ORIGINAL ARTICLE July-August, Vol. 13 No. 4, 2014: 364-375 A phase 2 study of filibuvir in combination with pegylated IFN alfa and ribavirin for chronic HCV Maribel Rodriguez-Torres,* Eric M. Yoshida,** Patrick Marcellin,*** Subasree Srinivasan,****, Vivek S. Purohit,**** Cunshan Wang,**** Jennifer L. Hammond**** * Fundación de Investigación and San Juan Bautista School of Medicine, San Juan, Puerto Rico, USA. ** University of British Columbia and Vancouver General Hospital, Vancouver, B.C. Canada. *** Service d’Hépatologie, Hôpital Beaujon, Université Paris-Diderot, Clichy, France. **** Pfizer, Global Innovative Pharma Business Unit, Groton, CT, and Collegeville, PA, USA. No longer affiliated with Pfizer. ABSTRACT Objectives. Filibuvir is a non-nucleoside inhibitor of hepatitis C virus (HCV) polymerase. This study evalua- ted the safety and efficacy of filibuvir plus pegylated interferon alfa-2a (pegIFN)/ribavirin. Material and methods. Treatment-naïve, HCV genotype-1 patients were randomized to receive filibuvir 300 or 600 mg twice daily (BID) or placebo plus pegIFN (180 μg/wk) and ribavirin (1,000/1,200 mg BID) for 24 weeks. Filibu- vir patients who achieved defined response through week 24 discontinued therapy at week 24. All other patients continued on open-label pegIFN/ribavirin through week 48. The primary endpoint was the propor- tion of patients who achieved sustained virologic response (SVR) defined as HCV RNA < 15 IU/mL at end of treatment (weeks 24 or 48) and week 72. Results. Overall, 288 patients were randomized and treated. SVR was achieved by 41.7, 39.6, and 45.8% of patients in the filibuvir 300 mg, 600 mg, and placebo arms, respec- tively. While the addition of filibuvir to pegIFN/ribavirin improved on-treatment virologic response parame- ters, this did not translate into improved SVR rates due to a high rate of virologic relapse following completion of therapy (300 mg: 35.9%; 600 mg: 42.9%; placebo: 25.4%). The most commonly reported adverse events were nausea, fatigue, headache, and insomnia, and were reported at similar rates across arms. Con- clusions. Filibuvir plus pegIFN/ribavirin did not improve the percentage of patients achieving SVR compared with administration of pegIFN/ribavirin alone. However, the agent was well tolerated and was associated with higher on-treatment virologic response parameters. Further evaluation of filibuvir in combination with other direct-acting antiviral agents may be considered. Key words. NS5B. Non-nucleoside inhibitor. Treatment naïve. Safety. Efficacy. INTRODUCTION studies in HCV-infected patients demonstrated a dose-dependent reduction in HCV RNA concentra- Filibuvir (FLV; Pfizer Inc, New York, NY, USA) tions following administration of FLV monotherapy is a non-nucleoside inhibitor (NNI) of the hepatitis for 7-10 days, with mean maximum reductions of > C virus (HCV) ribonucleic acid (RNA)-dependent 2.0 log10 IU/mL at doses ≥ 450 mg twice daily RNA polymerase. In vitro, FLV exhibits potent (BID).2 When administered in combination with activity against HCV polymerases and replicons de- pegylated interferon alfa-2a (pegIFN) and ribavirin rived from genotype 1 strains of HCV, with equipo- (RBV) for 4 weeks, a significant increase in the rate tent activity against the 1a and 1b subtypes.1 Initial of rapid virologic response (RVR) was observed compared with administration of pegIFN/RBV alone (60-75% vs. 0%, respectively); however, con- tinued follow-up of patients determined that the ini- Correspondence and reprint request: Jennifer L. Hammond, Ph.D. Pfizer Global Innovative Pharma Business Unit, 500 Arcola Road, Collegeville, tial response to FLV therapy did not translate into PA 19426, USA. higher rates of sustained virologic response (SVR), Tel.: +1 484 865 4094. Fax: +1 860 686 5542 and it was hypothesized this was due to the short E-mail: [email protected] duration of FLV administration.3 Manuscript received: March 26, 2014. The present study was conducted to determine Manuscript accepted: April 6, 2014. whether longer duration of FLV administered in 365 FLV plus pegIFN and RBV for HCV infection. , 2014; 13 (4): 364-375 combination with pegIFN/RBV would significantly Study design increase the proportion of patients who achieved SVR. This was a multicenter, multinational, double- Patients were randomized in a 1:1:1 ratio to receive blind, randomized, placebo-controlled Phase 2b FLV dosed at 300 or 600 mg BID or matching placebo study to assess the safety and efficacy of FLV dosed in combination with pegIFN/RBV, and were stratified at 300 or 600 mg BID in combination with pegIFN according to screening HCV RNA level (≤ 400,000 and RBV in treatment-naïve HCV genotype 1 infect- IU/mL or > 400,000 IU/mL) and by participation in a ed patients. semen sub-study. FLV or matching placebo was administered during the first 24 weeks of the study MATERIAL AND METHODS only. Those patients randomized to either of the