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Ist HCV Protease Inhibitor: 2nd study presented at AASLD
Reported by Jules Levin
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Yesterday at AASLD Boerhinger Ingleheim researchers presented study data publicly for the first time on the first HCV protease inhibitor in patients with chronic hepatitis C virus with genotype 1 who had advanced liver fibrosis but no cirrhosis. 200mg twice daily was administered by a solution since a capsule formulation has not been developed yet. BILN 2061, the protease inhibitor, was administered for two days to 10 patients. All patients regardless of genotype had at least a 2 log drop in viral load, 4 patients had at least a 3 log drop. All patients were genotype 1. Following completion of the 2 day study viral load increased in all patients back towards baseline within 1-7 days. At all time points the sensitive TMA assay was positive in all patients. See yesterday's report on the NATAP web site for more details.
BILN 2061 is a potent and specific inhibitor of HCV serine protease. It's a product of rational drug development by Boerhinger Ingleheim. In pre-clinical studies BILN 2061 was orally bioavailable in several animal species. Pre-clinical toxicology data support administration of repeated doses in humans, there was no evidence of genotoxicity. The investigators said there is no validated animal model to assess the potential pharmacologic response to BILN 2061.
Today, Boerhinger Ingleheim researchers presented study results from using BILN 2061 in 31 patients with chronic HCV, genotype 1, and minimal liver fibrosis (Ishak score 0-2). BILN 2061 was administered for two days twice a day using 3 different dosing regimens. Liver biopsy was obtained within prior 12 months. HCV viral load was >50,000 copies/ml (Amplicor). Patients were excluded if they had bridging fibrosis or higher grade fibrosis.
Among the 31 patients 24 were male, average age was 47. The 3 dose regimens were 25, 200, or 500 mg twice daily. 17 of 31 patients had prior HCV therapy and 12/17 were non-responders. The other 5 were either relapsers or breakthroughs. All 31 patients completed the study and were 100% adherent, direct observed therapy was used. There were no relevant drug-induced changes in vital signs, routine laboratory findings or ECG observed.
Three types of viral load testing was used in this study: Roche Cobas Amplicor Monitor v 2.0 (lower level of detection 1500 copies/ml); bDNA v 3.0 (Bayer), lower limit of detection 600 IU/ml); TMA (Bayer) with lower limit of detection 5 IU/ml.
At the 25 mg dose HCV viral load took a sharp dive down in 24 hours but went up and down again in the next 24 hours. Using the 200 mg dose viral load took a sharp decline in the first 24 hours and continued declining for the 48 hour period of drug administration. Using the 500 mg dose all patients had steep viral load declines in both the 24 hours and 48 hours after initiating therapy. It did appear as though there was a slightly better decline for all patients using the higher dose. The decline curve in the 200 mg dose group was less steep for 2 patients. But in the 500 mg dose group all patients had same steep decline.The 500 mg dose seemed to be the most potent.
Using either the 200 or 500 mg dose just all patients had 2 or more log reduction in viral load. But only 3/8 patients using the 200 mg dose and 7/8 patients using the 500 mg dose had 3 or more log reduction in viral load. There were 8 patients in the 200 mg dose group and 8 in the 500 mg dose group, but 9 were in the 25 mg dose group. In the 25 mg dose group 9 patients had 1 log or more viral load reduction, 7/9 had 2 or more log reduction, and only 3 had 3 or more log reduction.
The study authors summarized. Viral load decreased by 1 log or more (bDNA) in 25/25 patients treated with BILN 2061 (25, 200, or 500 mg twice daily). Viral load response was similar in pre-treated and treatment naive patients and in high and low viral load, it appeared to me that the highest viral loads were about 2 million. The TMA assay was always positive. Viral load returned to baseline within 1-7 days of completing BILN 2061 treatment. Further studies are planned.
Possible drug related adverse events: headache (5/25), mild fatigue (2/25), diarrhea (1/25), nausea (2/25), mild eosinophillia (1/25).
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