbbVie Pharmaceuticals, consists of the protease inhibitor ABT-450, the non-nucleoside NS5B polymerase inhibitor ABT-333, and the novel NS5A inhibitor ABT-267. When used in combination with ribavirin, it reportedly produces sustained virologic response rates of up to 99% in patients with hepatitis C.

Barry Bernstein, MD, vice president of infectious disease at AbbVie, and his team evaluated the safety and efficacy of this interferon-free regimen in combination with ribavirin to determine whether toxic events would lead to dose reductions in ribavirin and whether that would have any effect on treatment outcome.

Ribavirin is a key component of effective hepatitis C treatment, but often it cannot be used at optimum therapeutic levels when combined with interferon — the current standard of care.

Dr. Bernstein presented the results here at the 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention. 

In the AVIATOR trial, first presented last year at the annual meeting of the American Association for the Study of the Liver Diseases, patients were treated with the interferon-free combination with or without ribavirin for 12 or 24 weeks.

In the study cohort, 159 patients were treatment-naïve and 88 were previous nonresponders to ribavirin. Median age was 50 years, and was 86% of the cohort was white. All patients had chronic infection with hepatitis C genotype 1 and plasma HCV RNA levels above 50,000 IU/mL.

The primary end points were safety and sustained virologic response at 24 weeks.

Four patients (1.6%) discontinued treatment because of adverse events, 1 patient experienced a serious adverse event (arthralgia), and 16 patients (6.5%) had hemoglobin levels below 10 g/dL.

In 24 of the 247 (10%) patients, the dose of ribavirin was reduced because of adverse events. Of these, 20 were treatment-naïve and 4 were previous nonresponders.

The incidence of ribavirin dose reductions was similar in the 12- and 24-week treatment groups.

The most common adverse events were anemia, with 10 events reported, and fatigue, with 3 events reported. Other events, with 2 reports each, were diarrhea, dizziness, and pruritus.

There were more adverse events in treatment-naïve patients than in nonresponders.

All 24 patients whose dose of ribavirin was reduced achieved a sustained virologic response at 24 weeks. For those without a dose reduction, 92.1% of the treatment-naïve patients and 94.0% of the nonresponders achieved a sustained virologic response at 24 weeks

"Significantly, ribavirin dose reduction occurred less frequently than in previous studies of peg-interferon-containing regimens," said Dr. Bernstein. As important, he noted, is the fact that when dose reductions did occur, response rates were not negatively affected.

Toward Interferon-free Treatment

Preliminary trials to determine drug–drug interactions with HIV medications are near completion, and a trial of this drug combination in patients coinfected with HIV and hepatitis C will start soon, Dr. Bernstein said.

These results, if they hold up, will be very significant for people coinfected with HIV and hepatitis C, said Tom Campbell, MD, a principal investigator of the Colorado AIDS Clinical Trial Unit. "The exciting thing is that they don't require the use of interferon, which is very poorly tolerated, particularly in people with coinfection."

The need for interferon-free regimens is clear. "We have patients who are waiting for new drugs before they are willing to be treated, particularly those who have less advanced hepatitis C infection who don't need immediate treatment," Dr. Campbell explained. He acknowledged that "it will be a few years before these drugs are approved for HIV and hepatitis C coinfection, so it is a bit of a gamble to wait."

However, he understands the reluctance of these patients to be treated now. "It's a decision that the patient should make in consultation with their care provider."

Dr. Bernstein is an employee of AbbVie Pharmaceuticals. Dr. Campbell has disclosed no relevant financial relationships.

7th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention: Abstract TUAB0103. Presented July 2, 2013.

http://www.medscape.com/viewarticle/807674

The State Of The Hepatitis C Pill Race: Gilead Vs. AbbVie

Investment commentary

The State Of The Hepatitis C Pill Race: Gilead Vs. AbbVie

 

Jun 20 2013

Peter Geschek

Gilead Sciencies (GILD) is believed to be leading the hepatitis C pill race, but AbbVie (ABBV) is not far behind. According to Scott Brun, AbbVie's head of pharmaceutical development, AbbVie may even win the race.

In June, at the Goldman Sachs Annual Global Healthcare Conference, he said:

"I'll say that it is a very tight race and like I said we're executing extremely well and I think we've got a very good shot at being first, but it's close."

Gilead

In a Phase II trial, Gilead's all-oral hepatitis C treatments sofosbuvir and ledipasvir, an NS5A inhibitor, cured 95 percent of patients after eight weeks of the therapy.

Sofosbuvir, which Gilead acquired in 2012 in the famous $11 billion acquisition of Pharmasset, has proved itself in four completed Phase III studies.

In May, following the encouraging interim results from a Phase II trial of sofosbuvir and ledipasvir, Gilead Sciences announced plans for a Phase III trial of a fixed dose of the two drugs. Called ION-3, the study will test a once-daily fixed-dose combination therapy of the two drugs both with and without ribavirin for eight weeks, as well as without ribavirin for 12 weeks. Six hundred non-cirrhotic, new-to-treatment patients with genotype 1 of the virus will participate in the trial.

In June, Gilead received a priority review designation from the FDA, a step that can save about four months in the approval process.

Confident in approval, Gilead is getting ready for the launch of sofosbuvir in the first quarter of 2014 in the U.S. and the second quarter in Europe by preparing sales teams and arranging training opportunities for physicians.

AbbVie

According to Brun, Gilead's advantage is overstated.

AbbVie is running 6 Phase III trials in 30 countries around the world with over 2200 patients.

It is running a dedicated study in cirrhotic patients, who are the hardest to treat of all. Cirrhosis means the liver is scarred, and it functions poorly. Cirrhosis is considered the final stage of chronic liver disease. AbbVie's treatment represents a possible cure, even for these hard-to-treat patients.

