- Email: [email protected]
143 EFFICACY AND SAFETY OF INCREASING DOSES OF THE CYCLOPHILIN INHIBITOR DEBIO 025 IN COMBINATION WITH PEGYLATED INTERFERON ALPHA-2A IN TREATMENT NAIVE CHRONIC HCV PATIENTS
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Sunday, 27 April
143 EFFICACY AND SAFETY OF INCREASING DOSES OF THE CYCLOPHILIN INHIBITOR DEBIO 025 IN COMBINATION WITH PEGYLATED INTERFERON ALPHA-2A IN TREATMENT NAIVE CHRONIC HCV PATIENTS
144 SUPPRESSION OF SERUM HCV RNA LEVELS DURING MAINTENANCE PEGINTERFERON (PEGIFN) ALFA-2A THERAPY AND CLINICAL OUTCOMES IN THE HALT-C TRIAL
R. Flisiak1 , S.V. Feinman2 , M. Jablkowski3 , A. Horban4 , W. Kryczka5 , W. Halota6 , J.E. Heathcote7 , G. Mazzella8 , C. Vandelli9 , J.S. Liz10 , R. Crabb´e10 , P. Scalfaro10 , H. Porchet10 . 1 Department of Infectious Diseases, Medical University, Bialystok, Poland; 2 Mount Sinai Hospital, Toronto, Canada; 3 Clinic for Infectious Diseases, Medical University, Lodz, 4 Hospital for Infectious Diseases, Warsaw, 5 Department of Infectious Diseases, Regional Hospital, Kielce, 6 Department of Infectious Diseases, Medical University, Bydgoszcz, Poland; 7 Department of Medicine, University of Toronto, Toronto, Canada; 8 Department of Internal Medicine and Gastroenterology, University of Bologna, Bologna, 9 Department of Medicine, University of Modena and Reggio Emilia, Modena, Italy; 10 Debiopharm SA, Lausanne, Switzerland E-mail: [email protected]
M.L. Shiffman1 , C. Morishima2 , K.L. Lindsay3 , J.C. Hoefs4 , J.L. Dienstag5 , G. Szabo6 , W.M. Lee7 , E.C. Wright8 , for the HALT-C Trial Group9 . 1 Hepatology Section, Virginia Commonwealth University Medical Center, Richmond, VA, 2 Department of Laboratory Medicine, University of Washington, Seattle, WA, 3 Division of Gastroenterology and Liver Disease, University of Southern California, Los Angeles, CA, 4 Division of Gastroenterology, University of California – Irvine, Irvine, CA, 5 Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 6 Liver Center, University of Massachusetts Medical School, Worcester, MA, 7 Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX, 8 Department of Health and Human Services, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA E-mail: [email protected]
Introduction: Debio 025 is a selective cylophilin inhibitor with potent in vitro and in vivo anti-HCV effect. Methods: We investigated different dosing regimens of Debio 025 in combination with pegylated Interferon alpha-2a (Peg-IFN) 180 microg/week in treatment naive chronic HCV mono-infected patients. Ninety patients were randomised, in a double-blind, placebo-controlled phase II study to receive either of the following treatment regimens for 29 days: – Peg-IFN + Placebo – Peg-IFN + Debio 025: 200 mg/day – Peg-IFN + Debio 025: 600 mg/day – Peg-IFN + Debio 025: 1000 mg/day – Debio 025: 1000 mg/day Patients were stratified according to HCV genotype (2/3 GT 1&4 and 1/3 GT 2&3). Results (ITT population): In patients with GT 1/4 (n = 12 per arm), the HCV-RNA reduction at day 29 was −4.75 (SE±0.57) log10 IU/mL in the Peg-IFN + Debio 025 1000 mg arm as compared to −2.49 (± 0.56) in the Peg-IFN + Placebo and −2.20 (± 0.69) in the Debio 025 1000 mg monotherapy arms. In the groups with 200 and 600 mg of Debio 025 in combination with Peg-IFN, the HCV-RNA reductions were respectively −1.8 (±0.45) and −4.61 (±0.57) log10 IU/mL. The number of subjects with undetectable viral load (Roche TaqMan LOD 15 IU/mL) at day 29 was 3/12 in the Peg-IFN + Placebo and the Debio 25 monotherapy arms, and increased to 8/12 in the Peg-IFN + Debio 025 1000 mg group. In GT 2&3 patients, 4 out of 6 subjects reached undetectable HCV-RNA levels with Debio 025 monotherapy. The mean reduction of HCV-RNA in this group was −4.22 (±0.54) log10 IU/mL and confirmed the antiviral effect in GT 2 and 3. ANOVA showed a significant difference between treatments on HCV-RNA reduction (p < 0.01). Safety: At lower doses the safety profile was comparable to placebo. At 1000 mg, 5 of 24 patients developed reversible increases of conjugated bilirubin resulting in hyperbilirubinaemia (Total bilirubin >3 mg/dl, range 3.1−8.1). Conclusion: Debio 025 at doses of 600 and 1000 mg daily for 29 days shows an important additive anti-HCV effect when co-administered with Peg-IFN alpha-2a in treatment naive HCV patients.
