- Email: [email protected]
2008 DOSE-RANGING, THREE-DAY MONOTHERAPY STUDY OF THE HCV NS3 PROTEASE INHIBITOR GS-9256
LATE-BREAKING ABSTRACTS
Background: BI207127 is a specific non-nucleoside inhibitor of the HCV RNA-dependent RNA polymerase in-vitro which showed potent antiviral effect during 5-day monotherapy in HCV patients. Methods: In a double-blind, parallel group comparison, 57 HCV genotype-1 patients with compensated liver disease were treated for 28 days with 400, 600 or 800 mg BI207127 or placebo tid as tablets in combination with peg-interferon-alfa2A and ribavirin (PegIFN/RBV). Treatment naïve patients (TN; n = 27) were randomized in a 2:2:2:3 ratio to one of the 3 BI207127 doses or placebo, and treatment experienced patients (TE, all previous PegIFN/RBV non-responders; n = 30;) in a 1:1:1 ratio to the 3 BI207127 doses. Plasma HCV RNA was measured by Roche COBAS TaqMan assay. Results: Mean age was 48.9+10.9 years, BMI 25.5±3.8 kg/m2 , mean baseline HCV RNA 6.6 (log10 IU/mL). BI207127 demonstrated a potent antiviral activity especially in TN patients as shown in the table. One and 4 TE patients prematurely discontinued due to AE in the 600 and 800 mg dose groups. One drug-related SAE was reported in the 800 mg dose group (progressive rash, recovering after discontinuation of study treatment). Rash/photosensitivity reactions were reported more frequently at 600 and 800 mg BI207127 (7/16 and 8/17 vs. 2/16 and 2/8 at 400 mg and placebo). Most rashes (6/7 at 600, 4/8 at 800 mg) resolved during continued BI207127 treatment. No relevant changes were observed in safety laboratory parameters. Conclusions: BI207127 in combination therapy with PegIFN/RBV induced a strong antiviral response. The best efficacy/tolerability profile was observed at 600 mg tid and support further study of BI207127 in combination regimens for the treatment of chronic HCV infection. S466
Treatment
TN
<25 IU/ml (LLOQ)
<10 IU/ml (LLOD)
Rebound
Median decrease (log10 )
<25 IU/ml (LLOQ)
<10 IU/ml (LLOD)
Rebound
2007 4 WEEK THERAPY WITH THE NON-NUCLEOSIDIC POLYMERASE INHIBITOR BI207127 IN COMBINATION WITH PEGINTERFERON-ALFA2A AND RIBAVIRIN IN TREATMENT NAIVE AND TREATMENT EXPERIENCED CHRONIC HCV GT1 PATIENTS D. Larrey1 , A. Lohse2 , V. de Ledinghen3 , C. Trepo4 , T. Gerlach5 , J.-P. Zarski6 , A. Tran7 , P. Mathurin8 , R. Thimme9 , K. Arasteh ´ 10 , 11 12 13 C. Trautwein , A. Cerny , N. Dikopoulos , M. Schuchmann14 , M.H. Heim15 , G. Gerken16 , J. Stern17 , K. Wu17 , N. Abdallah18 , B. Girlich19 , S. Josepf17 , B. Wulf20 , F. Berger21 , J. Steffgen20 , BI207127 Study Group. 1 Hepato-Gastro-Enterology and transplantation service, Hˆ opital Saint Eloi, Montpellier, France; 2 Universit¨ atsklinikum Hamburg-Eppendorf, Hamburg, Germany; 3 CHU de Bordeaux Hˆ opital Haut-Levˆeque Pessac, Bordeaux, 4 Hotel Dieu Hospital, Lyon, France; 5 Kantonsspital, St. Gallen, Switzerland; 6 CHU de Grenoble Hˆ opital A Michallon, Grenoble, 7 Hˆ opital Archet, Nice, 8 Hˆ opital Claude Huriez, Lille, France; 9 Medizinische Universit¨ atsklinik Freiburg, Freiburg im Breisgau, 10 EPIMED GmbH Berlin, Berlin, 11 Universit¨ atsklinikum Aachen, Aachen, Germany; 12 Clinica Luganese Moncucco, Lugano, Switzerland; 13 Universit¨ atsklinik Ulm, Ulm, 14 Universit¨ atsmedizin Mainz, Mainz, Germany; 15 Universit¨ atsspital Basel, Basel, Switzerland; 16 Medizinische Universit¨ atsklinik Essen, Essen, Germany; 17 Boehringer Ingelheim, Ridgefield, CT, USA; 18 Boehringer Ingelheim, Reims, France; 19 Boehringer Ingelheim, Basel, Switzerland; 20 Boehringer Ingelheim, Biberach, 21 Boehringer Ingelheim, Ingelheim, Germany E-mail: [email protected]
Median HCV RNA decrease at day 28 Median decrease (log10 )
SVR was observed in naïve patients 24 weeks after the completion of therapy. SVR in IL28 genotype TT patients was greater for triple therapy compared to SOC or historical controls, suggesting a potentially greater treatment effect in this high risk patient group. These data support further development of GI-5005 in combination with SOC and novel combination use with direct acting antiviral agents.
