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Roche HCV Polymerase Inhibitor: two preclinical studies
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Reported by Jules Levin
ICAAC, Sept 30, 2006, San Francisco
Resistance Profile for 4'-Azido-Cytidine (R1479), Reveals Lack of Cross Resistance with 2'-C-Methyl-Cytidine, Interferon-Alfa and Ribavirin
I. NAJERA, S. LE POGAM, W. JIANG, V. LEVEQUE, S. RAJYAGURU, H. MA, H. KANG, S. JIANG, S. ALI, K. KLUMPP, D. SMITH, J. SYMONS, N. CAMMACK;
Roche Palo Alto LLC, Palo Alto, CA.
At the 2006 ICAAC meeting just completed in San Francisco there was encoraging data reported for several new orally administered HCV drugs still in early development. HCV-796, MK-0608, and R1626 are 3 polymerase inhibitors for HCV therapy. HCV-796 is just entered phase II study in patients. R1626 is soon to enter phase II in patients. And MK-0608 is still in preclinical but shows so far the most potency although in animal studies. HCV-796 showed a 1.4 HCV viral load log reduction in a 2 week monotherapy study in patients. R1626 showed a 1.2 log reduction in a 2 week monotherapy study in patients. MK-0608 showed from 4.6 to 5.7 log reductions in 6 chimpanzees. This is very potent and is similar to viral load reductions seen in patients with the HCV protease inhibitor VX-950. In addition to these drugs, there are a number of others at various stages of development. At ICAAC study data reported suggest these HCV polymerase drugs may not be cross-resistant. Combination therapy of these oral agents will be studied.
Background: The HCV polymerase is an attractive target for the development of new and HCV-specific antiviral compounds. 2'-C-Methyl-Cytidine and 4'-Azido-Cytidine (R1479) are potent inhibitors of both genotype 1b and genotype 1a-polymerase driven replicon replication. The corresponding 5'-triphosphate derivatives are potent and selective inhibitors of the recombinant genotype 1b and 1a HCV polymerase mediated RNA synthesis.
Methods: In this study, we used the HCV subgenomic replicon system to select and characterize HCV variants with reduced susceptibility to 2'-C-Methyl-Cytidine and to R1479 and investigated potential cross resistance with Interferon-alfa and Ribavirin.
Results: Characterization of resistant replicons to 2'-C-Methyl-Cytidine identified S282T in the NS5B coding region as the mutation conferring resistance to this compound, similar to results obtained with other 2'-methylated nucleoside analogs. Mutations S96T and S96T in combination with N142T were associated with low level resistance to the nucleoside analog R1479.
Conclusions: No cross resistance was observed between R1479 and 2'-C-Me-Cytidine, Interferon alfa or Ribavirin. This data will allow the optimization of new polymerase inhibitors and their use in combination therapy.
R1479 is a Potent Inhibitor of HCV RNA Replication Across Genotype 1a and 1b Clinical Isolates
I. NAJERA, S. LE POGAM, A. KOSAKA, S. HU, P. DIETRICH, S. JIANG, H. KANG, A. SESHAADRI, J. SYMONS, J. USUKA, K. KLUMPP, N. CAMMACK;
Roche Palo Alto LLC, Palo Alto, CA.
R1479 (4'-Azido-Cytidine) is a potent inhibitor of replication of the laboratory optimized genotype 1b strain Con1 and genotype 1a strain H77 replicons. HCV shows a high degree of genetic heterogeneity. Selection of resistance could be 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 and resistance selection is affected by the HCV intrinsic genetic heterogeneity.
The sensitivity of subgenomic HCV replicons encoding the NS5B from 30 treatment naïve HCV clinical isolates to R1479 and to two non nucleoside polymerase inhibitors (benzothiadiazine derivative NNI-1 and thiophene-2-carboxylic acid derivative NNI-2) was determined. To determine the frequency of mutations associated with resistance to R1479 and to non-nucleoside inhibitors within the HCV quasispecies from treatment naïve patients, clonal sequence analysis was performed on 7 different clinical isolates and a total of 720 individual full length HCV NS5B sequences were generated.
This study showed that R1479 is a potent inhibitor of HCV replication across 30 different genotype 1a and 1b clinical isolates and that the in vitro selected R1479-resistance mutations were not observed among the 720 NS5B polymerase variants. Mutations related to resistance to the non-nucleoside inhibitors NNI-1 and to NNI-2 were present as minority species in samples of treatment naïve patients.
The higher frequency of non nucleoside inhibitor resistance mutations as compared to the absence of resistance mutations to the nucleoside analog R1479 in the HCV quasispecies of treatment naïve HCV patients suggests a potential for faster development of clinically significant resistance for non-nucleosides NNI-1 and NNI-2 as compared to the nucleoside inhibitor R1479.
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