Table 1. Characteristics of inhibitor classes.
| Inhibitor class | Resistance | Potency | Lead compoundsa | Developmental stage |
|---|---|---|---|---|
| DAAs | ||||
| NS3-NS4A protease inhibitors | ||||
| First generation | Low-medium barrier | High toward genotype 1, lower toward genotypes 2 and 3 | Telaprevir (Incivek, Incivo) | Approved |
| Boceprevir (Victrelis) | Approved | |||
| Simeprevir (TMC-435) | Phase 3/NDA | |||
| Faldaprevir (BI201335) | Phase 3 | |||
| Vaniprevir (MK-7009) | Phase 3 | |||
| Asunaprevir (BMS-650032) | Phase 3 | |||
| ABT-450 | Phase 3 | |||
| Danoprevir (RG7227) | Phase 2 | |||
| Sovaprevir (ACH-1625) | Phase 2 | |||
| Vedroprevir (GS-9451) | Phase 2 | |||
| Second generation | Medium barrier | High; expected to be pan-genotypic | MK-5172 | Phase 2 |
| Neceprevir (ACH-2684) | Phase 2 | |||
|
| ||||
| NS5A inhibitorsb | Low-medium barrier | Very high | Daclatasvir (BMS-790052) | Phase 3 |
| Ledipasvir (GS-5885) | Phase 3 | |||
| ABT-267 | Phase 3 | |||
| GSK2336805 | Phase 2 | |||
| ACH-3102 | Phase 2 | |||
| IDX-719 | Phase 2 | |||
| MK-8742 | Phase 2 | |||
| PPI-668 | Phase 2 | |||
| GS-5816 | Phase 2 | |||
|
| ||||
| NS5B polymerase inhibitors | ||||
| Nucleoside/nucleotide analogs | Medium-high barrier | High; pan-genotypic | Sofosbuvir (GS-7977) | Phase 3/NDA |
| Mericitabine (RG7128) | Phase 2 | |||
| VX-135 | Phase 2 | |||
| Non-nucleoside analogsc | Low barrier, escape mutants have high fitness | Medium-high; highly genotype or subtype specific | ABT-333 (Palm-I/C) | Phase 3 |
| BI207127 (Thumb-I/A) | Phase 3 | |||
| BMS-791325 (Thumb-I/A) | Phase 2 | |||
| Lomibuvir (VX-222) (Thumb-II/B) | Phase 2 | |||
| ABT-072 (Palm-I/C) | Phase 2 | |||
| Setrobuvir (RG7790) (Palm-I/C) | Phase 2 | |||
| GS-9669 (Thumb-II/B) | Phase 2 | |||
| TMC647055 (Thumb-I/A) | Phase 2 | |||
|
| ||||
| HTAs | ||||
| Cyclophilin inhibitors | Resistance reported in vitro only | Medium, pan-genotypic | Alisporivir (DEBIO-025) | Phase 3 (on holdd) |
| SCY-635 | Phase 2 | |||
| miR-122 antagonists | No resistance, though recombinant resistance mutants were reported in vitro | High, pan-genotypic | Miravirsen (SPC3649) | Phase 2 |
| Entry inhibitors | No resistance, though recombinant resistance mutants were reported in vitro | Unknown | TX-5061 | Phase 2 |
NDA, new drug application currently under evaluation.
This table was assembled from inhibitor classes currently in clinical studies, with the aim of including the most promising compounds (in phases 2 and 3) of each class. Any bias in selection is unintended. Updates to the HCV antiviral pipeline can be found online at websites such as http://www.pipelinereport.org/, http://www.natap.org/or http://hcvadvocate.blogspot.ca/.
Some genotype limitations for first-generation inhibitors. It is anticipated that second-generation inhibitors will address these concerns
Owing to the low resistance barrier, these will only be useful in combination with other DAAs. The allosteric NS5B target site is noted for the individual inhibitors.
Currently on clinical hold because of cases of pancreatitis when combined with peg-IFN-α and ribavirin. Could hold promise for IFN-free regimens.