TE
400 mg 600 mg 800 mg Placebo
−5.1 −5.6 −5.4 −1.4
4/6 6/7 6/6 0/8
3/6 4/7 3/6 0/8
0/6 0/7 0/6 0/8
−2.9 −4.2 −4.5 n.a.
1/10 3/9 2/11 n.a.
0/10 2/9 2/11 n.a.
2/10 2/9 1/11 n.a.
2008 DOSE-RANGING, THREE-DAY MONOTHERAPY STUDY OF THE HCV NS3 PROTEASE INHIBITOR GS-9256 E.J. Lawitz1 , T.C. Marbury2 , B.D. Vince3 , N. Grunenberg4 , M. Rodriguez-Torres5 , M.P. De Micco6 , J.N. Tarro7 , M.J. Shelton8 , S. West8 , J. Zong8 , A. Bae8 , K. Wong9 , H.-M. Mo9 , D. Oldach8 , W. Delaney9 , F. Rousseau8 . 1 Alamo Medical Research, San Antonio, TX, 2 Orlando Clinical Research Center, Orlando, FL, 3 Vince & Associates Clinical Research, Inc., Overland Park, KS, 4 Charles River Clinical Services Northwest, Tacoma, WA, 5 Fundacion De Investigacion De Diego, Santurce, Puerto Rico, 6 Advanced Clinical Research Institute, Anaheim, CA, 7 Columbia Research Group, Portland, OR, 8 Gilead Sciences, Inc, Durham, NC, 9 Gilead Sciences, Inc, Foster City, CA, USA E-mail: [email protected] Background and Aims: GS-9256 is a novel HCV NS3 protease inhibitor (in-vitro EC50 of ~20 nM in HCV 1b replicon assays). The aims of this study were to evaluate the safety, antiviral activity, pharmacokinetics (PK), and resistance outcomes of GS-9256 monotherapy in genotype 1 (GT1) HCV subjects. Methods: A randomized, double-blind, placebo-controlled multiple ascending dose study was conducted in treatment-naïve HCV subjects (GT1). GS-9256 or placebo was administered for 3 days at 25 mg, 75 mg, and 200 mg BID and 300 mg QD as capsule or oral solution. Results: GS-9256 was well tolerated, with significant activity even at the lowest dose studied. 53/54 enrolled subjects completed dosing. There were no SAEs or Grade 3/4 laboratory abnormalities. All treatment-emergent AEs were mild to moderate in severity (headache and diarrhea were most common, occurring in <20% of subjects). Median HCV RNA declined sharply through Day 2 in a dose-dependent manner. Median changes from baseline in HCV RNA at Day 4 were −1.1, −2.7, −2.6, and −2.9 log10 IU/mL for the 25 mg (capsule), 75 mg (capsule), 75 mg (solution), and 200 mg (solution) BID regimens respectively. Median HCV RNA change from baseline at Day 4 was −2.6 log10 IU/mL for 300 mg QD (solution). GS-9256 exposure was greater than dose proportional and median half life ranged from ~7 to 14 hours. For 75 mg BID, 200 mg BID and 300 mg QD, Day 3 mean Ctau was >10-fold above protein-binding adjusted mean EC50 for GT1. PK was similar for capsule and solution. PK correlated well with HCV RNA suppression. Genotypic analyses identified the NS3 protease mutations R155K, D168G/E/N/V or A156V. At the end of the 3-day dosing period, these mutations were more common in subjects with the most profound HCV RNA reductions and there was no evidence of HCV RNA rebound during the 3-day dosing period. In vitro, these mutations displayed reduced GS-9256 susceptibility, but wild-type sensitivity to IFN-a, ribavirin, and Gilead’s non-nucleoside NS5B inhibitor, GS-9190. Conclusions: GS-9256 is an attractive candidate for development in combination with PEG/RIBA and other direct-acting HCV agents.
