(RG7128) and danoprevir; Australians Hepatitis C treatment breakthrough

Hepatitis C treatment breakthrough

Kate Hagan
March 15, 2011

A NEW treatment for hepatitis C trialled in patients at The Alfred hospital has cut debilitating side effects and reduced treatment times, creating the potential for many more patients to be cured of the disease.

About 250,000 Australians have hepatitis C but only 5 per cent choose to have the current treatment due to multiple side-effects such as psychotic episodes, depression, insomnia and muscle aches and pains.

Current treatment involves weekly injections of interferon - a protein that fights the virus but causes the side effects - as well as twice-daily tablets for up to seven weeks.

But researchers have found that a combination drug without interferon is even more effective, curing some patients of the disease within two weeks in a recent trial.

The study, published in The Lancet and funded by the drug company Roche, involved 88 patients from six hospitals in Australia and New Zealand, including The Alfred.

The Alfred hospital's director of gastroenterology, Associate Professor Stuart Roberts, said the success of the combination drug - which inhibits enzymes that cause the virus to multiply - was an exciting breakthrough.

About 70 per cent of people with hepatitis C develop a chronic form of the virus. One-fifth of those patients develop cirrhosis - a scarring of the liver that can lead to cancer.

The blood-borne virus can be spread by sharing drug-injecting equipment such as needles, through needlestick injuries in healthcare settings, or from blood transfusions before 1990 that may not have been screened for the virus.

''The interferon-free treatment … will see a lot more people taking up treatment because of the lack of major side effects,'' Professor Roberts said.

''It may also open up opportunities to increase treatment outside specialist centres in the hospitals because there is less requirement for intensive care and monitoring of patients.

''Introducing this treatment as standard practice is a few years off, but this study provides a proof of concept that it can be effective,'' he said.

While the current treatment produces a 50 per cent cure rate, Professor Roberts said the new treatment may be up to 80 per cent effective and would be used far more widely.

''At the moment many patients elect to manage themselves conservatively and don't undergo treatment,'' he said.

''Treatment, when successful, can not only arrest the progression of the disease but often it will reduce in severity as the liver remodels itself.''

Hepatitis C infections have increased in Victoria, with 662 new cases reported by doctors during the second quarter of 2009 - 25 per cent more than in the same period in 2008.

The article did not have a link to the lancet abstract....I'm sure you have seen this, but here it is folks;
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The Lancet, Volume 376, Issue 9751, Pages 1467 - 1475, 30 October 2010
doi:10.1016/S0140-6736(10)61384-0Cite or Link Using DOI
Published Online: 15 October 2010

Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial

Original TextDr Edward J Gane MD a , Stuart K Roberts MD b, Catherine AM Stedman MD c, Prof Peter W Angus MD d, Brett Ritchie MD e, Rob Elston PhD f, David Ipe MS f, Peter N Morcos PharmD f, Linda Baher BS f, Isabel Najera PhD f, Tom Chu MD f, Uri Lopatin MD f, M Michelle Berrey MD g, William Bradford MD h, Mark Laughlin MD f, Nancy S Shulman MD f, Patrick F Smith PharmD f

Summary

Background
Present interferon-based standard of care treatment for chronic hepatitis C virus (HCV) infection is limited by both efficacy and tolerability. We assessed the safety, tolerability, and antiviral activity of an all-oral combination treatment with two experimental anti-HCV drugs—RG7128, a nucleoside polymerase inhibitor; and danoprevir, an NS3/4A protease inhibitor—in patients with chronic HCV infection.

Methods
Patients from six centres in New Zealand and Australia who were chronically infected with HCV genotype 1 received up to 13 days oral combination treatment with RG7128 (500 mg or 1000 mg twice daily) and danoprevir (100 mg or 200 mg every 8 h or 600 mg or 900 mg twice daily) or placebo. Eligible patients were sequentially enrolled into one of seven treatment cohorts and were randomly assigned by interactive voice or web response system to either active treatment or placebo.

Patients were separately randomly assigned within each cohort with a block size that reflected the number of patients in the cohort and the ratio of treatment to placebo. The random allocation schedule was computer generated. Dose escalation was started in HCV treatment-naive patients; standard of care treatment-experienced patients, including previous null responders, were enrolled in higher-dose danoprevir cohorts. Investigators, personnel at the study centre, and patients were masked to treatment allocation. However, the pharmacist who prepared the doses, personnel involved in pharmacokinetic sample analyses, statisticians who prepared data summaries, and the clinical pharmacologists who reviewed the data before deciding to initiate dosing in the next cohort were not masked to treatment allocation. The primary outcome was change in HCV RNA concentration from baseline to day 14 in patients who received 13 days of combination treatment. All patients who completed treatment with the study drugs were included in the analyses. This study is registered with ClinicalTrials.gov, NCT00801255.

Findings
88 patients were randomly assigned to a study drug treatment regimen (n=74 over seven treatment groups; 73 received at least one dose of study drug) or to placebo (n=14, all of whom received at least one dose).

The median change in HCV RNA concentration from baseline to day 14 ranged from −3·7 to −5·2 log10 IU/mL in the cohorts that received 13 days of combination treatment. At the highest combination doses tested (1000 mg RG7128 and 900 mg danoprevir twice daily), the median change in HCV RNA concentration from baseline to day 14 was −5·1 log10 IU/mL (IQR −5·6 to −4·7) in treatment-naive patients and −4·9 log10 IU/mL in previous standard of care null responders (−5·2 to −4·5) compared with an increase of 0·1 log10 IU/mL in the placebo group. The combination of RG7128 and danoprevir was well tolerated with no treatment-related serious or severe adverse events, no grade 3 or 4 changes in laboratory parameters, and no safety-related treatment discontinuations.
Interpretation

This oral combination of a nucleoside analogue polymerase inhibitor and protease inhibitor holds promise as an interferon-free treatment for chronic HCV.

Funding
Roche Palo Alto.

New Future Hepatitis C Treatments: Interferon-sparing combinations

In Case You Missed It...........

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Hepatitis C virus treatment: interferon-sparing combinations

Liver International

Special Issue: Proceedings of the 4th Paris Hepatitis Conference.

The publication of this supplement was supported by an unrestricted educational grant from F. Hoffmann-Laroche Ltd.

Volume 31, Issue Supplement s1, pages 62–67, January 2011

Edward Gane

Article first published online: 4 JAN 2011
DOI: 10.1111/j.1478-3231.2010.02383.x
© 2011 John Wiley & Sons A/S

Author Information
New Zealand Liver Transplant Unit, Auckland, New Zealand
* Correspondence: Correspondence Edward Gane, New Zealand Liver Transplant Unit, 15th Floor Support Building, Auckland City Hospital, Park Road, Grafton, Auckland 92024, New Zealand Tel: 642 154 8371 Fax: 649 529 4061 e-mail: edgane@adhb.govt.nz

Keywords:
direct acting antiviral (DAA); Hepatitis C; pegylated interferon; polymerase inhibitor; protease inhibitor; standard-of-care (SOC)

Abstract

An estimated million people have chronic hepatitis C virus (HCV) infection. With current treatment success rates, by 2030, more than 40% will be cirrhotic and the number of cases with end-stage liver disease is projected to treble.

Current standard-of-care is the combination of pegylated interferon plus ribavirin for 24–48 weeks. Unfortunately this is associated with poor efficacy (45% in HCV GT1; 75% in GT2 and 65% in GT 3) and tolerability.

Many patients are either unsuitable for or decline current treatment infection because of the significant side-effects associated with this treatment, including those with decompensated cirrhosis or sever psychiatric illness. It is hoped that the development of direct acting antiviral agents (DAAs) will address this huge unmet medical need.

The addition of a protease inhibitor to pegylated interferon plus ribavirin is associated with increase in efficacy and shortened duration of therapy in patients with HCV GT1 and is likely to become the new standard-of-care. However, triple therapy will not be suitable for patients with non-1 HCV infection, or contraindications to interferon.

