Virologic Response Rates of Weight-Based Taribavirin Versus Ribavirin in Treatment-Naive Patients with Genotype 1 Chronic Hepatitis C Fred Poordad,1 Eric Lawitz,2 Mitchell L. Shiffman,3 Tarek Hassanein,4 Andrew J. Muir,5 Bruce R. Bacon,6 Jamie Heise,7 Deanine Halliman,7 Eric Chun,7 and Janet Hammond7 Ribavirin-induced hemolytic anemia can prompt dose reductions and lower sustained virologic response (SVR) rates in the treatment of patients with chronic hepatitis C. The study aimed to determine if weight-based dosing of taribavirin (TBV), an oral prodrug of ribavirin (RBV), demonstrated efficacy comparable to RBV while maintaining its previ- ously demonstrated anemia advantage with fixed dose administration. A U.S. phase 2b randomized, open-label, active-controlled, parallel-group study was conducted in 278 treatment-naive patients infected with genotype 1 who were stratified by body weight and baseline viral load. Patients were randomized 1:1:1:1 to receive TBV (20, 25, or 30 mg/kg/ day) or RBV (800-1400 mg/day) with pegylated interferon alfa-2b for 48 weeks. The SVR rates in this difficult-to-cure patient demographics (mean age, 49 years; 61% male; 30% African American or Latino; high viral load; advanced fibrosis; and mean weight, 82 kg) were 28.4%, 24.3%, 20.6%, and 21.4% in the 20, 25, and 30 mg/kg TBV groups and the RBV group, respectively. There were no statistical differences in the efficacy analyses. Ane- mia rates were significantly lower (P < 0.05) in the 20 and 25 mg/kg/day TBV treatment groups (13.4% and 15.7%, respectively) compared to RBV (32.9%). The most common adverse events in all groups were fatigue, diarrhea, and insomnia. Diarrhea, reported in 38% of TBV patients versus 21% of RBV patients, was generally mild and not dose-limit- ing. Conclusion: All TBV doses demonstrated efficacy and tolerability comparable to that of RBV; however, the 25 mg/kg dose demonstrated the optimal balance of safety and effi- cacy. Anemia rates were significantly lower for TBV given at 20-25 mg/kg than RBV. These data suggest weight-based dosing with TBV provides a safe and effective treatment alterna- tive to RBV for chronic hepatitis C. American Association for the Study of Liver Diseases. (HEPATOLOGY 2010;00:000-000) ibavirin (RBV) is essential for the treatment of chronic hepatitis C virus (HCV) infection. Abbreviations: AE, adverse event; ESA, erythropoiesis-stimulating agent; R When used in combination with peginterferon EVR, early virologic response; FW, follow-up week; Hb, hemoglobin; HCV, alfa (peg-IFN alfa), it significantly enhances on-treat- hepatitis C virus; IFN, interferon; ITT, intent to treat; RBV, ribavirin; SVR, ment virologic response and reduces relapse.1-3 RBV sustained virologic response; TBV, taribavirin; TW, treatment week; WBD, weight-based dosing. has been demonstrated to be essential in achieving From the 1Cedars-Sinai Medical Center, Los Angeles, CA; 2Alamo Medical high rates of sustained virologic response (SVR) when Research, San Antonio, TX; 3McGuire Research Institute, McGuire Veterans 4 used in combination with direct-acting antiviral Administration Medical Center, Richmond, VA; Southern California Liver 4-6 Centers, San Clemente, CA; 5Duke Clinical Research Institute, Duke University, agents. One of the most significant toxicities of 5,7 Durham, NC; 6Saint Louis University School of Medicine, St. Louis, MO; and RBV is hemolytic anemia. When used as monother- 7Valeant Pharmaceuticals North America, Aliso Viejo, CA. apy, RBV-induced hemolytic anemia is marginal Received April 24, 2010; accepted June 22, 2010. because of a compensatory reticulocytosis.8,9 However, Address reprint requests to: Fred Poordad, M.D., Hepatology and Liver Transplantation, Cedars-Sinai Medical Center, 8635 West 3rd Street, Los peg-IFN alfa suppresses the bone marrow and signifi- Angeles, CA 90048. E-mail: [email protected]; fax: 310-423-0584. cantly reduces reticulocytosis. Therefore, anemia asso- Copyright VC 2010 by the American Association for the Study of Liver Diseases. ciated with the combination of IFN and RBV therapy Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hep.23827 is much greater. Approximately 25%-30% of patients Potential conflict of interest: Nothing to report. receiving peg-IFN and RBV develop a decline of 4 g 1 2 POORDAD ET AL. HEPATOLOGY, Month 2010 or greater in hemoglobin (Hb).1,2,10 This significantly neutropenia (absolute neutrophil count <1200 Â impairs quality of life and leads to dose reduction and 103/lL), thrombocytopenia (<90 Â 103 platelets/lL) premature discontinuation of treatment in 15%-30% or serum creatinine levels 1.5 mg/dL. Additional of patients.1,3,11,12 Decreasing the dose of RBV to exclusion criteria included chronic hepatic disease below 10.6 mg/kg body weight/day during the first 12 other