AbbVie's HCV portfolio includes experimental medicines with three different mechanisms of action. The compounds in the studies are ABT-450/r (protease inhibitor and ritonavir), ABT-267 (NS5A inhibitor) and ABT-333 (non-nucleoside polymerase inhibitor).

AbbVie's treatment will require three pills in the morning and one at night, according to Brun. In a Phase II trial with the drugs, 90 percent of patients who completed the eight-week regimen had the virus cleared from their body.

Some analysts consider AbbVie's treatment cumbersome compared to Gilead's because it requires four pills a day. But according to Brun, this is a very manageable regimen when you consider the situation of the HIV infected patients who receive Ritonavir (AbbVie's drug for HIV) boosted regimens for a lifetime on a much more complicated schedule. It is a matter of patient education.

AbbVie also is working on next generation programs already: ABT-493 is a protease inhibitor and ABT-530 is an NS5A inhibitor, both with very favorable pharmacologic characteristics, and neither will need Ritonavir boosting.

AbbVie also testing a regimen in Japan for genotype 1b patients requiring two pills once a day for 12 weeks with no Ribavirin. It is using the co-formulation of the ABT-450 and ABT-267 with Ritonavir. This combination is also being prepared for western markets.

Combos

Competitiors to Gilead and AbbVie, including Medivir (MVRBF.PK), Johnson & Johnson (JNJ), Bristol-Myers Squibb (BMY), Merck (MRK) and Vertex Pharmaceuticals (VRTX), among others, are all developing new oral hep C treatments.

The major challenge to development of an all-oral, interferon-free treatment is drug resistance.

Hep C circulates in the blood as a mixture of viruses with various sequences. It has been estimated that pre-existing drug resistance variants with one, two, three and even four mutations may be present in most hep C-infected patients and account for the rapid development of drug resistance on exposure to direct-acting antiviral drugs.

For a successful treatment it maybe necessary to use several direct-acting antiviral drugs in combination, and each of the components in a combination should have potent antiviral activity, possess non-overlapping resistance profile, and have limited or manageable drug interactions combined with minimal adverse effects.

There are a great number of combos tested in clinical trials.

Medivir has posted stellar interim data from its Phase 2a study of its hep C treatment simeprevir combined with Gilead's sofosbuvir. Medivir is a Swedish company working in partnership with Johnson & Johnson on this project. The combo therapy cleared the virus in 100 percent of genotype 1 patients.

Vertex's drug is also testing its experimental drug, VX-135 with Medivir's simeprevir.

While Gilead is unlikely to pursue a partnership with Medivir and J&J since the company is developing a combination of its own therapies, doctors may prescribe the pair off-label, provided the price is reasonable and payers are willing to pay for it.

Investors' summary

The hep C market is bigger than HIV.

Intravenous drug use, dirty tattoo parlors, tainted blood transfusions and carriers infecting offspring are some of the ways that millions of people around the world have contracted hepatitis C.

Hepatitis C attacks the liver and can lead to liver cancer. The virus affects about 150 million people worldwide and the market for new pills is estimated at $20 billion. Gilead's drug is projected to have annual sales of $6.03 billion by 2016, according to an average of 10 analysts estimates compiled by Bloomberg.

The introduction of pills will increase the overall market. Gilead estimates that 150,000 patients may seek treatment in the U.S. when these new drugs hit the market, which compares to the current 85,000 patients.

For both Gilead and AbbVie, a success in the hep C market is vitally important.

Gilead acquired Pharmasset in the 2011 buyout for about $11 billion, and at that time, some analysts believed that wager to be way too high. Now investors are anxious to see a return on it.

AbbVie currently is getting most of its earnings from its arthritis drug Humira, the world's best-selling drug, which is facing a patent expiry in several years, and a success with the hep C therapy would go a long way in strengthening its pipeline.

The prize each competitor in the race hopes to win is huge: a share of a $20 billion market. There is tremendous pent-up demand for oral therapies that can quickly wipe out hep C without using interferon.

At the Goldman Sachs conference, an analyst asked Abbvie if it is planning to challenge Gilead on the drug's price since Gilead has a much higher cost base as a result of having purchased Pharmasset for billions. The answer was that Abbvie does not price its products in this manner, and its pricing is based on estimating the value to the patients.

In the hep C race, "Gilead will be first, AbbVie will be on roughly the same timeline, Bristol-Myers will be somewhere after that," said Marshall Gordon, a New York-based analyst with Legg Mason Inc.'s ClearBridge Investments affiliate.

"To be fair, Gilead's drug looks better, but not that much better," Gordon said.

Source - Seeking Alpha

Source: The State Of The Hepatitis C Pill Race: Gilead Vs. AbbVie

http://seekingalpha.com/article/1513452-the-state-of-the-hepatitis-c-pill-race-gilead-vs-abbvie?source=feed

Related
Drew Armstrong @ Bloomberg  - Jun 13, 2013 : AbbVie Says It Can Be First With All-oral hepatitis C drugs

All-Oral Regimens Work in HCV

All-Oral Regimens Work in HCV

By Michael Smith, North American Correspondent, MedPage Today

Published: March 05, 2013
Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania

ATLANTA – All-oral regimens under investigation for hepatitis C virus (HCV) were able to cure up to 95% of patients who had never been treated for the virus, a researcher said here.

Action Points

Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Note that in these two open label studies, excellent HCV cure rates were attainable in treatment-naive patients using various all-oral regimens.

Be aware that cure rates were significantly worse in patients who had failed prior therapy.

But in combined 48-week data from two small clinical trials, only 47% of people who had previously had unsuccessful HCV therapy were cured, according to Eric Lawitz, MD, of the University of Texas Health Science Center in San Antonio.

