TMC435 Beats Standard Therapy Regardless of HCV Genotype

SUMMARY: TMC435 improves response rates of genotype 1 previous non-responder hepatitis C patients, researchers report at EASL 2011. Further, adding TMC435 helps overcome the effects of unfavorable IL28B gene pattern and high IP-10 levels.

By Liz Highleyman

TMC435 is an investigational once-daily oral hepatitis C virus (HCV) NS3/4A protease inhibitor currently in Phase 3 trials in both treatment-naive patients and prior non-responders or relapsers.

At the European Association for the Study of the Liver's International Liver Congress (EASL 2011) last week in Berlin, an international team of investigators presented findings from the ASPIRE trial in a late-breaker poster.

ASPIRE is an ongoing Phase 2b placebo-controlled trial evaluating the safety, tolerability, efficacy, and pharmacokinetics of TMC435 as part of a combination regimen with pegylated interferon alfa-2a (Pegasys) plus ribavirin for chronic hepatitis C patients with hard-to-treat HCV genotype 1.

The trial included 462 participants who did not respond or relapsed following at least 1 prior course of pegylated interferon plus ribavirin. The population included null-responders (< 2 log reduction in HCV RNA by week 12 of treatment), partial responders (>2 log reduction at week 12 but detectable at the end of treatment), and relapsers (undetectable at the end of treatment, but became detectable within 24 weeks after completing therapy).

About two-thirds of participants were men, most (about 90%) were white, and the median age was 50 years. About 40% had HCV genotype 1a and 60% had 1b. Approximately 20% had liver cirrhosis (Metavir F4). About 18% across all arms had the favorable IL28B CC gene pattern and the least favorable TT pattern, with the remainder having the CT pattern. People with HIV or hepatitis B coinfection were excluded.

Participants were randomly allocated to 7 treatment arms:

	100 mg TMC435 once-daily + pegylated interferon/ribavirin for 12 weeks, followed by pegylated interferon/ribavirin + placebo for 36 weeks;
	150 mg TMC435 once-daily + pegylated interferon/ribavirin for 12 weeks, followed by pegylated interferon/ribavirin + placebo for 36 weeks;
	100 mg TMC435 once-daily + pegylated interferon/ribavirin for 24 weeks, followed by pegylated interferon/ribavirin + placebo for 24 weeks;
	150 mg TMC435 once-daily + pegylated interferon/ribavirin for 24 weeks, followed by pegylated interferon/ribavirin + placebo for 24 weeks;
	100 mg TMC435 once-daily + pegylated interferon/ribavirin for 48 weeks;
	150 mg TMC435 once-daily + pegylated interferon/ribavirin for 48 weeks;
	Pegylated interferon/ribavirin for 48 weeks (standard therapy control arm).

The EASL poster described results from a planned interim analysis at week 24.

Results

	At 24 weeks, the benefit of adding TMC435 was most evident among prior partial responders followed by prior null responders, while prior relapsers in all arms did well.
	24-week response rates were as follows:
	Prior relapsers:
	At week 4, rapid virological response (RVR; HCV RNA < 25 IU/mL) rates were 79% for patients who received 100 mg TMC435 + pegylated interferon/ribavirin and 84% for those who used 150 mg TMC435 + pegylated interferon/ribavirin (arms combined), compared with just 4% for standard therapy recipients. At week 12 the corresponding rates were 88%, 95%, and 31%, respectively. At week 24, response rates were as follows:   100 mg TMC435 for 12 weeks + pegylated interferon/ribavirin: 96%; 100 mg TMC435 for 24 or 48 weeks (combined) + pegylated interferon/ribavirin: 92%; 150 mg TMC435 for 12 weeks + pegylated interferon/ribavirin: 96%; 150 mg TMC435 for 24 or 48 weeks (combined) + pegylated interferon/ribavirin: 96%; Standard therapy: 83%
	Prior partial responders:
	Week 4 RVR were 56% for patients who received 100 mg TMC435 + pegylated interferon/ribavirin and 67% for those who used 150 mg TMC435 + pegylated interferon/ribavirin, compared with no standard therapy recipients. At week 12 the corresponding rates were 76%, 92%, and 10%, respectively. At week 24, response rates were as follows:   100 mg TMC435 for 12 weeks + pegylated interferon/ribavirin: 86%; 100 mg TMC435 for 24 or 48 weeks + pegylated interferon/ribavirin: 83%; 150 mg TMC435 for 12 weeks + pegylated interferon/ribavirin: 86%; 150 mg TMC435 for 24 or 48 weeks + pegylated interferon/ribavirin: 89%; Standard therapy: 20%
	Prior null responders:
	Week 4 RVR rates were 36% for patients who received 100 mg TMC435 + pegylated interferon/ribavirin and 40% for those who used 150 mg TMC435 + pegylated interferon/ribavirin, compared with no standard therapy recipients. At week 12, the corresponding rates were 63%, 64%, and 21%, respectively. At week 24, response rates were as follows:   100 mg TMC435 for 12 weeks + pegylated interferon/ribavirin: 70%: 100 mg TMC435 for 24 or 48 weeks + pegylated interferon/ribavirin: 74%; 150 mg TMC435 for 12 weeks + pegylated interferon/ribavirin: 70%; 150 mg TMC435 for 24 or 48 weeks + pegylated interferon/ribavirin: 87%; Standard therapy: 45%
	Overall, 6% of patients receiving TMC435 met a stopping rule due to lack of response, compared with half of standard therapy recipients.
	18% of TMC435 recipients, overall, experienced viral breakthrough.
	Viral breakthrough and virological failure occurred most often among prior null responders, followed by partial responders and then relapsers.
	The overall incidence of adverse events (mostly mild or moderate) was similar across all treatment arms, except TMC435 recipients had more flu-like symptoms and pruritis (itching).
	About 6% of TMC435 recipients reported serious adverse events and discontinued due to adverse events, compared with about 2% in the control group.

