Merck's New HCV Polymerase Inhibitor Drug Reduces HCV Viral Load by 5.7 Log in 7 Days in Chimps
Reported by Jules Levin
15th International HIV Drug Resistance Workshop
June 13-17, 2006, Sitges, Spain
"Robust Suppression of Viral Replication in HCV Infected Chimpanzees by Nucleoside Inhibitor MK-0608"
This morning at the opening oral session at the Workshop David Olsen from Merck reported for the first time publicly the very impressive but early data results from the study of a new HCV polymerase inhibitor drug in chimpanzees.
Olsen's Summary
- MK-0608 dosed once daily at 2 mg/kg results in rapid, multi-log reductions in viral load in HCV-infected chimpanzees
- ≥ 5.7 log10
- Robust antiviral efficacy is not limited to protease inhibitors for HCV
- role of innate immunity in rapid responders to PIs ??
- S282T resistance mutation detected
- Is chimpanzee efficacy predictive of efficacy in humans ?
Its 7 years since Merck launched a major effort to identify small molecule inhibitors of key viral enzymes: NS3/4A protease and NS5B polymerase
NS5B polymerase
- Viral polymerases are target for 22/37 approved antiviral drugs
- Catalytic center of the viral RNA replication machinery
- synthesis of (-) and (+) -strand RNA
- Inhibitors of NS5B polymerase inhibit HCV RNA replication in cell culture, animal models and man
NS5B: Five Inhibitor Binding Sites
In theory, polymerase inhibitors can bind in different places and can be combined together in a regimen or used sequentially if they have different resistance mutations.
Is it possible to achieve robust drops in vload with a polymerase inhibitor?
MK-0608 Potency Profile (nM)
Merck reports the IC50 for the Merck drug is 120 nM for genotype 1 & the IC50 for NM283 is 200 nM, less Merck drug is needed. 250 nM of the Merck drug needed for EC50 in replicon for I think its also genotype 1 vs 7000 nM for NM283. MK-0608 is also active against genotype 2 as displayed below in this table. Also, in this table Merck reports about a 1 log viral load reduction was observed in the chimp with NM283 (at 8 & 16.6 milligrams/kg) and this was equivalent to about 1 log viral load reduction in the patient NM283 study.
- NM283 = prodrug of 2'-beta-Me-C