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It is hoped that the combination of multiple DAAs which target different steps of HCV replication should provide interferon-free treatment regimen.

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Current and planned studies will determine which combination (protease, nonnucleoside polymerase, nucleoside polymerase, NS5A, cyclophyllin B inhibitors), how many DAAs and duration of therapy will be required to optimise cure. It will also be important to minimise the emergence of multi-resistance, which would jeopardise future retreatment options

Chronic hepatitis C is the global ‘epidemic’ of the new millennium, with an estimated 200 million people currently infected with the hepatitis C virus. The incidence of hepatitis C virus (HCV) infection has decreased by more than 50% over the last decade, reflecting reduced exposure risk (1, 2). Although the size of the population with chronic HCV infection has been stable since 2000 (3), this is an ageing cohort and the proportion of this cohort with cirrhosis will double over the next decade from 16 to over 35% (4). As a result, the annual rate of both HCV-related hepatocellular carcinoma and HCV-related-mortality is projected to triple again by 2030 (5–7). The only way to prevent this projected health burden is to reduce the pool of infected patients through successful antiviral therapy.

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Less then 10% of the infected population has been treated and less than half of these have been cured.

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However, less then 10% of the infected population has been treated, and less than half of these have been cured. It is estimated that these numbers would need to increase almost 10-fold to prevent the projected increase in HCV-related complications (1, 8). Unfortunately, current treatment options are limited by both efficacy and tolerability.

The current standard of care (SOC) treatment for chronic HCV infection is 48 weeks of combination therapy with subcutaneous injections of pegylated interferon (PEG-IFN) plus orally administered ribavirin. SOC achieves a sustained virological response (SVR) in only 45% of patients infected with HCV genotype (GT)1 and 65% of those infected with GT2 or 3 (9).

HCV GT1 is the predominant genotype globally, accounting for between 55 and 95% of infections. Baseline patient predictors of non-response to SOC other than HCV genotype include older age, advanced fibrosis, high body mass index, insulin resistance and African ethnicity.

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(IL)28B gene

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IL28B gene and hepatitis c treatment

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A specific inherited polymorphism on chromosome 19 at rs12979860, close to the interleukin (IL)28B gene, is strongly associated with SVR across all patient groups (T/T vs. T/C or C/C), independent of all other predictors including ethnic origin (10).

Subsequently, several other independent genome-wide association studies have also identified additional SNPs, in the IL28B region, associated with response to treatment (11–13). In those patients with favourable baseline predictors of response, adherence to therapy is an important determinant of outcome.

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PEG-IFN and ribavirin are associated with significant adverse effects

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Both PEG-IFN and ribavirin are associated with significant adverse effects, from flu-like symptoms, fever, rash, anorexia, thyroid dysfunction, to dose-related life-threatening cytopaenias and mood disorders.

Side effects result in a dose reduction in 60–80% of patients and treatment withdrawal in 5–10%.

Another inherited polymorphism on Chromosome 20 at rs1127354, which determines the activity of inosine triphosphatase, reliably predicts protection from ribavirin-induced haemolysis (A/A and C/A vs. C/C) (14).

In addition, many patients never start SOC because of real or perceived medical or psychosocial contraindications to either IFN or ribavirin. Many more defer therapy because of anecdotal stories about severe adverse effects.

Finally, there is a large and growing pool of largely GT1 patients who have not previously responded to PEG-IFN-a and ribavirin treatment, in whom retreatment no alternative treatment options are currently available. New therapeutic approaches offering improvements in efficacy, safety and tolerability are urgently needed to address these unmet medical needs.

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Direct-acting antivirals and triple therapy

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The five steps in HCV replication that are potential targets for direct-acting antivirals (DAAs) include initial binding of HCV to hepatocyte surface receptors (via LDLR and CD81), translation and polyprotein processing (via the HCV protease complex), RNA replication (via the HCV RNA-dependent polymerase complex), virion assembly and maturation, followed by release from the hepatocyte (Fig. 1).

To date, the most successful approaches have been targeting the HCV protease (via inhibition of NS3A4 protease) and the HCV polymerase complex (via inhibition of NS5A, NSAb and indirectly through NS3A4). The in vitro replicon and transgenic models for HCV replication and the application of rapid screening techniques for small molecules have triggered an explosion in drug development.

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90 protease and polymerase inhibitors have entered clinical development

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Over the last 5 years, more than 90 protease and polymerase inhibitors have entered clinical development, of which several have halted because of toxicity (BILN2061, NM283, HCV796, R1626) and many more have been abandoned because of preclinical toxicity signals or lack of clinical efficacy.

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Figure 1.

Targets for direct-acting antivirals against the hepatic C virus (HCV).

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The DAAs closest to being marketed are the protease inhibitors, boceprevir and telaprevir. Phase 3 global registration studies of both will be completed this year and these protease inhibitors are expected to be the first DAAs to gain regulatory approval as add-on therapy to current SOC PEG-IFN plus ribavirin. The benefits in terms of efficacy will be significant – 48 weeks of boceprevir plus SOC increased the SVR rates in treatment-naïve GT1 patients from 38 to 66%, while 12 weeks of telaprevir plus 24 weeks SOC increased the SVR rates from 43 to 75% (15, 16).

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Telaprevir

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Jan 20 (Reuters) - Vertex Pharmaceuticals Inc said its experimental treatment for Hepatitis C "Telaprevir" got priority review status from health regulators in the United States and Canada.Cambridge, Massachusetts-based Vertex, which had asked the U.S. Food and Drug Administration for a priority review of data from telaprevir in November, said the agency set an action date for May 23 to decide on the approval.

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Boceprevir

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Jan 6th Boceprevir Receives FDA Priority Review and EMA Accelerated AssessmentWHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck, known as MSD outside the United States and Canada, announced today that regulatory applications for boceprevir, Merck's investigational oral hepatitis C virus (HCV) protease inhibitor, were submitted in 2010 and have been accepted for expedited review in both the U.S. and the European Union.

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Triple therapy / Telaprevir with SOC / Boceprevir with SOC

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Triple therapy may also offer hope in treatment-experienced patients, especially previous responder relapsers and partial responders (17– 19).

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Both have specific toxicities (notably anaemia and dysgeusia with boceprevir and anaemia and rash with telaprevir) :

Not be suitable for patients either intolerant of or with contraindications to IFN or ribavirin, including patients with decompensated cirrhosis or following solid organ transplantation.

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However, both have specific toxicities (notably anaemia and dysgeusia with boceprevir and anaemia and rash with telaprevir), which increased the rate of treatment withdrawal in the DAA combination arms.

Although triple therapy (addition of either telaprevir or boceprevir to PEG-IFN plus ribavirin) is likely to become the new SOC in late 2011, this will not be suitable for patients either intolerant of or with contraindications to IFN or ribavirin, including patients with decompensated cirrhosis or following solid organ transplantation.

Also, the efficacy of this triple therapy will probably be reduced in treatment-experienced patients, especially those who were non-responders to a previous treatment with SOC.

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Moreover, although telaprevir has similar antiviral activity against HCV GT2, this agent has no effect in patients with HCV GT3 infection (20, 21).

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All current protease inhibitors and most non-nucleoside polymerase inhibitors in development are active primarily against HCV GT1.

"PEG-IFN plus ribavirin will remain the SOC for non-GT1"

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Genotype 1 patients who do not respond to this new triple therapy will have developed resistance to protease inhibitors

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HCV until nucleoside polymerase inhibitors and cyclophyllin inhibitors enter clinical practice. Finally, the 30–40% of GT1 patients who do not respond to this new triple therapy will have developed resistance to protease inhibitors, which will limit future treatment options. Therefore, although the addition of a single DAA to PEG-IFN and ribavirin may improve cure and shorten the treatment duration of SOC, this approach will not meet the needs of many difficult-to-treat patient groups.