On the other hand, treatment only lasted 12 weeks, the regimens were well-tolerated, and the handful of relapses took place soon after the end of therapy, Lawitz reported at the Conference on Retroviruses and Opportunistic Infections.

The key element of the trials – which actually tested two slightly different 4-drug regimens – was that patients were not given pegylated interferon, a backbone of standard HCV therapy that is difficult to tolerate and has dangerous side effects.

"We're in a state of paradigm shift," Lawitz told reporters before presenting the data, "in transition from interferon to the era of DAAs" – direct-acting agents that target HCV directly, rather than boosting the immune system, as interferon does.

His analysis looked at outcomes after treatment with regimens based on ribavirin and ABT-450, an NS3/4A protease inhibitor that is co-administered with ritonavir (Norvir). The drugs were combined with one of two non-nucleoside inhibitors of the HCV NS5B polymerase, ABT-072 or ABT-333.

The initial trial included 11 treatment-naïve patients with genotype 1 HCV, who were given 12 weeks of therapy with ribavirin, ABT-450/ribavirin, and ABT-072.

The second trial substituted ABT-333 for ABT-072 and had three cohorts – two with treatment-naïve patients who got different doses of ABT-333 (150 or 250 milligrams daily), and one with people who had previously failed interferon-based therapy, who also got the lower dose of ABT-333.

The primary endpoint was the 24-week sustained virologic response (SVR24) -- the proportion of patients with undetectable virus 24 weeks after the end of therapy – that is usually regarded as a cure.

In the first trial, Lawitz reported that 91% of the patients reached the SVR24. In the second, the two treatment-naïve cohorts had SVR24 rates of 95% and 86%, while just 47% of those who had previously failed therapy before reached the milestone.

The IL28B polymorphism, which has variants that confer a greater risk of failing therapy, had no effect, Lawitz reported. Of the eight patients who relapsed, only two were among the treatment-naïve group and only one relapsed more than 12 weeks after the end of therapy, he reported.

There were no deaths or serious adverse events, he said, although one adverse event – an asymptomatic elevation in liver enzymes without any increase in bilirubin -- led to premature discontinuation by a treatment-naïve patient. The liver enzymes returned to normal after the drugs were stopped.

In addition, four patients had adverse events assessed as severe – hyperbilirubinemia, fatigue, pain, and vomiting – but none required interrupting the study drugs or stopping treatment, Lawitz reported.

One implication of the study might be that treating sicker patients will require more drugs or more time than treating people with less severe disease, commented Juergen Rockstroh, MD, of the University of Bonn, who was not involved in the study but who moderated the session at which it was presented.

"For easy-to-treat patients, two drugs (and ribavirin) will be just fine," he told MedPage Today. But in the previous null responders, he noted, less than half of the patients were cured.

"This is really saying that we're going to have interferon-free treatment for basically everyone who's treatment-naïve," Rockstroh said. What Lawitz's data suggest, he added, is that a more aggressive strategy will be needed for everyone else.

Primary source: Conference on Retroviruses and Opportunistic Infections
Source reference:
Lawitz E, et al "12 weeks of ABT-450/Ritonavir, non-nucleoside inhibitor and ribavirin achieved SVR24 in >90% of treatment-naive Hepatitis C Virus GT1 patients and 47% of prior non-responders" CROI 2013; Abstract 38.

The study was supported by Abbott. Lawitz reported financial links with Abbott, Achillion, Boehringer Ingelheim, BMS, Gilead, GSK, Idenix, Janssen, Merck, Novartis, Presidio, Roche, Santaris, and Vertex. Thomas made no disclosures. Rockstroh reported financial links with Abbott, Boehringer Ingelheim, BMS, Bionor, Gilead, Merck, Janssen, Tibotec, Vertex, GSK, ViiV Healthcare, and Pfizer

Source - http://www.medpagetoday.com/MeetingCoverage/CROI/37678

S.A. doctors find faster, better way to beat hepatitis

S.A. doctors find faster, better way to beat hepatitis
Jennifer R. Lloy, Express-News
Updated 11:41 pm, Monday, January 7, 2013

Two local physicians who studied therapies for liver-damaging hepatitis C have found that a new drug combination wipes out the virus quicker and without the harmful side effects of the current treatment. 

Poordad and Dr. Eric Lawitz, liver specialists and professors at the University of Texas Health Science Center, authored the study with several other physicians. It was published Thursday in the New England Journal of Medicine.

Abbott Laboratories created the two investigational drugs, preliminarily called ABT-450 and ABT-333, and funded the study of 50 South Texas patients, Poordad said...

Read more,,,,,

New therapeutic strategies in HCV: polymerase inhibitors

Review Article

New therapeutic strategies in HCV: polymerase inhibitors

 

Ludmila Gerber, Tania M. Welzel, Stefan Zeuzem^*

 

Article first published online: 3 JAN 2013

 

 

 

DOI: 10.1111/liv.12068

© 2012 John Wiley & Sons A/S

Issue

Liver International

 

Special Issue: Proceedings of the 6th Paris Hepatitis Conference, International Conference on the Management of Patients with Viral Hepatitis

 

Volume 33, Issue Supplements 1, pages 85–92, February 2013

 

Additional Information

 

How to Cite

Gerber, L., Welzel, T. M. and Zeuzem, S. (2013), New therapeutic strategies in HCV: polymerase inhibitors. Liver International, 33: 85–92. doi: 10.1111/liv.12068

Author Information

1. Klinikum der J.W. Goethe Universität, Frankfurt am Main, Germany
2.  Correspondence Stefan Zeuzem, MD, Professor of Medicine, Chief \x96 Department of Medicine I, J.W. Goethe University Hospital, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
   Tel: +49 (0)69 6301 6899 or 4544
   Fax: +49 (0)69 6301 6448

antiviral therapy;
hepatitis C;
non-nucleoside polymerase inhibitors;
nucleoside polymerase inhibitors

Abstract

The characterization of the viral life cycle facilitated the development of directly acting antiviral drugs. Among those, several inhibitors of the viral RNA-dependent RNA polymerase have proven effectiveness in clinical trials. The characteristics of different nucleos(t)ide and non-nucleoside polymerase inhibitors, as well as their clinical applications and combinations with other classes of directly acting antiviral drugs are reviewed herein.