FLV arms who achieved HCV RNA < 15 IU/mL by week 4 Patients and whose HCV RNA level remained < 15 IU/mL through week 24 discontinued all therapy at week 24. All patients provided written informed consent. All other patients continued on open-label pegIFN/ The study is registered with ClinicalTrials.gov RBV through week 48 (Figure 1). Patients and investi- (NCT00987337). The protocol and informed consent gators were unblinded to treatment assignment at forms were approved by independent ethics commit- week 24 to determine eligibility to discontinue therapy. tees at all study centers in accordance with national All patients had a screening visit up to 28 days procedures. The studies were conducted according to before the start of dosing; visits at baseline, weeks 2 the ethical principles in the Declaration of Helsinki4 and 4, and monthly visits thereafter through week and in compliance with all Good Clinical Practice 24. Patients who discontinued therapy at week 24 guidelines, local laws, and regulations. had follow-up visits at weeks 36, 48, and 72. Pa- Patients from 70 sites in North America (United tients who required therapy beyond week 24 contin- States and Canada), Europe (Belgium, France, ued to have monthly visits through week 48, and Germany, Hungary, and Spain), and Asia (Republic follow-up visits at weeks 60 and 72. of Korea) were screened for inclusion in the study. An independent data monitoring committee was Treatment-naïve (no prior treatment with IFN ± responsible for periodic assessments of safety and ef- RBV or investigational anti-HCV agents) male and ficacy data, and made recommendations concerning female patients aged ≥ 18 years were eligible for in- continuation, termination, or other modifications to clusion in the study. All patients were required to the trial based on the observed beneficial or adverse be HCV seropositive, infected with a genotype 1 effects of the treatment under study. All sponsor strain (VERSANT HCV Genotype 2.0 Assay, Inno- personnel responsible for the conduct of the trial, genetics, Ghent, Belgium), and have plasma HCV with the exception of the sponsor study program- RNA levels ≥ 10,000 IU/mL at screening. In addi- mer, remained blinded to the results provided to the tion, a non-cirrhotic fibrosis classification (i.e., data monitoring committee. Ishak score ≤ 4 or equivalent) from a liver biopsy obtained within 24 months of screening was re- Follow-up* quired for enrollment. FLV 300 mg + pegIFN/RBV Patients were excluded if they were co-infected pegIFN/RBV Follow-up with either HIV or hepatitis B, had evidence of se- Follow-up* vere or decompensated liver disease or liver disease FLV 600 mg + pegIFN/RBV unrelated to HCV infection, or had any pre-existing pegIFN/RBV Follow-up medical condition or laboratory abnormality that made them unsuitable for treatment with pegIFN/ Placebo + pegIFN/RBV pegIFN/RBV Follow-up RBV. Additional exclusion criteria included an ab- 0244872 normal electrocardiogram (ECG) suggestive of clini- Week cally significant cardiac disease or QTc > 450 ms at screening, and history of solid organ transplant, or Figure 1. Study schematic. *Patients randomized to either active alcohol or substance abuse sufficient to pre- of the FLV groups who achieved HCV RNA < 15 IU/mL by week vent adherence to study medication and/or follow- 4, and whose HCV RNA level remained < 15 IU/mL through week 24 discontinued all therapy at week 24. All other up. Lastly, female patients who were pregnant or patients continued on oped-label pegIFN/RBV through week nursing and male patients whose female partner was 48. FLV: filibuvir. pegIFN: pegylated interferon alfa-2a. RBV: pregnant were excluded. ribavirin. 366 Rodriguez-Torres M, et al. , 2014; 13 (4): 364-375 Stopping rules take FLV and RBV with food (at least a light meal). The use of clinically significant inhibitors of cyto- Patients who met the following criteria discon- chrome P450 (CYP) 3A4 or sensitive CYP3A4 sub- tinued FLV/placebo but were allowed to remain on strates was not permitted owing to the potential for pegIFN/RBV at the discretion of the investigator: uncharacterized interactions with FLV. The use of <1 log reduction in HCV RNA relative to baseline erythropoietin or granulocyte colony-stimulating by week 4; HCV RNA > 15 IU/mL at week 12; or factors to treat hematologic toxicities associated > 2 log increase in HCV RNA from nadir. Patients with pegIFN/RBV therapy was not permitted. who met any of the following criteria were required to discontinue all therapy (FLV/placebo, pegIFN, Dose rationale and RBV): < 2 log reduction in HCV RNA relative to baseline by week 12; HCV RNA > 15 IU/mL at FLV doses of 300 mg BID and 600 mg BID were se- week 24; two or more consecutive HCV RNA meas- lected based on an exposure response analysis of re- urements > 1,000 IU/mL following achievement of sults from a 10-day monotherapy study2 and results HCV RNA < 15 IU/mL.