icon-    folder.gif   Conference Reports for NATAP  
 
  EASL
43rd Annual Meeting of the European Association For The Study Of The Liver
Milan, Italy
April 23-27, 2008
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Potent Antiviral Activity of 2nd Generation HCV Nucleotide Inhibitors, IDX102 and IDX184, in HCV-infected Chimps
 
 
  Reported by Jules Levin
43rd EASL Meeting, April 3-27, 2008, Milan, Italy
 
D Standring, Lanford, E Cretto-Scott, L Liklider, M Larsson, C Pierra, G Gosselin, C Perigaud, D Sureraux, B Mayes, A Mouss ad J Seldon
 
IDX Liver Targeting: Conclusions
 
IDX184 is a potent and selective inhibitor of HCV in itro
 
Additive to synergistic wit PI, IFN, and ribavirin in vitro
 
Preferetially activated in human primary hepatocytes
-- Delivers high levels of nucleoside-TP
 
Low systemic exposure/high level TP cinfirmed in PK studies
-- Expected to limit off-target toxicities
 
Potent antiviral activity in vivo in HCV-1 chimpanzees
 
First Generation HCV Nucleosides
 
NM283: prodrug of NM107
-- 2-C-methyl cytidne analog
 
R1626: prodrug of R1479
-- 4-azido cytidine analog
 
R7128: prodrug of PSI-6130
-- 2-fluoro 2-C methyl cytidine analog
 
Limitations:
--Low levels of nucleoside TP in the liver (high dose/limited potency)
--High systemic exposure (off target side effects: GI, hematological)

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IDX102 & IDX184
Second Generation HCV Nucleotides

 
Liver targeting technology delivers nucleoside monophosphate (Nuc-MP) to liver
 
Generate high level of Nuc-TP in the liver
 
Minimize syatemic exposure of the prodrug and metabolites
 
Potential for efficacy at low doses:
--Expected to enhance risk benefit rofile of nucleoside clas
--Suitable for combination therapy
 
IDX184 selected as current clinical candidate

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Additional IDX184 In Vitro Activity Data
 
IDX184 Nuc-TP metabolie is potently active against purified polymerases from HCV genoypes 1a 1b, 2a, 3a -- IC50 ranges from 80-290 nM
 
No activity against human cellular DNA polymerases alpha, beta, and y and RNA polymerase II
 
IDX184 (2.5uM) eradicates HCV replicon RNA after long-term 14 day treatmen in vitro
 
IDX selects for NS5B S282T resistance mutation in replicon model -- Resistance emerges slowly
 
No cross resistance between IDX184 and HCV NNIs or PIs
 

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