Journal of Hepatology 2010 vol. 52 | S459–S471
LATE-BREAKING ABSTRACTS Phase 2 evaluation of GS-9256 in combination with GS-9190 with or without ribavirin is currently underway. 2009 SAFETY AND ANTIVIRAL ACTIVITY OF ANA598 IN COMBINATION WITH PEGYLATED INTERFERON a2A PLUS RIBAVIRIN IN TREATMENT-NAIVE GENOTYPE-1 CHRONIC HCV PATIENTS E. Lawitz1 , M. Rodriquez-Torres2 , V.K. Rustgi3 , T. Hassanein4 , M.H. Rahimy5 , C.A. Crowley5 , J.L. Freddo5 , A. Muir6 , J. McHutchison6 . 1 Alamo Medical Research, San Antonio, TX, 2 Fundaci´ on de Investigaci´ on de Diego, Santurce, PR, 3 Metropolitan Research, Fairfax, VA, 4 SCTI Research Foundation, Liver Center, San Clemente, 5 Anadys Pharmaceuticals, Inc, San Diego, CA, 6 Duke Clinical Research Institute, Durham, NC, USA E-mail: [email protected] Background: ANA598 is a potent non-nucleoside inhibitor of HCV polymerase. ANA598 was well tolerated in HCV patients at 200 mg, 400 mg and 800 mg bid for 3 days, and resulted in rapid reduction in HCV RNA (median EOT range 2.3 to 2.9 log10 ). This study evaluates safety and antiviral activity of ANA598 with PEGIFN and ribavirin (SOC). 12-week results for the first cohort (200 mg bid) are reported here; 400 mg bid cohort is in progress and will be presented. Methods: ANA598-504 is an ongoing double-blind, placebocontrolled Phase 2 study to assess safety, antiviral activity and PK of ANA598 in genotype-1 patients. Patients receive ANA598 or placebo with SOC for 12 weeks at 200 mg bid or 400 mg bid, both given with a loading dose of 800 mg q12h on day 1. Patients who achieve undetectable virus at weeks 4 and 12 are randomized to SOC alone for 12 or 36 additional weeks. Results: 44 patients received at least one dose in the first cohort (29 received ANA598 and 15 placebo). Four patients voluntarily withdrew from the study. One patient discontinued ANA598 and 3 patients discontinued placebo due to failure to reach a 1 log10 decline in HCV RNA by Week 4, but continued to receive SOC. Forty patients (30 1a and 10 1b) completed 12 weeks of treatment. No serious AEs were reported. The most common AEs were those associated with SOC. Occurrence of rash was similar between ANA598 (12/29, 41%) and placebo (5/15, 33%). Only one patient discontinued ANA598 due to an AE (Grade 3 rash at Week 8). All other rashes reported in ANA598-treated patients were Grade 1. The table shows a summary of antiviral activity. No patient demonstrated viral breakthrough (>1 log increase). ANA598 plasma levels also achieved steady state by Week 1. Patients (%) with undetectable virus (<15 IU/mL) by week Week 4 Week 6 Week 8 Week 10 Week 12* (RVR) (cEVR) ANA598 + SOC (n = 26) 56 Placebo + SOC (n = 14) 20
65 27
69 47
73 54
73 71
Conclusions: The combination of ANA598 with SOC was well tolerated and ANA598 accelerated the rate of achieving undetectable virus in genotype-1 patients.
