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Alisporivir - A Host-targeting Antiviral, Provides Low Viral Breakthrough Rate and High Barrier to Resistance in HCV Genotype 1 Treatment-naïve Patients in the Phase IIb ESSENTIAL Study
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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
Abstract
Background: 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.
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