 

Abbreviations
DAA directly acting antiviral

eRVR extended rapid virological response

HCV hepatitis C virus

HCC hepatocellular carcinoma

PEG-IFN pegylated interferon

PI protease inhibitors

RVR rapid viral response

RBV ribavirin

SOC standard of care

SVR sustained virological response

 

According to the World Health Organization (WHO), about 3% of the world's population has been infected with the hepatitis C virus (HCV). Of those, approximately 170 million are chronic HCV carriers at risk of developing cirrhosis and hepatocellular carcinoma (HCC) contributing to a large percentage of liver transplantations in Europe and the United States [1].

 

For almost a decade, the combination of pegylated interferon (PEG-IFN) and ribavirin (RBV) has been the standard of care (SOC) producing sustained virological response (SVR) rates of ~50% in treatment-naive patients infected with HCV genotype 1 and 70–90% in patients infected with HCV genotypes 2 and 3 [2]. Recently, this therapeutic backbone has been supplemented by the addition of first- generation protease inhibitors (Telaprevir, Boceprevir) directly targeting the viral NS3/4A protease. This ‘triple therapy’ improved SVR rates to 70–80% in treatment-naive patients infected with HCV genotype 1 [3, 4].

 

The development of directly acting antiviral (DAA) HCV therapeutics was facilitated by the adaptation of HCV to a cell culture system allowing the description of the HCV lifecycle and identification of potential novel drug targets. In addition to protease inhibitors (PI), these targets include inhibitors of the non-structural NS5A enzyme, a protein possibly involved in HCV replication, and nucleoside/nucleotide analogue and non-nucleoside inhibitors of the HCV RNA-dependent RNA polymerase (RdRp/NS5B) [5-7].

 

The following sections provide an overview of novel therapeutic strategies involving nucleoside/nucleotide analogue and non-nucleoside inhibitors of the HCV RNA-dependent RNA polymerase (RdRp/NS5B).

 

Function and biological role of the Hepatitis C Virus (HCV) polymerase inhibitor

A highly structured association of RNA and viral proteins, of cellular proteins and cofactors, and of rearranged intracellular lipid membranes derived from the endoplasmic reticulum are essential for replication of the viral RNA genome [8]. The key enzyme in this process is NS5B, a RNA-dependent RNA polymerase, catalysing the synthesis of a complementary negative-strand RNA by using the positive-strand RNA genome as a template. Numerous RNA strands of positive polarity are produced by NS5B activity from this negative-strand RNA and serve as templates for further replication and polyprotein translation [9].
 

Schematically, the NS5B protein has the shape of a right hand with an active site located within the palm domain and encircled of a thumb and a finger domain (Fig. 1). The thumb domains act as regulator of nucleic acid binding and the catalytic efficiency of the enzyme's active site, while the palm domains coordinate the function of the active site and carry out the nucleotidyl transfer reaction [10].
 

Figure 1. NS5B polymerase structure and molecular target sites. Ribbon model of the NS5B polymerase from PDB structure 2IJN. Palm, thumb and fingers are coloured in red, green and blue respectively, with finger loops coloured in yellow. Active site with bound inhibitor (blue space-filling model) and non-nucleoside inhibitor (NNI) sites 1–4 are indicated.

Figure 1. NS5B polymerase structure and molecular target sites. Ribbon model of the NS5B polymerase from PDB structure 2IJN. Palm, thumb and fingers are coloured in red, green and blue respectively, with finger loops coloured in yellow. Active site with bound inhibitor (blue space-filling model) and non-nucleoside inhibitor (NNI) sites 1–4 are indicated.

Two classes of NS5B inhibitors have been developed: nucleoside/nucleotide and non-nucleoside polymerase inhibitors.

Nucleoside/nucleotide analogue polymerase inhibitors

Nucleoside/nucleotide analogues act as natural polymerase substrates leading to termination of RNA chain elongation by inhibition of the active site of the HCV RdRp.

Mostly synthetic prodrugs of nucleotides are administered to facilitate resorption, and additional steps of intracellular phosphorylation are required to gain full functional activity as a nucleosid triphosphate.
 

Because of high conservation of the active site of the HCV RdRp across all HCV genotypes, these drugs have pan-genotype equivalent antiviral activity in vitro. In vivo data have not yet been completed. In vitro, nucleosidic inhibitors display a low ‘genetic barrier to resistance’ as drug resistance can be observed with single amino acid substitutions. However, because of the poor fitness of resistant variants in the presence of nucleosidic inhibitors, these agents are considered to have a high overall ‘barrier’ to resistance.

Non-nucleoside polymerase inhibitors

Non-nucleoside inhibitors bind outside the active site and target allosteric sites on the surface of the enzyme, downregulating the RdRp activity through induction of conformational changes (Fig.1).

Non-nucleoside inhibitors are so far specific for HCV genotype 1. The efficacy against genotype 1 subtypes, however, may differ. The barrier to resistance of non-nucleoside inhibitors is considered to be low.
 

Four groups of non-nucleoside inhibitors have entered clinical development
(summarized in Table 1).

