Provided by NATAP
by Jules Levin
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)
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 treatme
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 Austr
Vertex QUAD Therapy Yielded 83-93% SVR with 12 weeks duration ... www.natap.org/2012/APASL/APASL_11.htm
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
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 ANA5
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
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
GS-7977 + PEG/RBV in HCV Genotype 1: The ATOMIC Trial An End To Response-Guided Therapy - (04/20/1
GS-7977 Phase 2 Trials: Concordance of SVR4 with SVR12 and SVR24 in HCV Genotypes 1-3 - (04/20/1
EASL 2011
Gilead Studies
Therapeutic Efficacy of a TLR7 Agonist for HBV Chronic Infection in Chimpanzees - (04/07/1
Three-Day, Dose-Ranging Study of the HCV NS5A Inhibitor GS-5885 - (04/06/1
GS-6620: A Liver Targeted Nucleotide Prodrug with Potent Pan-Genotype Anti-Hepatitis C Virus Activity In Vitro - (04/06/11)
Preclinical Properties of the Novel HCV NS3 Protease Inhibitor GS-9451 - (04/06/1
Preclinical Characterization of GS-9620, A Potent and Selective Oral TLR7 Agonist - (04/06/1
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