- Email: [email protected]
748 EFFICACY OF STANDARD OF CARE THERAPY FOLLOWING EXPERIMENTAL DEBIO 025 TREATMENT IN PATIENTS WITH CHRONIC HEPATITIS C
POSTERS Conclusion: Administration of narlaprevir (with or without ritonavir) plus Peg-IFN for two weeks followed by SOC for 24 or 48 weeks resulted in 81% and 38% SVR in treatment-naïve and experienced patients, respectively. 747 PHARMACOKINETICS OF THE HCV POLYMERASE INHIBITOR ABT-072 FOLLOWING SINGLE AND MULTIPLE DOSING IN HEALTHY ADULT VOLUNTEERS E. Dumas, W. Awni, D. Cohen, B. Bernstein, A. Nada, Y.L. Chiu, C. Klein. Abbott Laboratories, Abbott Park, IL, USA E-mail: [email protected] Background: ABT-072 is a novel NS5B polymerase inhibitor being developed for the treatment of HCV genotype 1 infection. ABT072 was previously administered to healthy adult volunteers as single and multiple doses up to 320 mg. This study examined the pharmacokinetics of escalating single and multiple oral doses of ABT-072 tablets at higher doses in healthy subjects. Methods: The pharmacokinetics of single and multiple escalating doses of ABT-072 tablets were assessed in a two-period, doubleblind, placebo-controlled fashion in 44 healthy adult subjects. In each of the 4 sequential dose groups in Period 1, subjects were randomized to receive single oral doses of either ABT-072 (400, 600, 800 and 1200 mg) or placebo. In Period 2 after a 4 day washout, subjects from the 400 and 800 mg single oral dose groups received ABT-072 or placebo once-daily (QD) for 7 days at the same dose they received in Period 1. Samples were collected throughout the study for pharmacokinetic analysis. Results: Considering the results from this study and an earlier study with ABT-072, the pharmacokinetics of ABT-072, Cmax and AUC, increased in a dose proportional fashion from 100 to 1200 mg. Maximum plasma concentrations (Cmax ) of ABT-072 were achieved approximately 3 hours after dosing with a half-life (t1/2 ) of 9–10 hours. Mean Cmax and AUC24 values were ~50% and 70% higher, respectively, on Day 7 compared to Day 1 following ABT-072 800 mg QD for 7 days. Steady state levels were reached by Day 2. ABT-072 was generally well tolerated at all doses studied. No dose limiting toxicity was observed. Conclusions: The pharmacokinetics of ABT-072 were doseproportional up to the highest dose studied, 1200 mg, with 50% to 70% accumulation following 7 days of dosing at doses up to 800 mg QD. ABT-072 was well tolerated. 748 EFFICACY OF STANDARD OF CARE THERAPY FOLLOWING EXPERIMENTAL DEBIO 025 TREATMENT IN PATIENTS WITH CHRONIC HEPATITIS C R. Flisiak1 , M. Woynarowski2 , M. Jablkowski3 , W. Halota4 , W. Kryczka5 , A. Horban6 , A. Czauz-Andrzejuk1 , J. Bialkowska3 , M. Pawlowska4 , D. Zarebska-Michaluk5 , J. Kierkus7 , R. Crabbe´ 8 , J. Liz8 . 1 Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bialystok, 2 Medical Network SA, Warszawa, 3 Department for Infectious and Liver Diseases, Medical University of Lodz, Lodz, 4 Department of Infectious Diseases and Hepatology, Nicolaus Copernicus University, Collegium Medicum, Bydgoszcz, 5 Department of Infectious Diseases, Provincial Hospital, Kielce, 6 Warsaw Medical University and Hospital of Infectious Diseases, 7 The Children’s Memorial Health Institute, Warszawa, Poland; 8 Debiopharm SA, Lausanne, Switzerland E-mail: fl[email protected] Background and Aims: Debio 025 is a cyclophilin inhibitor with high anti-HCV activity, particularly in combination with PegIFNa2a, which was confirmed in a phase 2 study (Flisiak R et al. Hepatology 2009; 49: 1460). The aim of this study was to follow the virological and biochemical response in patients who completed the initial phase 2 study and who afterwards received standard of
