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5 New Potent HCV Protease inhibitors
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by Jules Levin at AASLD
These 2 HCV protease inhibitors look good in early studies. The Abbott once-daily protease ABT-450 showed a 4 log viral load reduction after 3 days monotherapy in this poster titled:
"Initial Antiviral Activity of the HCV NS3 Protease Inhibitor ABT-450 When Given with Low-dose Ritonavir as 3-Day Monotherapy:
Preliminary Results of Study M11-602 in Genotype 1 (GT1) HCV-infected Treatment-naïve Subjects", see graph below. Abbott also reported 4 weeks data in a poster here in combination with peg/rbv. Subjects were randomized to one of 3 doses of ABT-450/r (50/100 mg, 100/100 mg or 200/100 mg) or placebo once daily for 3 days, followed by ABT-450/r or placebo in combination with standard of care (SOC) consisting of pegylated interferon alfa-2a 180 µg/week + weight-based ribavirin 1000-1200 mg/day through week 1.
The new Merck also once-daily HCV protease MK5172 also looks very good: "Safety and Antiviral Activity of MK-5172, a Novel HCV NS3/4a Protease Inhibitor with Potent Activity Against Known Resistance Mutants, in Genotype 1 and 3 HCV-Infected Patients". The protease has activity against genotype 1 and 3. Multiple oral doses of 400 mg MK-5172 qd for 7 days were generally well tolerated in HCV-infected patients. Mean maximum reductions from baseline of HCV viral RNA (Ses) were 5.4 (0.21) and 3.98 (0.22) log10 IU/mL for GT 1 and 3, respectively. Merck's MK-7009 looks potent as well showing high SVR rates in the study reported at AASLD, see table below.
As well, the new data reported for the Tibotec protease TMC435 shows potency with 95% achieving week 24 response rate. Danoprevir the Roche protease also looks potent with 92% week 12 response rates in the ATLAS Study presented here at AASLD but the study was performed before Roche decided to boost danoprevir with low-dose ritonavir. Danoprevir and ABT-450 are boosted with ritonavir which I expect is associated with increased potency.
NS5A inhibitors look potent and re in development by several companies with BMS's NS5A the furthest along in development as it is being studied in combination with their protease and results were reported at this AASLD looking at the combination of these 2 orals without peg/rbv in null-responders, and also they reported the early results of 4 drugs, the 2 orals + peg/rbv in null-responders, so we will have SVR rates, cure rates, from this study next year.
Tibotec's TMC435
Roche's danoprevir
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