New Protease Inhibitors

There were so many new drugs for HCV presented at EASL, there are about 7 protease inhibitors and 10 polymerase inhibitors being studied now in patients at various stages of develoment. Some of the polymerase inhibitors will be able to be combined. A NRTI like R7128, the Rocjhe/Pharmasset drug, can be combined with a NNRTI, but also some NNRTI can be combined because they bind at different sites. So what that means is that if a patient took a protease regimen and failed and got resistance we hope and expect other types of regimens might work. Several protease inhibitor might be effective against telaprevir and boceprevir resistance but its way to early to know and I suggest not counting on this. But the Enata/Abbott protease and the new Schering protease are able to achieve high blood levels and perhaps they might suppress resistance virus like Kaletra could suppress saquinavir resistance for some patients. Researchers are in very early stages of trying to develop a second generation protease that might effectively suppress resistant virus from telaprevir, but I prefer to be cautious if I can have that luxury. So the SVR rates with telaprevir in phase 2 are 65% in genotype naives but 39% in prior nonresponders but they don't break out the SVR rates for null responders so if they could it would be less than 39%. We expect to get data in null responders from their phase 3 studies. This means if you can wait for better therapy you might want to. The INFORM Study conducted by Roche with Pharmasset & Intermune showed at EASL the results of combining 2 oral drugs, their 2 orals the protease ITMN191/R7227 + R7128 the NRTI. The potency was very good, additive. In monotherapy ITMN191 gives a 4 log drop and R7128 about 2.7 logs. Roche is rushing ahead in the next set of studies. So 2 orals + Peg/RBV is on the horizon and will be more potent than one protease + peg/RBV especially for prior nonresponders. At some point we will have combinations of 3 or more orals with peg/RBV and then we can expect 80-90% SVR rates for all patients including African-Americans, I think. Of course the companies are planning to conduct studies to see if they can get rid of peg/RBV and we will see if thats possible. One eminent researcher, Eugene Schiff from the University of Miami, told me he is very confident that within 5 years we will have regimens without peg/RBV, I am not as sure but we will see. Right below here is a link to the first study in patients at a conference, reported at EASL, for the peginterferon that BMS recently bought. This IFN promises to have not to have the major side effects associated with interferon, this is an early study so more studies have to be conducted, but this study showed potency, take a look. In sum, HCV drug resistance is an important concern, resistance to a protease monotherapy can develop within a few days and adding peg/RBV reduces the risk a lot which is why we see 65% SVR rates with those 3 drugs, but there is a risk particularly for nonresponders and moreo for null responders to prior IFN. When making treatment decisions bear this in mind
Jules Levin NATAP