- Email: [email protected]
1056 MK-7009 SIGNIFICANTLY IMPROVES RAPID VIRAL RESPONSE (RVR) IN COMBINATION WITH PEGYLATED INTERFERON ALFA-2A AND RIBAVIRIN IN PATIENTS WITH CHRONIC HEPATITIS C (CHC) GENOTYPE 1 INFECTION
S384
LATE-BREAKING ABSTRACTS
Laboratory parameters did not show any relevant changes from baseline. Plasma drug levels exhibited supra-proportional pharmacokinetics from 400 mg on. The 1st phase of VL decline was correlated with the early BI 207127 plasma exposure. Conclusions: BI 207127, given as monotherapy p.o., demonstrated reliable antiviral activity against HCV genotype 1. Further clinical development of this high-potential direct antiviral in combination therapy is warranted. 1055 ANTIVIRAL ACTIVITY OF ANA598, A POTENT NONNUCLEOSIDE POLYMERASE INHIBITOR, IN CHRONIC HEPATITIS C PATIENTS E. Lawitz1 , M. Rodriguez-Torres2 , M. DeMicco3 , T. Nguyen4 , E. Godofsky5 , J. Appleman6 , M. Rahimy6 , C. Crowley6 , J. Freddo6 . 1 Alamo Medical Research, San Antonio, TX, USA; 2 Fundaci´ on de Investigaci´on de Diego, Santurce, Puerto Rico; 3 Advanced Clinical Research Institute, Anaheim, CA, 4 Research and Education Inc, San Diego, CA 5 University Hepatitis Center at Bach and Godofsky, Sarasota, FL, 6 Anadys Pharmaceuticals, Inc, San Diego, CA, USA E-mail: [email protected] Background: ANA598 is a non-nucleoside inhibitor of HCV polymerase with potent in-vitro antiviral activity. ANA598 was well tolerated at single doses up to 3000 mg in healthy subjects. Plasma exposure generally increased with increasing doses and increased several fold after consumption of food. Plasma t1/ 2 averaged ~24 hours. Initial results from an ongoing Phase 1b trial in HCV patients are reported here. Methods: Study ANA598–502 is a randomized, double-blind, placebocontrolled, multiple ascending dose trial designed to evaluate safety, tolerability and antiviral activity of orally administered ANA598 in treatmentnaive patients with chronic HCV genotype 1 infection. Patients were treated with ANA598 (or matching placebo) at doses of 200 mg, 400 mg or 800 mg each given BID for 3 days . Viral load at day 4 (12 hours after the last dose) was compared to baseline HCV RNA levels. Plasma drug levels were measured 12 hours following each dose for assessment of trough concentration. HCV RNA levels were measured using the COBAS AmpliPrep/COBAS TaqMan HCV test. Results: At the 200 mg bid dose level, 6 genotype 1b and 5 genotype 1a patients received ANA598. The age range for the 13 patients (including placebo) was 21–61; there were 8 males and 5 females. Median viral load at baseline was 2,540,000 IU/ml (range 191,000 to 14,700,000 IU/ml). The median viral load decline at the end of treatment was 2.4 log 10 (with a range of 0.4–3.4 log 10). The 5 1a patients demonstrated a median viral load decline of 1.5 log 10; the 6 1b patients demonstrated a median decline of 2.6 log 10. No patient showed evidence of viral rebound while on ANA598. ANA598 was well tolerated and no serious adverse events were reported. Conclusions: ANA598 dosed 200 mg BID for 3 days as monotherapy demonstrated potent antiviral activity, with median viral load decline of 2.4 log 10 in treatment naive genotype 1 patients. This abstract will be updated with data from the 400 mg and 800 mg BID cohorts. Further studies are planned with ANA598 in combination with SOC.
