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HCV-796 Polymerase Inhibitor Shows 1.5 log Viral Load Reduction
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Reported by Jules Levin
42nd EASL, Barcelona
April 11-15, 2007
Antiviral Activity of the Non-Nucleoside Polymerase Inhibitor, HCV-796, in Combination with Pegylated Interferon Alfa-2b in Treatment-Naive Patients With Chronic Hepatitis C Virus
Stephen Villano,1 Donald Raible,2 Dawn Harper,2
John Speth,2 Priyamvada Chandra,2 Paula Shaw,3 Geraldine Bichier 4
1 Clinical Research & Development, ViroPharma, Incorporated, Exton, PA;
2 Clinical Pharmacology, Wyeth Research, Collegeville, PA;
3 Northwest Kinetics, Tacoma, WA
4 Center for Clinical Trials Research, Univ. of Florida, Gainesville, FL
HCV RNA Change from Baseline
Genotype 1
Previously reported 14 day monotherapy study results was that a reduction in viral load of -1.4 log was seen. In this study you can see a 1.5 to 2 log viral load reduction. The peg alone arm showed about a 1.2 log reduction; the 100mg HCV-796+peg arm showed about a 3 log reduction; the other arms all showed about a 3 log reduction.
BACKGROUND
--Chemical Class: Benzofuran
--Orally bioavailable
--Target: HCV NS5B RdRp
--Mechanism: Non-competitive allosteric inhibitor (Non-nucleoside)
In vitro:
-- Active against RdRp Enzyme (Genotypes 1, 2, 3, 4)
-- Replicon Activity:
1a replicon: EC50 = 4.5 + 2.0 nM
1b replicon: EC50 = 8.6 + 4.0 nM
In vivo: antiviral activity in chimeric mice infected with HCV
STUDY DESIGN
Randomized, double-blind, placebo-controlled dose-ranging study
Subjects with chronic HCV infection
-- HCV treatment-naive; any HCV genotype
Day -1 and Day 7: PEG-IFN
pegylated interferon alfa-2b; 1.5 _g/kg/dose
Days 1-14: HCV-796 or placebo
-- 100, 250, 500, or 1000 mg BID
Objectives: Safety, PK, Antiviral activity
STUDY POPULATION (key criteria)
Age 18 to 64 years
Treatment-naive subjects with chronic HCV
Any HCV genotype
No other known causes of liver disease
No advanced or decompensated liver disease
Plasma HCV RNA ≥ 104 IU/mL at screening
Human immunodeficiency virus (HIV) negative
ALT less than 5x upper limit of normal
METHODS
All subjects monitored as inpatients during the 14-day treatment period
Baseline HCV genotyping
-- TRUEGENE HCV 5'NC Genotyping Kit (Bayer HealthCare)
Plasma HCV RNA Assessments by PCR
-- AMPLICOR HCV MONITOR (Roche Diagnostics)
Standard safety assessments
PK profiles Day 1 and Day 14
BASELINE PATIENT CHARACTERISTICS
46 patients in 1 of 4 peg+HCV-796 arms and 19 patients receiving peg alone. 68% genotype 1, baseline HCV RNA: 6.2-6.7 log.
RESULTS
SAFETY
Safety profile of HCV-796 + PEG was generally consistent with known effects of interferons
--Virtually all subjects had headache, chills, myalgia, or fever - most starting on Day -1 after first dose of PEG
No dose-limiting toxicities identified across the range of study doses
Serious AEs:
PEG: (1) pneumonia [Day 15]
1000 mg + PEG: (1) seizure, rhabdomyolysis [Day 1]
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