The Hepatitis C Treatment Pipeline

NS5a Inhibitors

Although NS5a inhibitors are very potent, these drugs have a low resistance barrier, especially in HCV genotype 1a. Nonetheless, HCV has already been cured with an NS5a inhibitor combined with a protease inhibitor. This drug class is expected to become an important part of DAA regimens, since NS5a inhibitors may have pan-genotypic activity. So far, little is known about the side effect profile of NS5a inhibitors, since they have mainly been studied with peginterferon, ribavirin, and other DAAs; headache was reported in early studies.

Non-Nucleoside Polymerase Inhibitors

The hepatitis C virus offers more than one binding site for non-nucleoside polymerase inhibitors, so it may be possible to combine drugs from this class with one another, and with DAAs from other classes. Unfortunately, non-nucleoside polymerase inhibitors are active only against HCV genotype 1, and have a low resistance barrier. Side effects include headache, abdominal pain, nausea, fatigue, rash, and elevated bilirubin.

Nucleoside and Nucleotide Polymerase Inhibitors

Although several candidates never made it out of phase II due to toxicity, the current nucleoside and nucleotide polymerase inhibitor candidates hold great promise. Early results from trials of Pharmasset's PSI-7797 have generated hope that nucleotides may become the next backbone of HCV treatment -- or the treatment itself.

Simplicity is king; nucleoside and nucleotide polymerase inhibitors may bypass current complexities of HCV treatment, such as IL28-B genotype, baseline viral load, race, HIV status, and HCV genotype. These drugs are not magic bullets, but nucleosides and nucleotides offer the potential to dramatically simplify and shorten HCV treatment, along with other desirable elements: a high resistance barrier, once-daily dosing, good tolerability, and pan-genotypic activity. Side effects include dizziness, fatigue, headache, and fever.

Host-Targeting Agents

Resistance to host-targeting agents (HTAs) is less likely to occur than DAA resistance, making these drugs an attractive addition to HCV treatment. There are different types of HTAs. Entry inhibitors work by blocking viral entry into host cells. Cyclophilin inhibitors work by binding to cellular proteins that regulate the immune system; some drugs in this class are immunosuppressants. Both Debio 025 and SCY-635 bind to host cell proteins that may facilitate HCV replication without immunosuppressive activity. Cyclophilin inhibitors may have pan-genotypic activity. Unfortunately, resistance to these drugs has been characterized. Side effects include muscle weakness, low platelets, headache, nausea and elevated bilirubin, which was reversible upon discontinuation.