care (SOC) medication. Additionally, the possible risk of adverse events related to the initial therapy with Debio 025 was evaluated during the SOC treatment period. Patients and Methods: The study was carried out in 29 patients who received any dose of Debio 025 plus weekly Peg-IFNa2a for 29 days, followed by 21 days of drug-free follow-up, at which point they started treatment with a standard regimen of Peg-IFNa2a plus ribavirin. The studied population consisted of 23 males and 6 females with mean age 31±9 years who signed informed consent; 20 were infected with HCV genotype 1 or 4 (group A) and 9 with genotype 3 (group B). The dose and duration of therapy was adjusted to genotype and final evaluation was done 24 weeks after the end of treatment. Results: Mean compliance was 95% for Peg-IFNa2a and 96% for ribavirin. The percentage of patients with undetectable HCV-RNA at SOC treatment initiation was 38% and increased up to 66% by the end of follow-up (SVR). Corresponding rates for group A were 25% and 65%, respectively; whereas no change was observed for group B (67%). The rate of patients with abnormal ALT decreased from 17% before SOC therapy to 3% at the end of follow-up. The treatment was well tolerated without serious or unexpected adverse events. Conclusions: The initial effect of a 29-day administration with Debio 025 on HCV-RNA levels was maintained by follow-on treatment with SOC. This resulted in a particularly high SVR rate of 67% in patients infected with HCV genotype 1 or 4. There were no adverse events that could be traced back to the initial treatment with Debio 025. 749 EARLY ON-TREATMENT RESPONSES DURING PEGYLATED IFN PLUS RIBAVIRIN ARE INCREASED FOLLOWING 13 DAYS OF COMBINATION NUCLEOSIDE POLYMERASE (RG7128) AND PROTEASE (RG7227) INHIBITOR THERAPY (INFORM-1) E. Gane1 , S. Roberts2 , C. Stedman3 , P. Angus4 , B. Ritchie5 , R. Elston6 , D. Ipe6 , P. Morcos6 , L. Baher6 , I. Najera6 , T. Chu6 , M. Mannino6 , M. Berry7 , W. Bradford8 , M. Laughlin6 , N. Shulman6 , P. Smith6 . 1 Auckland Clinical Studies, Auckland, New Zealand; 2 Gastroenterology, The Alfred Hospital, Melbourne, VIC, Australia; 3 Christchurch Clinical Studies, Christchurch, New Zealand; 4 Gastroenterology, Austin Hospital, Melbourne, VIC, 5 Gastroenterology, Royal Adelaide Hospital, Adelaide, SA, Australia; 6 Roche Palo Alto LLC, Palo Alto, CA, 7 Pharmasset Inc., Princeton, NJ, 8 InterMune, Inc., Brisbane, CA, USA E-mail: [email protected] Introduction: Treatment with potent direct acting antiviral (DAA) combinations could enhance the efficacy of pegylated IFN plus ribavirin (Standard-of-Care; SOC), through reduction in circulating HCV RNA and/or reconstitution of innate host immune responses. Methods: INFORM-1 was a randomized, double-blind, placebocontrolled trial of combination of a nucleoside polymerase inhibitor (RG7128) plus a protease inhibitor (RG7227). After 13 days of RG7227/RG7128, patients commenced SOC. IFN-naïve patients and one cohort each of treatment-experienced (relapsers and partial responders) and null responders (documented <1 Log reduction in HCV RNA with SOC at week 4, and/or <2 Log reduction after 12 weeks SOC) were enrolled. Early on-treatment virologic responses during the follow-up SOC were evaluated at Study Day 42 (Rapid Virologic Response after 4 weeks of SOC) and at Study Day 98 (complete Early Virologic Response after 12 weeks). Duration of SOC was 24 weeks in those with RVR and 48 weeks in those without. Results: All 55 patients who received 13 days of combination DAA achieved profound reductions in HCV RNA without evidence of treatment emergent resistance. On-treatment virologic responses are summarized in the table. Sustained virologic responses (SVR) will be presented.
