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Fw: NATAP/EASL: HCV Drug R1626, Lack of Pre-Existing Mutations

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  • alleypat
    ... From: nataphcv@natap.org To: nataphcv@natap.org ; nataphcvhiv@natap.org ; natapindustry@natap.org ; natapdoctors@natap.org Sent: Friday, April 27, 2007
    Message 1 of 1 , Apr 27, 2007
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      ----- Original Message -----
      From: nataphcv@...
      To: nataphcv@... ; nataphcvhiv@... ; natapindustry@... ; natapdoctors@...
      Sent: Friday, April 27, 2007 6:14 AM
      Subject: NATAP/EASL: HCV Drug R1626, Lack of Pre-Existing Mutations


      NATAP http://natap.org/
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      R1479, a Novel Hepatitis C Polymerase Inhibitor: Lack of Pre-Existing Resistance Mutations Supports the Observed In Vivo High Barrier to Resistance

      Reported by Jules Levin
      EASL, April 2007, Barcelona, Spain

      S. LE POGAM, A. KOSAKA, S. HU, H. KANG, A. SESHAADRI, J. SYMONS, K. KLUMPP, N. CAMMACK and I. NAJERA
      Roche Palo Alto USA

      INTRODUCTION
      The Hepatitis C virus (HCV) is a +-strand RNA virus from the Flaviviridae family

      R1479 (4'-Azido-Cytidine) is a potent inhibitor of replication of the laboratory optimized genotype 1b Con1 and genotype 1a H77 replicons

      R1626, prodrug of R1479, has shown a maximum mean (median) HCV RNA reduction of 3.7 (4.1) log10 at 4500 mg BID dose

      The high genetic heterogeneity of HCV, due to the error-prone nature of its RNA-dependent RNA polymerase, represents an opportunity for the virus to evade antiviral treatment. Selection of resistance could be therefore facilitated by the presence of minority drug resistant variants within the viral quasispecies

      The aim of the study was to understand whether the inhibitory activity of HCV polymerase inhibitors is affected by the intrinsic viral genetic heterogeneity.

      AUTHOR CONCLUSIONS
      R1479 and 2'-C-Me-C are as active against genetically diverse NS5B isolates as against reference replicons

      Non nucleoside inhibitors, benzothiadiazine and thiophene-2- carboxylic acid, showed greater variability in activity across NS5B isolates

      No R1479 or 2'-C-Me-C resistance mutations in treatment naïve clinical isolates were found

      Palm and Thumb resistance mutations exist in treatment naïve clinical isolates

      The existence of natural NNI-resistance mutations among the treatment naïve patients suggests a potential for faster development of clinically significant resistance for non nucleoside therapies

      These findings are consistent with the lack of resistance observed in HCV infected subjects upon 14 day treatment with R1626

      METHODS

      HCV Phenotypic and Genotypic Characterization of NS5B Clinical Isolates
      (PhenoAlto assay)

      The sensitivity of subgenomic HCV replicons encoding the NS5B from 63 treatment naïve HCV clinical isolates (16 GT 1b and 47 GT 1a) to R1479, 2'-C-Me-C and 2 non-nucleoside inhibitors was determined

      The frequency of pre-existing mutations associated with resistance to different classes of polymerase inhibitors was determined:
      -- by direct sequencing of NS5B from 63 treatment naïve clinical isolates (consensus sequences)
      -- by clonal sequence analysis of 764 HCV variants from 9 clinical isolates

      RESULTS 1

      NS5B Clinical Isolates from Treatment Naïve Patients can replicate in vitro

      92 % of NS5B clinical isolates are replication competent (_,_) and allow phenotypic evaluation

      _,_ phenotypic characterization not possible due to no or very low replication


      R1479 and 2'-C-Me-C are Potent Inhibitors of NS5B Clinical Isolates



      Lines represent the 3-fold maximum variability of the assay
      _,_ laboratory optimized replicons Con1 and H77

      R1479 and 2'-C-Me-C are equipotent across NS5B clinical isolates (_,_)


      Variable Potency for Thumb and Palm Inhibitors across NS5B Clinical Isolates


      Variable potency of Palm and Thumb inhibitors across GT 1a and 1b NS5B clinical isolates (_,_) compared to the laboratory optimized replicons Con1 and H77 (_,_)

      RESULTS 2

      Characterization of Genetic Diversity in the Consensus NS5B Sequences of 63 clinical isolates

      No pre-existing S96T (R1479)- or S282T (2'-C-Me-C) resistance mutations were found within the 63 clinical isolates

      Pre-existing polymorphism at the known Palm and Thumb NNI-resistance amino acid residues were found in 30/63 clinical isolates

      Prevalence of Pre-Existing Polymorphism at known Palm and Thumb resistance amino acid residues

      In white, amino acid residues related to NNI-resistance. Number of clinical isolates containing the specified resistance mutation are indicated in %
      _ Palm I-related amino acid residue, _ Palm II-related amino acid residue,
      _ Thumb I-related amino acid residue, _ Thumb II-related amino acid residue


      Characterization of Quasispecies Genetic Diversity in 9 NS5B clinical isolates that do not have polymorphism at the known Palm and Thumb NNI-resistance amino acid residues in their consensus sequence

      764 HCV variants from 1 GT 1b and 8 GT 1a clinical isolates were characterized

      All 9 clinical isolates show the presence of polymorphism at one or multiple known NNI-resistance amino acid residues at a low frequency

      Frequency of Pre-Existing Polymorphism at known Palm and Thumb resistance amino acid residues in the quasispecies of 9 clinical isolates

      In white, amino acid residues related to NNI-resistance. *Number of clinical isolates containing the specified resistance mutation. In parenthesis, range of frequency of observed mutation within each isolate (in %)
      _ Palm I-related amino acid residue, _ Palm II-related amino acid residue,
      _ Thumb I-related amino acid residue, _ Thumb II-related amino acid residue




      **************************************
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