Oral Presentations

Session Title: Parallel Session: LATE-BREAKERS
Presentation Date: 02 APR, 2011

QUADRUPLE THERAPY WITH BMS-790052, BMS-650032 AND PEG-IFN/RBV FOR 24 WEEKS RESULTS IN 100% SVR12 IN HCV GENOTYPE 1 NULL RESPONDERS

A. Lok¹*, D. Gardiner², E. Lawitz³, C. Martorell⁴, G. Everson⁵, R. Ghalib⁶, R. Reindollar⁷, V. Rustgi⁸, F. McPhee⁹, M. Wind-Rotolo¹⁰, A. Persson¹⁰, K. Zhu², D. Dimitrova², T. Eley², T. Guo⁹, D. Grasela², C. Pasquinelli^2
1Medicine, University of Michigan, Ann Arbor, MI, ²Bristol-Myers Squibb Research and Development, Hopewell, NJ, ³Alamo Medical Research, San Antonio, TX, ⁴The Research Institute, Springfield, MA, ⁵University of Colorado-Denver, Aurora, CO, ⁶The Liver Institute at Methodist Dallas, Dallas, TX, ⁷Carolinas Center for Liver Disease Research Dept, Statesville, NC, ⁸Metropolitan Research, Fairfax, VA, ⁹Bristol-Myers Squibb Research and Development, Wallingford, CT, ¹⁰Bristol-Myers Squibb Research and Development, Princeton, NJ, USA. *aslok@med.umich.edu

Background: Only ~30% of null responders to pegIFN/RBV achieve SVR when retreated with pegIFN/RBV plus telaprevir, thus, this population maintains a high unmet medical need. BMS-790052 is a potent HCV NS5A replication complex inhibitor while BMS-650032 is a potent HCV NS3 protease inhibitor. AI447011 is a randomized, open label, Phase 2a study exploring the antiviral activity and safety of BMS-790052 (60 mg QD) and BMS-650032 (600 mg BID) alone (Group A) or with pegIFN/RBV (Group B) for 24 weeks in a sentinel cohort of HCV GT 1 null responders. The primary objective was to determine the proportion of subjects achieving undetectable HCV RNA (< 10 IU/mL) 12 weeks post-treatment (SVR12).
Methods: Twenty-one subjects (11 Group A, 10 Group B), 19 of whom had unfavorable IL28B genotypes (rs12979860 CT/TT) were treated in the sentinel cohort. Null response was defined as an HCV RNA decrease < 2 log10 following 12 weeks of pegIFN/RBV. An interim analysis was performed when all subjects not experiencing viral breakthrough reached 12 weeks post-treatment.
Results: Seven (63.6%) Group A subjects had undetectable HCV RNA by week 4; 5 remained undetectable at end of treatment; 4 (2/9 GT1a and 2/2 GT1b) achieved SVR12, while 1 experienced viral relapse 4 weeks post-therapy. Six subjects in Group A (all GT1a) experienced viral breakthrough on therapy, all had pegIFN/RBV added to their regimen and 4 subsequently achieved undetectable HCV RNA. Analysis of post-breakthrough viral sequences revealed emergence of variants resistant to both antivirals in all cases. Six (60%) Group B subjects had undetectable HCV RNA by week 4 and all 10 achieved SVR12. Diarrhea was the most common AE (71.4%) and was mainly mild to moderate; six subjects experienced ALT >3x ULN all had total bilirubin < 2x ULN. Six subjects (all receiving pegIFN/RBV) experienced Grade 3/4 neutropenia. No SAEs or discontinuations due to AEs occurred.
Conclusions: Two antivirals alone can lead to SVR in some difficult-to-treat subjects. Inclusion of pegIFN/RBV with the 2 direct-acting antivirals suppresses the emergence of resistance variants resulting in a 100% rate of SVR12. Enrollment of additional cohorts of patients is ongoing to validate these results.