In this week 24 interim analysis, the researchers concluded, "treatment-experienced patients who previously failed [pegylated interferon/ribavirin] achieved significantly greater on-treatment virologic response rates following treatment with a TMC435-containing regimen, compared with placebo/[pegylated interferon/ribavirin] control."

"Safety and tolerability were generally similar between TMC435-containig regimen and placebo/[pegylated interferon/ribavirin] control group," they added.

Impact of IL28B and IP-10

In a related oral presentation, Jeroen Aerssens described findings from the multinational PILLAR study of TMC435 in previously untreated HCV genotype 1 patients, focusing on the influence of IL28B gene pattern and pre-treatment levels of interferon-gamma inducible protein 10 (IP-10). Having the unfavorable IL28B TT gene pattern and high IP-10 level are both associated with poorer response to interferon-based therapy.

In this study participants were randomly allocated to receive either 75 mg or 150 mg TMC435 in combination with pegylated interferon/ribavirin for various durations, or else standard therapy.

During the first 24 weeks of treatment, the favorable IL28B CC gene pattern and low baseline serum IP-10 levels were associated with the highest virological response rates among standard therapy recipients. However, among patients treated with TMC-435 combination therapy, virological response rates were high overall regardless of IL28B or IP-10.

"The addition of TMC435 to [pegylated interferon/ribavirin] reduces the impact of IL28B genotype and/or baseline serum IP-10 on virologic response up to 24 weeks of treatment," the researchers concluded.

Investigators will compare response rates among participants with different IL28B gene patterns and IP-10 levels in Phase 2b and 3 trials to determine the effect of these factors on sustained virological response.

Investigator affiliations:

Abstract 18: JW Goethe University Hospital, Frankfurt, Germany; Queen Marys University of London, London, UK; University of North Carolina at Chapel Hill, NC; Hôpital Henri-Mondor, Université Paris-Est Créteil, France; Toronto Western Hospital Liver Centre, Toronto, Canada; Russian State Medical University, Moscow, Russia; Cedars-Sinai Medical Center, Los Angeles, CA; Tibotec BVBA, Mechelen, Belgium; Tibotec Inc, Yardley, PA.

Abstract 199: Department of Translational Genomics & Genetics, Department of Infectious Disease and Vaccines, Department of Enabling Biology, Global Clinical Virology, Department of Statistics, Department of Clinical Development, Tibotec, Beerse, Belgium; University of North Carolina at Chapel Hill, Chapel Hill, NC.

Abstract 1099: Tibotec BVBA, Beerse, Belgium; Department of Gastroenterology and Hepatology, Academic Medical Center Amsterdam, Amsterdam, Netherlands, Tibotec BVBA, Mechelen, Belgium; Tibotec Pharmaceuticals, Ltd., County Cork, Ireland; Tibotec Inc., Yardley, PA.

4/8/11

References
S Zeuzem, GR Foster, MW Fried, et al. The ASPIRE trial: TMC435 in treatment-experienced patients with genotype-1 HCV infection who have failed previous pegIFN/RBV treatment. 46th Annual Meeting of the European Association for the Study of the Liver (EASL 2011). Berlin. March 30-April 3. Abstract 6.

J Aerssen, G Fanning, A Scholliers, et al. Impact of IL28B genotype and pretreatment serum IP-10 in treatment-naive genotype-1 HCV patients treated with TMC435 in combination with peginterferon alfa-2a and ribavirin in PILLAR study. 46th Annual Meeting of the European Association for the Study of the Liver (EASL 2011). Berlin. March 30-April 3. Abstract 6.

O Lenz, J de Bruijne, L Vijgen, et al. Treatment outcome and resistance analysis in HCV genotype 1 patients previously exposed to TMC435 monotherapy and re-treated with TMC435 in combination with pegIFN alfa 2a/ribavirin. 46th Annual Meeting of the European Association for the Study of the Liver (EASL 2011). Berlin. March 30-April 3. Abstract 1099.

Other Source

Medivir. Medivir Announces Positive Phase 2b 48-week (SVR24) Interim Results of TMC435 in Treatment-Naive Patients Chronically Infected With Genotype-1 Hepatitis C Virus. Press release. February 22, 2011.

Tibotec. Tibotec Advances Global Clinical Research Program for TMC435 in HCV; Will Present Four Abstracts Evaluating Safety and Efficacy at EASL. Press release. March 29, 2011.