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HCV Protease Inhibitor Danoprevir Promising in Early Trial

Experimental HCV protease inhibitor danoprevir (formerly RG7227 and ITMN-191) was safe and showed good antiviral activity at higher doses in a 14-day study of treatment-naive and previously treated genotype 1 chronic hepatitis C patients.

By Liz Highleyman

The development of direct-acting antiviral agents that interfere with various steps of the hepatitis C virus (HCV) lifecycle will revolutionize treatment, especially for difficult-to-treat patients.

The first 2 HCV protease inhibitors -- boceprevir (Victrelis) and telaprevir (Incivek) -- were approved in May, and a large number of novel and next-generation agents are currently in the development pipeline. Initially these drugs will be used with standard therapy consisting of pegylated interferon (Pegasys or PegIntron) plus ribavirin, but all-oral regimens are currently under study.

As reported in the June 2011 Journal of Hepatology, Nicole Forestier and Stefan Zeuzem from J.W. Goethe University in Frankfurt and colleagues assessed the safety, pharmacokinetics, and antiviral activity of the selective HCV NS3/4A serine protease inhibitor danoprevir in a placebo-controlled 14-day multiple-ascending-dose study.

This analysis included 4 cohorts of treatment-naive patients randomly assigned to receive 100 mg or 200 mg danoprevir every 8 hours (3-times-daily) or the same doses every 12 hours (twice-daily), as well as 1 cohort of prior pegylated interferon/ribavirin non-responders who received 300 mg danoprevir every 12 hours; cohorts also included placebo recipients.


Among treatment-naive participants, maximal HCV RNA viral load decreases were 3.9 log IU/mL in the 200 mg 3-times-daily group and 3.2 log IU/mL in the 200 mg twice-daily group.
At the end of the 14-day treatment period, viral declines in these 2 cohorts were within 0.1 log IU/mL of the viral load nadir, or lowest level.
Non-responders experienced "more modest" HCV RNA reductions than those seen in the treatment-naive 200 mg cohorts, despite receiving a higher dose.
Nearly 30% of participants (10 of 37) experienced viral rebound during treatment, with a higher risk among those with HCV subtype 1b.
Rebound was associated with the NS3 R155K mutation in people with both HCV 1b and 1a.
Danoprevir was generally safe and well-tolerated.
Adverse events were typically mild and transient, and were not associated with dose level.

"Danoprevir was safe and well tolerated when administered for 14 days in patients with chronic HCV genotype 1 infection," the study authors concluded. "These results support further clinical evaluation of danoprevir in patients with chronic HCV."

Due to delays in publishing, more recent data have since been presented at hepatitis conferences and in other journals.

Studies have shown that danoprevir reaches higher concentrations and has more potent antiviral activity when boosted with ritonavir (Norvir), a drug used in small doses to boost several HIV drugs. Boosting enables less frequent dosing, giving danoprevir a potential advantage over boceprevir and telaprevir, both of which are taken 3 times daily.

Results from the INFORM-1 trial showed that danoprevir plus the HCV polymerase inhibitor mericitabine (RG7128) reduced HCV viral load by about 5 logs over 14 days in both treatment-naive and previously treated patients. But drug resistance was a concern, underling the need for potent combination regimens.

Most recently, investigators reported this spring at the European Association for the Study of the Liver (EASL) meeting that while nearly 90% of genotype 1b prior non-responders treated with ritonavir-boosted danoprevir plus pegylated interferon/ribavirin experienced early virological response at week 12, half of patients with genotype 1a experienced viral breakthrough, demonstrating the importance of HCV subtype as a predictor of treatment response.

"The barrier to virologic rebound in subtype 1b HCV appears to be higher than that in subtype 1a HCV owing to a reliance on the R155K substitution for viral escape in both subtypes," the authors of the present study suggested. "The lower incidence of viral rebound in subtype 1b compared to subtype 1a may reflect the requirement for 2 nucleotide substitutions to generate R155K in subtype 1b compared to the single nucleotide substitution required in subtype 1a."

Investigator affiliations: J.W. Goethe Universität, Frankfurt, Germany; CHU Montpellier, France; Pontchaillou Hospital, Rennes, France; Hôpital Beaujon, Clichy, France; Centre CAP, Montpellier, France; Biotrial, Rennes, France; Genentech, Inc., South San Francisco, CA; InterMune, Inc., Brisbane, CA.


N Forestier, D Larrey, D Guyader, et al. Treatment of chronic hepatitis C patients with the NS3/4A protease inhibitor danoprevir (ITMN-191/RG7227) leads to robust reductions in viral RNA: A phase 1b multiple ascending dose study. Journal of Hepatology 54(NUM):1130-1136 (abstract). June 2011.
























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