Twelve-Week Interim Analysis of HCV Protease Inhibitor Danoprevir is Positive

Bob Roehr

November 01, 2010

November 1, 2010 (Boston, Massachusetts) — The investigational protease inhibitor danoprevir, which targets the hepatitis C virus (HCV), combined with the standard of care for HCV infection — peg-interferon alpha-2a and ribavirin — produces rapid and profound reductions in HCV RNA.

Norah Terrault, MD, from the University of California at San Francisco, presented data from a 12-week interim analysis of the ATLAS trial here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting. Last month, Roche, which is sponsoring the study, secured full rights to the compound from collaborator InterMune.

Entry criteria were noncirrhotic treatment-naïve adults (predominately genotype 1 virus) with serum HCV RNA levels of 50 000 IU/mL or more and without advanced fibrosis.

All patients were administered a standard of care regimen of pegylated interferon alpha-2a plus weight-based ribavirin, and were randomized, for 12 weeks, to placebo or 1 of 3 danoprevir groups: 300 mg every 8 hours, 600 mg every 12 hours, or 900 mg every 12 hours. When danoprevir was stopped, all patients continued on standard therapy for an additional 24 or 48 weeks, depending on whether or not they achieved a rapid virologic response

The second part of the study was a planned continuation of danoprevir to week 24, but that "never was undertaken" because of incidents of reversible grade 4 ALT elevations in 3 patients in the 900 mg group, the highest dose of the study, said Dr. Terrault. Patients already enrolled in the 900 mg group were rerandomized to 300 or 600 mg.

The principle measure of efficacy was an undetectable HCV RNA level (<15 IU/mL); measurements were taken at baseline and at weeks 2, 4, and 12. Missing data points were considered to be nonresponders.

Dr. Terrault reported that the interim analysis of those who completed 12 weeks of danoprevir therapy was based on 62 patients receiving 300 mg (93%), 61 receiving 600 mg (94%), and 8 receiving 900 mg (16%).

At week 2, levels of HCV RNA were undetectable in 52% of the 300 mg group, 57% of the 600 mg group, 62% of the 900 mg group, and 0% of the placebo group. At week 4, that progressed to 73%, 86%, 86%, and 7%, respectively; and at week 12, to 88%, 89%, 92%, and 43%.

"In all triple combination arms, there was demonstration of potent antiviral effects that were greater than [peg-interferon alpha-2a] and ribavirin alone," Dr. Terrault summarized.

Viral resistance to danoprevir emerged in the low-dose (300 mg) group in 2 patients at week 2 and in 5 patients at weeks 4 and 12. In the 600 mg group, patients fared better, with 3 developing treatment-emergent resistance by week 12. No patients developed resistance in the highest-dose (900 mg) group, but the cumulative exposure was significantly less because of the emerging toxicity and discontinuation of that dosing regimen. All of the resistance was seen in patients with HCV genotype 1a.

Rates of most common adverse events in the danoprevir groups were at least twice as high as those seen with standard care alone. Often, there was little difference in the incidence of adverse effects with an increase in the dose of danoprevir.

Although the serious adverse event of grade 4 ALT elevation was most likely to occur at the highest dose of the drug (3 incidents) and led to the discontinuation of that dosing, there also was 1 incident among the 60 patients in the 600 mg group. Dr. Terrault said that "modeling the available pharmacokinetics data showed a relationship between danoprevir exposure, specifically AUC and the likelihood of having ALT elevation."

This information has been incorporated into the ongoing Dauphin study, which uses lower doses of danoprevir that are boosted with the pharmaco-inhibitor ritonavir, as is the case with many protease inhibitors used to treat HIV infection. Preliminary work suggests that this might maintain a more steady state of danoprevir in the blood and reduce toxicity.

Hepatologist Scott L. Friedman, MD, from Mount Sinai School of Medicine in New York City, who was not involved with the study, acknowledged that danoprevir, as currently formulated, seems to have a fairly narrow therapeutic window between a dose that is tolerable but can allow for the development of viral resistance and one that results in significant toxicities.

There are a lot of HCV protease inhibitors in development in that space. It is going to be interesting to see "which drugs win the race, in which wave, and in which combination," Dr. Friedman said, quickly adding that he is not about to make any predictions.

Roche is underwriting the study of danoprevir. Dr. Terrault reports receiving grant/research support and serving on an advisory committee or review panel for Roche. Dr. Friedman, who is immediate past president of AASLD, has disclosed no relevant financial relationships.

The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract 32. Presented October 31, 2010.

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