2010 Q2WEEK CONTROLLED-RELEASE-INTERFERON-ALPHA2B + RIBAVRIN REDUCES FLU-LIKE SYMPTOMS >50% AND PROVIDES EQUIVALENT EFFICACY IN COMPARISON TO WEEKLY PEGYLATED-INTERFERON-ALPHA2B + RIBAVIRIN IN TREATMENT-NAIVE-GENOTYPE-1-CHRONIC-HEPATITIS-C: RESULTS FROM EMPOWER, A RANDOMIZED-OPEN-LABEL12-WEEK-COMPARISON IN 133 PATIENTS W.A. Long1 , D. Takov2 , K. Tchernev3 , I. Kotzev4 , A. Rigney1 , Z. Krastev5 , S. Stoynov6 , R. Balabanska7 , E. Lawitz8 , Z. Younossi9 , R. Ghalib10 , E. Zuckerman11 , R. Safadi12 , R. Tur-Kaspa13 , N. Assy14 , Y. Lurie15 . 1 Biolex Therapeutics, Pittsboro, NC, USA; 2 Military Medical Academy, 3 UMHAT “Alexandrovska”, Sofia, 4 UMHAT “St. Marina”, Varna, 5 UMHAT “St. Ivan Rilski”, 6 UMHAT ‘Queen Giovanna – ISUL’ EAD, 7 Tokuda Hospital, Sofia, Bulgaria; 8 Alamo Medical Research, San Antonio, TX, 9 Inova Health Systems, Falls Church, VA, 10 The Liver Institute at Methodist Dallas, Dallas, TX, USA; 11 Carmel Medical Center, Haifa, 12 Holy Family Hospital Nazareth, Nazareth, 13 Rabin Medical Center, Petah-Tikva, 14 Rebekah Ziv Medical Center, Zefat, 15 Sourasky Medical Center, Tel Aviv, Israel E-mail: [email protected] Background and Aim: The aim of this study was to test the hypothesis that 480ug controlled-release-interferon-alpha2b (CR2b) dosed q2weeks reduces flu-like symptoms (FluSxs) but retains equal efficacy compared to pegylated interferon alpha2b (PEG2b) dosed weekly in treatment-naïve-genotype-1 (G1) chronic HCV patients treated with weight-based ribavirin. Methods: EMPOWER is a 12-week, randomized, open-label Phase 2b trial designed with 85% power to detect a 50% reduction in flu-like symptoms in patients treated with 480 ug CR2b [Locteron® , Biolex Therapeutics, Pittsboro, NC, USA] versus PEG2b [PegIntron® , Schering Plough, Kenilworth, NJ, USA], both in combination with weight-based ribavirin. Patients were enrolled in two contributing trials (SELECT-2 & 480STUDY) specifically designed to provide jointly the sample sizes required for the hypothesis test in EMPOWER. HCV RNA was measured weekly for three weeks and then every other week. Safety labs were measured weekly for three weeks and monthly thereafter. Adverse events including a pre-specified cluster of flu-like symptoms (FluSxs) were collected during weekly clinic visits for 12 weeks. FluSxs were also collected daily for 12 weeks by patient self-report using the internet (ePRO). Other measurements include serial measurements of BDI, HQLQ, SF-36, and days missed from work. Results: Preliminary results from 101/133 enrolled patients are available (n = 48 on q2week-480ug-CR2b, n = 53 on PEG2b). Mean declines in Log10 HCV RNA from baseline were equivalent. FluSxs (arthralgia, chills, fever, headache, or myalgia reported at weekly clinic visits) counts during the first week were 50 versus 109 on q2week-480 ug-CR2b vs. PEG2b, and total FluSxs counts during the 12 weeks were 109 versus 314 on q2week-480 ug-CR2b vs. PEG2b. Total days missed from work were 82 versus 109 for q2week480 ug-CR2b versus PEG2b. Neutrophil counts <750 occurred in 13% (6/48) and 8% (4/53) respectively for q2week-480 ug-CR2b and PEG2b; no neutrophil counts <500 were reported in the first 12 weeks. Conclusions: In these 101 patients, q2week-480 ug-CR2b over 12 weeks provided (a) >50% reduction in FluSxs that preceded the possible impact of the q2week dosing interval, and (b) equivalent antiviral efficacy. Days missed from work may also be reduced. Final 12-week results from all 133 patients (including ePRO) will be presented at the meeting.
