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New HCV Drugs- Protease Inhibitors & Polymerase inhibitors and Drug Resistance
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from Jules Levin
EASL, May 1, 2006, Vienna, Austria
At EASL, Vertex reported VX-950 reduced HCV RNA a median of -4.4 logs in 14-day study and -5.5 14-day study of the combination of VX-950+Pegasys, all performed in treatment-naive patients . Schering reported again the -1.5 HCV RNA reduction they found in a 14-day study of SCH 503034 montherapy in treatment-experienced patients. For the first time they reported a -1 log reduction in 14-day study of SCH 503034 monotherapy in treatment-naive patients. The commentary below is regarding HCV drug resistance & HCV protease inhibitors.
As I leave Vienna today & return to NYC a very important message is the potential development and risk associated with newly developed HCV protease inhibitors. You should recall 10 years ago the impact of HIV drug resistance, particularly drug resistance associated with HIV protease inhibitors & NNRTIs. Emerging out of the 41st EASL conference in Vienna this year 2006 is a message from regarding HCV protease inhibitors. Early during the meeting Vertex Pharmacueticals reported results from drug resistance research conducted in accordance with the 14-day monotherapy study of their new HCV protease inhibitor VX-950. They used an assay they reported detected drug resistant mutation variants present at about 5% of frequency. They reported single and double drug resistance mutations emerged during therapy and later double mutation changes emerged, and IC50s increased. After VX-950 therapy stopped at the 14-day mark HCV viral load increased and resitance mutations started to not be detected and wild-type virus started to emerge. By the time of 3-7 months later wild-type virus was about 65% for the patient group who had viral "breakthrough" on therapy, about 90% for the patient group who had viral "plateau" on therapy and for the patients who had vira; "continuing decline" on therapy. The presentation by Vertex was called elegant research by a number of researchers & doctors in the audience.
These findings suggest that like in HIV, HCV drug resistance is a concern, certainly at this point in time. That until we see longer term clinical study results we need to pay attention to this issue. also during the EASL meeting Vertex reported the results from the small 14-day study which included some patients receiving VX-950 plus Pegasys and after 14-days it appeared that the combination fully suppressed the patients HCV viral load and Vertex reported that after VX-950 was stopped due to study protocol and patients remained on Pegasys/RBV all patients remained with undetectable HCV RNA.
So, as with HIV it appears combination therapy in HCV may be crucial to full suppression of HCV. Of note, Schering Plough reported the results of their HCV protease inhibitor 14-day study. They reported only 1 patient had 1 HCV drug mutation. I went to the microphone after the presentation and asked why they only reported this 1 mutation finding after Vertex had such an elegant presentation. The presenter said to me and the entire audience that they used an assay which was not sensitive and the Schering PI SCH 503034 was not potent enough for resistance to emerge. For several days numerous people came up to me to discuss my question & the response and this was a hot topic at the meeting.
The important point here is that HCV drug resistance is an important point to be concerned about, that combination therapy appears to be important in suppressing HCV & in preventing cross-resistance to drugs in the same class, and that exposing onself to a new oral antiviral HCV drug until we better understand the impact of drug resistance for HCV drugs can put one at risk for drug resistance unless full suppression is achieved.
Several HCV polymerase inhibitor drugs are in development. Prior to EASL NM-283 was the only drug reporting study data from patient studies. For the first time, Roche reported the first results of their HCV polymerase inhibitor R1626, which resulted in a median viral load reduction of -1.2 logs in 14-day study. HCV polymerase inhibitors are similar to HIV nucleosides and resistance is not expected to emerge as easily and not expected to present as much of a resistance concern as HCV protease inhibitors.
Several additional HCV protease inhibitors are in earlier stages of development than VX-950 & SCH 503034. But we do not know yet clinical data and resistance profiles. Intermune reported at EASL in a poster that in in vitro testing their HCV protease inhibitor was effective against the mutation associated with VX-950 resistance, but this is a preliminary test in the test tube, not findings in patients.
Jules Levin
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