Table 1. Polymerase inhibitors in clinical development

				Efficiency / log decline (log10 IU/ml)
	Generic name	Phase of development		Monotherapy	Combination	Comment
Nucleosidic inhibitors
NM-283 (Idenix)	Valopicitabin	Phase I	discontinued	0.87 (15 d)	3.90-4.56 (IFN)	Gastrointestinal side effects
R-1626 (Roche)		Phase II	discontinued	2.6-3.7 (14 d)	5.2 (IFN/R)	Neutropenia, lymphopenia, neurotoxicity
INX-189/BMS-986094 (Inhibitex/BMS)		Phase III	discontinued	0.6-4.25 (7 d)	0.75-3.79 (R/7 d)	Liver and severe cardiac & renal toxicity
PSI-938/GS-938 (Pharmasset/Gilead)		Phase III	discontinued	4.8-5.8 (14 d)		Hepatotoxicity
Alios-2200 (Alios)		Phase I	ongoing	4.54 (7 d)	n.a.
Alios-2158 (Alios)		Phase I	ongoing	n.a.	n.a.
R-7128/RG-7128 (Roche)	Mericitabine	Phase II	ongoing	2.7 (14 d)	5.00
PSI-7977/GS-7977 (Pharmasset/Gilead)	Sofosbuvir	Phase III	ongoing	4.7 (7 d)	6.4 (IFN/R)
Non-nucleosidic inhibitors
Thumb I inhibitors
BILB-1941 (Boehringer Ingelheim)		Phase I	discontinued	> 1 (5 d)	/	gastro-intestinal side effects
MK-3281 (Merk)		Phase I	discontinued	3.75 (7 d)	/	gastro-intestinal side effects
BI-207127 (Boehringer Ingelheim)		Phase II	ongoing	0.6-3.1 (5 d)	5.6 (IFN/R)
Thumb II inhibitors
VX-759 (Vertex)		Phase I	discontinued	2.5 (10 d)	3.7 (VX222)	low anti-viral efficacy
VX-916 (Vertex)		Phase I	discontinued	1.5 (3 d)	/	low anti-viral efficacy
GS-9669 (Gilead)		Phase I	ongoing	3.5 (3 d)	/
PF-00868554 (Pfizer)	Filibuvir	Phase II	ongoing	0.68-2.13 (8 d)	3.44-4.43 (IFN/R)
VX-222 (Vertex)		Phase II	ongoing	3.1-3.4 (3 d)	ongoing
Palm I inhibitors
ABT-333 (Abbott)		Phase I	ongoing	0.7-1.5 (2 d)	3.5-4.0 (IFN/R)
ABT-072 (Abbott)		Phase I	ongoing	1.19-2-3 (2 d)	(ABT-450/-333)
ANA-598 (Roche)	Setrobuvir	Phase II	ongoing	2.4-2.9 (3 d)	outstanding
Palm II inhibitors
HCV-796 (ViroPharma/Wyeth)	Nesbuvir	Phase I	discontinued	1.4 (14 d)	/	hepatotoxicity
IDX-375 (Idenix)		Phase I	discontinued	0.5-1.1 (1 d)	/	hepatotoxicity
GS-9190 (Gilead)	Tegobuvir	Phase II	ongoing	1.4-1.7 (8 d)	5.7 (9256/IFN/RBV)

Thumb I inhibitors (benzimidazole site): MK-3281 (Merck, Rahway, New Jersey, USA), B ILB1941 and BI 207127 (Boehringer-Ingelheim, Ingelheim am Rhein, Germany) are thumb I site inhibitors. Pre-existing NS5B substitutions known to reduce sensitivity were identified e.g. for BILB1941 at positions V494I/A, I424V and P496A [11].
 

Thumb II inhibitors (thiophene site): filibuvir (PF-00868554/Pfizer, New York, USA), VX-759, VX-916 and VX-222 (Vertex, Cambridge, Massachusetts, USA) bind to the thumb II site. Variants at position M423 known to confer resistance to filibuvir from in vitro studies were also selected in most patients in vivo. For VCH-759 as well as VCH-916, viral breakthroughs with selection of resistant variants conferring high (M423T/V/I) and medium (L419V/M, I482L/V/T, V494A/I) levels of resistance were described [11].
 

Palm I inhibitors (benzothiadiazine site): ABT-333, ABT-072 (both Abbott, Abbott Park, Illinois, USA) and Setrobuvir (ANA598; Anadys/Roche, Basel, Switzerland) are inhibitors of the palm I site. Several variants (M414T, G554D, D559G) were described from in vitro replicon studies to confer resistance to ANA598. Mutations associated with resistance in patients treated with ABT-333 were observed at positions C316Y and Y448C [11].
 

Palm II inhibitors (benzofuran site): nesbuvir (HCV-796/ViroPharma/Wyeth, Exton, Pennsylvania, USA) and IDX-375 (Idenix, Cambridge, Massachusetts, USA) act at the palm II site. The C316Y mutation in NS5B is associated with resistance to HCV-796 in vitro and in vivo [11].

Polymerase inhibitors in clinical trials

Nucleoside and non-nucleoside inhibitors have been investigated in combination with PEG-IFN and RBV and in PEG-IFN-free therapeutic regimens.

Nucleos(t)ide inhibitors

Several drugs in clinical development were discontinued because of clinically significant side effects including valopicitabine (NM-283), R-1626, PSI-938 and BMS-986094 (formerly known as INX-189) (Table 1).
 

Promising clinical data have been presented for the following HCV nucleos(t)ide analogues that have entered phase 2/3 clinical testing: mericitabine (RG-7128; prodrug of the pyrimidine (cytosine) nucleoside analogue PSI-6130) and sofosbuvir (PSI-7977/GS-7977; chirally pure isomer form of PSI-7851; prodrug of the nucleotide pyrimidine (uridine) analogue GS-7411). Early results were recently reported for ALS-2200, a novel nucleotide pyrimidine analogue polymerase inhibitor with a median reduction in HCV-RNA of 4.54 log₁₀ after 7 days of dosing [12].

