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New HCV Drugs: non nucleoside polymerase inhibitors
  by Jules Levin, NATAP http://www.natap.org
Many observers have written off the class of HCV drugs non nucleoside polymerase inhibitors because resistance can develop quickly but does it really matter if this drug is used in combination with 2 other potent HCV drugs??? HCV protease is a potent class (3-4.5 or even 5 logs for a few proteases), as well HCV nucleotide is also a potent class (4.5 logs) and of course a big reason it's liked is because resistance is very hard to develop or won't at all. And of course NS5A is a potent class of drug (4-5 logs). The non nucleoside polymerase inhibitors in development have shown a wide range of potency from 1.3 logs to 3.5 logs on average). Here is a review of this 'can't get no respect' class. What is interesting about this class is several of these drugs are fairly well along in development and are not far at all away from becoming avaliable. In phase 3 right now however are GS7977, a potent 4.5 log nucleotide, BMS052, a potent 5 log NS5A, and 2 once daily proteases BI1335 & TMC435. Combining GS-7977 with BMS052 provides on average 9 to 9.5 logs potency & 100% cure rate was reported in naive gt1 patients in small study of about 40 patients at EASL, and a null responder study is ongoing combining TMC435 + GS7977 which on average has a 8.5 log potency. If you combined a protease + BMS052+GS7977 you are talking about a 13-14 log potency. And Vertex just announced their nucleotide ALS2200 showed 4.5 logs in the initial study, while we wait for the initial results from their 2nd nucleotide ALS2158, what about the possibility of combining 2 nucleotides, we dont know exactly what that would produce. Pharmasset combined their 2 nucleotides before Gilead bought them and although they had some additive benefits it wasn't double the potency. So that's why the non nucleosides 'can't get no respect'. Still, 80% of HCV-infected remain undiagnosed, efforts to identify by screening this large pool of patients is almost totally absent at this time, so there remains a very large patient pool not yet even knowing they have HCV. In addition, there is the global pool of patients outside the US. In Western & in moreso in Eastern Europe where access even now to telaprevir & boceprevir is very limited due to the costs of the drugs & the failing economies, but this is true in other parts of the globe as well. In places like India, Asia, So & Central America etc access will be a challenge. So there is a lot of time before many patients can be identified & access treatment. It is estimated well over 120 million have HCV globally, with as much as only 8 million in the US. How will the rest of the world get access & what classes of drugs will be in the regimens they might have access to??? What role will pricing play & distribution systems? Another factor is GS-7977+Rbv is a simple 2 drug combination being studied now with phase 3 data in gt1 and gt2/3 in coinfected & monoinfected. This combination is potent but obviously not as potent as some other combinations, although in gt2/3 patients in a small study 100% were cured. But gt1 remains the major concern where other combinations with more potent oral drugs besides RBV will be used. Here is a review of non nucleoside polymerase inhibitors. Gilead has 2 non-nucleoside polymerase inhibitors. Roche bought & has been developing ANA598, a non nucleoside polymerase inhibitor. BMS791325 is a non-nucleoside polymerase inhibitor. Abbott has 2 of these: ABT-072 & ABT-333. Boerhinger Ingelheim has a potent non nucleoside polymerase inhibitor BI207127, which has been studied in combination with their protease BI1335, which is currently in phase 3 completing in about 1 to 1.5 years, the most recent results were reported at EASL 2012. Vertex has a potent non nucleoside VX222. .
EASL: The efficacy and safety of the interferon-free combination of BI 201335 and BI 207127 in genotype 1 HCV patients with cirrhosis: Interim analysis from SOUND-C2 - (04/20/12)
EASL: SVR4 and SVR12 with an interferon-free regimen of BI 201335 AND BI 207127, +/- ribavirin, in treatment-naïve patients with chronic genotype-1 HCV infection: Interim results of SOUND-C2 - (04/22/12)
Safety, pharmacokinetics and antiviral effect of BI 207127, a novel ... www.natap.org/2009/EASL/EASL_08.htm Safety, pharmacokinetics and antiviral effect of BI 207127, a novel HCV RNA polymerase inhibitor, after 5 days' oral treatment
VX-222 Vertex NNRTI Polymerase Inhibitor 3 Days Monotherapy www.natap.org/2010/EASL/EASL_02.htm VX-222 Vertex NNRTI Polymerase Inhibitor 3 Days Monotherapy. Reported by Jules Levin EASL Apr 14-18 2010. Vienna Austria
