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HCV Treat Now or Wait?? What's Currently in Phase 3 Now, Drug Development Timeline; Liver Transplant Treatment/Studies; New study in advanced hepatic fibrosis: TMC435+GS7977 (+/-RBV) for treatment-naives & null responders
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9 & Soon 11 New HCV Drugs in Phase 3
Boehringer Ingelheim Enrolls First Patients in Pivotal Phase 3 Interferon-Free Hepatitis C Trial Program - (01/17/13)
GILEAD PROVIDES UPDATE ON HEPATITIS C DEVELOPMENT PROGRAMS - update on GS-7977+GS-5885+Rbv in null responders in Electron - (01/07/13)
New GS7977+GS5885 Studies/Phase 3 - (01/02/13)
HCV IFN-Free Therapies/Regimens - (01/02/13)
HCV, Who Should Be Treated Now? - (12/18/12)
Interferon free therapy with direct acting antivirals for HCV- (01/08/13)
Liver International February 2013
Proceedings of the 6th Paris Hepatitis Conference, International Conference on the Management of Patients with Viral Hepatitis
Tarik Asselah and Patrick Marcellin
Treat or Wait in HCV? A Series of Challenging Case Vignettes
In this series of case vignettes, Jordan J. Feld, MD, MPH; Michael W. Fried, MD; Mark S. Sulkowski, MD; and Stefan Zeuzem, MD, weigh the risks and benefits of treating now vs waiting for future therapies in 9 unique case scenarios.
Patients with HCV and F1 and F2 fibrosis stage: treat now or wait? - (01/13/13)
Liver International Feb 2013
Mitchell L. Shiffman1 and Yves Benhamou2
from Jules: the article above was recently published and there are some interesting thoughts & suggestions in it but I differ with some statements in it. The authors say: "subosfovir will be taken with PEG-IFN/RBV in patients with HCV genotype 1", in discussing whether one should wait for GS7977 to be treated, but that statement by the authors may or may not be true. Right now in phase 3 are a few new protease inhibitors, GS7977 and a few NS5A inhibitors. Gilead, Boerhinger Ingelheim, Abbott, Janssen & BMS are in phase 3 studying combinations of their own drugs. Merck, Vertex, BMS, Roche & Achillion are in phase 2 with combinations of multiple oral drugs in IFN-free regimens. Most of these new oral drugs are taken once-daily but a couple of them are twice daily. So for example, Gilead is studying GS7977+GS5885+RBV, that is their non-nuc polymerase, their NS5A + RBV. So the question is will insurers or payers allow patients & clinicians to combine drugs not very well studied together, although there is a phase 2 study of GS7977+BMS052 (an NS5A) with 100% cure rates with 12 weeks therapy in easier to treat treatment-naives. Ongoing is a study in harder-to-treat null responders with TMC435+GS7977. Take a look at my link to ongoing phase 3 studies, it appears now that these studies will complete at different times suggesting that the FDA approval for each will come sequentially, in other words they won't all be available at the same time. GS7977's 1st approval appears to be in GT2/3 with RBV in combination and the study was started early on in this sequence. BMS started phase 3 with their NS5A in combination with Peg/Rbv for GT1 in late 2011 similar in time to when Janssen started their phase with studying TMC435+Peg/Rbv for GT1. Boerhinger Ingelheim started their phase 3 program with their new protease early on in combination again with Peg/rbv but started a new phase 3 study in 2012 with an IFN-free regimen of BI 201335 (protease) and BI 207127 (non-nucleoside polymerase inhibitor administered twice-daily), plus ribavirin. Abbott started their phase 3 in late 2012 study an IFN-free 4 drug combination of ABT450 (protease), ABT267 (NS5A), ABT333 and RBV so expected FDA approval will be later. Gilead started phase 3 of their combination of GS7977+GS5885 (NS5A) + Rbv for GT1 in late 2012. Also in phase 3 now is PegLambda which studies show is as potent as current peg-interferons but safer, more tolerable & easier to tolerate. TMC435 is being studied in phase 3 with Peg/Rbv but there is this study ongoing starting, which will have 180 participants and Janssen will have additional data with the combination of TMC435+GS7977:
My feeling is that some payers might allow combinations of oral drugs that do not necessarily have FDA approval because they were studied together in large phase 3 studies, so long as there is good phase 2 data confirming efficacy & safety. So I am providing additional context for the articles published "....Treat Now or Wait...". For patients with advanced disease who might want to add peginterferon to a multi-oral drug regimen to feel more confident in an SVR PegLambda is expected to be available.
