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940 SAFETY, TOLERABILITY AND PHARMACOKINETICS OF THE HCV POLYMERASE INHIBITOR VCH-222 FOLLOWING SINGLE DOSE ADMINISTRATION IN HEALTHY VOLUNTEERS AND ANTIVIRAL ACTIVITY IN HCV-INFECTED INDIVIDUALS
S342
Poster Session − Saturday, April 25
were evaluated in vitro in systems derived from human and/or animal species. Results: In rats and dogs, VCH-222 displayed low total body clearance with excellent oral bioavailability (greater than 30%). The exposure of VCH-222 in rat liver was 5-fold higher than in plasma. Excretion studies in bile-duct cannulated rats indicated that, upon oral and iv administration, [14 C]-VCH-222 was excreted mainly intact in bile or as glucuronide adducts. VCH-222 was metabolically stable in human microsomes and hepatocytes. Both oxidation and glucuronidation pathways were observed. Phenotyping studies indicated that several enzymes were involved in the biotransformations of VCH-222 (CYP1A1, 2A6, 2B6, 2C8, CYP 3A4, UGT1A3). In in vitro studies, VCH-222 demonstrated limited potential to cause human CYP inhibition or CYP induction. The absorption potential of VCH-222 was shown to be acceptable based on its good permeability in Caco-2 cell monolayer and minimal recognition by intestinal efflux proteins. In addition, VCH-222 had no significant effect of digoxin permeability. Based on sandwich-cultured hepatocyte studies, VCH-222 is predicted to be actively transported in liver and to have a low biliary clearance in humans. Conclusion: VCH-222 has a good oral bioavailability and ADME properties in terms of permeability, metabolic behaviours and distribution in hepatic tissue/cell. VCH-222 is neither a CYP inhibitor/inducer nor a Pgp inhibitor reducing the likelihood of VCH-222 to be involved in drug interactions. From these data, a favorable pharmacokinetic profile is expected in humans. 940 SAFETY, TOLERABILITY AND PHARMACOKINETICS OF THE HCV POLYMERASE INHIBITOR VCH-222 FOLLOWING SINGLE DOSE ADMINISTRATION IN HEALTHY VOLUNTEERS AND ANTIVIRAL ACTIVITY IN HCV-INFECTED INDIVIDUALS C. Cooper1 , R. Larouche2 , B. Bourgault3 , N. Chauret3 , L. Proulx3 . 1 The Ottawa Hospital, Ottawa, Ontario, 2 Anapharm, A Pharmanet Company, Montreal, Quebec, 3 ViroChem Pharma Inc., Laval, Quebec, Canada E-mail: [email protected] Background and Aims: VHC-222 is a novel non-nucleoside inhibitor of the HCV NS5B polymerase. It has demonstrated potent in-vitro antiviral activity in genotype 1a and 1b replicon systems with IC90 values of 65 and 41 nM (29 and 18 ng/mL), respectively. Methods: A Phase I, randomized, double-blind, ascending, single dose trial was conducted to evaluate the safety, tolerability, pharmacokinetics and food effect of VCH-222. Healthy subjects were randomized into four treatment cohorts (250, 500, 1000 and 1500 mg). All doses were administered in the fasted state with the exception of the 500 mg-fed group. An open cohort of 6 subjects with HCV genotype-1 infection was dosed with 750 mg bid for 3 days. Results: VCH-222 was well tolerated at all doses tested. There have been no serious adverse events and all adverse events observed were classified as mild to moderate with no apparent dose relationship. There have been no clinically significant changes in other safety assessments. Under fasted condition, the rate and extent of absorption (Cmax and AUC) appeared relatively proportional between the doses of 250 and 1,500 mg. The halflife was approximately 4 hours and the plasma levels observed at 24 h (C24 h ) were above the IC90 replicon values in all cohorts. In the subjects treated for 3 days with 750 mg bid there was a 2-fold increase in Cmax and AUC observed between Day 1 and Day 3. Preliminary efficacy results on the first 4 treatment-naive subjects dosed for 3 days reveal a mean log10 reduction of 3.2 (range 3.0−3.3) within 24 hours of dosing and of 3.7 (range 3.2−4.2) on Day 4. Conclusions: VCH-222 was safe and well tolerated up to 1,500 mg administered as a single dose or at 750 mg bid for 3 days. In terms of exposure versus in vitro potency, excellent pharmacokinetic properties were exhibited. In vivo, high HCV virological potency was demonstrated.
