non-nucleoside polymerase inhibitors;
nucleoside polymerase inhibitors
DAA directly acting antiviral
Two classes of NS5B inhibitors have been developed: nucleoside/nucleotide and non-nucleoside polymerase inhibitors.
Nucleoside/nucleotide analogue polymerase inhibitors
Non-nucleoside polymerase inhibitors
(summarized in Table 1).
|Efficiency / log decline (log10 IU/ml)|
|Generic name||Phase of development||Monotherapy||Combination||Comment|
|NM-283 (Idenix)||Valopicitabin||Phase I||discontinued||0.87 (15 d)||3.90-4.56 (IFN)||Gastrointestinal side effects|
|R-1626 (Roche)||Phase II||discontinued||2.6-3.7 (14 d)||5.2 (IFN/R)||Neutropenia, lymphopenia, neurotoxicity|
|INX-189/BMS-986094 (Inhibitex/BMS)||Phase III||discontinued||0.6-4.25 (7 d)||0.75-3.79 (R/7 d)||Liver and severe cardiac & renal toxicity|
|PSI-938/GS-938 (Pharmasset/Gilead)||Phase III||discontinued||4.8-5.8 (14 d)||Hepatotoxicity|
|Alios-2200 (Alios)||Phase I||ongoing||4.54 (7 d)||n.a.|
|Alios-2158 (Alios)||Phase I||ongoing||n.a.||n.a.|
|R-7128/RG-7128 (Roche)||Mericitabine||Phase II||ongoing||2.7 (14 d)||5.00|
|PSI-7977/GS-7977 (Pharmasset/Gilead)||Sofosbuvir||Phase III||ongoing||4.7 (7 d)||6.4 (IFN/R)|
|Thumb I inhibitors|
|BILB-1941 (Boehringer Ingelheim)||Phase I||discontinued||> 1 (5 d)||/||gastro-intestinal side effects|
|MK-3281 (Merk)||Phase I||discontinued||3.75 (7 d)||/||gastro-intestinal side effects|
|BI-207127 (Boehringer Ingelheim)||Phase II||ongoing||0.6-3.1 (5 d)||5.6 (IFN/R)|
|Thumb II inhibitors|
|VX-759 (Vertex)||Phase I||discontinued||2.5 (10 d)||3.7 (VX222)||low anti-viral efficacy|
|VX-916 (Vertex)||Phase I||discontinued||1.5 (3 d)||/||low anti-viral efficacy|
|GS-9669 (Gilead)||Phase I||ongoing||3.5 (3 d)||/|
|PF-00868554 (Pfizer)||Filibuvir||Phase II||ongoing||0.68-2.13 (8 d)||3.44-4.43 (IFN/R)|
|VX-222 (Vertex)||Phase II||ongoing||3.1-3.4 (3 d)||ongoing|
|Palm I inhibitors|
|ABT-333 (Abbott)||Phase I||ongoing||0.7-1.5 (2 d)||3.5-4.0 (IFN/R)|
|ABT-072 (Abbott)||Phase I||ongoing||1.19-2-3 (2 d)||(ABT-450/-333)|
|ANA-598 (Roche)||Setrobuvir||Phase II||ongoing||2.4-2.9 (3 d)||outstanding|
|Palm II inhibitors|
|HCV-796 (ViroPharma/Wyeth)||Nesbuvir||Phase I||discontinued||1.4 (14 d)||/||hepatotoxicity|
|IDX-375 (Idenix)||Phase I||discontinued||0.5-1.1 (1 d)||/||hepatotoxicity|
|GS-9190 (Gilead)||Tegobuvir||Phase II||ongoing||1.4-1.7 (8 d)||5.7 (9256/IFN/RBV)|
Thumb I inhibitors (benzimidazole site): MK-3281 (Merck, Rahway, New Jersey, USA), B ILB1941 and BI 207127 (Boehringer-Ingelheim, Ingelheim am Rhein, Germany) are thumb I site inhibitors. Pre-existing NS5B substitutions known to reduce sensitivity were identified e.g. for BILB1941 at positions V494I/A, I424V and P496A .
Polymerase inhibitors in clinical trials
Nucleos(t)ide inhibitors in clinical trials with interferon
Mericitabine (RG 7128)
Sofosbuvir (GS-7977, formerly PSI-7977)
Nucleos(t)ide inhibitors in clinical trials without interferon
Mericitabine (RG 7128)
Breakthrough rates were higher among patients not receiving RBV and showed in all patients, the selection of danoprevir-resistant variants, while only one patient showed the NS5B S282T polymerase mutation associated with resistance to mericitabine. Neutropenia or treatment emergent liver toxicity was not observed .
Non-nucleoside inhibitors in clinical trials with interferon
Non-nucleoside inhibitors in clinical trials without interferon
ABT-072 and ABT-333
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