The primary analysis of the HALT-C Trial demonstrated that PEGIFN maintenance therapy did not reduce complications of cirrhosis, HCC, liver transplantation (LT) or mortality in patients with chronic HCV and advanced fibrosis or cirrhosis (AASLD 2007). This analysis assessed the relationship between viral suppression and clinical outcomes. Methods: 764 patients who failed to achieve SVR with PEGIFN 180 mg/week and ribavirin during the HALT-C lead-in phase were evaluated. 378 were randomized to maintenance PEGIFN (90 mg/week) and 386 received no additional treatment for 3.5 years (controls). No patient had a history of CTP > 6, ascites, hepatic encephalopathy (HE), variceal hemorrhage (VH) or HCC. HCVRNA was measured by Roche COBAS™ Monitor and/or Amplicor v.2.0 tests. Results: During lead-in treatment 425 (56%) patients had <2 log decline in HCVRNA from their pre-treatment baseline; 178 (23%) had >4 log decline and/or became HCVRNA undetectable with subsequent breakthrough or relapse. After randomization, serum HCVRNA remained within 1 log of pre-treatment values in 381 (99%) control and 273 (72%) maintenance patients. Only 30/88 patients with >4 log suppression in HCVRNA during lead-in treatment maintained this degree of viral suppression with maintenance PEGIFN. Clinical outcomes (2-point CTP increase, ascites, HE, VH, HCC, LT, death) occurred in significantly fewer patients with profound decline in HCVRNA during the lead-in. When HCVRNA declined by <2 logs, 2−4 and >4 logs from the pre-treatment baseline during leadin treatment outcomes occurred in 20%, 23% and 7% of patients on maintenance PEGINF and 20%, 13% and 10% in controls (both p < 0.05). Outcomes occurred in 18%, 22% and 12% of patients on maintenance PEGIFN when HCVRNA was continuously suppressed by these same amounts (p = NS). 13/29 patients with repeatedly undetectable HCVRNA over 3.5 years on maintenance PEGIFN achieved SVR. Conclusions: A significant decline in clinical outcomes was observed in patients with chronic HCV and advanced fibrosis or cirrhosis who achieved a profound decline in HCVRNA (>4 log and/or undetectable with subsequent breakthrough or relapse) with full-dose PEGIFN and ribavirin whether or not they remained on maintenance therapy. Whether additional clinical benefit can be derived when profound HCVRNA suppression is maintained with PEGIFN remains unproven.
Sunday, 27 April
143 EFFICACY AND SAFETY OF INCREASING DOSES OF THE CYCLOPHILIN INHIBITOR DEBIO 025 IN COMBINATION WITH PEGYLATED INTERFERON ALPHA-2A IN TREATMENT NAIVE CHRONIC HCV PATIENTS
144 SUPPRESSION OF SERUM HCV RNA LEVELS DURING MAINTENANCE PEGINTERFERON (PEGIFN) ALFA-2A THERAPY AND CLINICAL OUTCOMES IN THE HALT-C TRIAL
R. Flisiak1 , S.V. Feinman2 , M. Jablkowski3 , A. Horban4 , W. Kryczka5 , W. Halota6 , J.E. Heathcote7 , G. Mazzella8 , C. Vandelli9 , J.S. Liz10 , R. Crabb´e10 , P. Scalfaro10 , H. Porchet10 . 1 Department of Infectious Diseases, Medical University, Bialystok, Poland; 2 Mount Sinai Hospital, Toronto, Canada; 3 Clinic for Infectious Diseases, Medical University, Lodz, 4 Hospital for Infectious Diseases, Warsaw, 5 Department of Infectious Diseases, Regional Hospital, Kielce, 6 Department of Infectious Diseases, Medical University, Bydgoszcz, Poland; 7 Department of Medicine, University of Toronto, Toronto, Canada; 8 Department of Internal Medicine and Gastroenterology, University of Bologna, Bologna, 9 Department of Medicine, University of Modena and Reggio Emilia, Modena, Italy; 10 Debiopharm SA, Lausanne, Switzerland E-mail: [email protected]
M.L. Shiffman1 , C. Morishima2 , K.L. Lindsay3 , J.C. Hoefs4 , J.L. Dienstag5 , G. Szabo6 , W.M. Lee7 , E.C. Wright8 , for the HALT-C Trial Group9 . 1 Hepatology Section, Virginia Commonwealth University Medical Center, Richmond, VA, 2 Department of Laboratory Medicine, University of Washington, Seattle, WA, 3 Division of Gastroenterology and Liver Disease, University of Southern California, Los Angeles, CA, 4 Division of Gastroenterology, University of California – Irvine, Irvine, CA, 5 Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 6 Liver Center, University of Massachusetts Medical School, Worcester, MA, 7 Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX, 8 Department of Health and Human Services, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA E-mail: [email protected]
