Su1062 Comparisons of Populations in Faldaprevir Phase III Studies Based on Pegylated Interferon...
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AASLD Abstracts response (SVR12) in 96% and 83%, respectively, of treatment-naïve patients with chronic genotype (GT) 1a HCV infection. RBV treatment is associated with known toxicity. To further evaluate the contribution of RBV to the efficacy and assess its risk benefit balance in the DAA combination treatment, we investigated the efficacy and safety of co-formulated ABT-450/r/ABT-267 and ABT-333 (3D regimen) with and without RBV, in non-cirrhotic, treatment-naïve adults with chronic GT1a HCV infection. Methods: In this double-blind, randomized, multicenter phase 3 study, subjects were randomized (1:2, stratified by IL28B genotype CC vs. non-CC) to 12 weeks of treatment with ABT-450/r/ABT-267 (150mg/ 100mg/25mg QD) and ABT-333 (250mg BID), with either weight-based RBV (1000mg or 1200mg daily divided BID, Arm A) or placebo for RBV (Arm B). Results: 100 subjects received 3D+RBV (Arm A) and 205 received 3D+placebo (Arm B). The baseline characteristics were well balanced (Table). Intent-to-treat SVR12 rates were 97.0% in Arm A and 90.2% in Arm B (Table). Adverse events (AEs) were generally mild or moderate; the most frequent AEs in Arms A and B were fatigue (46% and 35%), headache (25% and 28%), and nausea (21% and 13%), with no statistically significant differences between arms for these events. No subjects discontinued from Arm A; 2 subjects (1.0%) discontinued from Arm B due to AEs. Two serious AEs observed in Arm A, anemia and pancreatitis (in a subject with history of pancreatitis), were assessed as treatment related, vs. 0 in Arm B. In Arm A, 42% of subjects experienced hemoglobin decrease to below the lower limit of normal while on treatment, vs. 3.9% in Arm B (P<0.001); 4 subjects in Arm A and 0 in Arm B (P=0.011) had hemoglobin <100 g/L. A greater percentage of subjects in Arm A experienced total bilirubin >2x upper limit of normal compared with Arm B (8.0% vs 2.4%, P=0.034). Conclusions: In this study, the 3D regimen with or without ribavirin for 12 weeks achieved SVR12 rates ≥90% in treatment-naïve adults with Hepatitis C virus genotype 1a infection. SVR rates were higher with RBV. Both regimens were well tolerated with <1% of subjects discontinuing due to AEs. aN=98; bN=194. Su1062 Comparisons of Populations in Faldaprevir Phase III Studies Based on Pegylated Interferon α-2A and Ribavirin-Predicted Responsiveness and Impact on Achieving Svr12 Peter Ferenci, Donald M. Jensen, Douglas T. Dieterich, Ira M. Jacobson, Manuel Romero- Gomez, Graham Foster, Tarik Asselah, Curtis Cooper, Cristina Tural, Adrian Streinu- Cercel, Stephen D. Ryder, Massimo Puoti, Edward Tam, Jose Luis Calleja, Marina Núñez, Anne-Marie Quinson, Wulf Böcher, Florian Voss, Joseph Scherer Background: Faldaprevir, a potent HCV NS3/4A inhibitor, demonstrated high SVR rates combined with pegylated interferon/ribavirin (PR) in chronic HCV-infected patients in the Phase III STARTVerso1-4 trials. OPTIMRVR, a previously validated tool for predicting RVR in treatment-naïve GT-1 and GT-4 patients treated with PR, was assessed for each population, with higher scores indicating better chance of achieving RVR. Methods: All treated patients enrolled in the STARTVerso1-4 trials were included. OPTIMRVR scores (a function of baseline viral load, IL28B and a non-invasive measure of degree of fibrosis) were calculated, summarised across populations and compared using rank-sum methods. Results: Mean Week 4 changes in log 10 HCV RNA for placebo-treated patients were -2.81, -2.44, -1.92 (P= 0.0054) for treatment-naïve, relapsers and partial responders, respectively, and -2.75, -2.60, -2.30 after adjusting for OPTIMRVR (P=0.1770) suggesting OPTIMRVR provides at least a partial explanation for differences in PR activity across populations. Summaries of OPTIMRVR scores across populations are provided in the Table. Consistent with lower placebo response in STARTVerso1-3 for mono-infected relapsers versus treatment-naïve patients (Week 4 HCV RNA <25 IU/mL: 8% vs 19%), significant differences were observed in OPTIMRVR scores between the two populations (P=0.0003). Scores were lower for treatment-naïve and slightly higher