Patients of all IL28B Genotypes have High SVR Rates when Treated with VX-222 in Combination with Telaprevir/Peginterferon/Ribavirin in the ZENITH Study - (04/24/12)
Vertex QUAD Therapy Yielded 83-93% SVR with 12 weeks duration ... www.natap.org/2012/APASL/APASL_11.htm
A Phase 2a Study of BMS-791325, an NS5B Polymerase Inhibitor, With Peginterferon Alfa-2a and Ribavirin in Treatment-Naive Patients With Genotype 1 Chronic Hepatitis C Virus Infection - (04/25/12)
EASL 2012: GS-9669, A Novel NS5B Non-Nucleoside Thumb Site II Inhibitor, Demonstrates Potent Antiviral Activity, Favorable Safety Profile and Potential for Once-Daily - (04/24/12)
Nonclinical and Cross-genotypic Profiles of GS-9669, a Novel HCV NS5B Non-nucleoside Thumb Site II Inhibitor - (04/06/11)
Antiviral, pharmacokinetic and safety data for GS-9190, a non - NATAP www.natap.org/2007/AASLD/AASLD_39.htm Antiviral, pharmacokinetic and safety data for GS-9190, a non-nucleoside HCV NS5B polymerase inhibitor, in a phase-1 trial in HCV genotype 1
ANA598 HCV Polymerase Inhititor Safety & Activity + Peg/Rbv in ... www.natap.org/2010/EASL/EASL_20.htm At 8 weeks, ANA598 400 mg bid plus Peg/Rbv resulted in 72% of patients achieving undetectable levels of virus. No patient receiving ANA598
12-Week Effiacy and Safety of ABT-072 or ABT-333 with Pegylated ... www.natap.org/2011/APSL/APSL_02.htm In a previous clinical trial, subjects receiving two days of ABT-072 monotherapy had a mean maximum HCV RNA decrease from baseline of 1.3 log10 IU/mL
EASL: Gilead, Bristol Hep C Drug Data Arrives at EASL: 100% Cure Rate with Bristol's phase II study of daclatasvir plus Gilead's GS-7977 in patients with genotypes 1, 2, and 3: SVR4 (early cure) rate in the genotype 1 patients: 100%. In genotype 2/3 patients, the SVR4 rate was 91%. - (04/23/12)
EASL: Potent Viral Suppression With the All-Oral Combination of Daclatasvir (NS5A Inhibitor) and GS-7977 (Nucleotide NS5B Inhibitor), +/- Ribavirin, in Treatment-Naive Patients With Chronic HCV GT1, 2, or 3 (100% SVR gt1, 91% gt2) - (04/19/12)
BMS-766, a Novel HCV NS5A Inhibitor With Enhanced Resistance Coverage - (04/06/11)
EASL 2012
Once Daily GS-7977 Plus Ribavirin in HCV Genotypes 1-3: The ELECTRON Trial- (04/21/12)
GS-7977 + PEG/RBV in HCV Genotype 1: The ATOMIC Trial An End To Response-Guided Therapy - (04/20/12)
GS-7977 Phase 2 Trials: Concordance of SVR4 with SVR12 and SVR24 in HCV Genotypes 1-3 - (04/20/12)
The Effect of Hepatic Impairment on the Safety, Pharmacokinetics, and Antiviral Activity of GS-7977 in Hepatitis C Infected Subjects Treated for Seven Days - (04/24/12)
GS-6620, A Liver-Targeted Nucleotide Prodrug, Exhibits Antiviral Activity and Favorable Safety Profile Over 5 Days in Treatment Naïve Chronic HCV Genotype 1 Subjects - (05/04/12)
EASL 2011
Gilead Studies

Four-Week Treatment with GS-9256 and Tegobuvir (GS-9190) +/- RBV +/- PEG, Results in Enhanced Viral Suppression on Follow-up PEG/RBV Therapy, in Genotype 1a/1b HCV Patients - (04/05/11)
Therapeutic Efficacy of a TLR7 Agonist for HBV Chronic Infection in Chimpanzees - (04/07/11)
Anti-Viral Efficacy and Induction of an Antibody Response Against Surface Antigen with the TLR7 Agonist GS-9620 in the Woodchuck Model of Chronic HBV Infection - (04/07/11)
Three-Day, Dose-Ranging Study of the HCV NS5A Inhibitor GS-5885 - (04/06/11)
A Phase 2b Trial Comparing 24 to 48 Weeks Treatment with Tegobuvir (GS-9190)/PEG/RBV to 48 Weeks Treatment with PEG/RBV for Chronic Genotype 1 HCV Infection - (04/06/11)
GS-6620: A Liver Targeted Nucleotide Prodrug with Potent Pan-Genotype Anti-Hepatitis C Virus Activity In Vitro - (04/06/11)
Emergence and Persistence of NS5B Mutations Following Combination Treatment with Tegobuvir (GS-9190) plus Standard of Care--Long-Term follow-Up from the Phase 2b Study GS-US-196-0103 - (04/06/11)
Preclinical Properties of the Novel HCV NS3 Protease Inhibitor GS-9451 - (04/06/11)
GS-6620, A Novel Anti-Hepatitis C Virus Nucleotide Prodrug, Has A High In Vitro Barrier To Resistance - (04/06/11)
Nonclinical and Cross-genotypic Profiles of GS-9669, a Novel HCV NS5B Non-nucleoside Thumb Site II Inhibitor - (04/06/11)
Preclinical Characterization of GS-9620, A Potent and Selective Oral TLR7 Agonist - (04/06/11)
A Phase-I, Randomized, Double-Blind, Placebo-Controlled Study To Evaluate The Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Escalating Oral Doses of GS-9620 In Healthy Subjects - (04/06/11)
Genotypic and Phenotypic Characterization of HCV Resistance From a Multiple Dose Clinical Trial of GS-9451, a Novel NS3 Protease Inhibitor - (04/06/11)
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