Journal of Hepatology 2010 vol. 52 | S459–S471
S467
Background: BI207127 is a specific non-nucleoside inhibitor of the HCV RNA-dependent RNA polymerase in-vitro which showed potent antiviral effect during 5-day monotherapy in HCV patients. Methods: In a double-blind, parallel group comparison, 57 HCV genotype-1 patients with compensated liver disease were treated for 28 days with 400, 600 or 800 mg BI207127 or placebo tid as tablets in combination with peg-interferon-alfa2A and ribavirin (PegIFN/RBV). Treatment naïve patients (TN; n = 27) were randomized in a 2:2:2:3 ratio to one of the 3 BI207127 doses or placebo, and treatment experienced patients (TE, all previous PegIFN/RBV non-responders; n = 30;) in a 1:1:1 ratio to the 3 BI207127 doses. Plasma HCV RNA was measured by Roche COBAS TaqMan assay. Results: Mean age was 48.9+10.9 years, BMI 25.5±3.8 kg/m2 , mean baseline HCV RNA 6.6 (log10 IU/mL). BI207127 demonstrated a potent antiviral activity especially in TN patients as shown in the table. One and 4 TE patients prematurely discontinued due to AE in the 600 and 800 mg dose groups. One drug-related SAE was reported in the 800 mg dose group (progressive rash, recovering after discontinuation of study treatment). Rash/photosensitivity reactions were reported more frequently at 600 and 800 mg BI207127 (7/16 and 8/17 vs. 2/16 and 2/8 at 400 mg and placebo). Most rashes (6/7 at 600, 4/8 at 800 mg) resolved during continued BI207127 treatment. No relevant changes were observed in safety laboratory parameters. Conclusions: BI207127 in combination therapy with PegIFN/RBV induced a strong antiviral response. The best efficacy/tolerability profile was observed at 600 mg tid and support further study of BI207127 in combination regimens for the treatment of chronic HCV infection. S466
Treatment
TN
<25 IU/ml (LLOQ)
<10 IU/ml (LLOD)
Rebound
Median decrease (log10 )
<25 IU/ml (LLOQ)
<10 IU/ml (LLOD)
Rebound
2007 4 WEEK THERAPY WITH THE NON-NUCLEOSIDIC POLYMERASE INHIBITOR BI207127 IN COMBINATION WITH PEGINTERFERON-ALFA2A AND RIBAVIRIN IN TREATMENT NAIVE AND TREATMENT EXPERIENCED CHRONIC HCV GT1 PATIENTS D. Larrey1 , A. Lohse2 , V. de Ledinghen3 , C. Trepo4 , T. Gerlach5 , J.-P. Zarski6 , A. Tran7 , P. Mathurin8 , R. Thimme9 , K. Arasteh ´ 10 , 11 12 13 C. Trautwein , A. Cerny , N. Dikopoulos , M. Schuchmann14 , M.H. Heim15 , G. Gerken16 , J. Stern17 , K. Wu17 , N. Abdallah18 , B. Girlich19 , S. Josepf17 , B. Wulf20 , F. Berger21 , J. Steffgen20 , BI207127 Study Group. 1 Hepato-Gastro-Enterology and transplantation service, Hˆ opital Saint Eloi, Montpellier, France; 2 Universit¨ atsklinikum Hamburg-Eppendorf, Hamburg, Germany; 3 CHU de Bordeaux Hˆ opital Haut-Levˆeque Pessac, Bordeaux, 4 Hotel Dieu Hospital, Lyon, France; 5 Kantonsspital, St. Gallen, Switzerland; 6 CHU de Grenoble Hˆ opital A Michallon, Grenoble, 7 Hˆ opital Archet, Nice, 8 Hˆ opital Claude Huriez, Lille, France; 9 Medizinische Universit¨ atsklinik Freiburg, Freiburg im Breisgau, 10 EPIMED GmbH Berlin, Berlin, 11 Universit¨ atsklinikum Aachen, Aachen, Germany; 12 Clinica Luganese Moncucco, Lugano, Switzerland; 13 Universit¨ atsklinik Ulm, Ulm, 14 Universit¨ atsmedizin Mainz, Mainz, Germany; 15 Universit¨ atsspital Basel, Basel, Switzerland; 16 Medizinische Universit¨ atsklinik Essen, Essen, Germany; 17 Boehringer Ingelheim, Ridgefield, CT, USA; 18 Boehringer Ingelheim, Reims, France; 19 Boehringer Ingelheim, Basel, Switzerland; 20 Boehringer Ingelheim, Biberach, 21 Boehringer Ingelheim, Ingelheim, Germany E-mail: [email protected]
Median HCV RNA decrease at day 28 Median decrease (log10 )
SVR was observed in naïve patients 24 weeks after the completion of therapy. SVR in IL28 genotype TT patients was greater for triple therapy compared to SOC or historical controls, suggesting a potentially greater treatment effect in this high risk patient group. These data support further development of GI-5005 in combination with SOC and novel combination use with direct acting antiviral agents.