for relapsers for co-infected patients. Conclusions: OPTIMRVR provided insight and confirmation of the results observed in the Phase III faldaprevir programme, in particular for comparing across mono-infected populations. A lower OPTIMRVR score was observed for mono-infected relapsers compared with treatment-naïve patients, consistent with the results of lower responses for placebo patients. OPTIMRVR* by faldaprevir Phase III population S-978 AASLD Abstracts *Comparisons based on Wilcoxon Rank Sum Test. Su1063 Long Term Follow-Up of Patients Treated With Sofosbuvir in the Phase 3 Studies Fission, Positron, Fusion and Neutrino Kimberly Beavers, Stephen D. Shafran, Hongmei Mo, John McNally, Diana M. Brainard, William T. Symonds, Mario Chojkier, Alessandra Mangia Introduction: We report the results from an interim analysis of long term follow-up of patients who were treated with SOF based regimens in the Phase 3 Studies FISSION, POSITRON, FUSION and NEUTRINO. Methods: Patients in the SOF Phase 3 studies who achieved SVR were offered enrollment in a SVR Registry and those who did not achieve SVR were offered enrollment in a Resistance Registry. Periodic laboratory evaluations, clinical assessment of liver disease, and quality of life assessments (SF-36) were performed for up to 3 years. Results. 487 patients representing 65% of those eligible from the Phase 3 studies have enrolled into the SVR Registry with a median (range) follow-up of 24 (1-49) weeks. 114 patients representing 52% of those eligible from the Phase 3 studies have enrolled in the Resistance Registry with median (range) follow-up of 25 (1-49) weeks. Demographic and disease characteristics of the populations in both studies are presented below. All patients in the SVR registry have maintained SVR through follow up. 60% of subjects have discontinued from the Resistance Registry primarily due to the availability of SOF-based re- treatment protocols for patients not achieving SVR in the Phase 3 studies. There were no significant changes in laboratory evaluations, liver disease assessments or SF-36 scores in either study. One patient had newly diagnosed hepatocellular carcinoma during the Resistance Registry. Conclusions: This interim analysis of the SVR Registry indicates that SVR achieved with SOF-based treatment is durable. Further follow-up will be necessary to determine the impact of SVR on disease regression. Demographics and Disease Characteristics of Patients in Long Term Follow Up Su1064 Early Viral Kinetics Do Not Predict Treatment Outcome With Sofosbuvir + Ribavirin for 12 or 24 Weeks in HCV Genotype 2/3 Patients in the Valence Trial Stefan Zeuzem, Robert Flisiak, Rob H. Hyland, Ari Illeperuma, Diana M. Brainard, William T. Symonds, John G. McHutchison, Rafael Esteban Background: Sofosbuvir (SOF) + ribavirin (RBV) for 12 or 24 weeks led to high SVR rates in genotype 2 or 3 HCV-infected patients, respectively, in the Phase 3 VALENCE study. We analyzed viral kinetics to determine the relationship to SVR12. Methods: Treatment- naïve or treatment-experienced patients infected with HCV genotype 2 or 3 were randomized to receive SOF+RBV for 12 weeks or placebo. The study was amended to extend treatment duration to 24 weeks for patients with genotype 3 infection. HCV RNA was measured using the COBAS TaqMan® HCV Test, v2.0 with the High Pure System. The primary end point was SVR12. The predictive value of viral response at Weeks 2 and 4 was calculated; potential viral kinetic (VK) differences in subgroups were evaluated. Results: 73 patients with HCV genotype 2 and 250 patients with genotype 3 received 12 or 24 weeks of SOF+RBV respec- tively. The predictive value of viral response at Weeks 2 and 4 is depicted in the table. No difference in VK was noted comparing cirrhosis status, IL28B genotype, or SVR12 outcome. Conclusions: 12 or 24 weeks of treatment with SOF+RBV was highly efficacious in genotype 2 or 3 HCV-infected patients, respectively. The majority of subjects achieved HCV RNA <LLOQ, TND at Week 4. On-treatment viral kinetics were not predictive of response. Accordingly, there is no role for response guided therapy with these regimens.
Transcript of Su1062 Comparisons of Populations in Faldaprevir Phase III Studies Based on Pegylated Interferon...