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Towards an all oral regimen

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The successful development of an all-oral, IFN-free regimen of multiple DAAs should address this current extensive unmet medical need and could potentially become the standard of care for all patients with chronic HCV infection.

The rationale for this approach is based on the current human immunodeficiency virus (HIV) treatment paradigm, in which a combination of different DAA agents, which target different steps of viral replication, has been shown to increase viral suppression as well as delay or prevent the emergence of antiviral resistance.

There is a rapidly increasing list of potential candidates for such a combination including NS3 helicase inhibitors, NS3/4A protease inhibitors, cyclophyllin B inhibitors, NS5A inhibitors, NS5B nucleoside inhibitors and NS5B non-nucleoside inhibitors (see Table 1). The primary criteria for a DAA combination should be to increase antiviral efficacy without increasing toxicity. The combination of DAAs should exhibit in vivo at least additive and preferably synergistic antiviral efficacy [i.e. rather than interference as observed with telbivudine plus lamivudine in patients with hepatitis B virus (HBV) infection].

The combination should lack cross resistance and should prevent virological breakthrough from the emergence of resistance mutants to either or both DAAs. Finally, the combination should lack direct drug interactions and overlapping toxicities. The first in vitro study of combination DAAs was performed in the replicon model (22)

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The addition of RG7128, a nucleoside polymerase inhibitor, to RG7227, a protease inhibitor, provided additive viral suppression and completely prevented the development of phenotypic resistance to the protease inhibitor

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The addition of RG7128, a nucleoside polymerase inhibitor, to RG7227, a protease inhibitor, provided additive viral suppression and completely prevented the development of phenotypic resistance to the protease inhibitor. Similar in vitro effects have been demonstrated for other DAA combinations, including a protease inhibitor plus a non-nucleoside polymerase inhibitor and also the combination of two nucleoside polymerase inhibitors (23, 24).

The in vivo efficacy of combining DAAs was first reported in chimpanzees treated with a combination of Merck NS3/4A protease inhibitor MK-7009 and non-nucleoside inhibitor MK-608 for 7 days, whereby both had rapid and sustained viral suppression and one animal eradicated the HCV infection (25).

The first study of combination DAAs in patients was the proof-of-concept INFORM-1 study completed last year (26). In this randomised, placebo-controlled double-blind trial, 87 patients with HCV GT1 infection were randomised to receive up to 13 days of either oral combination therapy with RG7128, a nucleoside polymerase inhibitor, and RG7227/danaprevir, an NS3/4A protease inhibitor or with matched placebos. Both agents had already been administered to patients for 12 weeks in combination with SOC. Direct drug interactions between RG7128 and danaprevir were considered very unlikely, because of the different mechanisms of action and routes of elimination and the lack of overlapping toxicities identified in any of the preclinical or human clinical studies.

This combination achieved profound antiviral suppression, greater than the additive effects of either treatment alone. The median reduction in HCV RNA from baseline was 5 logs, falling below the level of detection in 88% in the cohort who received the highest dose of both RG7128 (1000 mg b.i.d.) and danaprevir (900 mmg b.i.d.).

No evidence of the emergence of resistance to either compound was observed during this study. This combination was well tolerated, with no serious adverse events, treatment-related dose modifications, discontinuations or study withdrawals.

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INFORM-1 study Final cohort of patients who received the highest dose of RG7227 and RG7128, 100% achieved ETR after 24 weeks SOC

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An important observation was that antiviral efficacy was similar in treatment-naïve and treatment-experienced patients including non-responders. Because the total duration of therapy was only 13 days, all patients rolled over into SOC. The rates of RVR, EVR and ETR were markedly increased by the 2 weeks of pretreatment. In the final cohort of patients who received the highest dose of RG7227 and RG7128, 100% achieved ETR after 24 weeks SOC.

Although SVR results are still pending, the benefit of pretreatment with combination DAA on subsequent responses to SOC suggests that the strategy of combination of DAA lead-in before starting SOC could be an alternative strategy to IFN-free DAA therapy. However, the primary goal of combination DAA therapy in HCV infection will be to provide a safe and effective substitute for IFN regimens in all treatment-naïve and -experienced patients. Although the new treatment paradigm for HCV is based on HIV, the goals are very different.

In HIV infection, a cure is not achievable because it is impossible to eradicate infection from lymphocytes and macrophage reservoirs and from nuclear integration. Therefore, lifelong combination DAA therapy is needed to maintain viral suppression and prevent disease progression. In HCV infection, however, replication is entirely cytoplasmic and limited to hepatocytes. Therefore, viral eradication should be possible with short-course combination DAA.

The duration of combination DAA necessary to eradicate HCV infection is unknown. The early viral kinetic profile of single DAA therapy demonstrates a rapid Phase 1 decline in serum HCV RNA levels of 3–4 log in the initial 36 h, attributed to the clearance of free virions from the circulation. The addition of a second DAA appears to increase this initial slope, suggesting at least additive effects of both agents.

This is followed by Second Phase decline in serum HCV RNA of 1-1.2 log/week, attributed to the loss of infected hepatocytes (Fig. 2). This rate of viral decline continues until the infection is eradicated, unless DAA-resistant variants emerge. Therefore, based on the estimated total body viral burden of 1011 virions, between 8 and 12 weeks of DAA therapy should be sufficient to eradicate HCV infection in most patients.

The addition of a second DAA targeting a different step of HCV replication and lacking cross resistance should both increase the slope of the Phase 1 decline as well as prevent virological breakthrough during Phase 2.

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Figure 2.

Early viral kinetic profile of combined direct-acting antivirals' therapy. HCV, hepatic C virus.

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Early viral kinetic profile of combined direct-acting antivirals' therapy. HCV, hepatic C virus. A finite duration of combination DAA therapy without IFN assumes that viral suppression alone will eradicate HCV, which seems reasonable in the absence of evidence of either viral latency or extrahepatic reservoirs of replication (as seen in HBV). Another important factor for the maintenance of end-of-treatment response may be the indirect effect of combination DAA therapy on host immune responses.

In chronic HCV infection, the HCV NS3 protease may directly impair host IFN responses through the inhibition of phosphorylation of IFN regulatory factor-3 (27). Administration of the NS3/4A protease inhibitor should restore this immune responsiveness. Chronic HCV infection is also associated with high levels of IP-1(CXCL-10), a chemokine involved in lymphocyte chemotaxis, reflecting endogenous IFN activation levels. High levels of IP-10 during SOC are correlated with the risk of post-treatment relapse (28). In the INFORM study, the rapid and profound viral suppression achieved with 13 days of combination RG7128 and danaprevir (5 logs within 14 days) correlated with normalisation of IP-10 levels (29).

Furthermore, it has been shown that in non-responders, some IFN-stimulated genes were highly expressed; thus, preactivation of the IFN system in patients appears to limit the effect of IFN antiviral therapy (30). Current and future studies will determine whether the IL28 genotype influences sustained response rates in an IFN-free DAA regimen. Future studies of combination DAA therapy in chronic HCV should include the evaluation of HCV-specific and non-specific immune responses to determine whether immune reconstitution does occur and whether this is a prerequisite for the prevention of relapse after treatment withdrawal. First studies with all-oral treatments

The shift from triple therapy (single DAA plus SOC) to IFN-free combination DAA studies has been impeded by the reluctance of regulatory authorities to approve the combination of two experimental compounds still in early-phase clinical development.

However, such studies should be reasonable as long as safety data are available for each candidate DAA for the duration of the proposed treatment. The rapid emergence of resistant variants during monotherapy with either NS3/4a or NS5b non-nucleoside inhibitors has restricted the duration of DAA monotherapy studies to 3–5 days; thus, longer duration safety data must be obtained from studies of DAA in combination with SOC.

An additional requirement before embarking on combination DAA studies in patients should be data from preclinical and human clinical studies for each candidate DAA, confirming lack of cross-resistance, lack of overlapping toxicities and a low likelihood of any drug–drug interactions, which could affect antiviral activity, bioavailability or clearance.