TE
400 mg 600 mg 800 mg Placebo
−5.1 −5.6 −5.4 −1.4
4/6 6/7 6/6 0/8
3/6 4/7 3/6 0/8
0/6 0/7 0/6 0/8
−2.9 −4.2 −4.5 n.a.
1/10 3/9 2/11 n.a.
0/10 2/9 2/11 n.a.
2/10 2/9 1/11 n.a.
2008 DOSE-RANGING, THREE-DAY MONOTHERAPY STUDY OF THE HCV NS3 PROTEASE INHIBITOR GS-9256 E.J. Lawitz1 , T.C. Marbury2 , B.D. Vince3 , N. Grunenberg4 , M. Rodriguez-Torres5 , M.P. De Micco6 , J.N. Tarro7 , M.J. Shelton8 , S. West8 , J. Zong8 , A. Bae8 , K. Wong9 , H.-M. Mo9 , D. Oldach8 , W. Delaney9 , F. Rousseau8 . 1 Alamo Medical Research, San Antonio, TX, 2 Orlando Clinical Research Center, Orlando, FL, 3 Vince & Associates Clinical Research, Inc., Overland Park, KS, 4 Charles River Clinical Services Northwest, Tacoma, WA, 5 Fundacion De Investigacion De Diego, Santurce, Puerto Rico, 6 Advanced Clinical Research Institute, Anaheim, CA, 7 Columbia Research Group, Portland, OR, 8 Gilead Sciences, Inc, Durham, NC, 9 Gilead Sciences, Inc, Foster City, CA, USA E-mail: [email protected] Background and Aims: GS-9256 is a novel HCV NS3 protease inhibitor (in-vitro EC50 of ~20 nM in HCV 1b replicon assays). The aims of this study were to evaluate the safety, antiviral activity, pharmacokinetics (PK), and resistance outcomes of GS-9256 monotherapy in genotype 1 (GT1) HCV subjects. Methods: A randomized, double-blind, placebo-controlled multiple ascending dose study was conducted in treatment-naïve HCV subjects (GT1). GS-9256 or placebo was administered for 3 days at 25 mg, 75 mg, and 200 mg BID and 300 mg QD as capsule or oral solution. Results: GS-9256 was well tolerated, with significant activity even at the lowest dose studied. 53/54 enrolled subjects completed dosing. There were no SAEs or Grade 3/4 laboratory abnormalities. All treatment-emergent AEs were mild to moderate in severity (headache and diarrhea were most common, occurring in <20% of subjects). Median HCV RNA declined sharply through Day 2 in a dose-dependent manner. Median changes from baseline in HCV RNA at Day 4 were −1.1, −2.7, −2.6, and −2.9 log10 IU/mL for the 25 mg (capsule), 75 mg (capsule), 75 mg (solution), and 200 mg (solution) BID regimens respectively. Median HCV RNA change from baseline at Day 4 was −2.6 log10 IU/mL for 300 mg QD (solution). GS-9256 exposure was greater than dose proportional and median half life ranged from ~7 to 14 hours. For 75 mg BID, 200 mg BID and 300 mg QD, Day 3 mean Ctau was >10-fold above protein-binding adjusted mean EC50 for GT1. PK was similar for capsule and solution. PK correlated well with HCV RNA suppression. Genotypic analyses identified the NS3 protease mutations R155K, D168G/E/N/V or A156V. At the end of the 3-day dosing period, these mutations were more common in subjects with the most profound HCV RNA reductions and there was no evidence of HCV RNA rebound during the 3-day dosing period. In vitro, these mutations displayed reduced GS-9256 susceptibility, but wild-type sensitivity to IFN-a, ribavirin, and Gilead’s non-nucleoside NS5B inhibitor, GS-9190. Conclusions: GS-9256 is an attractive candidate for development in combination with PEG/RIBA and other direct-acting HCV agents.