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sresponse (SVR12) in 96% and 83%, respectively, of treatment-naïve patients with chronicgenotype (GT) 1a HCV infection. RBV treatment is associated with known toxicity. Tofurther evaluate the contribution of RBV to the efficacy and assess its risk benefit balancein the DAA combination treatment, we investigated the efficacy and safety of co-formulatedABT-450/r/ABT-267 and ABT-333 (3D regimen) with and without RBV, in non-cirrhotic,treatment-naïve adults with chronic GT1a HCV infection. Methods: In this double-blind,randomized, multicenter phase 3 study, subjects were randomized (1:2, stratified by IL28Bgenotype CC vs. non-CC) to 12 weeks of treatment with ABT-450/r/ABT-267 (150mg/100mg/25mg QD) and ABT-333 (250mg BID), with either weight-based RBV (1000mg or1200mg daily divided BID, Arm A) or placebo for RBV (Arm B). Results: 100 subjectsreceived 3D+RBV (Arm A) and 205 received 3D+placebo (Arm B). The baseline characteristicswere well balanced (Table). Intent-to-treat SVR12 rates were 97.0% in Arm A and 90.2%in Arm B (Table). Adverse events (AEs) were generally mild or moderate; the most frequentAEs in Arms A and B were fatigue (46% and 35%), headache (25% and 28%), and nausea(21% and 13%), with no statistically significant differences between arms for these events.No subjects discontinued from Arm A; 2 subjects (1.0%) discontinued from Arm B due toAEs. Two serious AEs observed in Arm A, anemia and pancreatitis (in a subject with historyof pancreatitis), were assessed as treatment related, vs. 0 in Arm B. In Arm A, 42% ofsubjects experienced hemoglobin decrease to below the lower limit of normal while ontreatment, vs. 3.9% in Arm B (P<0.001); 4 subjects in Arm A and 0 in Arm B (P=0.011)had hemoglobin <100 g/L. A greater percentage of subjects in Arm A experienced totalbilirubin >2x upper limit of normal compared with Arm B (8.0% vs 2.4%, P=0.034).Conclusions: In this study, the 3D regimen with or without ribavirin for 12 weeks achievedSVR12 rates ≥90% in treatment-naïve adults with Hepatitis C virus genotype 1a infection.SVR rates were higher with RBV. Both regimens were well tolerated with <1% of subjectsdiscontinuing due to AEs.
aN=98; bN=194.
Su1062
Comparisons of Populations in Faldaprevir Phase III Studies Based onPegylated Interferon α-2A and Ribavirin-Predicted Responsiveness and Impacton Achieving Svr12Peter Ferenci, Donald M. Jensen, Douglas T. Dieterich, Ira M. Jacobson, Manuel Romero-Gomez, Graham Foster, Tarik Asselah, Curtis Cooper, Cristina Tural, Adrian Streinu-Cercel, Stephen D. Ryder, Massimo Puoti, Edward Tam, Jose Luis Calleja, Marina Núñez,Anne-Marie Quinson, Wulf Böcher, Florian Voss, Joseph Scherer
Background: Faldaprevir, a potent HCV NS3/4A inhibitor, demonstrated high SVR ratescombined with pegylated interferon/ribavirin (PR) in chronic HCV-infected patients in thePhase III STARTVerso1-4 trials. OPTIMRVR, a previously validated tool for predicting RVRin treatment-naïve GT-1 and GT-4 patients treated with PR, was assessed for each population,with higher scores indicating better chance of achieving RVR. Methods: All treated patientsenrolled in the STARTVerso1-4 trials were included. OPTIMRVR scores (a function ofbaseline viral load, IL28B and a non-invasive measure of degree of fibrosis) were calculated,summarised across populations and compared using rank-sum methods. Results: Mean Week4 changes in log10 HCV RNA for placebo-treated patients were -2.81, -2.44, -1.92 (P=0.0054) for treatment-naïve, relapsers and partial responders, respectively, and -2.75, -2.60,-2.30 after adjusting for OPTIMRVR (P=0.1770) suggesting OPTIMRVR provides at least apartial explanation for differences in PR activity across populations. Summaries of OPTIMRVRscores across populations are provided in the Table. Consistent with lower placebo responsein STARTVerso1-3 for mono-infected relapsers versus treatment-naïve patients (Week 4HCV RNA <25 IU/mL: 8% vs 19%), significant differences were observed in OPTIMRVRscores between the two populations (P=0.0003). Scores were lower for treatment-naïve andslightly higher for relapsers for co-infected patients. Conclusions: OPTIMRVR providedinsight and confirmation of the results observed in the Phase III faldaprevir programme, inparticular for comparing across mono-infected populations. A lower OPTIMRVR score wasobserved for mono-infected relapsers compared with treatment-naïve patients, consistentwith the results of lower responses for placebo patients.OPTIMRVR* by faldaprevir Phase III population
S-978AASLD Abstracts
*Comparisons based on Wilcoxon Rank Sum Test.