1056 MK-7009 SIGNIFICANTLY IMPROVES RAPID VIRAL RESPONSE (RVR) IN COMBINATION WITH PEGYLATED INTERFERON ALFA-2A AND RIBAVIRIN IN PATIENTS WITH CHRONIC HEPATITIS C (CHC) GENOTYPE 1 INFECTION M.P. Manns1, E. Gane2 , M. Rodriguez-Torres3 , A. Stoehr4 , C.-T. Yeh5 , R. Wiedmann6 , P. Hwang7 , E. Quirk6 , J. Silber6 , A. Lee6 . 1 Department of Gastroenterology, Hepatology and Endocrinology, Medical School of Hannover, Hannover, Germany; 2 New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand; 3 Fundacion de Investigacion de Diego, Ponce School of Medicine, San Juan, Puerto Rico; 4 Institute for Interdisciplinary Medicine, Medical Care Center Hamburg, Hamburg, Germany; 5 Chang Gung Memorial Hospital, Taipei, Taiwan; 6 Clinical Research, Infectious Diseases/Vaccines, Merck, 7 Biostatistics, Merck, Inc., North Wales, PA, USA E-mail: [email protected] Background: MK-7009 is a noncovalent competitive inhibitor of HCV NS3/4A protease, with demonstrated safety and efficacy when administered as monotherapy for 8 days. We now present the primary analysis from an ongoing Phase IIa study of MK-7009 for 28 days in combination with pegylated-interferon and ribavirin (peg-IFN/RBV). Methods: This is a randomized, placebo-controlled, double-blind study of MK-7009 in treatment-naive CHC patients. MK-7009 was administered for 28 days with peg-IFN/RBV in 1 of 5 regimens: placebo, 300 mg BID, 600 mg BID, 600 mg QD, or 800 mg QD; all patients continue pegIFN/RBV for an additional 44 weeks. The primary endpoint was the percent of subjects with undetectable HCV RNA (<10 IU/mL by Roche Cobas Taqman) at day 28 (RVR). Results: 94 subjects (mean age 46.1 years, 59% male, mean baseline HCV RNA 6.70log10 IU/mL) were randomized and treated. MK-7009 in combination with peg-IFN/RBV was well tolerated, with no serious adverse events (SAEs) and no discontinuations due to an AE during the first 42 days. The most common AEs reported were nausea, headache, and flu-like symptoms. The incidence of nausea and vomiting appeared to be higher compared to placebo. The proportion of subjects who achieved RVR in the MK-7009-containing arms ranged from 69% to 82% (table), vs. 6% of the control (per-protocol population). Each of the MK-7009 doses tested met superiority criteria over the control regimen (p < 0.0001). Viral suppression continued after MK-7009 was stopped; HCV RNA was undetectable in 77−94% of the MK-7009-treated patients vs. 12% of control on day 42. Resistance mutation data will be presented. Conclusions: In this first study of MK-7009 in combination with pegIFN/RBV, MK-7009 is a well-tolerated and potent inhibitor of HCV. The results support further development of MK-7009 for HCV treatment. MK-7009 Dose group Pts. w RVR/ % RVR P value (vs. pcbo) % <10 IU/mL Pts treated Day 42 300 mg BID 600 mg BID 600 mg QD 800 mg QD placebo
12/16 15/19 11/16 14/17 1/18
75.0 78.9 68.8 82.4 5.6
<0.0001 <0.0001 <0.0001 <0.0001 n/a
87.5 89.5 76.5 94.1 11.8
LATE-BREAKING ABSTRACTS
Laboratory parameters did not show any relevant changes from baseline. Plasma drug levels exhibited supra-proportional pharmacokinetics from 400 mg on. The 1st phase of VL decline was correlated with the early BI 207127 plasma exposure. Conclusions: BI 207127, given as monotherapy p.o., demonstrated reliable antiviral activity against HCV genotype 1. Further clinical development of this high-potential direct antiviral in combination therapy is warranted. 1055 ANTIVIRAL ACTIVITY OF ANA598, A POTENT NONNUCLEOSIDE POLYMERASE INHIBITOR, IN CHRONIC HEPATITIS C PATIENTS E. Lawitz1 , M. Rodriguez-Torres2 , M. DeMicco3 , T. Nguyen4 , E. Godofsky5 , J. Appleman6 , M. Rahimy6 , C. Crowley6 , J. Freddo6 . 1 Alamo Medical Research, San Antonio, TX, USA; 2 Fundaci´ on de Investigaci´on de Diego, Santurce, Puerto Rico; 3 Advanced Clinical Research Institute, Anaheim, CA, 4 Research and Education Inc, San Diego, CA 5 University Hepatitis Center at Bach and Godofsky, Sarasota, FL, 6 Anadys Pharmaceuticals, Inc, San Diego, CA, USA E-mail: [email protected] Background: ANA598 is a non-nucleoside inhibitor of HCV polymerase with potent in-vitro antiviral activity. ANA598 was well tolerated at single doses up to 3000 mg in healthy subjects. Plasma exposure generally increased with increasing doses and increased several fold after consumption of food. Plasma t1/ 2 averaged ~24 hours. Initial results from an ongoing Phase 1b trial in HCV patients are reported here. Methods: Study ANA598–502 is a randomized, double-blind, placebocontrolled, multiple ascending dose trial designed to evaluate safety, tolerability and antiviral activity of orally administered ANA598 in treatmentnaive patients with chronic HCV genotype 1 infection. Patients were treated with ANA598 (or matching placebo) at doses of 200 mg, 400 mg or 800 mg each given BID for 3 days . Viral load at day 4 (12 hours after the last dose) was compared to baseline HCV RNA levels. Plasma drug levels were measured 12 hours following each dose for assessment of trough concentration. HCV RNA levels were measured using the COBAS AmpliPrep/COBAS TaqMan HCV test. Results: At the 200 mg bid dose level, 6 genotype 1b and 5 genotype 1a patients received ANA598. The age range for the 13 patients (including placebo) was 21–61; there were 8 males and 5 females. Median viral load at baseline was 2,540,000 IU/ml (range 191,000 to 14,700,000 IU/ml). The median viral load decline at the end of treatment was 2.4 log 10 (with a range of 0.4–3.4 log 10). The 5 1a patients demonstrated a median viral load decline of 1.5 log 10; the 6 1b patients demonstrated a median decline of 2.6 log 10. No patient showed evidence of viral rebound while on ANA598. ANA598 was well tolerated and no serious adverse events were reported. Conclusions: ANA598 dosed 200 mg BID for 3 days as monotherapy demonstrated potent antiviral activity, with median viral load decline of 2.4 log 10 in treatment naive genotype 1 patients. This abstract will be updated with data from the 400 mg and 800 mg BID cohorts. Further studies are planned with ANA598 in combination with SOC.