Nucleos(t)ide inhibitors in clinical trials with interferon

Mericitabine (RG 7128)

The PROPEL study investigated safety, tolerability and efficacy of 8 and 12 weeks of mericitabine (1000 mg BID) in combination with PEG-IFN/RBV in 408 treatment-naive patients with chronic HCV genotype 1 or 4 infection. The rapid viral response (RVR) rates were up to 62% in the treatment arms with mericitabine compared with 18% in the control arm with PEG-IFN/RBV alone. SVR rates, however, did not differ between patients receiving mericitabine in combination with PEG-IFN/RBV and patients who received placebo plus PEG-IFN/RBV for 48 weeks. In the response-guided arms, fewer patients achieved SVR (33–49%) because of high virological relapse rates [13].
 

The JUMP-C trial (phase 2) investigated the safety and efficacy of 24 weeks of response-guided therapy with mericitabine (1000 mg BID), PEG-IFN/RBV in 168 treatment-naive patients with HCV genotype 1 or 4 infection. Patients were randomized (1:1) to response-guided therapy with mericitabine plus PEG-IFN and RBV for 24 or 48 weeks or to placebo, PEG-IFN/RBV for 48 weeks. In the mericitabine treatment arm, therapy was stopped at week 24 in patients with an extended rapid virological response [eRVR], defined as undetectable HCV RNA (<15 IU/ml) from week 4 to 22. Patients without eRVR received PEG-IFN/RBV for another 24 weeks. Overall SVR rates were higher in patients treated with mericitabine plus PEG-IFN/RBV than in patients treated with PEG-IFN/RBV alone (58% vs. 36%). Among 49 patients (60%) who achieved an eRVR with mericitabine plus PEG-IFN/RBV and discontinued therapy at week 24, the SVR rate was 78%. Combination therapy with mericitabine was safe, well-tolerated, demonstrated a high resistance barrier and a low potential for pharmacokinetic drug–drug interactions [14].
 

The MATTERHORN study, another phase 2 trial, is an ongoing study evaluating the efficacy and safety of various combinations of mericitabine and ritonavir-boosted danoprevir and PEG-IFN/RBV in patients with HCV genotype 1 infection.
 

The ongoing phase 2 DYNAMO I and II studies investigate quadruple therapy with mericitabine in combination with the protease inhibitors boceprevir or telaprevir and PEG-IFN/RBV in HCV genotype 1 non-responders to PEG-IFN/RBV.

Sofosbuvir (GS-7977, formerly PSI-7977)

The combination of sofosbuvir (400 mg QD), PEG-IFN and RBV was assessed for 12 weeks in 25 treatment-naive patients infected with HCV genotypes 2/3 in an open-label, uncontrolled pilot study (PROTON). Of the patients, who completed therapy (n = 24), 100% achieved an SVR. Based on these favourable results, the PROTON study was expanded to treatment-naive patients infected with HCV genotype 1. Patients were randomized 2:2:1 to different dose groups of sofosbuvir (200 or 400 mg QD) for 12 weeks plus PEG-IFN/RBV for 24 weeks. Patients without RVR were continued on PEG-IFN/RBV through week 48. Reported SVR rates were 88, 91% and <50% for sofosbuvir 200, 400 mg and the control group respectively [15, 16].
 

The ELECTRON study investigated sofosbuvir (400 mg QD) and RBV for 12 weeks in combination with 0, 4, 8 or 12 weeks PEG-IFN. All patients (n = 10 per group) achieved an SVR after 12 weeks of therapy [17].
 

The ATOMIC study, a Phase 2 randomized open-label trial investigated sofosbuvir in combination with PEG-IFN/RBV in 316 non-cirrhotic HCV genotype 1, 4 and 6 patients. Patients infected with HCV genotype 1 were randomized to 12 or 24 weeks sofosbuvir, PEG-IFN/RBV, or 12 weeks of the triple combination followed by re-randomization (1:1) to receive additional 12 weeks of either sofosbuvir alone or sofosbuvir plus RBV. Also, 16 patients infected with HCV genotypes 4 and 6 were randomized to the 24-week regimen of sofosbuvir plus PEG-IFN/RBV. Results of an interim analysis showed SVR rates of 90% in patients who received 12 weeks of the triple combination [18].

The phase III trial NEUTRINO, a single-arm study, evaluating a 12-week course of sofosbuvir plus PEG-IFN/RBV in 300 patients infected with HCV genotypes 1, 4, 5 and 6 is currently ongoing.

Nucleos(t)ide inhibitors in clinical trials without interferon

Nucleos(t)ide analogues were also investigated in combination with RBV, NS3/4A protease inhibitors, NS5A inhibitors and/or other nucleotide inhibitors in IFN-free treatment regimens.

Mericitabine (RG 7128)

The INFORM-1 study provided first proof of principle that suppression of HCV RNA with an interferon-free combination of mericitabine and danoprevir (NS3/4 protease inhibitor) is effective. Different doses of mericitabine in combination with danoprevir were administered for 14 days to patients infected with HCV genotype 1. At the highest combination doses tested (1000 mg mericitabine and 900 mg danoprevir BID), the median change in HCV RNA concentration from baseline to day 14 was −5.1 log(10) IU/ml in treatment-naive patients and −4.9 log(10) IU/ml in previous null-responders to PEG-IFN/RBV therapy[19].
 