941 JTK-652 IS A NOVEL HCV ENTRY INHIBITOR: RESULTS OF A PHASE 1 STUDY EVALUATING SAFETY, TOLERABILITY AND ANTIVIRAL ACTIVITY IN CHRONIC HEPATITIS C PATIENTS J. de Bruijne1 , J. Bergmann2 , C. Weegink1 , K. van Nieuwkerk3 , R. de Knegt2 , J. van de Wetering de Rooij4 , A. van Vliet4 , R. Molenkamp5 , J. Schinkel5 , H. Reesink1 , H. Janssen2 . 1 Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, 2 Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, 3 Department of Gastroenterology and Hepatology, VU Medical Center, Amsterdam, 4 PRA International, Zuidlaren, 5 Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands E-mail: [email protected] Background: JTK-652, a novel HCV entry inhibitor, showed potent inhibitory activity against HCV genotype 1a and 1b pseudotyped viruses bearing HCV E1E2 envelope proteins in HepG2 cells and human primary hepatocytes. Treatment with single ascending doses of JTK-652 or placebo (6:3 ratio), ranging from 100 mg to 1200 mg, was safe and well tolerated in 18 healthy male subjects. Treatment with multiple ascending doses of 400 mg (n = 9) and 800 mg (n = 9) JTK-652 TID or placebo (6:3 ratio) for 14 days was safe and well tolerated in 8/12 healthy male subjects. Four subjects (400 mg, n = 1; 800 mg, n = 3) developed an almost generalized drug eruption of mild intensity. This study evaluated safety, tolerability, pharmacokinetics and antiviral activity of JTK-652 in HCV genotype 1 infected patients. Methods: The study was randomized, double blind and placebo controlled. Ten HCV genotype 1 infected patients (naive (n = 2) and treatmentexperienced (n = 8), HCV RNA 10e5 IU/mL) received an oral dose of 100 mg JTK-652 TID or placebo (8:2 ratio) for 4 weeks. Results: Eight patients completed the study (7 active, 1 placebo). Premature discontinuation occurred in 2 patients (1 active, 1 placebo) on day 13 and day 19, respectively, due to an almost generalized drug eruption of mild intensity. This rash disappeared within days after stopping JTK652 administration and additional treatment was not necessary. No other clinically significant adverse events (AEs) were considered to be related to study drug administration. No significant clinical laboratory, vital signs, ECG or physical examination abnormalities were observed. JTK-652 was found to be well tolerated, all AEs were mild in severity. At day 29 (end of treatment) no significant changes in HCV RNA compared to baseline were observed in the individual patients; mean HCV RNA change from baseline was +0.19 IU/mL at end of treatment. Conclusion: Results from this phase 1 study indicated that, beside a mild drug eruption in 1 patient, JTK-652 was safe and well tolerated at a 100 mg TID dose level. However, plasma HCV RNA levels did not decline during 28 days of dosing. Further development of this compound was stopped. 942 VIRAL KINETIC MODELING DURING TREATMENT WITH INTERFERON LAMBDA-1A IN GENOTYPE 1 CHRONIC HEPATITIS C PATIENTS M.G. Dodds1 , D.F. Hausman2 , D.M. Miller1 . 1 Preclinical Development, 2 Clinical Development, ZymoGenetics, Inc, Seattle, WA, USA E-mail: [email protected] Background and Aims: Peginterferon lambda-1a (PEG-IFN-l1a) is a novel Type III interferon that binds to a unique cell surface receptor and induces an intracellular antiviral response similar to that induced by IFN-a. As the expression of the IFN-l receptor is more limited than the IFN-a receptor, we hypothesize that treatment of chronic hepatitis C (CHC) with PEG-IFN-l1a will result in fewer toxicities and an improved therapeutic index. As part of ongoing trial in treatment-relapsed chronic hepatitis C patients, changes in viral mRNA were analyzed using a mathematical model to assess the dose-response relationship of PEG-IFN-l1a.