A Study of TMC435 in Combination With PSI-7977 (GS7977) in Chronic Hepatitis C Genotype 1-Infected Prior Null Responders To Peginterferon/Ribavirin Therapy or HCV Treatment-Naive Patients
Patient must have had a liver biopsy within 3 years before screening (or between screening and baseline visit) or patient must have had a liver biopsy at any time in the past which showed Metavir F3 or F4 fibrosis
Verified January 2013 by Janssen R&D Ireland
http://clinicaltrials.gov/ct2/show/NCT01466790?term=tmc435+gs7977+null&rank=1
The purpose of this study is to investigate the efficacy and safety of TMC435 plus PSI-7977 (GS7977) with or without ribavirin in patients who are chronically infected with genotype 1 hepatitis C virus (HCV) and who did not respond to prior peginterferon/ribavirin therapy or are HCV treatment-naive (patients who never received treatment for HCV infection).
This is a Phase IIa, randomized (the study medications are assigned by chance), open label (all people know the identity of the intervention) study of TMC435 plus PSI-7977 (GS7977) with or without ribavirin. The study consists of a screening phase (6 weeks); a treatment phase (12 or 24 week period); and a posttreatment phase (follow-up period up to Week 48). Approximately 180 patients will be enrolled in this study. Patients will be sequentially enrolled into two cohorts in this study. Cohort 1 (90 patients) will include patients without advanced hepatic fibrosis who did not respond to previous PegIFN/ribavirin therapy and Cohort 2 (90 patients) will include only patients with advanced hepatic fibrosis who did not respond to previous PegIFN/ribavirin therapy or are HCV treatment-naive. Safety will be evaluated throughout the study and will include evaluations of adverse events, clinical laboratory tests, electrocardiogram, vital signs, and physical examination. The entire study duration for each participant will be approximately 48 weeks.
Shiffman & Benhamou also say:
from Jules: the statement "Future HCV treatments will probably also be less effective in patients with advanced fibrosis and cirrhosis" may not be true and depends on which group of patients, how progressed their disease is. I believe that patients with stage 3 or treatable phase 4 pre-cirrhosis & cirrhosis will be able to put together regimens with very high SVR rates if not 100% with IFN-free combinations after several of the ongoing phase 3 studies are completed & FDA approval.
When deciding whether to treat a patient with HCV now, or to defer treatment, most clinicians would decide to treat patients with bridging fibrosis and cirrhosis (Metavir stages 3 and 4) now because they have an increased risk of hepatic decompensation and hepatocellular carcinoma. There is a feeling by many that patients with less severe fibrosis can wait for better or less toxic therapies. The irony of this approach is that HCV treatment is more successful in patients with mild than advanced fibrosis. This is true whatever the baseline factors including genotype, race and IL28B status and whether patients are being treated with PEG-IFN/RBV dual therapy or triple therapy with a protease inhibitor [2-5]. Future HCV treatments will probably also be less effective in patients with advanced fibrosis and cirrhosis. Excluding patients with mild fibrosis from treatment now will only reduce the overall SVR rate in the treated population, increase the overall cost per SVR, and most importantly increase the risk that a patient who could be 'cured' of HCV now fails to achieve SVR in the future.
LIVER TRANSPLANT Treatment/STUDIES
GS-7977 Liver Transplant Studies - (01/08/13)
Telaprevir & Boceprevir in Liver Transplantation - (12/15/12)
Telaprevir Post Liver Transplant - (12/15/12)
Telaprevir-based triple therapy in liver transplant patients with hepatitis C virus: A 12-week pilot study providing safety and efficacy data - (12/15/12)
Boceprevir HCV Liver Transplant - (12/15/12)
New therapies against HCV: Expected risks and challenges associated with their use in the liver transplant setting - (12/15/12)
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