November 9, 2010 (Boston, Massachusetts) — The second wave of hepatitis C virus (HCV) protease inhibitors includes TMC435, an NS3/4A protease inhibitor being developed by Tibotec/Johnson & Johnson. The compound has a 40-hour half life, which makes it amenable to once-a-day dosing.
Michael Fried, MD, from the University of North Carolina at Chapel Hill, presented an interim 24-week analysis of the ongoing phase 2b Protease Inhibitor TMC435 Trial Assessing the Optimal Dose and Duration as Once Daily Anti-Viral Regimen (PILLAR) here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting.
All 386 patients received a backbone regimen of standard of care, consisting of pegylated-interferon plus ribavirin, for 24 weeks, and were then randomized to add either 75 mg or 150 mg oral TMC435 once daily for 12 or 24 weeks. The fifth group received standard of care for only 48 weeks. Each study group consisted of 75 to 79 patients.
A response-guided treatment algorithm allowed patients in the TMC435 groups to discontinue therapy at week 24 "if they had HCV RNA [levels] less than 25 IU and were also undetectable at treatment weeks 12, 16, and 20. Patients who did not meet these virological criteria were eligible to continue pegylated-interferon and ribavirin for up to 48 weeks," Dr. Fried said. All patients are being followed for 72 weeks.
The primary end point was sustained virologic response. Secondary end points included assessment of antiviral activity, viral breakthrough, safety, tolerability, and IL28B status. Patients were stratified by race and HCV genotype (1a vs 1b).
The study population had a strong female presence (44.8%), was predominately white (93.8%), had a median age of 46.5 years, and had a body mass index of 25.0 kg/m2. The viral load was high; in 85.8%, HCV RNA level was 800,000 IU/mL or higher. Cirrhosis was an exclusionary factor, but fibrosis was present in 13.7% of patients.
Dr. Fried said that all TMC435 groups "had a rapid and steep decline in HCV RNA during the first 4 weeks of treatment that was maintained throughout the 12- or 24-week dosing period."
A more than 5 log decline in viremia was recorded by week 2 in patients in the TMC435 groups, which was maintained throughout the course of treatment. In contrast, the control group showed a much slower slope of decline, needing about 8 weeks to achieve a 4 log decline, and it never achieved the same depth of decline in HCV RNA as the TMC435 groups.
The portion of patients with very low or undetectable HCV RNA (<25 IU/mL) at week 4 ranged from 88% to 96% in the TMC435 groups, compared with 16% in the control group. At week 12, undetectable HCV RNA was recorded in 91% of those randomized to 12 weeks of TMC435 treatment, 97% in those randomized to 24 weeks of TMC435, and 69% in those randomized to the control group, respectively. At week 24, the numbers were 94%, 97%, and 82%, respectively, he said.
"According to the response-guided treatment algorithm used in the study, between 79% and 86% of patients in the TMC435 arms were able to discontinue treatment at week 24 by achieving the defined biological response criteria," said Dr. Fried. Patients in the control group have not yet completed their longer course of therapy.
A subset of nearly half of the patients on TMC435, with sustained virologic responses ranging from 88% to 97%, had completed all treatment and were available for week 12 follow-up evaluation.
Viral breakthrough by week 24 occurred in 2.5% to 7.8% of the TMC435 groups, compared with 3.9% of the control group. There was no correlation between dose of the drug and breakthrough, although patients on the longer course of treatment did have lower rates of breakthrough.
A retrospective analysis by IL28B genotype showed that TMC435 did increase response rates across all genotypes, and it narrowed the differences between the 3 genetic variations. It also confirmed that those with the CC allele perform better than those with the CT or TT alleles. The higher dose of TMC435 appears to result in a slightly deeper suppression of viremia than the lower dose, particularly among those with the TT allele. Dr. Fried said.
Treatment breakthroughs "were mostly in the CT and TT [allelic] groups" and were less likely to occur in the higher-dose groups, Dr. Fried reported. Resistance was most often found at points "155, 80, and some unique ones at the 168 residue" of the HCV genotype, he added. This provides some encouragement that regimens containing TMC435 will help ameliorate some of the negative effects of the IL28B genotype."
Rates of discontinuation and adverse events with TMC435 were similar to those seen with standard of care alone. There were increases in bilirubin, particularly with the higher dose of TMC435; however, "most were considered to be grade 1" and generally were within the upper limit of normal. The bilirubin increase peaked around week 2 and then declined slightly over time. He said that "this suggests that the mild, reversible increase in bilirubin is not due to hepatotoxicity."
Planning for phase 3 studies is underway.
One member of the audience called the data "very clean and very encouraging," but he wondered if the increase in bilirubin might be an issue. Dr. Fried reiterated that "it was completely reversible and was not progressive during the course of therapy. It is clearly related to a transporter mechanism, as opposed to hepatotoxicity, so I don't think it is going to be a major issue."
Session cochair Douglas R. LaBrecque, MD, director of Liver Services at University of Iowa Health Care in Iowa City, later told Medscape Medical News that "relatively low levels of bilirubin by themselves are not dangerous. From the limited data, it appears that it went away as soon as therapy was done."
This study was sponsored by Tibotec. Dr. Fried reports ongoing research and consulting contacts with the sponsor and several competing companies. Dr. LaBrecque has disclosed no relevant financial relationships.
The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract LB-5. Presented November 1, 2010.