INFORM-1 fulfilled all of these requirements but was performed in Australia and New Zealand, because the conservative regulatory environment of the FDA and EMEA did not allow this study to be performed in either Europe or the US at that time.

The success of this proof-of-concept and widespread enthusiasm in the HCV field over these results will push the regulatory authorities to modify their previously conservative position. Following the INFORM proof-of-concept study, seven Phase 2 studies of combination DAA studies are already entering Phase 2 clinical trials in patients with treatment-naïve HCV infection (see Table 2), with many more planned. All studies include an NS3/4a protease inhibitor with or without ritonavir boosting, combined with an agent targeting the HCV polymerase complex – either a non-nucleoside NS5b (n=4), nucleoside NS5b (n=1) or an NS5a inhibitor (n=2).

The potential advantage of the nucleoside polymerase inhibitor is the relatively high genetic barrier to resistance and the low prevalence of pre-existing nucleoside polymerase resistance. In a recent survey, no treatment-naïve GT 1 patients had detectable signature S282T mutations, while the prevalence of mutations conferring resistance to either NS3/4a inhibitors or non-nucleoside polymerase inhibitors could be detected in more than 8% of treatment-naïve patients (31). However, it is not clear whether these pre-existing mutations will affect the response to combination DAA therapy.

Most of these mutations are associated with decreased replicative fitness and none confer cross-resistance to either NS3/4a inhibitors or non-nucleoside polymerase inhibitors. Unlike INFORM-1, the aim of these studies is curative, with combination DAAs administered for 12–24 weeks.

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Most study designs incorporate response-guided therapy, with the 2-week rather than the 4-week RVR adopted as a predictor of efficacy (and shortened treatment duration)

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Although IFN-free, most studies have retained ribavirin as a third oral agent (based on observations of higher relapse rates in the ribavirin-sparing treatment arms in the telaprevir plus SOC studies) (32). However, the impact of ribavirin on the efficacy and tolerability of combination DAA therapy needs to be established.

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Summary

The addition of a protease inhibitor to PEG-IFN plus ribavirin will increase the cure rate in both treatment-naïve and treatment-experienced patients and is likely to become the new SOC. However, there will still be a large ‘unmet need’, including patients unable to or unwilling to receive IFN or ribavirin therapy and previous non-responders to SOC

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The rationale for combining different DAAs is to increase viral suppression and prevent or delay the emergence of antiviral resistance

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The ultimate goal is to develop a short-duration, IFN-free oral combination, with excellent tolerability and efficacy in both treatment-naïve and treatment-experienced patients.

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Conflicts of interest

Edward Gane is a member of local or international Advisory Boards and Invited Speaker for GSK, Roche, Pharmasset, Abbott, Novartis and Merck.

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HCV antiviral activity andresistance analysis in chronically infected chimpanzees treated with NS3/4A protease and NS513 polymerase inhibitors. J Hepatol 2007; 46: S298. 26 Gane E, Roberts S, Stedman C, et al.

Interferon-free oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and protease inhibitor (danoprevir/RG7227) for the treatment of chronic hepatitis C genotype 1 infection: results of the INFORM-1 trial.

Lancet 2010; 376: 1467–75. 27 Foy E, Li K, Wang C, et al. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science 2003; 300: 1145–8. 28 Lagging M, Romero AI, Westin J, et al. IP-10 predicts viral response and therapeutic outcome in difficult-to-treat patients with HCV genotype 1 infection. Hepatology 2006; 44: 1617–25. 29 Shulman N, Smith P, Ipe D, et al.

Reduction of IP10, a biomarker of endogenous IFN, during therapy with two direct-acting antiviral agents (DAA-combo) in INFORM−1 suggests that reducing HCV RNA with IFN−free therapy may enhance response to Interferons. 16th International Symposium on HCV and Related Viruses, October 3–7 2009, Nice, France. 30 Asselah T, Bieche I, Narguet S, et al. Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C. Gut 2008; 57: 516–24. 31 Kuntzen T, Timm J, Berical A, et al.

Naturally occurring dominant resistant mutations to HCV protease and polymerase inhibitors in treatment-naive patients.

Hepatology 2008; 48: 1769–78. 32 Hézode C, Forestier N, Dusheiko G, et al.

Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009; 360: 183–50.

Hepatitis C:Update and Background On Danoprevir (RG7227/ITMN-191)

Update and Background On Danoprevir (RG7227/ITMN-191)

What Pharmaceutical Company Is Behind Danoprevir (RG7227/ITMN-191)?
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In October 2010 Roche acquired the rights to InterMune HCV Protease Inhibitor Danoprevir.
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See Article: "October 07, 2010 Roche buys full rights to danoprevir from InterMune Roche today announced that it has bought full worldwide development and commercialization rights to danoprevir (RG7227/ITMN-191) ... more"
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What Is Danoprevir (ITMN-191) ?
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Danoprevir (ITMN-191) = (RG7227 formerly R7227 also known as ITMN-191) is a investigational protease inhibitor, which targets the hepatitis C virus, used in combination with the standard of care for HCV infection; peg-interferon alpha-2a and ribavirin. It has demonstrated rapid and profound reductions in HCV RNA. However data has shown Direct-acting Drugs Danoprevir plus RG7128 Suppress HCV without Interferon.
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*NOTE
You may remember when "TelaPREVIR" was referred to as VX-950. As a drug moves through the pipeline the number/alpha is eventually dropped.
So for now "DanoPREVIR" =ITMN-191(RG7227)
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What trials have been or are being conducted with Danoprevir (ITMN-191) ?
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Roche Collaborates With Inter Mune and Pharmasset;

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The HYPE:

The INFORM-1 trial is a combination regimen using two directly targeted oral anti-HCV agents. The HCV Polymerase Inhibitor RG7128 plus the Protease Inhibitor DanoPREVIR =(ITMN-191/RG7227 ) which suppresses HCV Viral Load without Interferon or Ribavirin.
INFORM-1 trial - The results from a 14 day INFORM-1 trial showed the drugs were safe when administered together and resulted in a sustained viral load reduction. .

