Replies to post #288 on InterMune Inc. (ITMN)

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INCIDENCE OF VIROLOGIC ESCAPE OBSERVED DURING ITMN-191 (R7227) MONOTHERAPY IS GENOTYPE DEPENDENT, ASSOCIATED WITH A SPECIFIC NS3 SUBSTITUTION, AND SUPPRESSED UPON COMBINATION WITH PEGINTERFERON ALFA-2A/RIBAVIRIN

http://www.abstractserver.com/easl2009/planner/sp.php?go=abstract&action=abstract_iplanner&absno=682&

C. Sarrazin1, J. Hong2, S. Lim2, X. Qin2, S. Susser1, B. Bradford2, S. Porter2, S. Zeuzem1, S. Seiwert2
1J.W. Goethe Universität, Frankfurt, Germany, 2Intermune, Inc., Brisbane, USA

Background: In a phase 1 multiple ascending dose study in genotype-1 chronic HCV patients, 14 day treatment with the NS3 protease inhibitor ITMN-191 alone was safe, well tolerated, and resulted in multi-log10 HCV viral load reductions. Combination of ITMN-191 with peginterferon alfa-2a/ribavirin (SOC) for 14 days resulted in HCV RNA below quantification (< 25 IU/mL) in the majority of all treated patients in q12h and q8h cohorts to date.
Methods: Virologic response (VR) patterns were defined by end of treatment (EOT) and nadir HCV RNA. NS3 protease domain was amplified and population sequenced. Amplicons were inserted into a novel NS3 phenotyping vector and used for clonal sequencing.
Results: Patients receiving ITMN-191 as monotherapy (n=40) displayed continuous decline, plateau, and breakthrough VR profiles. Genotype-1b patients experienced breakthrough less frequently than genotype-1a patients (4/24 or 17% vs. 10/16 or 63%, respectively). By population analysis, all 10 genotype-1a breakthrough patients carried R155K at EOT. R155K was observed in all 4 genotype-1b breakthrough patients, but in 3 the population analysis evidenced a complex R155 substitution pattern. Clonal sequencing in these patients indicated R155K was dominant, but R155Q and other less frequent R155 variants were present. NS3 substitutions observed in vitro were absent in breakthrough patients- with the notable exception of D168E in a single genotype 1b breakthrough patient who also displayed the most complex substitution pattern. Importantly, virologic breakthrough was not observed in either genotype when ITMN-191 was combined with SOC.
Conclusions: The scope of NS3 substitutions allowing virologic escape appears to be largely restricted to R155K in patients receiving ITMN-191 monotherapy, which is consistent with previous in vitro studies and in contrast to the numerous paths to viral breakthrough associated with telaprevir monotherapy. The lower incidence of viral escape in genotype-1b patients compared to genotype-1a may relate to the higher genetic barrier to R155K in genotype-1b (2 rather than 1 nucleotide substitutions required). Of most clinical relevance, combination with SOC prevented viral breakthrough in all patients studied to date. Thus, while R155 substitution is observed in some patients receiving ITMN-191 monotherapy and is associated with virologic escape, combination with SOC abrogates virologic escape.