HCV Protease ITMN-191 + Peg/RBV for 14 Days

HCV Protease ITMN-191 + Peg/RBV for 14 Days

EASL April 23-26 2009
Copenhagen, Denlark
Reported by Jules Levin

In a phase I study ITMN-191 reduced viral load a median of 3.8 logs as monotherapy for 14 days in treatment-naive genotype 1 patients. In this study looking at various doses of ITMN-191 plus peg/RBVHCV viral load was reduced by 5.3 to 5.7 logs after 14 days of dosing. The authors reported "Adverse events were generally mild and transient and without association to treatment group or dose level. No serious adverse events were observed during the study treatment period. No AE led to early discontinuation of study treatment. The most frequently reported AEs among patients treated with ITMN-191 +peg/RBV were headache, myalgia, and fatigue". Tomorrow Saturday Rohe is reporting results from the INFORM Study, which is the first study of 2 oral HCV drugs: ITMN-191 + R7128, a polymerase inhibitor from Roche and Pharmasset. Roche is studying 2 oral drugs combined with peg/RBV.

Presentation Date: Apr 24, 2009

ANTIVIRAL ACTIVITY AND SAFETY OF ITMN-191 IN COMBINATION WITH PEGINTERFERON ALFA-2A AND RIBAVIRIN IN PATIENTS WITH CHRONIC HEPATITIS C VIRUS (HCV)
N. Forestier1, D. Larrey2, P. Marcellin3, Y. Benhamou4, D. Guyader5, W. Bradford6, S. Porter6, A. Patat7, R. Rouzier8, S. Zeuzem1, 1J.W. Goethe Universität, Frankfurt, Germany, 2CHU Montpellier, Montpellier, 3Hôpital Beaujon, Clichy, 4Assistance Publique Hôpitaux de Paris, Paris, 5CHU Hôpital Ponchaillou, Rennes, France, 6Intermune, Inc., Brisbane, CA, USA,7Biotrial, Rennes, 8Centre CAP, Montpellier, France

Background: ITMN-191 is a potent HCV NS3/4A protease inhibitor that achieves high liver concentrations following oral administration. In a phase 1 multiple ascending dose study, ITMN-191 was safe and demonstrated substantial antiviral activity when administered for 14 days to treatment-naïve HCV genotype-1 patients. The present study was designed to evaluate ITMN-191 in combination with standard of care (SOC) in patients with HCV genotype-1 infection.

Methods: In a double-blind, placebo-controlled, multiple ascending dose study, treatment-naïve HCV genotype-1 patients were randomized (8:2) to receive ITMN-191 or placebo in combination with peginterferon alfa-2a (180 mg SC weekly) and ribavirin (1000-1200 mg PO BID) for 14 days. Patients were sequestered in a Phase I research facility for 16 days and completed standard clinical and laboratory evaluations.

Results: Dosing has been completed in five cohorts in this ongoing study. Based on preliminary blinded data, ITMN-191 appears generally safe and well tolerated. Adverse events (AE) were predominantly mild to moderate and consistent with the well described AE profile of SOC. No AE´s lead to treatment discontinuation and there were no SAE´s during study treatment. A single unrelated SAE of viral gastroenteritis occurred following completion of study treatment. HCV RNA levels declined rapidly and were below the limit of quantitation in the majority of ITMN-191 treated patients in all q12h and q8h dosing cohorts at Day 15 (Table 1). No virologic rebound was observed during study treatment.

Conclusion: ITMN-191 appears generally safe and well tolerated when administered in combination with SOC to HCV genotype-1 patients for 14 days. The addition of ITMN-191 to SOC resulted in substantial and sustained decreases in HCV RNA in each of the first 5 cohorts. Higher q12h doses are currently being studied.

Dose N Median Change HCV RNA Log10(IU/mL) Below Limit of Quantitation
(<25 IU/mL) Undetectable
(<9.3 IU/mL)
Placebo 10 -2.0 1/10 (10%) 0/10 (0%)
100 mg q8h 8 -5.5 6/8 (75%) 1/8 (13%)
200 mg q8h 8 -5.7 7/8 (88%) 4/8 (50%)
400 mg q12h 7 -4.7 4/7 (57%) 1/7 (14%)
300 mg q8h 7 -5.6 5/7 (71%) 4/7 (57%)
600 mg q12h 8 -5.4 6/8 (75%) 1/8 (13%)
[Day 15 HCV RNA Results]