On April 25, 2009, Roche, InterMune, Inc., and Pharmasset announced the first results from our initial study of an interferon-free regimen for the treatment of patients chronically infected with HCV.
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This study, INFORM-1, combined for the first time in patients two oral, direct acting antiviral drugs, RG7128 and RG7227, an inhibitor of the HCV NS3/4 protease, which is being developed by InterMune, Inc., in collaboration with Roche.
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INFORM-1 was a randomized, double-blind, ascending dose Phase 1 trial. Patients receiving the combination of RG7227 and RG7128 for 13 days, without pegylated interferon or ribavirin, experienced a median change from baseline HCV RNA of -4.8 to -5.2 log10 IU/mL in the highest doses tested.
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The addition of RG7128 to RG7227 resulted in sustained HCV RNA reductions over the dosing period, with approximately 63% of patients having levels of virus in their blood below the limit of the quantification of the diagnostic assay (less than 40 IU/mL). Furthermore, 25% of patients in the highest dosage groups were below the limit of detection of the virus in their blood (less than 15 IU/mL) on the 14th day of dosing.
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The combination was well tolerated over 13 days, with no treatment-related serious adverse events (SAEs), dose reductions or discontinuations. Pharmacokinetic analysis confirmed that there were no drug-drug interactions between the compounds.
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In February 2010, Roche announced that it had decided to conduct longer duration studies, which will commence after Roche identifies the optimal dose of ritonavir-boosted danoprevir (RG7227) from ongoing studies. Roche is continuing to conduct dose ranging safety and efficacy studies of danoprevir.
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Direct-acting Drugs Danoprevir plus RG7128 Suppress HCV without Interferon.
10/22/10
SUMMARY: Results from the INFORM-1 trial, which evaluated 2 experimental agents that target different steps of the hepatitis C virus (HCV) lifecycle, showed that a combination of direct-acting drugs can suppress viral replication without interferon or ribavirin. As described in the October 14, 2010 advance online edition of The Lancet, the HCV protease inhibitor danoprevir (RG7227 or ITMN-191) plus the polymerase inhibitor RG7128 reduced HCV RNA by about 5 logs in both treatment-naive and previously treated patients, and caused no serious side effects in this 14-day study
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Polymerase inhibitor RG7128
The Phase 1 Studies
During September 2008, we completed the clinical activities in Part 3 of a Phase 1 clinical trial with RG7128 that was initiated by Roche and us in October 2006 under an IND filing.
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This expanded Phase 1 trial was a multiple center, observer-blinded, randomized and placebo-controlled study designed to investigate the pharmacokinetics, pharmacodynamics, safety, tolerability and food effect of RG7128 in healthy volunteers and in patients chronically infected with HCV genotype 1, 2 or 3.
This Phase 1 trial also provided antiviral potency data over 14 and 28 days in patients chronically infected with HCV genotype 1 and following 28 days of treatment in patients chronically-infected with HCV genotypes 2 or 3. This adaptive Phase 1 study was comprised of three parts:
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Part 1 was a single ascending dose study conducted in 46 healthy volunteers. The primary objective of Part 1 was to assess the safety, tolerability and pharmacokinetics of RG7128 following single ascending doses under fasting conditions.
The secondary objective of Part 1 was to explore the effect of food on the pharmacokinetics of RG7128. Single oral doses of RG7128 were administered to 46 healthy volunteers in five sequential dose groups (500 mg, 1500 mg, 4500 mg, 6000 mg and 9000 mg) and one food effect group (1500 mg).
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Results from the single ascending dose portion of the study indicated:
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All doses of RG7128 studied (500 mg to 9000 mg) were generally safe and well-tolerated.
All patients completed the study, and none experienced gastrointestinal adverse events or serious adverse events during the study.
No hematologic or other safety laboratory abnormalities of clinical significance were noted.
No maximum tolerated dose was identified.
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Part 2 was a multiple ascending dose study conducted in 40 patients chronically infected with HCV genotype 1 who had previously failed interferon therapy. The primary objective of Part 2 was to assess the safety, tolerability and pharmacokinetics of RG7128 after once-daily ("QD") or twice-daily ("BID") dosing for 14 days. The secondary objective was to assess antiviral efficacy by measuring the change in HCV RNA.
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Results from the multiple ascending dose portion of the study indicated:
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RG7128 demonstrated potent, dose-dependent antiviral activity in four patient cohorts (8 active, 2 placebo per cohort) receiving 750 mg or 1500 mg administered either QD or BID for 14 days as monotherapy.
The maximum decrease in HCV RNA from baseline was demonstrated in the patient cohort that received 1500 mg BID. RG7128 demonstrated mean HCV RNA decreases from baseline of 0.9 log (87.4% reduction), 1.5 log (96.8% reduction), 2.1 log (99.2% reduction) and 2.7 log (99.8% reduction) in patients receiving 750 mg QD, 1500 mg QD, 750 mg BID and 1500 mg BID, respectively.
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Based on the mean data, all four dose groups reached nadir values at Day 15.
A maximum 4.2 log (99.9% reduction) HCV RNA decrease was demonstrated in a patient following 14 days of monotherapy with 1500 mg BID of RG7128, a value also below the level of detection, which was less than 15 International Units per milliliter (IU/ml).
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There was no evidence of viral rebound in any dose cohort during the 14 days of dosing.
RG7128 was generally safe and well tolerated over 14 days of treatment of patients chronically infected with HCV genotype 1 who had previously failed interferon therapy. There were no serious adverse events, no adverse events requiring dose modification, and no dose-related gastrointestinal adverse events.
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Part 3 was a 4-week study of RG7128 in combination with the current standard of care for chronic HCV infection, Pegasys (pegylated interferon) plus Copegus (ribavirin) in 81 treatment-naïve patients chronically infected with HCV genotype 1, and additionally, in 25 prior treatment non-responders, or patients who did not achieve an SVR with previous interferon-based therapy, who were chronically infected with HCV genotypes 2 or 3. The primary objective of this study was to assess the safety, tolerability, and pharmacokinetics of RG7128 in the clinically-relevant setting of combination therapy with the current standard of care for chronic HCV infection.
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The secondary objective of Part 3 was to evaluate the short-term change in HCV RNA. The study included three oral dose regimens of RG7128 (500 mg, 1500 mg and 1000 mg—cohorts 1,2 and 3, respectively) in patients chronically infected with HCV genotype 1 and one oral dose regimen of RG7128 (1500 mg—cohort 4) in patients chronically infected with HCV genotypes 2 or 3.
All four dose regimens were administered twice-daily with Pegasys plus Copegus for 4 weeks. Dose cohorts 1, 2 and 4 enrolled 25 patients, with 20 patients randomized to receive RG7128 and five patients randomized to receive placebo, and cohort 3 enrolled 31 patients, with 25 patients randomized to receive RG7128 and six patients randomized to receive placebo, all administered in combination with standard of care.
After completing four weeks of the triple combination regimen and a follow-up of four weeks of Pegasys plus Copegus, all patients are scheduled to receive up to 40 weeks of open-label standard of care dosing under a separate protocol.
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Results from cohorts 1, 2 and 3 in 81 treatment-naïve patients chronically infected with HCV genotype 1 indicated:
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Following 4 weeks of treatment with RG7128 500mg BID with Pegasys plus Copegus (cohort 1), patients achieved a mean 3.8 log10 IU/mL decrease in HCV RNA and 30% (6 of 20) achieved HCV RNA below the limit of detection (less then 15 IU/ml), or rapid virologic response ("RVR").
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Following 4 weeks of treatment with RG7128 1500mg BID with Pegasys plus Copegus (cohort 2), patients achieved a mean 5.1 log10 IU/mL decrease in HCV RNA and 85% (17 of 20) achieved RVR.
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Following 4 weeks of treatment with RG7128 1000mg BID with Pegasys plus Copegus (cohort 3), patients achieved a mean 5.1 log10 IU/mL decrease in HCV RNA and 88% (22 of 25) patients achieved RVR. Following 4 weeks of treatment with placebo with Pegasys plus Copegus, patients achieved a mean 2.9 log10 IU/mL decrease in HCV RNA and 18.75% (3 of 16) achieved RVR.
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For cohorts 1, 2 and 3 in treatment-naïve genotype 1 patients, safety and tolerability for the 4-week treatment period were similar for RG7128 with Pegasys plus Copegus compared to placebo with Pegasys plus Copegus.
There were no serious adverse events reported during the 4-week treatment periods of triple therapy, and most of the adverse events reported were of mild to moderate intensity. Headache and fatigue were the most frequently reported adverse events in patients who received active RG7128 plus Pegasys plus Copegus, with an overall frequency of 66% and 42% reporting at least one of these events, respectively. These events were also the most frequently reported adverse events in patients who received placebo with Pegasys and Copegus.
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In general, the adverse events reported were consistent with the clinical safety profile for Pegasys and Copegus, including the frequency and severity of these adverse events, as well as any general body system observations. Grade 3/4 neutropenia was observed in 31% of the placebo patients and in 12% to 30% of the RG7128 patients in each active dosing cohort. Grade 3 changes in hemoglobin were observed in 19% of the placebo patients and in 31% of the RG7128 patients. There were no clinically significant changes in hepatic, renal, or other safety laboratory parameters, vital signs, or electrocardiograms. Overall, there was no clinical evidence of any major organ toxicities related to RG7128. One patient in the active treatment group discontinued the study during the 4 week treatment period due to lower-gastrointestinal adverse events. At the time of study discontinuation, this patient had undetectable HCV RNA. RG7128 was generally safe and well-tolerated when administered for 4 weeks in combinations with Pegasus plus Copegus in patients with HCV genotype 1. Results from the 1500 mg dose cohort (cohort 4) in 25 prior treatment non-responders, or patients who did not achieve an SVR with previous interferon-based therapy, and who were chronically infected with HCV genotypes 2 or 3 indicated:
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Following 4 weeks of treatment with RG7128 1500mg BID with Pegasys plus Copegus (cohort 4), patients achieved a mean 5.0 log10 IU/mL decrease in HCV RNA and 95% (19 of 20) patients achieved RVR. Following 4 weeks of treatment with placebo with Pegasys plus Copegus, patients achieved a mean 3.7 log10 IU/mL decrease in HCV RNA and 60.0% (3 of 5) achieved RVR. Safety and tolerability during the 4-week treatment period were similar for RG7128 with Pegasys plus Copegus compared to placebo with Pegasys plus Copegus. There were no serious adverse events reported during the 4-week treatment period, and most of the adverse events reported were of mild to moderate intensity.
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One subject discontinued RG7128, Pegasys and Copegus due to protocol specified stopping criteria (not treatment-emergent), and ECG changes. Adverse events reported in cohort 4 were similar to those reported in Cohorts 1-3. Grade 3/4 neutropenia was observed in 0% of the 5 placebo patients and in 20% of the 20 RG7128 patients in the active dosing cohort. Grade 3 changes in hemoglobin were observed in 20% of the placebo patients and in 25% of the RG7128 patients. There were no clinically significant changes in hepatic, renal, or other safety laboratory parameters, vital signs, or electrocardiograms. As seen in the patients infected with HCV genotype 1, there was no clinical evidence of any major organ toxicities related to RG7128. RG7128 was generally safe and well-tolerated when administered for 4 weeks in combination with Pegasus plus Copegus in patients with HCV genotypes 2 and 3.
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Tell me more about RG7128
RG7128 is being developed by Pharmasset and Roche through our collaboration to develop nucleoside polymerase inhibitors for the treatment of chronic hepatitis C virus (HCV) infections. RG7128 is a prodrug of a molecule we discovered named PSI-6130, an oral cytidine nucleoside analog.
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What is a prodrug?
A prodrug is a chemically modified form of a molecule designed to enhance the absorption, distribution and metabolic properties of that molecule. PSI-6130 is the active component of RG7128. PSI-6130 was shown to be an inhibitor of HCV replication, specifically targeting the HCV RNA polymerase .
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PROPEL Study
On April 24, 2009, Roche began dosing a Phase 2b study with RG7128. The Phase 2b trial was anticipated to enroll approximately 400 treatment-naive, genotype-1 or genotype-4 HCV-infected patients. The trial will evaluate the dose and duration of treatment of RG7128 in combination with Pegasys plus Copegus, the current standard of care (SOC). The primary efficacy endpoint of the trial will be the proportion of patients that achieve an SVR.
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In May 2010, we announced that all 408 patients enrolled in the study had completed their scheduled 8 or 12 weeks of the triple combination portion of the assigned treatment (RG7128 plus SOC).
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In June, we announced that Roche had submitted two abstracts to the AASLD Liver meeting discussing the results from an interim analysis of the PROPEL study.
Top line results indicated that treatment with RG7128 administered with SOC for 8 or 12 weeks was safe and well tolerated and the on-treatment efficacy data demonstrated that more then 80% of patients had undetectable HCV RNA in all cohorts receiving the 12 week triple regimen compared to less then 50% for the placebo/SOC cohort. A second abstract indicated that there were no viral rebounds or resistance related breakthroughs during the first 8 or 12 weeks of triple combination therapy.
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JUMP-C Study
In early 2010, Roche initiated a 24 week Phase 2b trial called JUMP-C with RG7128 in combination with SOC in treatment-naïve patients with HCV genotypes 1 and 4 in order to evaluate the safety and efficacy of RG7128 in combination with standard of care for longer durations. Patients who achieve an RVR on the combination of RG7128 1000mg BID with SOC will stop all therapy at the end of the first 24 weeks, the first "24+0" trial of its kind. Patients were enrolled at sites in the US and Canada. The data from this study could provide the flexibility for combining RG7128 with direct acting antivirals currently in development with varying durations of therapy. In May 2010, we announced that Roche had completed enrollment of the trial.
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In the third quarter 2010, Roche is anticipated to initiate a "rollover" study enrolling patients from both the PROPEL and "24+0" trials. Patients considered non-responders in the placebo and SOC arms will be offered the opportunity to receive 24 weeks of RG7128 plus SOC, followed by 24 weeks of SOC. .