Poster Session − Saturday, April 25
were evaluated in vitro in systems derived from human and/or animal species. Results: In rats and dogs, VCH-222 displayed low total body clearance with excellent oral bioavailability (greater than 30%). The exposure of VCH-222 in rat liver was 5-fold higher than in plasma. Excretion studies in bile-duct cannulated rats indicated that, upon oral and iv administration, [14 C]-VCH-222 was excreted mainly intact in bile or as glucuronide adducts. VCH-222 was metabolically stable in human microsomes and hepatocytes. Both oxidation and glucuronidation pathways were observed. Phenotyping studies indicated that several enzymes were involved in the biotransformations of VCH-222 (CYP1A1, 2A6, 2B6, 2C8, CYP 3A4, UGT1A3). In in vitro studies, VCH-222 demonstrated limited potential to cause human CYP inhibition or CYP induction. The absorption potential of VCH-222 was shown to be acceptable based on its good permeability in Caco-2 cell monolayer and minimal recognition by intestinal efflux proteins. In addition, VCH-222 had no significant effect of digoxin permeability. Based on sandwich-cultured hepatocyte studies, VCH-222 is predicted to be actively transported in liver and to have a low biliary clearance in humans. Conclusion: VCH-222 has a good oral bioavailability and ADME properties in terms of permeability, metabolic behaviours and distribution in hepatic tissue/cell. VCH-222 is neither a CYP inhibitor/inducer nor a Pgp inhibitor reducing the likelihood of VCH-222 to be involved in drug interactions. From these data, a favorable pharmacokinetic profile is expected in humans. 940 SAFETY, TOLERABILITY AND PHARMACOKINETICS OF THE HCV POLYMERASE INHIBITOR VCH-222 FOLLOWING SINGLE DOSE ADMINISTRATION IN HEALTHY VOLUNTEERS AND ANTIVIRAL ACTIVITY IN HCV-INFECTED INDIVIDUALS C. Cooper1 , R. Larouche2 , B. Bourgault3 , N. Chauret3 , L. Proulx3 . 1 The Ottawa Hospital, Ottawa, Ontario, 2 Anapharm, A Pharmanet Company, Montreal, Quebec, 3 ViroChem Pharma Inc., Laval, Quebec, Canada E-mail: [email protected] Background and Aims: VHC-222 is a novel non-nucleoside inhibitor of the HCV NS5B polymerase. It has demonstrated potent in-vitro antiviral activity in genotype 1a and 1b replicon systems with IC90 values of 65 and 41 nM (29 and 18 ng/mL), respectively. Methods: A Phase I, randomized, double-blind, ascending, single dose trial was conducted to evaluate the safety, tolerability, pharmacokinetics and food effect of VCH-222. Healthy subjects were randomized into four treatment cohorts (250, 500, 1000 and 1500 mg). All doses were administered in the fasted state with the exception of the 500 mg-fed group. An open cohort of 6 subjects with HCV genotype-1 infection was dosed with 750 mg bid for 3 days. Results: VCH-222 was well tolerated at all doses tested. There have been no serious adverse events and all adverse events observed were classified as mild to moderate with no apparent dose relationship. There have been no clinically significant changes in other safety assessments. Under fasted condition, the rate and extent of absorption (Cmax and AUC) appeared relatively proportional between the doses of 250 and 1,500 mg. The halflife was approximately 4 hours and the plasma levels observed at 24 h (C24 h ) were above the IC90 replicon values in all cohorts. In the subjects treated for 3 days with 750 mg bid there was a 2-fold increase in Cmax and AUC observed between Day 1 and Day 3. Preliminary efficacy results on the first 4 treatment-naive subjects dosed for 3 days reveal a mean log10 reduction of 3.2 (range 3.0−3.3) within 24 hours of dosing and of 3.7 (range 3.2−4.2) on Day 4. Conclusions: VCH-222 was safe and well tolerated up to 1,500 mg administered as a single dose or at 750 mg bid for 3 days. In terms of exposure versus in vitro potency, excellent pharmacokinetic properties were exhibited. In vivo, high HCV virological potency was demonstrated.