INFORM-SVR, a phase 2b trial, subsequently investigated a 12 or 24 week interferon-free regimen of ritonavir-boosted danoprevir (DNV/r, 100/100 mg), and mericitabine (1000 mg BID) with or without RBV in treatment-naive HCV genotype 1 infected patients. Patients with undetectable HCV RNA at week 2 and week 10 were re-randomized at week 12 to stop therapy or to continue until week 24. Rapid viral response was similar and comparable in both arms (91 and 93% respectively). Owing to high relapse rates, however, the 12-week treatment arm was prematurely stopped. Furthermore, patients randomized to the RBV-free group were offered to continue on PEG-IFN/RBV therapy because of insufficient SVR rates. The data show SVR in 71% of HCV genotype 1b patients, but only in 26% of the genotype 1a-infected patients who received 24 weeks of DNV/r, mericitabine and RBV treatment. Higher SVR rates were reported among patients who were rapid virological responders. Among patients with undetected HCV-RNA at week 2, 80% with genotype 1b and 31% with genotype 1a achieved SVR. IL28B genotype appeared to have less impact on SVR rates.

Breakthrough rates were higher among patients not receiving RBV and showed in all patients, the selection of danoprevir-resistant variants, while only one patient showed the NS5B S282T polymerase mutation associated with resistance to mericitabine. Neutropenia or treatment emergent liver toxicity was not observed [20].
 

The currently ongoing phase II study ANNAPURNA evaluates the safety, tolerability, and efficacy of combination treatment with mericitabine (1000 mg BID), ritonavir-boosted danoprevir (DNV/r 100/100 mg), setrobuvir (ANA-598) and RBV administered for 12–14 or 24–26 weeks to treatment-naive patients or for 24–26 weeks to non-responders to PEG-IFN/RBV therapy with chronic hepatitis C genotype 1 infection.

Sofosbuvir (GS-7977/PSI-7977)

In the ELECTRON trial, the interferon-free combination of sofosbuvir and RBV achieved 100% SVR rates in treatment-naive patients infected with HCV genotype 2/3. In subsequent cohorts, patients with HCV genotype 1 infection and prior non-response to PEG-IFN/RBV received sofosbuvir and RBV for 12 weeks, but showed high relapse rates after the end of 12 weeks of treatment (89%). Reported SVR4 rates in treatment-naive patients infected with genotype 1 or treatment-experienced patients infected with genotype 2/3 receiving sofosbuvir and RBV for 12 weeks were 88 and 80% respectively [17].
 

The QUANTUM study, a phase 2b study, was planned as the first interferon-free, pan-genotypic, all-nucleotide study, combining a pyrimidine and a purine analogue, sofosbuvir and PSI-938 with or without RBV for 12 weeks. However, PSI-938 had to be discontinued because of liver toxicity. An SVR rate of 59% was reported for 17 HCV genotype 1 patients [21].
 

Three ongoing US studies for patients with HCV genotype 2/3 infection are FISSION, POSITRON, and FUSION. FISSION will compare 12 weeks of treatment with sofosbuvir and RBV to 24 weeks of PEG-IFN/RBV therapy. POSITRON evaluates the same combination for 12 weeks in interferon ineligible or intolerant patients. FUSION will examine treatment-experienced patients exploring 12 or 16 weeks of treatment with sofosbuvir and RBV.
 

Furthermore, a phase 3 study (VALENCE) was recently started to investigate the combination of sofosbuvir and RBV for 12 weeks in treatment-naive and treatment-experienced patients with HCV genotype 2 and 3 infection also in Europe.
 

Different oral combinations of sofosbuvir (400 mg QD) plus daclatasvir (BMS-790052, 60 mg QD) with/without RBV were tested in an open-label Phase 2a pharmaceutical cross-collaboration in treatment-naive non-cirrhotic HCV genotype 1-, 2- and 3-infected patients. SVR rates were 88, 100, and 79% respectively [22]. Furthermore, a combination study of simeprevir (TMC435) plus sofosbuvir is ongoing and a phase III study, investigating the combination of sofosbuvir and GS-5885 (NS5A inhibitor), is currently in preparation.

Non-nucleoside inhibitors

Several non-nucleoside inhibitors were discontinued from clinical development for different reasons. BILB1941 and MK-3281 were discontinued because of gastrointestinal side events [23-25], VX-759 and VX-916 showed only low-to-medium antiviral activity [26, 27], nesbuvir (HCV-796) and IDX-375 showed elevation of liver enzymes [27].
 

Currently, BI 207127, VX-222, ABT-072, ABT-333, setrobuvir (ANA-598), filibuvir and tegobuvir (GS-9190) are still investigated in clinical trials.

Non-nucleoside inhibitors in clinical trials with interferon

BI 207127

The SOUND C1 trial evaluated the combination of the non-nucleoside polymerase inhibitor BI 207127 with the protease inhibitor BI 201335 and RBV for 4 weeks followed by BI 201335 and PEG-IFN/RBV in treatment-naive patients with HCV genotype 1 infection. The RVR rates ranged from 73% (genotype 1a) to 100% (genotype 1b). An SVR rate of 94% was achieved in the group receiving a higher dose of BI 207127 (600 mg; TID) [28].

VX-222

The Phase 2 ZENITH study was designed to evaluate the antiviral activity of the protease inhibitor telaprevir and two dose levels of VX-222 administered with or without PEG-IFN/RBV for 12 or 24 weeks in treatment-naive patients with genotype 1 infection. This quad regimen led to SVR rates of 82–93% [29].

Setrobuvir (ANA-598)

Setrobuvir was studied at different doses in combination with PEG-IFN and RBV in treatment-naive and treatment-experienced patients with HCV genotype 1. Both doses of setrobuvir demonstrated a favourable safety and tolerability profile through 12 weeks. SVR was achieved in 8 of 11 patients (73%) who received 24 weeks of treatment [30].