1056 MK-7009 SIGNIFICANTLY IMPROVES RAPID VIRAL RESPONSE (RVR) IN COMBINATION WITH PEGYLATED INTERFERON ALFA-2A AND RIBAVIRIN IN PATIENTS WITH CHRONIC HEPATITIS C (CHC) GENOTYPE 1 INFECTION M.P. Manns1, E. Gane2 , M. Rodriguez-Torres3 , A. Stoehr4 , C.-T. Yeh5 , R. Wiedmann6 , P. Hwang7 , E. Quirk6 , J. Silber6 , A. Lee6 . 1 Department of Gastroenterology, Hepatology and Endocrinology, Medical School of Hannover, Hannover, Germany; 2 New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand; 3 Fundacion de Investigacion de Diego, Ponce School of Medicine, San Juan, Puerto Rico; 4 Institute for Interdisciplinary Medicine, Medical Care Center Hamburg, Hamburg, Germany; 5 Chang Gung Memorial Hospital, Taipei, Taiwan; 6 Clinical Research, Infectious Diseases/Vaccines, Merck, 7 Biostatistics, Merck, Inc., North Wales, PA, USA E-mail: [email protected] Background: MK-7009 is a noncovalent competitive inhibitor of HCV NS3/4A protease, with demonstrated safety and efficacy when administered as monotherapy for 8 days. We now present the primary analysis from an ongoing Phase IIa study of MK-7009 for 28 days in combination with pegylated-interferon and ribavirin (peg-IFN/RBV). Methods: This is a randomized, placebo-controlled, double-blind study of MK-7009 in treatment-naive CHC patients. MK-7009 was administered for 28 days with peg-IFN/RBV in 1 of 5 regimens: placebo, 300 mg BID, 600 mg BID, 600 mg QD, or 800 mg QD; all patients continue pegIFN/RBV for an additional 44 weeks. The primary endpoint was the percent of subjects with undetectable HCV RNA (<10 IU/mL by Roche Cobas Taqman) at day 28 (RVR). Results: 94 subjects (mean age 46.1 years, 59% male, mean baseline HCV RNA 6.70log10 IU/mL) were randomized and treated. MK-7009 in combination with peg-IFN/RBV was well tolerated, with no serious adverse events (SAEs) and no discontinuations due to an AE during the first 42 days. The most common AEs reported were nausea, headache, and flu-like symptoms. The incidence of nausea and vomiting appeared to be higher compared to placebo. The proportion of subjects who achieved RVR in the MK-7009-containing arms ranged from 69% to 82% (table), vs. 6% of the control (per-protocol population). Each of the MK-7009 doses tested met superiority criteria over the control regimen (p < 0.0001). Viral suppression continued after MK-7009 was stopped; HCV RNA was undetectable in 77−94% of the MK-7009-treated patients vs. 12% of control on day 42. Resistance mutation data will be presented. Conclusions: In this first study of MK-7009 in combination with pegIFN/RBV, MK-7009 is a well-tolerated and potent inhibitor of HCV. The results support further development of MK-7009 for HCV treatment. MK-7009 Dose group Pts. w RVR/ % RVR P value (vs. pcbo) % <10 IU/mL Pts treated Day 42 300 mg BID 600 mg BID 600 mg QD 800 mg QD placebo
12/16 15/19 11/16 14/17 1/18
75.0 78.9 68.8 82.4 5.6
<0.0001 <0.0001 <0.0001 <0.0001 n/a
87.5 89.5 76.5 94.1 11.8