Feb 2010
Roche has also announced that it will not conduct the previously planned 28 day INFORM-2 study, designed to evaluate the combination of RG7128 with RG7227, InterMune's HCV protease inhibitor, with and without pegylated interferon and ribavirin.
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Roche has decided instead to conduct longer duration studies, including the INFORM-3 clinical study of RG7128 and RG7227 with and without pegylated interferon and ribavirin. .

Pharmasset Announces Complete Enrollment of RG7128 Phase 2b Clinical Study
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Roche is continuing to conduct dose ranging safety and efficacy studies of RG7227, and has announced a consequent delay of the INFORM-3 clinical study.
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Roche has initiated a 24 week Phase 2b study with RG7128 in combination with pegylated interferon and ribavirin in treatment-naïve patients with HCV genotypes 1 and 4 in order to evaluate the safety and efficacy of RG7128 in combination with standard of care for longer durations.
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The data from this study could provide the flexibility for combining RG7128 with direct acting antivirals currently in development with varying durations of therapy. This study is currently enrolling at sites in the US and Canada and is expected to complete enrollment in the second quarter.

Nov 2010

Danoprevir Plus Pegasys and Ribavirin
Low rate of viral load rebound observed among treatment-naive genotype 1 patients with chronic hepatitis C treated with danoprevir (RG7227) plus Peg-IFN α-2a (40KD) (PEG ASYS) plus ribavirin: interim analysis
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Direct-Acting Antivirals DAA Combination
RG7128 (Polymerase Inhibitor) In Combination with RG7227 (Danoprevir) Protease Inhibitor
Company Name: Pharmasset Is now in : Phase II .

Nov. 23, 2010/ RG7128 in combination with SOC/Geno 2 or 3 delayed until 2011
In addition, Roche is planning to initiate a Phase 2b study of RG7128 in combination with SOC in patients with HCV genotypes 2 or 3 during the first half of 2011.
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Roche is also planning to initiate a Phase 3 program for RG7128 during 2011 and plans to submit a marketing application for RG7128 to one or more regulatory authorities in 2013.
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J Hepatol.
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Dec 8 2010
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Treatment of Chronic Hepatitis C Patients with the NS3/4A Protease Inhibitor Danoprevir (ITMN-191/RG7227) Leads to Robust Reductions in Viral RNA: A Phase 1b Multiple Ascending Dose Study. .
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Forestier N, Larrey D, Guyader D, Marcellin P, Rouzier R, Patat A, Smith P, Bradford W, Porter S, Blatt L, Seiwert SD, Zeuzem S.
J.W. Goethe Universität, Frankfurt, Germany. .

(TN) = treatment-naïve (NR) = non-responders .

Abstract
Danoprevir is a potent and selective inhibitor of the hepatitis C virus (HCV) NS3/4A serine protease. The present study assessed the safety, pharmacokinetics and antiviral activity of danoprevir in a randomized, placebo-controlled, 14-day multiple ascending dose study in patients with chronic HCV genotype 1 infection.

Four cohorts of treatment-naïve (TN) patients (100 mg q12h, 100 mg q8h, 200 mg q12h, 200 mg q8h) and one cohort of non-responders (NR) to prior pegylated interferon alfa-ribavirin treatment (300 mg q12h) were investigated.