Introduction: Debio 025 is a selective cylophilin inhibitor with potent in vitro and in vivo anti-HCV effect. Methods: We investigated different dosing regimens of Debio 025 in combination with pegylated Interferon alpha-2a (Peg-IFN) 180 microg/week in treatment naive chronic HCV mono-infected patients. Ninety patients were randomised, in a double-blind, placebo-controlled phase II study to receive either of the following treatment regimens for 29 days: – Peg-IFN + Placebo – Peg-IFN + Debio 025: 200 mg/day – Peg-IFN + Debio 025: 600 mg/day – Peg-IFN + Debio 025: 1000 mg/day – Debio 025: 1000 mg/day Patients were stratified according to HCV genotype (2/3 GT 1&4 and 1/3 GT 2&3). Results (ITT population): In patients with GT 1/4 (n = 12 per arm), the HCV-RNA reduction at day 29 was −4.75 (SE±0.57) log10 IU/mL in the Peg-IFN + Debio 025 1000 mg arm as compared to −2.49 (± 0.56) in the Peg-IFN + Placebo and −2.20 (± 0.69) in the Debio 025 1000 mg monotherapy arms. In the groups with 200 and 600 mg of Debio 025 in combination with Peg-IFN, the HCV-RNA reductions were respectively −1.8 (±0.45) and −4.61 (±0.57) log10 IU/mL. The number of subjects with undetectable viral load (Roche TaqMan LOD 15 IU/mL) at day 29 was 3/12 in the Peg-IFN + Placebo and the Debio 25 monotherapy arms, and increased to 8/12 in the Peg-IFN + Debio 025 1000 mg group. In GT 2&3 patients, 4 out of 6 subjects reached undetectable HCV-RNA levels with Debio 025 monotherapy. The mean reduction of HCV-RNA in this group was −4.22 (±0.54) log10 IU/mL and confirmed the antiviral effect in GT 2 and 3. ANOVA showed a significant difference between treatments on HCV-RNA reduction (p < 0.01). Safety: At lower doses the safety profile was comparable to placebo. At 1000 mg, 5 of 24 patients developed reversible increases of conjugated bilirubin resulting in hyperbilirubinaemia (Total bilirubin >3 mg/dl, range 3.1−8.1). Conclusion: Debio 025 at doses of 600 and 1000 mg daily for 29 days shows an important additive anti-HCV effect when co-administered with Peg-IFN alpha-2a in treatment naive HCV patients.
The primary analysis of the HALT-C Trial demonstrated that PEGIFN maintenance therapy did not reduce complications of cirrhosis, HCC, liver transplantation (LT) or mortality in patients with chronic HCV and advanced fibrosis or cirrhosis (AASLD 2007). This analysis assessed the relationship between viral suppression and clinical outcomes. Methods: 764 patients who failed to achieve SVR with PEGIFN 180 mg/week and ribavirin during the HALT-C lead-in phase were evaluated. 378 were randomized to maintenance PEGIFN (90 mg/week) and 386 received no additional treatment for 3.5 years (controls). No patient had a history of CTP > 6, ascites, hepatic encephalopathy (HE), variceal hemorrhage (VH) or HCC. HCVRNA was measured by Roche COBAS™ Monitor and/or Amplicor v.2.0 tests. Results: During lead-in treatment 425 (56%) patients had <2 log decline in HCVRNA from their pre-treatment baseline; 178 (23%) had >4 log decline and/or became HCVRNA undetectable with subsequent breakthrough or relapse. After randomization, serum HCVRNA remained within 1 log of pre-treatment values in 381 (99%) control and 273 (72%) maintenance patients. Only 30/88 patients with >4 log suppression in HCVRNA during lead-in treatment maintained this degree of viral suppression with maintenance PEGIFN. Clinical outcomes (2-point CTP increase, ascites, HE, VH, HCC, LT, death) occurred in significantly fewer patients with profound decline in HCVRNA during the lead-in. When HCVRNA declined by <2 logs, 2−4 and >4 logs from the pre-treatment baseline during leadin treatment outcomes occurred in 20%, 23% and 7% of patients on maintenance PEGINF and 20%, 13% and 10% in controls (both p < 0.05). Outcomes occurred in 18%, 22% and 12% of patients on maintenance PEGIFN when HCVRNA was continuously suppressed by these same amounts (p = NS). 13/29 patients with repeatedly undetectable HCVRNA over 3.5 years on maintenance PEGIFN achieved SVR. Conclusions: A significant decline in clinical outcomes was observed in patients with chronic HCV and advanced fibrosis or cirrhosis who achieved a profound decline in HCVRNA (>4 log and/or undetectable with subsequent breakthrough or relapse) with full-dose PEGIFN and ribavirin whether or not they remained on maintenance therapy. Whether additional clinical benefit can be derived when profound HCVRNA suppression is maintained with PEGIFN remains unproven.