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Potent Antiviral Activity of 2nd Generation HCV Nucleotide Inhibitors, IDX102 and IDX184, in HCV-infected Chimps
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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
-- 2Õ-C-methyl cytidne analog
R1626: prodrug of R1479
-- 4Õ-azido cytidine analog
R7128: prodrug of PSI-6130
-- 2Õ-fluoro 2Õ-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)
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
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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