InterMune Inc. (ITMN)

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COMBINATION OF THE NS3/4A PROTEASE INHIBITOR ITMN-191 WITH THE ALLOSTERIC NS5B POLYMERASE INHIBITOR ITMN-8020 ENHANCES REPLICON CLEARANCE AND REDUCES THE EMERGENCE OF DRUG RESISTANT VARIANTS

http://www.abstractserver.com/easl2009/planner/sp.php?go=abstract&action=abstract_iplanner&absno=459&

H. Tan, G. Wang, C. Moy, K. Kossen, R. Rajagopalan, S. Misialek, D. Ruhrmund, L. Hooi, N. Snarskaya, A. Stoycheva, B. Buckman, S. Seiwert, L. Beigelman
Intermune, Inc., Brisbane, USA

Background: ITMN-191 is an inhibitor of the HCV NS3/4A protease, and ITMN-8020 is an allosteric inhibitor of the HCV NS5B polymerase. ITMN-191 is being evaluated in phase 1b studies in combination with the current SOC and in the INFORM-1 clinical study in combination with R7128, a nucleoside inhibitor of NS5B. Due to the potential for drug resistance with NS3 protease inhibitors and presumably with allosteric NS5B polymerase inhibitors, we examined the antiviral effect of ITMN-191 and ITMN-8020 alone and in combination.
Methods: In the HCV clearance assay, cells harboring an HCV genotype-1b replicon were treated for 2 weeks with ITMN-191, ITMN-8020, or a combination of inhibitors in the absence of G418 selection for replicon retention. Cells were counted and aliquots harvested for RT-PCR-based quantification of replicon RNA levels under G418 selection over 3 subsequent weeks. In the colony formation assay, cells were treated with ITMN-191 at ~1.1X, ~11X, or ~17X its EC50 either alone or in the presence of ITMN-8020 at ~1X, ~10X, or ~15X its EC50. After 3 weeks in culture with G418, cells were fixed and stained or total cellular RNA extracted.
Results: In an HCV clearance assay, ITMN-191 at 15X its EC50 eliminated HCV replicon in the absence of G418 selective pressure for replicon retention while 15X the EC50 of ITMN-8020 did not. Addition of the lowest tested concentration of ITMN-191 (1.9X EC50) to ITMN-8020 at 15X its EC50 resulted in replicon clearance, demonstrating significant combined antiviral effect. In the colony formation assay in the presence of G418 selective pressure for replicon retention, ITMN-8020 at 15X its EC50 reduced but did not eliminate cell colonies resulting from HCV replicon persistence. However, addition of ITMN-191 at 11X its EC50 prevented formation of any cell colonies, indicating the combined antiviral effects of the two agents forced replicon elimination in a dose-dependent fashion.
Conclusions: The combination of ITMN-191 with ITMN-8020 in vitro results in enhanced antiviral activity and suppression of drug-resistant variants. These findings suggest that the combination of these two agents may represent a viable therapeutic approach, resulting in antiviral activity greater than that observed with ITMN-191 alone.