than HCV, human immunodeficiency virus, or weeks of treatment has been shown to increase relapse hepatitis B coinfection; severe psychiatric disorders; al- rates and reduce SVR in both treatment-naive patients coholism or drug addiction within 1 year of screening; and during retreatment.11,13,14 use of erythropoiesis-stimulating agents (ESAs); and Taribavirin (TBV), formerly known as Viramidine, presence of comorbid conditions considered significant is a nucleoside analogue and oral prodrug of RBV that by the investigator. is converted from TBV to RBV by adenosine deami- Study Design. This was a phase 2b, multicenter, nase. Its structural difference from RBV, a positively randomized, open-label, active-control, and parallel- charged carboxamidine group at position 3, signifi- group trial. Although the study was open-label, the cantly reduces the ability of this agent to enter red sponsor was blinded to treatment allocation and viral cells. Because accumulation of RBV within red blood load results until treatment week 12. Patients were en- cells is the primary mechanism causing hemolytic ane- rolled at 51 centers in the United States. Patients were mia, TBV should therefore be associated with signifi- stratified by serum HCV RNA titers (780,000 cantly less anemia. IU/mL or >780,000 IU/mL) and baseline weight Two previous phase 3 clinical trials, ViSER 1 and (75 or >75 kg). An interactive voice response system ViSER 2 (Viramidine’s Safety and Efficacy versus Rib- was used to randomize patients in a 1:1:1:1 ratio to avirin), compared a fixed dose of TBV 600 mg twice a receive weight-based TBV 20 mg/kg/day, 25 mg/kg/ day to weight-based dosing (WBD) of RBV 1000 mg/ day, or 30 mg/kg/day (Valeant Pharmaceuticals North 1200 mg (75 kg/>75 kg body weight), in combina- America, Aliso Viejo, CA) or weight-based RBV at tion with either peg-IFN alfa-2b or peg-IFN alfa-2a, 800, 1000, 1200, or 1400 mg/day (Copegus; Hoff- respectively.15,16 Both ViSER studies met the primary mann-La Roche, Nutley, NJ) in combination with safety endpoint defined as Hb < 10 g/dL or at least a peg-IFN alfa 2b (PegIntron; Schering Corp., Kenil- 2.5 g/dL decrease from baseline at any time point dur- worth, NJ). All patients received doses twice daily with ing therapy. Statistically less anemia was observed in their morning and evening meals. patients treated with TBV compared to RBV. How- Patients were treated for 48 weeks, but treatment ever, the primary efficacy endpoint of these studies—a was discontinued for evidence of nonresponse defined noninferior SVR between the TBV and RBV groups— as <2-log decline at week 12 or a positive viral load at was not achieved. Detailed subgroup analyses of the week 24. Study treatment was initiated on day 1 and data suggested the reasons for the lower SVR in TBV- clinic visits occurred at treatment weeks (TWs) 1, 2, treated patients were: fixed dose as opposed to WBD 3, 4, 8, 12, 18, 24, 30, 36, and 48, as well as post- and the selection of an inadequate dose. The present treatment follow-up weeks (FWs) 4, 12, 20, and 24. study explored several higher WBD regimens of TBV All patients who completed treatment with study drug to determine a dosage regimen that was able to deliver or discontinued treatment prematurely (except nonres- comparable responses to RBV with less anemia. ponders) immediately entered a 24-week follow-up period. Patients and Methods The study protocol was approved by the institu- tional review boards of participating institutions and Study Patients. Approximately 260 patients were was conducted in accordance with the Declaration of planned for enrollment in the study, with approxi- Helsinki and provisions of Good Clinical Practices. All mately 65 patients in each of the four treatment patients provided written informed consent. groups. Eligible patients were treatment-naive, at least Study Objective. The objective of this study was to 18 years of age, diagnosed with chronic HCV geno- select an optimal dose of TBV by comparing the effi- type 1 infection (>2000 copies/mL or >780 IU/mL), cacy and safety of three TBV dose levels versus RBV and showed histologic changes consistent with chronic based on body weight, both administered with peg- HCV as demonstrated on liver biopsy within 3 years IFN alfa-2b to therapy-naive compensated patients of screening. Patients were excluded from the study if with genotype 1 chronic hepatitis C. they had histologic evidence of cirrhosis (F4), low Hb Efficacy Assessments. The primary efficacy endpoint concentrations (men, <13 g/dL; women, <12 g/dL), was early virologic response (EVR) defined as the HEPATOLOGY, Vol. 000, No. 000, 2010 POORDAD ET AL. 3 proportion of patients with at least a 2-log decrease Pharmacokinetic Analyses. Serial plasma samples from baseline in serum HCV RNA levels at TW12.