Journal of Hepatology 2010 vol. 52 | S459–S471
LATE-BREAKING ABSTRACTS Phase 2 evaluation of GS-9256 in combination with GS-9190 with or without ribavirin is currently underway. 2009 SAFETY AND ANTIVIRAL ACTIVITY OF ANA598 IN COMBINATION WITH PEGYLATED INTERFERON a2A PLUS RIBAVIRIN IN TREATMENT-NAIVE GENOTYPE-1 CHRONIC HCV PATIENTS E. Lawitz1 , M. Rodriquez-Torres2 , V.K. Rustgi3 , T. Hassanein4 , M.H. Rahimy5 , C.A. Crowley5 , J.L. Freddo5 , A. Muir6 , J. McHutchison6 . 1 Alamo Medical Research, San Antonio, TX, 2 Fundaci´ on de Investigaci´ on de Diego, Santurce, PR, 3 Metropolitan Research, Fairfax, VA, 4 SCTI Research Foundation, Liver Center, San Clemente, 5 Anadys Pharmaceuticals, Inc, San Diego, CA, 6 Duke Clinical Research Institute, Durham, NC, USA E-mail: [email protected] Background: ANA598 is a potent non-nucleoside inhibitor of HCV polymerase. ANA598 was well tolerated in HCV patients at 200 mg, 400 mg and 800 mg bid for 3 days, and resulted in rapid reduction in HCV RNA (median EOT range 2.3 to 2.9 log10 ). This study evaluates safety and antiviral activity of ANA598 with PEGIFN and ribavirin (SOC). 12-week results for the first cohort (200 mg bid) are reported here; 400 mg bid cohort is in progress and will be presented. Methods: ANA598-504 is an ongoing double-blind, placebocontrolled Phase 2 study to assess safety, antiviral activity and PK of ANA598 in genotype-1 patients. Patients receive ANA598 or placebo with SOC for 12 weeks at 200 mg bid or 400 mg bid, both given with a loading dose of 800 mg q12h on day 1. Patients who achieve undetectable virus at weeks 4 and 12 are randomized to SOC alone for 12 or 36 additional weeks. Results: 44 patients received at least one dose in the first cohort (29 received ANA598 and 15 placebo). Four patients voluntarily withdrew from the study. One patient discontinued ANA598 and 3 patients discontinued placebo due to failure to reach a 1 log10 decline in HCV RNA by Week 4, but continued to receive SOC. Forty patients (30 1a and 10 1b) completed 12 weeks of treatment. No serious AEs were reported. The most common AEs were those associated with SOC. Occurrence of rash was similar between ANA598 (12/29, 41%) and placebo (5/15, 33%). Only one patient discontinued ANA598 due to an AE (Grade 3 rash at Week 8). All other rashes reported in ANA598-treated patients were Grade 1. The table shows a summary of antiviral activity. No patient demonstrated viral breakthrough (>1 log increase). ANA598 plasma levels also achieved steady state by Week 1. Patients (%) with undetectable virus (<15 IU/mL) by week Week 4 Week 6 Week 8 Week 10 Week 12* (RVR) (cEVR) ANA598 + SOC (n = 26) 56 Placebo + SOC (n = 14) 20
65 27
69 47
73 54
73 71
Conclusions: The combination of ANA598 with SOC was well tolerated and ANA598 accelerated the rate of achieving undetectable virus in genotype-1 patients.
