InterMune Inc. (ITMN): SUPPRESSION OF IN VITRO RESISTANCE DEVEL...

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Re: ghmm post# 289

Thursday, 03/19/2009 7:59:33 PM

Thursday, March 19, 2009 7:59:33 PM

SUPPRESSION OF IN VITRO RESISTANCE DEVELOPMENT AFTER TREATMENT OF THE HCV REPLICON WITH NS3/4A INHIBITOR ITMN-191 (R7227) IN COMBINATION WITH NUCLEOSIDE INHIBITOR R7128 OR R1626

http://www.abstractserver.com/easl2009/planner/sp.php?go=abstract&action=abstract_iplanner&absno=2479&

M. McCown, S. Rajyaguru, S. Kular, N. Cammack, I. Najera
Roche Palo Alto LLC, Palo Alto, USA

Background and aims: HCV specific inhibitors ITMN-191, which targets NS3/4A, and R7128 or R1626, which target NS5B, have entered into clinical development. These inhibitors have resulted in a maximum mean viral load reduction of 3.9, 2.7, and 3.7 Log10 IU/ml respectively during 14-day monotherapy studies. Nucleoside inhibitors present a higher barrier to resistance than either protease or non-nucleoside polymerase inhibitors. In this study we evaluated the benefits of combining ITMN-191 with either R7128 or R1626 for the reduction of resistance development.
Methods: HCV replicon cells were treated at 1X, 10X, and 15X EC50 with either ITMN-191, R7128, or R1626 either alone or in combination. After a three week selection, cellular RNA was extracted and the NS3 protease region was amplified and sequenced. The NS3 protease region from each selection was cloned into a NS3 protease shuttle replicon to determine their sensitivity to ITMN-191 and other protease inhibitors (e.g. Telaprevir, Boceprevir, TMC435530, MK-7009).
Results: Treatment of replicon cells at 10X or 15X the EC50 with either nucleoside inhibitor alone resulted in clearance of the replicon, whereas treatment with ITMN-191 alone selected for resistant colonies. Sequence changes in the NS3 protease region of the replicon colonies were observed and correlated with a decreased sensitivity to ITMN-191 as determined by the NS3 phenotypic assay. ITMN-191 remained more potent than the other tested NS3/4A inhibitors, even in the presence of the selected resistant mutants.
Combination of 10X EC50 of ITMN-191 with a low concentration (1X EC50) of either R1626 or R7128 reduced the number of ITMN-191-resistant colonies by 2.7 and 17-fold, respectively. In combination with 10X or 15X EC50 of either nucleoside, resistant replicons were suppressed.
Conclusions: Replicons resistant to ITMN-191 are readily selected during monotherapy. Combination of ITMN-191 with very low concentrations of a nucleoside inhibitor (either R1626 or R7128) reduced the in vitro development of resistant colonies. Combination with nucleoside inhibitor concentrations of ~EC90 suppressed development of resistance and cleared the replicon. These results support the investigation of a combination treatment including ITMN-191 and either R7128 or R1626 in HCV infected patients.