EASL Analysis, New Oral HCV Drugs What's Expected

EASL Analysis, New Oral HCV Drugs What's Expected

Reported by Jules Levin

I returned from Copenhagen on April 27 after enjoying a very exciting meeting and talking with many researchers about the development of the many promising new oral HCV drugs. There were about 25 new HCV drugs that new data was reported on at EASL in Copenhagen April 23-26 2009. The biggest story was the INFORM Study which is the first study of 2 oral HCV drugs in combination in patients, the study showed short-term efficacy/potency and safety for the combination of Roche's protease ITMN191 (R7227) and their polymerase NRTI R7128. This was the first proof of concept study for showing you can combine 2 oral HCV drugs, and the study importantly showed additive antiviral activity and safety. Of course further studies are planned to move this ahead. Of interest also was a poster on an early study of lambda interferon in patients which is a peginterferon that shows little or no interferon side effects. A major question is whether or not interferon and ribavirin can be eliminated from therapy. I have my doubts they can be and still achieve a 'cure' with time limited duration of therapy but many others are confident they can eliminate peg/RBV; many researchers and companies are planning the studies to answer this question, but if interferon is still needed at least for some patients a peginterferon like lambda without side effects would obviously be a tremendous breakthrough. Every major drug company has oral HCV drugs in development and presented data at EASL including Boerhinger who has a protease now in phase 2 & for the first time presented new data in patients on their polymerase inhibitor. Merck presented for the 2nd time on their protease this time in combination with peg/RBV with interesting and positive results, and for the first time presented new data on their polymerase. Tibotec presented 2 studies in naives and treatment-experienced patients on their once-a-day protease which looks potent. Of note, Schering presented for the first time their new protease, not boceprevir, that looks potent and will be boosted by ritonavir. Abbott has a comprehensive HCV drug program and they presented interesting preclinical data showing their protease to be potent and they had 2 posters on their 2 polymerase inhibitors. Of note there are 2 types of polymerase inhibitors, NNRTIs and NRTIs, and their are at least 2 types of NNRTIs. NNRTIs that can bind at different places may be able to be combined in a regimen and also along with a NRTI. At AASLD BMS presented their first data in patients on their NS5A inhibitor and it looked potent, and at this EASL Presidio, a biotech, presented preclinical data on their NS5A candidates. Of course as expected Vertex presented phase 2 data on telaprevir and Schering presented phase 2 data on boceprevir, and both of these proteases are now in phase 3 and expected to be ready for launch in mid 2011. Pfixer presented at EASL with a poster on their new HCV NNRTI filibuvir and it looks promising. HCV drug resistance appears to be of concern. With monotherapy drug resistance to the protease can emerge quickly, in 2 days. Combining peg/RBV with the protease can prevent resistance but if a patient develps viral failure, just like in HIV, drug resistance can emerge. In naives the results from phase 2 when using telaprevir+peg/RBV was about 65% SVR rate with 24 weeks therapy, in treatment-experienced prior nonresponders the SVR rate was 39% and this included both null and nonresponders. Also, 75% of prior relapsers and 57% of prior breakthroughs achieved SVR in phase 2 study. For boceprevir the data was 56% with 24 weeks with or without 4 week peg/RBV lead-in, and with 48 weeks 75% with 4 week lead-in and 67% without 4 week lead-in. So drug resistance is an important point to bear in mind as the proteases so far in development appear to be cross-resistant. So far there are no 2nd generation proteases that will be active against resistance like in HIV with for example darunavir. Researchers are looking for such proteases but they have not yet emerged. So be careful about acquiring drug resistance to a protease but it does appear as though other drugs will at some point in the future provide a regimen. For example, combining an NS5A inhibitor with 2 NNRTIs or an NNRTI+NRTI will be possibilities in the future. All in all, future therapy for HCV is promising for patients. After the expected launch in 2011 of telaprevir+peg/RBV and boceprevir+peg/RBV right behind that by perhaps 2 years will be Roche's 2 orals plus peg/RBV but the other companies are also developing their own multiple drug regimens and perhaps the companies will collaborate and do cross-company studies with their drugs. Vertex acquired ViroPharma's polymerase inhibitors and presented interesting data at EASL on VCH-222 which in early study showed a potent 3.7 log viral load reduction. So you can see we are headed towards regimens with 2, 3 and perhaps 4 oral HCV drugs in combination with peg/RBV and perhaps later without peg/RBV. With 2 orals plus peg/RBV I estimate 75-80% SVR rates and close to that for African-Americans and with 3 orals plus peg/RBV I estimate 85%-95% SVR rates for all including African-Americans. But to get to this point it will take some time. Briefly, regarding hepatitis B BMS reported entecavir resistance data out to 7 years and Gilead reported 2 years efficacy and resistance data on tenofovir and the data for both drugs looks good. The reports on all these presentations are linked to below and on the NATAP website. Jules Levin