Su1063
Long Term Follow-Up of Patients Treated With Sofosbuvir in the Phase 3Studies Fission, Positron, Fusion and NeutrinoKimberly Beavers, Stephen D. Shafran, Hongmei Mo, John McNally, Diana M. Brainard,William T. Symonds, Mario Chojkier, Alessandra Mangia
Introduction: We report the results from an interim analysis of long term follow-up ofpatients who were treated with SOF based regimens in the Phase 3 Studies FISSION,POSITRON, FUSION and NEUTRINO. Methods: Patients in the SOF Phase 3 studies whoachieved SVR were offered enrollment in a SVR Registry and those who did not achieveSVR were offered enrollment in a Resistance Registry. Periodic laboratory evaluations, clinicalassessment of liver disease, and quality of life assessments (SF-36) were performed for upto 3 years. Results. 487 patients representing 65% of those eligible from the Phase 3 studieshave enrolled into the SVR Registry with a median (range) follow-up of 24 (1-49) weeks.114 patients representing 52% of those eligible from the Phase 3 studies have enrolled inthe Resistance Registry with median (range) follow-up of 25 (1-49) weeks. Demographicand disease characteristics of the populations in both studies are presented below. Allpatients in the SVR registry have maintained SVR through follow up. 60% of subjects havediscontinued from the Resistance Registry primarily due to the availability of SOF-based re-treatment protocols for patients not achieving SVR in the Phase 3 studies. There were nosignificant changes in laboratory evaluations, liver disease assessments or SF-36 scores ineither study. One patient had newly diagnosed hepatocellular carcinoma during the ResistanceRegistry. Conclusions: This interim analysis of the SVR Registry indicates that SVR achievedwith SOF-based treatment is durable. Further follow-up will be necessary to determine theimpact of SVR on disease regression.
Demographics and Disease Characteristics of Patients in Long Term Follow Up
Su1064
Early Viral Kinetics Do Not Predict Treatment Outcome With Sofosbuvir +Ribavirin for 12 or 24 Weeks in HCV Genotype 2/3 Patients in the ValenceTrialStefan Zeuzem, Robert Flisiak, Rob H. Hyland, Ari Illeperuma, Diana M. Brainard,William T. Symonds, John G. McHutchison, Rafael Esteban
Background: Sofosbuvir (SOF) + ribavirin (RBV) for 12 or 24 weeks led to high SVR ratesin genotype 2 or 3 HCV-infected patients, respectively, in the Phase 3 VALENCE study.We analyzed viral kinetics to determine the relationship to SVR12. Methods: Treatment-naïve or treatment-experienced patients infected with HCV genotype 2 or 3 were randomizedto receive SOF+RBV for 12 weeks or placebo. The study was amended to extend treatmentduration to 24 weeks for patients with genotype 3 infection. HCV RNA was measured usingthe COBAS TaqMan® HCV Test, v2.0 with the High Pure System. The primary end pointwas SVR12. The predictive value of viral response at Weeks 2 and 4 was calculated; potentialviral kinetic (VK) differences in subgroups were evaluated. Results: 73 patients with HCVgenotype 2 and 250 patients with genotype 3 received 12 or 24 weeks of SOF+RBV respec-tively. The predictive value of viral response at Weeks 2 and 4 is depicted in the table. Nodifference in VK was noted comparing cirrhosis status, IL28B genotype, or SVR12 outcome.Conclusions: 12 or 24 weeks of treatment with SOF+RBV was highly efficacious in genotype2 or 3 HCV-infected patients, respectively. The majority of subjects achieved HCV RNA<LLOQ, TND at Week 4. On-treatment viral kinetics were not predictive of response.Accordingly, there is no role for response guided therapy with these regimens.
