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The Hepatitis C Treatment Pipeline

September 2011

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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.


Table 5. NS5a Inhibitors in Development
Agent/SponsorPhase and PopulationComments
ABT-267
Abbott Laboratories
Phase II, HCV genotype 1, treatment-naiveOnce daily dosing; not open as of May 2011
ACH 2928
Achillion Pharmaceuticals
Phase I expected in mid-2011Pan-genotypic activity
BMS 790052
Bristol Myers Squibb
Phase II/III HCV genotype 1, treatment-naive and treatment-experienced; HCV genotypes 2 and 3, treatment-naive; In African Americans and Latinos/Latinas with HCV genotype 1, treatment-naiveWith BMS 914143 (peginterferon lambda) and ribavirin, with or without BMS 650032 (protease inhibitor) 16-48 weeks

With PSI-7977, with or without ribavirin (genotypes 1, 2, and 3, treatment-naive)

With PEG-IFN/RBV (African Americans, Latinos/Latinas, and partial and null responders)
BMS 82483
Bristol Myers Squibb
Phase IIStudy withdrawn prior to enrollment
GS 5585
Gilead Sciences
Phase II; HCV genotype 1, treatment-naiveOnce daily; with GS 9451 (HCV protease inhibitor), tegobuvir (non-nucleoside polymerase inihibtor) and ribavirin

With PEG-IFN/RBV, with or without GS 9451 (protease inhibitor); IL 28B CC genotype only; 6-24 weeks of treatment. Not open as of 12 August 2011
PPI-461
Presidio
Phase Ib, HCV genotype 1, treatment-naiveOnce daily dosing (completed)


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.


Table 6. Non-nucleoside Polymerase Inhibitors in Development
Agent/SponsorPhase and PopulationComments
ABT 072
Abbott Laboratories
Phase II; HCV genotype 1, treatment-naive; PEG-IFN free studies limited to people with IL28B CC genotype onlyOnce daily; with PEG-IFN/RBV and with ABT-450/r (protease inhibitor) plus ribavirin
ABT 033
Abbott Laboratories
Phase II; HCV genotype 1, treatment-naive; PEG-IFN free studies limited to people with IL28B CC genotype onlyTwice daily; with PEG-IFN/RBV and in combination with ABT-450/r (protease inhibitor), plus ribavirin
Setrobuvir
ANA 598
Anadys Pharmaceuticals
Phase II; HCV genotype 1, treatment-naive and treatment-experiencedTwice daily; 28-48 weeks; with PEG-IFN/RBV
BI 207127
Boehringer Ingelheim
Phase I; HCV genotype 1, treatment-naiveTwice or thrice-daily dosing; with BI 201335 (protease inhibitor), with or without ribavirin
BMS 791323
Bristol Myers Squibb
Phase II: HCV genotype 1, treatment naiveTwice daily; with PEG-IFN/RBV
Filibuvir (PF-868554)
Pfizer
Phase II, HCV genotype 1, treatment-naiveTwice daily; with PEG-IFN/RBV, 24-48 weeks
Tegobuvir (GS 9190)
Gilead Sciences
Phase II, HCV genotype 1, treatment-naiveTwice-daily; with PEG-IFN/RBV

With PEG-IFN/RBV and GS 9451 (HCV protease inhibitor)

With GS 9451 (HCV protease inhibitor), GS 5885 (NS5a inhibitor), and ribavirin
TMC 647055
Tibotec Pharmaceuticals
Phase I, healthy volunteers and HCV genotype 1, treatment-naive 
TMC 649128
Medivir AB/Tibotec Pharmaceuticals
Phase Ia; healthy volunteers 
VCH 222
Vertex Pharmaceuticals
Phase I/II HCV genotype 1, treatment-naiveWith PEG-IFN/RBV

With telaprevir (HCV protease inhibitor) and PEG/RBV (dual therapy arm discontinued)


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.


Table 7. Nucleoside and Nucleotide Polymerase Inhibitors in Development
Agent/SponsorPhase and PopulationComments
Nucleotide Polymerase Inhibitors
GS 6620
Gilead Sciences
Phase I, HCV genotypes 1, 2, and 3; treatment naive 
IDX 184
Idenix
Phase I/II; male healthy volunteersOriginally studied with IDX 320, a protease inhibitor that has been discontinued due to liver toxicity; remains on partial clinical hold. Food effect being studied; phase IIb trial in combination with PEG-IFN/RBV open
INX-189
Inhibitex
Phase I in HCV genotype 1, treatment-naive has been completedOnce-daily dosing; FDA has fast-tracked development; Phase II expected in Q2/Q3 of 2011
PSI-938Phase I, HCV genotype 1, treatment-naiveOnce daily, studied in combination with PSI 7797; Phase II combination trials, with and without ribavirin, are expected in mid-2011
PSI 7797Phase I/II; HCV genotype 1, treatment-naive; followed by HCV genotypes 4,5,6; also being studied in HCV genotypes 2 and 3, treatment-naiveOnce-daily; with PEG-IFN/RBV for 12-24 weeks

With PEG-IFN/RBV for 12 weeks in HCV genotypes 2 and 3, with ribavirin, with or without peginterferon, and as montherapy for 12 weeks; with PEG-IFN/RBV for 8-12 weeks

With PSI 938 for up to 14 days; longer trial expected in mid-2011

With BMS 790052 (NS5a inhibitor), with or without ribavirin
Nucleoside Polymerase Inhibitors
Mericitabine (RG7128)
Genetech/Pharmasset
Phase II, HCV genotype 1 (naive and experienced) and genotype 4, (treatment-naive)With PEG-IFN/RBV (naive)

With ritonavir-boosted danoprevir (protease inhibitor), with or without ribavrin (naive)

With ritonavir-boosted danoprevir and ribavirin, with or without PEG-IFN (experienced)
RO5428029
Hoffman-La Roche
Phase I; healthy volunteers 
TMC 649128
Medivir AB/Tibotec Pharmaceuticals
Phase Ia; healthy volunteers 


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.


Table 8. Host Targeting Agents in Development
Agent/SponsorPhase and PopulationComments
Alispovir (DEBIO 025)
Novartis
Phase II/III; HCV genotype 1, treatment-naive

Also genotypes 3 and 3
Loading dose twice daily for 7 days, followed by once daily dosing
ITX 5061
iTherx
Phase Ib; HCV genotype 1, treatment-naive and liver transplant recipientsOnce daily
SCY-635
Scynexis Incorporated
Phase II; HCV genotype 1, treatment-naive, IL28B C/T or TT onlyTwice daily

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This article was provided by Treatment Action Group and HIV i-Base. It is a part of the publication 2011 Pipeline Report.
 
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