Bob Roehr

November 04, 2010

November 4, 2010 (Boston, Massachusetts) — A 4-week lead in the dosing of 2 oral small-molecule drugs was able to reduce the level of hepatitis C virus (HCV) RNA to undetectable levels in a small number of patients before either ribavirin (RBV) or an interferon/RBV combination was added to the regimen.

Results from the phase 2 pilot study were presented by Stefan Zeuzem, MD, from the Goethe University Hospital in Frankfurt, Germany, here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting. It involved 2 compounds in development by Gilead Sciences.

GS-9256 targets the serine NS3 protease. In an earlier 3-day trial, it showed a 2.9-log mean maximal reduction in HCV RNA levels at a dose of 75 mg taken twice daily. GS-9190 (tegobuvir) is a nonnucleoside polymerase inhibitor that targets the NS5B region of the viral RNA, and in earlier studies it has shown a 1.6-log maximum reduction during 1 week at a dose of 40 mg taken twice daily, Dr. Zeuzem explained.

The researchers enrolled treatment-naive genotype 1 patients with HCV RNA levels greater than 1000 IU/mL and randomly assigned them to 3 groups:

  • 9256 75 mg taken twice daily + 9190 40 mg taken twice daily (n = 16),

  • 9256 75 mg taken twice daily + 9190 40 mg taken twice daily + weight-based RBV (n = 15), and

  • 9256 75 mg taken twice daily + 9190 40 mg taken twice daily + weight-based RBV + pegylated interferon 180 μg every week (n = 15).

At the end of 4 weeks, all patients were continued on standard of care (SOC), consisting of pegylated interferon ± RBV. Patients in the first 2 groups who did not show at least a 2-log decline in HCV RNA levels by day 5 or who experienced viral breakthrough and relapse at any point during the first 4 weeks of the study could, at the discretion of the treating physician, immediately initiate SOC.

"The virologic response showed a median maximal change from baseline of 4.1, 5.1, and 5.7 log10 IU/mL decline in HCV RNA, respectively," said Dr. Zeuzem. "At day 14 of treatment, HCV RNA levels were below 25 in 1, 6, and 10 patients in the respective groups." At day 28, the numbers were 1/15, 5/13, and 14/14, respectively.

A significant portion of patients in the first group experienced viral breakthrough and were switched to SOC. Addition of RBV resulted in "a somewhat more profound" initial steep decline in viremia: "[C]learly the addition of ribavirin prevented the breakthrough in the majority of patients." The group using all 4 drugs did not experience viral breakthrough.

"The vast majority of patients, 11 of 15, rapidly selected for mutants in the protease region, typically at positions 168 and 155 [D168V/E/N, and/or R155K], as well as in the NS5B region at positions 445 and 448 [Y445H and Y448H]," Dr. Zeuzem said.

Adverse effects were most common in the group containing SOC. The maximum increase in bilirubin was 1.3, 1.6, and 3.0 times the upper limit of normal in the respective groups.

Dr. Zeuzem said the new drug combination "had robust antiviral activity. Interestingly, and perhaps also surprisingly, the addition of ribavirin demonstrated a substantially greater viral suppression," reduced the emergence of resistance, and was well tolerated. "The quad combination achieved 100% [rapid viral response] rates without breakthroughs."

During discussion, Dr. Zeuzem said this study supports the hypothesis that at least 1 mechanism of action of ribavirin is a direct antiviral effect on HCV, and that it does not work simply by modulating gene expression for production of interferon.

Evaluation of a 16-week course of the 4-drug combination is ongoing.

Responding to a question from the audience, Dr. Zeuzem said "the trough levels of the compounds were 40 to 50 times higher than the EC50, which is required for these compounds in vivo — well above what is required to maintain constant suppression of viral replication." There is no need to boost them, as is being considered with some other protease inhibitors, he added.

Session cochair Douglas R. LaBrecque, MD, director of Liver Services at University of Iowa Health Care, Iowa City, called the results promising but cautioned that the study was quite small and preliminary. It is likely to take several years before phase 3 data become available.

Gilead Sciences supported the study. Dr. Zeuzem is an academic investigator who participated in the study and has ongoing consulting and speaking arrangements with the company. Dr. LaBrecque has disclosed no relevant financial relationships.

The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting: Late-Breaking Abstract 1. Presented November 1, 2010.

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