SUMMARY: Tibotec's investigational hepatitis C virus (HCV) NS3/4A protease inhibitor, TMC435, produced good viral suppression in previously untreated genotype 1 patients when taken once-daily in combination with pegylated interferon plus ribavirin for 12 or 24 weeks, according to interim results from the PILLAR study presented this week at the American Association for the Study of Liver Diseases "Liver Meeting" (AASLD 2010) in Boston.

By Liz Highleyman

Current standard therapy for genotype 1 chronic hepatitis C consists of pegylated interferon (Pegasys or PegIntron) plus ribavirin for 48 weeks. Interferon-based therapy can cause difficult side effects, however, and only about half of people with this hard-to-treat HCV genotype achieve a cure with the first course of treatment.

Novel oral drugs that directly target steps of the viral lifecycle -- such as HCV protease and polymerase inhibitors -- are currently in development. Most studies to date have looked at these agents in combination with pegylated interferon plus ribavirin, though some have started to look at all-oral combinations.

After the Phase 2a OPERA trial demonstrated promising results (also reported at AASLD 2010), the Phase 2b PILLAR study (TMC435-C205 or NCT00882908) was designed to assess the safety and efficacy of TMC435 in combination with pegylated interferon alfa-2a (Pegasys) plus ribavirin in treatment-naive patients with HCV genotype 1.

This multinational trial included a total of 386 participants. Just over half were men, most (94%) were white, and the median age was about 47 years. About 45% had HCV genotype 1a, while 55% had genotype 1b. More than 85% had high HCV RNA viral load at baseline (>800,000 IU/mL) and 14% had advanced liver fibrosis (stage F3); those with cirrhosis (stage F4) were not eligible. About 30% had the favorable C/C IL28B gene pattern, a recently discovered marker that predicts good response to interferon.

Table 4. Mean (± SE) baseline and Day 7 hepatic parameters for each GT cohort.

Participants were randomly allocated into 5 treatment arms:

	75 mg once-daily TMC435 + 180 mcg/week pegylated interferon + 1000-1200 mg/day weight-adjusted ribavirin for 12 weeks, followed by pegylated interferon + ribavirin alone for another 12 weeks (TMC12-PR24 75mg);
	150 mg once-daily TMC435 + same doses of pegylated interferon + ribavirin for 12 weeks, followed by pegylated interferon/ribavirin for another 12 weeks (TMC12-PR24 150mg);
	75 mg once-daily TMC435 + same doses of pegylated interferon + ribavirin, all taken for 24 weeks (TMC24-PR24 75mg);
	150 mg once-daily TMC435 + same doses of pegylated interferon + ribavirin, all taken for 24 weeks (TMC24-PR24 150mg);
	Standard therapy consisting of the same doses of pegylated interferon + ribavirin for 48 weeks, with placebo (comparable to TMC435) for the first 24 weeks (Placebo24-PR48).

Patients in the TMC435 arms who achieved HCV RNA < 25 IU/mL at week 4, as well as undetectable at weeks 12, 16, and 20, were allowed to end all treatment at week 24. All other participants continued pegylated interferon + ribavirin through 48 weeks.

The investigators measured HCV levels regularly throughout treatment and follow-up. The primary endpoint will be sustained virological response at 24 weeks after completion of treatment, or SVR24, which is considered a cure. An interim measure -- sustained response at 12 weeks after finishing treatment, or SVR12 -- was reported at the AASLD meeting. The researchers also assessed viral breakthrough, safety, and tolerability.

Results

	Rapid virological response (RVR), or undetectable HCV RNA < 25 IU/mL at week 4 of therapy, was significantly more likely in all TMC435 arms compared with standard therapy:
	TMC12-PR24 75mg: 77%; TMC12-PR24 150mg: 76%; TMC24-PR24 75mg: 68%; TMC24-PR24 150mg: 79%; Placebo24-PR48: 5%.
	Rates of complete early virological response (EVR), or undetectable HCV RNA < 25 IU/mL at week 12, were high in all TMC435 arms:
	TMC12-PR24 75mg: 91%; TMC12-PR24 150mg: 94%; TMC24-PR24 75mg: 96%; TMC24-PR24 150mg: 97%; Placebo24-PR48: 58%.
	Response rates at week 24 (end-of-treatment for the TMC435 arms) remained high in the TMC435 arms, with standard therapy showing a gain:
	TMC12-PR24 75mg: 94%; TMC12-PR24 150mg: 94%; TMC24-PR24 75mg: 97%; TMC24-PR24 150mg: 95%; Placebo24-PR48: 82%.
	12-week sustained response, or SVR12, was reported for about 40% of patients who had reached this point in post-treatment follow-up (not yet available for standard therapy patients, who will complete treatment at week 48):
	TMC12-PR24 75mg: 97%; TMC12-PR24 150mg: 89%; TMC24-PR24 75mg: 93%; TMC24-PR24 150mg: 88%;
	79% to 86% of patients in TMC435 arms were able to end treatment at week 24, according to protocol-defined response criteria.
	The combined rate of viral breakthrough in the TMC435 arms was 4.9% vs 3.5% in the standard therapy arm; breakthrough rates were higher in the arms that received TMC435 for 12 rather than 24 weeks (6.4%-7.8% vs 2.5%-2.7%, respectively).
	Adding TMC435 to pegylated interferon/ribavirin increased response rates for patients with all IL28B genotypes.
	ALT and AST liver enzyme levels decreased significantly in all treatment arms.
	The most common adverse events were headache (46% in TMC435 arm vs 51% in placebo arm) and fatigue (42% vs 47%, respectively).
	Overall frequency of adverse events did not differ significantly between TMC435 and placebo arms.
	7.1% of patients in the TMC435 arms and 7.8% in the placebo arm experienced adverse events leading to treatment discontinuation, not a significant difference.
	There were no significant differences in frequencies of gastrointestinal symptoms, rash (28.5% vs 27.3%, respectively), or anemia (19.4% vs 20.8%, respectively).
	Patients in the 150 mg TMC435 dose arms, however, were significantly more likely to experience mild and reversible elevations in bilirubin.

