Nucleoside inhibitor MK-0608 mediates suppression of HCV replication for >30 days in chronically infected chimpanzees
Jules Levin, natap.org
There are 3 HCV polymerase inhibitors in patient studies now: HCV-796; R1626; NM283. HCV-796 & R1626 showed 1.2 o 1.4 log viral load reductions in 10 day studies. And there are 2 HCV protease inhibitors in patients studies: VX-950, which showed 4.4 log reductions in 14 day study in viral load, and SCH503034 which showed about 1.8 logs viral load reduction in 14 day study.
David Olsen et al from Merck reported in a poster on this last day at ICAAC new study results of a study reporting the effect of a new HCV polymerase inhibitor MK-0608 in chimpanzees. The first presentation of MK-0608 was at the HIV Drug Resistance Workshop in the Summer of 2006 where a 5.7 log reduction was seen in chimps after 7 days, and with one dose three logs reduction was seen.
The results reported an average reduction of 4.7 logs HCV RNA for 4 chimps who were treated. Three of 4 chimps had undetectable HCV RNA with a sensitive assay. But the baseline viral loads were lower for these 3 chimps than the chimp that saw a 5.7 log viral load reduction reported at the Resistance Workshop. Of note, until now we have seen these types of deep HCV RNA reductions only in HCV protease inhibitors.
Once-daily dosing of MK-0608 for 37 days in HCV chronically infected resulted in a rapid decrease in plasma viral RNA to below the limit of quantification (20 IU/ml) in 3 of 4 animals in less than 10 days.
Continued administration for up to 37 days resulted in sustained suppression of viral load to levels below detection that remained undetectable throughout the dosing period.
Viral load in the fourth chimpanzee (starting titer >106 IU/mL) decreased by 4.7 logs during dosing without the selection of resistant virus. All animals experienced a rebound in viral load upon cessation of dosing.
Author conclusions included that IV and oral dosing of MK-0608 to HCV infected chimpanzees resulted in significant reductions in viral load: >5 log reduction in viral load (mg/kg IV), no rebound during dosing and a delay in rebound after end of extended dosing The resistance genotype included mutations at amino acid 282, with reversion back to wild-type sequence suggesting this mutation impacts on viral fitness.
Olsen DB, Davies M, Handt L et al. The nucleoside inhibitor MK-0608 mediates suppression of HCV replication for >30 days in chronically infected chimpanzees. 46th ICAAC, Toronto 2006. Abstract V-1914a.