Tegobuvir (GS-9190)

The antiviral activity of tegobuvir and the NS3/4A protease inhibitor GS-9256 alone or in combination with RBV or PEG-IFN/RBV in treatment-naive patients with HCV genotype 1 was assessed in a phase II trial. Patients were randomized to 28 days of tegobuvir/GS-9256, tegobuvir/GS-9256/RBV or tegobuvir/GS-9256/Peg-IFN/RBV, followed by PEG-IFN/RBV for further 44 weeks. Rapid viral response was observed in 100% (14 of 14) of patients receiving tegobuvir/GS-9256/PEG-IFN/RBV [31]. Response-guided quadruple therapy with tegobuvir and GS-9256 plus PEG-IFN/RBV based on a virological response at week 2 enabled to shorten antiviral therapy to 16 weeks and yielded an SVR rate of 95% [32].
 

Because of pancytopenia in quadruple therapy combinations including tegobuvir, the polymerase inhibitors GS-9256 or GS-9451, Peg-IFN and RBV, dosing of tegobuvir was discontinued [33].

Non-nucleoside inhibitors in clinical trials without interferon

BI 207127

SOUND-C2 (n = 362), an open-label, randomized, phase IIb trial investigated safety and efficacy of the combination faldaprevir (BI 201335; protease inhibitor), BI 207127 with or without RBV for 16, 28, 40 weeks in genotype 1-infected treatment-naive patients, including 10% of patients with compensated cirrhosis. Patients were randomized to one of five treatment arms: (A) 120mg QD BI 201335 (1335_QD) plus 600mg TID BI 207127 (7127_TID) and RBV for 16 weeks, (B) 28 weeks, or (C) 40 weeks; (D) 1335_QD plus 600mg BID BI 207127 (7127_BID) and RBV for 28 weeks; (E) 1335 plus 7127_TID (no RBV) for 28 weeks. Randomization to Arm E was stopped prematurely according to FDA feedback on study design prior to data analysis. The RBV-sparing arm showed substantial but lower response rates than other arms of the trial.
 

This combination therapy achieved a SVR rate of 60% in treatment-naive patients with genotype 1 after 16 weeks of treatment, confirming the potent antiviral activity of this treatment regimen. In patients with liver cirrhosis, an SVR rate of 60% in HCV genotype 1a and up to 83% in HCV genotype 1b-infected patients was reported. The BID (for BI 207127) regimen demonstrated the most favourable safety and tolerability profile with a low rate of adverse event-related study discontinuations. Post-hoc subanalyses by IL28B genotype showed clinically important differences in SVR rates: HCV 1a (IL28B: non-CC) 32% vs. HCV 1a (IL28B: CC) 75% and HCV 1b (IL28B: CC and non-CC) 82–84% [34].

ABT-072 and ABT-333

In the PILOT trial, 11 treatment-naive, non-cirrhotic HCV genotype 1 infected patients expressing the IL28B CC genotype were treated with ABT-450/r (150/100 mg QD), ABT-072 (400 mg QD) and RBV for 12 weeks. The SVR rate was 91%.
 

Another study (Co-Pilot) investigated ABT-450/r in combination with ABT-333 and RBV in 33 treatment-naive HCV genotype-1 infected patients and 17 non-responders to previous PEG-IFN/RBV therapy. Therapy-naive patients were treated with two different doses of ABT-450/r (250/100 mg and 150/100 mg, Arm 1 and 2 respectively) while prior non-responders received open-label ABT-450/r (150/100 mg, Arm 3). ABT-333 was administered in a fixed dose of 400 mg QD across groups. SVR rates in treatment-naïve patients were independent of ABT-450/r dose and IL28B genotype (95 and 93% for arm 1 and 2 respectively. In previous non-responders (Arm 3), the SVR rate was 47% [35].

VX-222

The phase 2 ZENITH study was designed to evaluate the antiviral activity of the protease inhibitor telaprevir and VX-222 in a dual regimen, in addition with RBV as triple or with PEG-IFN/RBV as quadruple combination therapy in treatment-naive patients with genotype 1 infection. A proportion of 38% of patients receiving 100 mg VX-222 plus telaprevir and 50% of patients receiving 400 mg VX-222 plus telaprevir were able to undergo only 12 weeks of therapy because of RVR (undetectable HCV-RNA at week 2 and 8) and achieved SVR rates of 83 and 90% respectively [29].

Tegobuvir (GS-9190)

Another interferon-free study, investigating the combination of tegobuvir, GS-5885 (NS5A inhibitor), GS-9451 (NS3/4A protease inhibitor) and RBV for 12 and 24 weeks in treatment-naive and experienced HCV genotype 1 patients demonstrated SVR rates up to 89% in patients treated for 12 weeks and up to 100% in patients treated for 24 weeks. Viral breakthrough occurred only in GT1a-infected patients [36].

Conclusion

The optimal treatment regimens for patients with chronic hepatitis C must still be defined. In many trials, nucleos(t)ide and non-nucleoside polymerase inhibitors are key components. The high resistance barrier of the nucleoside analogue inhibitors provides a potential backbone in various interferon-free treatment combinations. The non-nucleoside inhibitors have complementary resistance profiles to protease inhibitors and NS5A inhibitors and are also positioned to become relevant components in combination trials. In the near future, polymerase inhibitors as key components could be clinically available if ongoing clinical trials continue to show promising results on efficacy, safety and tolerability.

Acknowledgements

We thank Dr C. Welsch for providing Figure 1.

Disclosure

Financial disclosures: Stefan Zeuzem – Consultancies for Abbott, Achillion, AstraZeneca, BMS, Boehringer-Ingelheim, Gilead, Idenix, Janssen, Merck, Novartis, Presidio, Roche, Santaris, Vertex. Tania M. Welzel – Consultancies for Novartis. Ludmila Gerber has no disclosure.

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