941 JTK-652 IS A NOVEL HCV ENTRY INHIBITOR: RESULTS OF A PHASE 1 STUDY EVALUATING SAFETY, TOLERABILITY AND ANTIVIRAL ACTIVITY IN CHRONIC HEPATITIS C PATIENTS J. de Bruijne1 , J. Bergmann2 , C. Weegink1 , K. van Nieuwkerk3 , R. de Knegt2 , J. van de Wetering de Rooij4 , A. van Vliet4 , R. Molenkamp5 , J. Schinkel5 , H. Reesink1 , H. Janssen2 . 1 Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, 2 Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, 3 Department of Gastroenterology and Hepatology, VU Medical Center, Amsterdam, 4 PRA International, Zuidlaren, 5 Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands E-mail: [email protected] Background: JTK-652, a novel HCV entry inhibitor, showed potent inhibitory activity against HCV genotype 1a and 1b pseudotyped viruses bearing HCV E1E2 envelope proteins in HepG2 cells and human primary hepatocytes. Treatment with single ascending doses of JTK-652 or placebo (6:3 ratio), ranging from 100 mg to 1200 mg, was safe and well tolerated in 18 healthy male subjects. Treatment with multiple ascending doses of 400 mg (n = 9) and 800 mg (n = 9) JTK-652 TID or placebo (6:3 ratio) for 14 days was safe and well tolerated in 8/12 healthy male subjects. Four subjects (400 mg, n = 1; 800 mg, n = 3) developed an almost generalized drug eruption of mild intensity. This study evaluated safety, tolerability, pharmacokinetics and antiviral activity of JTK-652 in HCV genotype 1 infected patients. Methods: The study was randomized, double blind and placebo controlled. Ten HCV genotype 1 infected patients (naive (n = 2) and treatmentexperienced (n = 8), HCV RNA 10e5 IU/mL) received an oral dose of 100 mg JTK-652 TID or placebo (8:2 ratio) for 4 weeks. Results: Eight patients completed the study (7 active, 1 placebo). Premature discontinuation occurred in 2 patients (1 active, 1 placebo) on day 13 and day 19, respectively, due to an almost generalized drug eruption of mild intensity. This rash disappeared within days after stopping JTK652 administration and additional treatment was not necessary. No other clinically significant adverse events (AEs) were considered to be related to study drug administration. No significant clinical laboratory, vital signs, ECG or physical examination abnormalities were observed. JTK-652 was found to be well tolerated, all AEs were mild in severity. At day 29 (end of treatment) no significant changes in HCV RNA compared to baseline were observed in the individual patients; mean HCV RNA change from baseline was +0.19 IU/mL at end of treatment. Conclusion: Results from this phase 1 study indicated that, beside a mild drug eruption in 1 patient, JTK-652 was safe and well tolerated at a 100 mg TID dose level. However, plasma HCV RNA levels did not decline during 28 days of dosing. Further development of this compound was stopped. 942 VIRAL KINETIC MODELING DURING TREATMENT WITH INTERFERON LAMBDA-1A IN GENOTYPE 1 CHRONIC HEPATITIS C PATIENTS M.G. Dodds1 , D.F. Hausman2 , D.M. Miller1 . 1 Preclinical Development, 2 Clinical Development, ZymoGenetics, Inc, Seattle, WA, USA E-mail: [email protected] Background and Aims: Peginterferon lambda-1a (PEG-IFN-l1a) is a novel Type III interferon that binds to a unique cell surface receptor and induces an intracellular antiviral response similar to that induced by IFN-a. As the expression of the IFN-l receptor is more limited than the IFN-a receptor, we hypothesize that treatment of chronic hepatitis C (CHC) with PEG-IFN-l1a will result in fewer toxicities and an improved therapeutic index. As part of ongoing trial in treatment-relapsed chronic hepatitis C patients, changes in viral mRNA were analyzed using a mathematical model to assess the dose-response relationship of PEG-IFN-l1a.