RESULTS:
Danoprevir was safe and well tolerated; adverse events were generally mild, transient and without association to treatment group or dose level. Danoprevir displayed a slightly more than proportional increase in exposure with increasing daily dose and was rapidly eliminated from the plasma compartment. Maximal decreases in HCV RNA were -3.9 log(10) IU/mL and -3.2 log(10) IU/mL in TN receiving 200 mg q8h and 200 mg q12h, respectively. End of treatment viral decline in these two cohorts was within 0.1 log(10) IU/mL of viral load nadir. HCV RNA reduction in NR was more modest than that observed in upper dose TN cohorts. The overall incidence of viral rebound was low (10/37) and was associated with R155K substitution in NS3 regardless of HCV subtype. .

CONCLUSION:
Danoprevir was safe and well tolerated when administered for 14 days in patients with chronic HCV genotype 1 infection. Treatment resulted in sustained, multi-log(10) IU/mL reductions in HCV RNA in upper dose cohorts. These results support further clinical evaluation of danoprevir in patients with chronic HCV.


Copyright © 2010. Published by Elsevier B.V.

Oral Therapy Against Hepatitis C

A Promising First Step for Combination Oral Therapy Against HCV
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In a short-term study, use of a protease inhibitor and a polymerase inhibitor together rapidly lowered HCV RNA levels.


Oral hepatitis C virus (HCV) protease inhibitors are expected to be approved in 2011. Adding these agents to standard HCV treatment (peginterferon plus ribavirin) improves the likelihood of sustained virologic response, but the interferon component must be given subcutaneously and has substantial side effects. In the industry-funded INFORM-1 study, researchers explored whether an interferon-free regimen containing two new oral anti-HCV agents — the protease inhibitor danoprevir, plus the nucleoside polymerase inhibitor RG7128 — could successfully suppress HCV replication.

Patients with chronic HCV genotype 1 infection but not cirrhosis or HIV infection were randomly assigned to receive placebo (n=14) or one of six different doses of danoprevir plus RG7128 (n=74) for 13 days. Treatment was directly observed in a clinical research unit.

At day 14, patients who received danoprevir plus RG7128 had marked declines in HCV RNA, with the median reduction ranging from 3.7 to 5.2 log10 IU/mL in the different dose groups; some patients achieved undetectable HCV RNA levels. At the highest doses tested, reductions in viral load were similar between patients who were treatment naive and those who had not responded to previous standard-of-care treatment. No phenotypic drug resistance was detected, although one patient with viral rebound did have a clone containing a danoprevir-resistance mutation.

Comment: This study shows that a combination of two oral investigational agents effectively suppresses HCV replication, at least in the short term. There has been an explosion of new direct-acting anti-HCV agents, and promising trial results were reported for many of them at the Liver Meeting this month in Boston. If longer-term studies show that combination therapy with new oral agents can eliminate viral replication, we may be able to cure HCV with pills alone. As an editorialist notes, we are "on the eve of a new era in HCV treatment."
Published in Journal Watch Infectious Diseases November 17, 2010
— Rajesh T. Gandhi, MD

Also See : AASLD 2010 Summary Of Hepatitis C Oral Inhibitors
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Citation(s):
Gane EJ et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): A randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet 2010 Oct 30; 376:1467.
Medline abstract (Free)
Thomas DL. Curing hepatitis C with pills: A step toward global control. Lancet 2010 Oct 30; 376:1441.
Medline abstract (Free)

Sunday Spotlight Hepatitis C Drug Danoprevir : (RG7227/ITMN-191) / Nov 28th

From NATAP RG7128

Low rate of viral load rebound observed among treatment-naive genotype 1 patients with chronic hepatitis C treated with danoprevir (RG7227) plus Peg-IFN α-2a (40KD) (PEG ASYS) plus ribavirin: interim analysis

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On This Blog:

RG7128
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RG7128, being developed jointly by Roche and Pharmasset
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Background on non-nucleoside polymerase inhibitors "(non-nucs), and nucleoside polymerase inhibitors (nucs)".
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Excerpt*

From biopharma report:

Both Vertex and Merck intend on launching new HCV treatments in 2011 based on a new class of compounds known as NS3 protease inhibitors (PI). These drugs herald a new breed of targeted medicines- sometimes called direct acting antivirals (DAA). The advantage is a significantly higher cure rate and shorter duration of treatment. However, these drugs are susceptible to viral resistance and require concurrent use with both interferon and ribavirin. A second type of compound focuses on inhibition of the NS5B polymerase. Of these there are two classes, non-nucleoside polymerase inhibitors (non-nucs), and nucleoside polymerase inhibitors (nucs). Both have been shown to be effective in combination with interferon + ribavirin, but non-nucs, like protease inhibitors, are also prone to mutation driven resistance.
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On the other hand, nucleoside polymerase inhibitors have a high barrier to resistance. In studies shown by Roche, no resistance was observed in cultures treated with R7128, its nucleoside polymerase inhibitor licensed from Pharmasset, for two weeks as monotherapy. Cultures treated with non-nucs or protease inhibitors all developed resistance. R7128 was also shown to reduce the formation of resistant colonies when added to either a non-nuc or PI. These studies show the flexibility of nucs in combination treatment.
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Pharmasset’s lead compound is currently in multiple Phase II trials. Results from the 12 week R7128 treatment portion of a 48 week triple combo PROPEL trial with interferon + ribavirin trial have been released showing high rapid virologic responses and a low rate of adverse events. Full SVR data will be available in 2011. A longer trial involving 24 weeks of dosing called JUMP-C is now dosing. Phase III studies are expected to begin in 2011 as well, with an NDA filing anticipated in 2013.
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PROPEL trialRG7128 plus peginterferon (pegIFN) alfa-2a with ribavirin (RBV) demonstrated high rapid virologic response (RVR) and complete early virologic response (cEVR) rates in treatment-naive patients with genotype 1 or 4 HCV infection
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RG7128 had safety profile similar to standard of careRG7128 not associated with treatment-emergent viral breakthrough or resistance
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See Slides @ NATAP High rates of early viral response, promising safety profile and lack of resistance-related breakthrough in HCV GT 1/4 patients treated with RG7128 plus PegIFN alfa-2a (40KD)/RBV: Planned Week 12 interim analysis from the PROPEL study
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INFORM-1 Trial
Roche is conducting a combination trial of R7128 with the protease inhibitor R7227 from Intermune. Results from a 14 day INFORM-1 trial showed the drugs were safe when administered together and resulted in a sustained viral load reduction. Continuing studies will add the drug Ritonavir to boost R7227 without increasing side effects
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From Doctors Guide:

INFORM-1 trial was designed to assess the safety, tolerability, and antiviral activity of an oral combination treatment with 2 experimental drugs, RG7128 (a polymerase inhibitor that blocks elongation of the new HCV RNA chain) and danoprevir (a protease inhibitor that blocks an enzyme the virus needs to replicate itself) in patients with chronic HCV.A total of 88 patients with HCV genotype 1 were recruited into 1 of 7 treatment groups and randomised to receive various doses and schedules of the combined treatment (n = 74) or placebo (n = 14) for up to 13 days. Some patients had never been treated before, while others had failed interferon-based standard therapy.
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Change in HCV RNA concentration was measured at the start of the study and at regular intervals during treatment up to day 14.
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Patients who had never been treated before who received the highest doses of the 2 drugs (1000 mg RG7128 and 900 mg danoprevir BID) had a median HCV RNA reduction after 14 days of 5.1 log10 IU/ml, compared with a reduction of 4.9 log10 IU/ml in patients who had shown no response to previous standard treatment, and an increase of 0.079 log10 IU/ml in patients taking placebo.The combined treatment of RG7128 and danoprevir was generally well tolerated with no treatment-related severe side-effects, and no safety-related treatment discontinuations.In addition, there was no evidence of treatment resistance, unlike the rapid development of resistance shown by some classes of direct-acting antiviral drugs when given as monotherapy.
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The balance of Pharmasset’s HCV pipeline consists of PSI-7977, which is enrolling patients in Phase IIb and PSI-938, which has completed Phase 1b. The company is planning studies combining these two nucs; initial data should be available Q1 next year. Phase II combo studies are expected to begin around the second or third quarter of 2011
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PROPEL: RG7128 Plus PegIFN alfa-2a/RBV Demonstrates High Rates of RVR and cEVR in Treatment-Naive Patients Infected With Genotype 1/4 HCV
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Also See :Hepatitis C Drugs: R7128 with the protease inhibitor R7227
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*Pharmasset Riding High on Nucs
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*See NATAP: New HCV Drugs: R7128 nucleoside, PSI7977 nucleotide, PSI938 nucleotide, ANA598 nnrti (rash), danoprevir protease, IMO-2125, a TLR agonist
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Pharmassets candidates nearing preparation for clinical development:RG7128, a pro-drug of PSI-6130 for the treatment of HCV, is entering a phase 2b clinical trial through a collaboration with Roche;PSI-7977, an isomer of PSI-7851 is a nucleotide analog for the treatment of HCV, and is currently in a phase 2b trial;PSI-352938 (PSI-938), a purine nucleotide analog for the treatment of HCV, recently completed a phase 1 trial.
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Slide Presentations:
IL28B SNP geographical distribution and antiviral responses in a 28-day phase 2a trial of PSI-7977 daily dosing plus PEG-IFN/RBV
JG. McHutchinson et al61st Annual Meeting of the American Association for the Study of Liver DiseasesBoston, MAOct 29-Nov 2, 2010

