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  62th Annual Meeting of the American Association for the Study of Liver Diseases San Francisco 2011 Nov 6-9 Back grey_arrow_rt.gif
Alisporivir - A Host-targeting Antiviral, Provides Low Viral Breakthrough Rate and High Barrier to Resistance in HCV Genotype 1 Treatment-na´ve Patients in the Phase IIb ESSENTIAL Study
  Reported by Jules Levin
AASLD 2011 Nov 4-8 SF
Bin Li,1 Joke Snoeck,2 Yanhua Tang,1 Christopher T. Jones,1 Choilai Tiongyip,1 Weibin Bao,3 Jing Yu,1 Anne-Mieke Vandamme,2 Gregoire Vuagniaux,3 Rafael Crabbe,3 Claudio Avila,5 Nikolai Naoumov,5 Kai Lin1 1Novartis Institutes for BioMedical Research, Inc, Cambridge MA, USA; 2Rega Institute and KU Leuven, Leuven, Belgium; 3Novartis Pharmaceuticals, East Hanover NJ, USA; 4Debiopharm SA, Lausanne, Switzerland; 5Novartis Pharma AG, Basel, Switzerland


Alisporivir (ALV) is an oral host-targeting cyclophilin inhibitor with pan-genotypic anti-HCV activity. In the phase IIb ESSENTIAL study, HCV genotype (GT) 1 treatment-naive patients receiving ALV in combination with Peg-IFNα2a/ribavirin (P/R) achieved 76% SVR. Here, we investigate the viral breakthrough (VB) events during the ESSENTIAL study and evaluate the factors associated with VB in ALV-treated patients.
Methods: Population sequencing of the entire HCV coding region was performed with samples at baseline and at VB. The HCV NS5A gene was further analyzed using clonal sequencing and pyrosequencing. Phenotypic analysis of NS5A from patient isolates was performed using GT1b replicon shuttle vector in vitro.
Results: A total of 215 intent-to-treat patients (43 GT1a; 172 GT1b) were treated with ALV in combination with P/R in the ESSENTIAL study. While on full-dose of ALV, 6/215 (2.8%) patients (1 GT1a; 5 GT1b) experienced VB, compared with 4/73 (5.5%) patients in the control (placebo with P/R) arm. No VB was observed until treatment Week 12. In 3 of 6 ALV-treated patients, VB occurred after P/R dose adjustment/stoppage; in 2 of the other 3 VBs, pharmacokinetics analysis revealed suboptimal ALV exposure. Population sequencing of HCV genome did not identify any genotypic change consistently associated with VB, confirmed by clonal sequencing of NS5A, the putative viral target of cyclophilins. A mutation previously reported to be associated with ALV treatment in vitro, D320E in NS5A domain II, was seen at the time of initial VB in 1 patient. However, phenotypic assays demonstrated only a slight (~3-fold) decrease in susceptibility to ALV with GT1b replicons bearing D320E alone or the entire NS5A of the patient isolate. These data suggest that the emergence of D320E or viral resistance is not the primary cause of VB. Importantly, a number of mutations that confer resistance to direct-acting antivirals (DAAs) including NS5A inhibitors were seen at baseline for patients who achieved RVR and subsequently SVR24 with ALV, supporting the in vitro data of lack of cross-resistance between ALV and DAAs.