2010 Q2WEEK CONTROLLED-RELEASE-INTERFERON-ALPHA2B + RIBAVRIN REDUCES FLU-LIKE SYMPTOMS >50% AND PROVIDES EQUIVALENT EFFICACY IN COMPARISON TO WEEKLY PEGYLATED-INTERFERON-ALPHA2B + RIBAVIRIN IN TREATMENT-NAIVE-GENOTYPE-1-CHRONIC-HEPATITIS-C: RESULTS FROM EMPOWER, A RANDOMIZED-OPEN-LABEL12-WEEK-COMPARISON IN 133 PATIENTS W.A. Long1 , D. Takov2 , K. Tchernev3 , I. Kotzev4 , A. Rigney1 , Z. Krastev5 , S. Stoynov6 , R. Balabanska7 , E. Lawitz8 , Z. Younossi9 , R. Ghalib10 , E. Zuckerman11 , R. Safadi12 , R. Tur-Kaspa13 , N. Assy14 , Y. Lurie15 . 1 Biolex Therapeutics, Pittsboro, NC, USA; 2 Military Medical Academy, 3 UMHAT “Alexandrovska”, Sofia, 4 UMHAT “St. Marina”, Varna, 5 UMHAT “St. Ivan Rilski”, 6 UMHAT ‘Queen Giovanna – ISUL’ EAD, 7 Tokuda Hospital, Sofia, Bulgaria; 8 Alamo Medical Research, San Antonio, TX, 9 Inova Health Systems, Falls Church, VA, 10 The Liver Institute at Methodist Dallas, Dallas, TX, USA; 11 Carmel Medical Center, Haifa, 12 Holy Family Hospital Nazareth, Nazareth, 13 Rabin Medical Center, Petah-Tikva, 14 Rebekah Ziv Medical Center, Zefat, 15 Sourasky Medical Center, Tel Aviv, Israel E-mail: [email protected] Background and Aim: The aim of this study was to test the hypothesis that 480ug controlled-release-interferon-alpha2b (CR2b) dosed q2weeks reduces flu-like symptoms (FluSxs) but retains equal efficacy compared to pegylated interferon alpha2b (PEG2b) dosed weekly in treatment-naïve-genotype-1 (G1) chronic HCV patients treated with weight-based ribavirin. Methods: EMPOWER is a 12-week, randomized, open-label Phase 2b trial designed with 85% power to detect a 50% reduction in flu-like symptoms in patients treated with 480 ug CR2b [Locteron® , Biolex Therapeutics, Pittsboro, NC, USA] versus PEG2b [PegIntron® , Schering Plough, Kenilworth, NJ, USA], both in combination with weight-based ribavirin. Patients were enrolled in two contributing trials (SELECT-2 & 480STUDY) specifically designed to provide jointly the sample sizes required for the hypothesis test in EMPOWER. HCV RNA was measured weekly for three weeks and then every other week. Safety labs were measured weekly for three weeks and monthly thereafter. Adverse events including a pre-specified cluster of flu-like symptoms (FluSxs) were collected during weekly clinic visits for 12 weeks. FluSxs were also collected daily for 12 weeks by patient self-report using the internet (ePRO). Other measurements include serial measurements of BDI, HQLQ, SF-36, and days missed from work. Results: Preliminary results from 101/133 enrolled patients are available (n = 48 on q2week-480ug-CR2b, n = 53 on PEG2b). Mean declines in Log10 HCV RNA from baseline were equivalent. FluSxs (arthralgia, chills, fever, headache, or myalgia reported at weekly clinic visits) counts during the first week were 50 versus 109 on q2week-480 ug-CR2b vs. PEG2b, and total FluSxs counts during the 12 weeks were 109 versus 314 on q2week-480 ug-CR2b vs. PEG2b. Total days missed from work were 82 versus 109 for q2week480 ug-CR2b versus PEG2b. Neutrophil counts <750 occurred in 13% (6/48) and 8% (4/53) respectively for q2week-480 ug-CR2b and PEG2b; no neutrophil counts <500 were reported in the first 12 weeks. Conclusions: In these 101 patients, q2week-480 ug-CR2b over 12 weeks provided (a) >50% reduction in FluSxs that preceded the possible impact of the q2week dosing interval, and (b) equivalent antiviral efficacy. Days missed from work may also be reduced. Final 12-week results from all 133 patients (including ePRO) will be presented at the meeting.
Journal of Hepatology 2010 vol. 52 | S459–S471
S467