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Clinical synergy of an anti-HCV nucleotide analog with SOC: Viral kinetics of PSI-7977 with SOC

E. Lawitz et al61st Annual Meeting of the American Association for the Study of Liver DiseasesBoston, MA

Oct 29-Nov 2, 2010

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High Rapid Virologic Response (RVR) with PSI-7977 daily dosing plus PEG-IFN/RBV in a 28-day Phase 2a trial
E. Lawitz et al61st Annual Meeting of the American Association for the Study of Liver DiseasesBoston, MAOct 29-Nov 2, 2010.....
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Danoprevir

Roche Acquired the rights to InterMune HCV Protease Inhibitor Danoprevir

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*Excerpt:
From Medscape:

The investigational protease inhibitor danoprevir, which targets the hepatitis C virus (HCV), combined with the standard of care for HCV infection — peg-interferon alpha-2a and ribavirin — produces rapid and profound reductions in HCV RNA..Entry criteria were noncirrhotic treatment-naïve adults (predominately genotype 1 virus) with serum HCV RNA levels of 50 000 IU/mL or more and without advanced fibrosis..All patients were administered a standard of care regimen of pegylated interferon alpha-2a plus weight-based ribavirin, and were randomized, for 12 weeks, to placebo or 1 of 3 danoprevir groups: 300 mg every 8 hours, 600 mg every 12 hours, or 900 mg every 12 hours. When danoprevir was stopped, all patients continued on standard therapy for an additional 24 or 48 weeks, depending on whether or not they achieved a rapid virologic response.The second part of the study was a planned continuation of danoprevir to week 24, but that "never was undertaken" because of incidents of reversible grade 4 ALT elevations in 3 patients in the 900 mg group, the highest dose of the study, said Dr. Terrault. Patients already enrolled in the 900 mg group were rerandomized to 300 or 600 mg.
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The principle measure of efficacy was an undetectable HCV RNA level (less then 15 IU/mL); measurements were taken at baseline and at weeks 2, 4, and 12. Missing data points were considered to be nonresponders.
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Dr. Terrault reported that the interim analysis of those who completed 12 weeks of danoprevir therapy was based on 62 patients receiving 300 mg (93%), 61 receiving 600 mg (94%), and 8 receiving 900 mg (16%).
At week 2, levels of HCV RNA were undetectable in 52% of the 300 mg group, 57% of the 600 mg group, 62% of the 900 mg group, and 0% of the placebo group.
At week 4, that progressed to 73%, 86%, 86%, and 7%, respectively; and at week 12, to 88%, 89%, 92%, and 43%..Viral resistance to danoprevir emerged in the low-dose (300 mg) group in 2 patients at week 2 and in 5 patients at weeks 4 and 12. In the 600 mg group, patients fared better, with 3 developing treatment-emergent resistance by week 12. No patients developed resistance in the highest-dose (900 mg) group, but the cumulative exposure was significantly less because of the emerging toxicity and discontinuation of that dosing regimen. All of the resistance was seen in patients with HCV genotype 1a.

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Side Effects
Rates of most common adverse events in the danoprevir groups were at least twice as high as those seen with standard care alone. Often, there was little difference in the incidence of adverse effects with an increase in the dose of danoprevir.Although the serious adverse event of grade 4 ALT elevation was most likely to occur at the highest dose of the drug (3 incidents) and led to the discontinuation of that dosing, there also was 1 incident among the 60 patients in the 600 mg group. Dr. Terrault said that "modeling the available pharmacokinetics data showed a relationship between danoprevir exposure, specifically AUC and the likelihood of having ALT elevation.".

AASLD:HCV Protease Inhibitor Danoprevir is Positive

Hepatic encephalopathy increases falls in cirrhotic patients
Last Updated: 2010-11-26 9:00:47 -0400

(Reuters Health)

By David Douglas
NEW YORK (Reuters Health) - Minimal hepatic encephalopathy (MHE) increases the risk of falls in patients with cirrhosis, Spanish researchers report in an October 26th online paper in the American Journal of Gastroenterology.
"MHE causes a decline in cognitive function and impairs the ability to perform daily activities in patients with cirrhosis," Dr. Germ�n Soriano, senior author on the study, told Reuters Health by email. "In the present study involving 130 cirrhotic patients and 43 controls, previous falls were more frequent in patients with MHE than in those without MHE and controls."
Dr. Soriano of Hospital de la Santa Creu i Sant Pau, Barcelona, and colleagues note that MHE can only be detected by psychometric or neurophysiological testing and is present in a variable proportion of patients depending on the populations studied and the criteria used for diagnosis.
In the current study, of the 130 patients, 34.6% exhibited MHE and of this group, 40% reported falls in the previous 12 months. This was true of only 12.9% of those without MHE and 11.6% of controls. In the MHE group, falls led to a greater need for primary health care services (8.8% versus none).

In the subset of 21 patients on psychoactive drugs, 75% with MHE reported falls compared to only 15.3% of those without the condition.
Independent risk factors associated with previous falls were MHE (odds ratio, 2.91), previous encephalopathy (odds ratio, 2.87) and antidepressant therapy (odds ratio, 3.91).
The researchers concede that the study was retrospective, but observe that in light of these findings future prospective studies are warranted. In particular, Dr. Soriano added, "Falls represented a significant cause for healthcare and hospitalization requirements in these patients."
SOURCE: http://link.reuters.com/map66q
Am J Gastroenterol 2010.

From HCV Advocate

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Disability & Benefits: Rumors, Myths, and a Little Truth

From Medical News Today

Study Highlights Liver Health Risk In UK
28 November 2010Growing groups of the so-called "worried well" are putting their lives at risk by shunning visits to their GP over alcoholic health related matters, according to new evidence. The study, which appears in Hepatology, based...

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Justice tough to find for Chinese who got HIV/AIDS through tainted blood
Tian Xi is among 1 million Chinese infected by transfusions at government-run hospitals. One million more were infected donating blood. The government has yet to apologize or investigate the coverup.
Los Angeles Times -

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Marin health employees warn budget cuts could endanger public healthBut the employees sounding the alarm caution such cuts are only the beginning. They say county health managers are preparing to close the public health laboratory and most of the county's remaining health clinics, which provide maternity care and treat patients suffering from tuberculosis, HIV/AIDS, hepatitis C and sexually transmitted diseases.

The Economic Burden of Late Entry Into Medical Care for Patients With HIV Infection - pdf attached-

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Reliable Culture of Human Embryonic Stem Cells
Human embryonic stem cells have enormous potential for use in pharmaceutical development and therapeutics; however, to realize this potential there is a requirement for simple and reproducible cell ...

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