 |
|
|
| |
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
|
| |
| |
Reported by Jules Levin
EASL 2009 Copenhagen
C. Sarrazin1, J. Hong2, S. R. Lim2, X. Qin2, C. Moy2, S. Susser1, B. Bradford2, S. Porter2, S. Zeuzem1, and S. Seiwert2
1J.W. Goethe Universität, Frankfurt, Germany; 2InterMune, Inc., Brisbane, CA
ABSTRACT
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 (VL) 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 q8hr 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 protease phenotyping vector and used for clonal sequencing.
Results: Patients receiving ITMN-191 as monotherapy (n=40) displayed continual 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 protease 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 protease 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.
RESULTS
REFERENCES
He, Y., King, M.S., Kempf, D. J., Lu, L., Lim, H. B., Krishnan, P., Kati, W., Middleton, T., Molla, A. 2008. Relative replication capacity and selective advantage profiles of protease inhibitor-resistant hepatitis C virus (HCV) NS3 protease mutants in the HCV genotype 1b replicon system. Antimicrobial Agents and Chemotherapy 52(3);1101-10.
Seiwert, S.D., Hong, J., Lim, S. R., Wang, T., Hua, H., and Blatt, L. M. 2007. Sequence variation of NS3/4A in HCV replicons exposed to ITMN-191 concentrations encompassing those likely to be achieved following clinical dosing. Journal of Hepatology 46(Supplemental Issue No. 1);S244-S245.
|
| |
|
|
|
|
|