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care (SOC) medication. Additionally, the possible risk of adverse events related to the initial therapy with Debio 025 was evaluated during the SOC treatment period. Patients and Methods: The study was carried out in 29 patients who received any dose of Debio 025 plus weekly Peg-IFNa2a for 29 days, followed by 21 days of drug-free follow-up, at which point they started treatment with a standard regimen of Peg-IFNa2a plus ribavirin. The studied population consisted of 23 males and 6 females with mean age 31±9 years who signed informed consent; 20 were infected with HCV genotype 1 or 4 (group A) and 9 with genotype 3 (group B). The dose and duration of therapy was adjusted to genotype and final evaluation was done 24 weeks after the end of treatment. Results: Mean compliance was 95% for Peg-IFNa2a and 96% for ribavirin. The percentage of patients with undetectable HCV-RNA at SOC treatment initiation was 38% and increased up to 66% by the end of follow-up (SVR). Corresponding rates for group A were 25% and 65%, respectively; whereas no change was observed for group B (67%). The rate of patients with abnormal ALT decreased from 17% before SOC therapy to 3% at the end of follow-up. The treatment was well tolerated without serious or unexpected adverse events. Conclusions: The initial effect of a 29-day administration with Debio 025 on HCV-RNA levels was maintained by follow-on treatment with SOC. This resulted in a particularly high SVR rate of 67% in patients infected with HCV genotype 1 or 4. There were no adverse events that could be traced back to the initial treatment with Debio 025. 749 EARLY ON-TREATMENT RESPONSES DURING PEGYLATED IFN PLUS RIBAVIRIN ARE INCREASED FOLLOWING 13 DAYS OF COMBINATION NUCLEOSIDE POLYMERASE (RG7128) AND PROTEASE (RG7227) INHIBITOR THERAPY (INFORM-1) E. Gane1 , S. Roberts2 , C. Stedman3 , P. Angus4 , B. Ritchie5 , R. Elston6 , D. Ipe6 , P. Morcos6 , L. Baher6 , I. Najera6 , T. Chu6 , M. Mannino6 , M. Berry7 , W. Bradford8 , M. Laughlin6 , N. Shulman6 , P. Smith6 . 1 Auckland Clinical Studies, Auckland, New Zealand; 2 Gastroenterology, The Alfred Hospital, Melbourne, VIC, Australia; 3 Christchurch Clinical Studies, Christchurch, New Zealand; 4 Gastroenterology, Austin Hospital, Melbourne, VIC, 5 Gastroenterology, Royal Adelaide Hospital, Adelaide, SA, Australia; 6 Roche Palo Alto LLC, Palo Alto, CA, 7 Pharmasset Inc., Princeton, NJ, 8 InterMune, Inc., Brisbane, CA, USA E-mail: [email protected] Introduction: Treatment with potent direct acting antiviral (DAA) combinations could enhance the efficacy of pegylated IFN plus ribavirin (Standard-of-Care; SOC), through reduction in circulating HCV RNA and/or reconstitution of innate host immune responses. Methods: INFORM-1 was a randomized, double-blind, placebocontrolled trial of combination of a nucleoside polymerase inhibitor (RG7128) plus a protease inhibitor (RG7227). After 13 days of RG7227/RG7128, patients commenced SOC. IFN-naïve patients and one cohort each of treatment-experienced (relapsers and partial responders) and null responders (documented <1 Log reduction in HCV RNA with SOC at week 4, and/or <2 Log reduction after 12 weeks SOC) were enrolled. Early on-treatment virologic responses during the follow-up SOC were evaluated at Study Day 42 (Rapid Virologic Response after 4 weeks of SOC) and at Study Day 98 (complete Early Virologic Response after 12 weeks). Duration of SOC was 24 weeks in those with RVR and 48 weeks in those without. Results: All 55 patients who received 13 days of combination DAA achieved profound reductions in HCV RNA without evidence of treatment emergent resistance. On-treatment virologic responses are summarized in the table. Sustained virologic responses (SVR) will be presented.
Journal of Hepatology 2010 vol. 52 | S183–S317
S291