"This interim analysis demonstrates that TMC435 in addition to pegylated interferon/ribavirin achieves RVR and complete EVR for the majority of patients," the researchers concluded. "Available data indicate that high SVR12 rates are observed in patients who completed therapy."
"In this analysis TMC435 was well tolerated in all treatment arms," they added.

"Chronic infection with HCV is a leading cause of cirrhosis, liver cancer, and liver transplantation worldwide," lead investigator Michael Fried from the University of North Carolina at Chapel Hill said in a press release issued by Tibotec. "We are extremely encouraged by these data for TMC435."

Researchers also reported results from a Phase 2a proof-of-concept study evaluating 200 mg once-daily TMC435 monotherapy for 7 days in treatment-naive people with HCV genotypes 2 through 6, which (with the possible exception of 4) respond better to interferon than genotype 1.

TMC435 monotherapy for 7 days "showed potent antiviral activity, with highest antiviral activity against genotype 4 and genotype 6, followed by genotype 5 and genotype 2," they concluded. However, "[n]o antiviral activity was seen against genotype 3." All adverse events were mild-to-moderate, with no discontinuations during the 7-day period.

TMC435 is also being evaluated in the international Phase 2b ASPIRE study for treatment-experienced HCV genotype 1 patients who did not achieve sustained response with a previous course of pegylated interferon/ribavirin.

Investigator affiliations:

Fried study (PILLAR): Director of Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC; Hospital Vall d'Hebron and Ciberehd, Barcelona, Spain; St. Vincent's Hospital, Sydney, NSW, Australia; Allgemeines Krankenhaus der Stadt Wien, Wien, Austria; Weill Cornell Medical College, New York, NY; Hopital Beaujon, Clichy, Paris, France; Klinikum der Johann-Wolfgang-Goethe-Universitat--Med. Klinik I, Frankfurt, Germany; Tibotec BVBA, Beerse, Belgium; Tibotec Inc., Titusville, NJ.

Lenz study (OPERA-1): Tibotec BVBA, Beerse, Belgium; Tibotec Inc, Yardley, PA.

Moreno study: Department of Gastroenterology and Hepatopancreatology, Erasme Hospital, Brussels, Germany; Medizinische Klinik m. S. Hepatologie und Gastroenterologie Charité, Campus Virchow-Klinikum, Universitatsmedizin Berlin, Berlin, Germany; Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; Chiang Mai University, Chiang Mai, Thailand; Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium; Department of Medicine I, J.W. Goethe University Hospital, Frankfurt, Germany; Tibotec BVBA, Mechelen, Belgium; Tibotec Inc., Titusville, NJ.

11/5/10

References

MW Fried, M Buti, GJ Dore, and others. Efficacy and safety of TMC435 in combination with peginterferon alfa-2a and ribavirin in treatment-naive genotype-1 HCV patients: 24-week interim results from the PILLAR study. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2010). Boston, October 29-November 2, 2010. Abstract LB-5.

O Lenz, L Vijgen, T Lin, and others. Virologic analysis of genotype-1-infected patients treated with once-daily TMC435 during the Optimal Protease inhibitor Enhancement of Response to therApy (OPERA)-1 study. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2010). Boston, October 29-November 2, 2010. Abstract 812.

C Moreno, T Berg, T Tanwandee, and others. A Phase IIa, open-label study to assess the antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2-6. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2010). Boston, October 29-November 2, 2010. Abstract 895.

Other Source

Tibotec. Week 24 interim results from phase 2b PILLAR study to be presented as late-breaker at AASLD. Press release. October 30, 2010.