Pegylated interferon (Peg-IFN)/ribavirin (RBV) treatment produces sustained virologic response (SVR) rates of approximately 50% in patients with chronic hepatitis C virus (HCV) and was standard of care for all chronic hepatitis C (CHC) patients for a decade.[1, 2] The approval of the first HCV NS3/4A protease inhibitors (PIs), boceprevir and telaprevir, has established a new era of direct-acting antiviral (DAA) therapy for CHC. Most importantly, the combination of a PI and Peg-IFN/RBV increases SVR rates in both treatment-naïve and previously treated patients with HCV genotype (G) 1 infection. Furthermore, response-guided therapy (RGT) is possible with both of these PIs, which decreases treatment duration for many patients. These benefits have established PI-based triple therapy as the new standard of care for HCV G1 patients.[3, 9]
Although boceprevir and telaprevir have efficacy advantages over Peg-IFNα-2a/RBV therapy, new issues include cost, an increased side-effect burden, potential for rapid emergence of resistance, potential for numerous drug-drug interactions and the inconvenience of thrice-daily dosing. High rates of anemia were observed in clinical trials of both telaprevir and boceprevir, and rash was prevalent in studies of telaprevir. These adverse effects were associated with treatment discontinuation in clinical trials and have negative implications for patient acceptability and treatment compliance in practice.
Mericitabine is an investigational nucleoside analog polymerase inhibitor that terminates viral RNA chain elongation by inhibition of the HCV NS5B RNA polymerase. The active site of the NS5B polymerase is highly conserved across all HCV genotypes, offering the potential of broad cross-genotype activity.
This phase IIb clinical trial (PROPEL) was conducted to evaluate the efficacy and safety of mericitabine, together with standard doses of Peg-IFNα-2a (40 kD)/RBV for 8 or 12 weeks, followed by Peg-IFNα-2a/RBV for up to 40 weeks, in treatment-naïve patients infected with HCV G1 or G4.
These results demonstrate that the combination of mericitabine plus Peg-IFNα-2a/RBV produces rapid suppression of HCV replication in patients with HCV G1 or G4 infection that is maintained throughout mericitabine treatment. High RVR rates were observed across all mericitabine treatment arms without any evidence of viral breakthrough or resistance to mericitabine. Over 80% of patients assigned to 12 weeks of treatment with mericitabine had undetectable HCV RNA levels at week 12, and among those assigned to a mericitabine dosage of 1,000 mg BID, the eRVR rate exceeded 50%.
Mericitabine produced consistently high VRs at weeks 4 and 12 of combination therapy, regardless of the extent of baseline fibrosis or host IL28B genotype. Indeed, approximately 50% of patients with cirrhosis or a non-CC genotype achieved an RVR after 4 weeks of treatment with mericitabine 1,000 mg BID plus Peg-IFNα-2a/RBV. In comparison, fewer than 10% of such patients achieved an RVR when treated with Peg-IFNα-2a/RBV in the control arm. These findings demonstrate that mericitabine has good activity in patients with difficult-to-cure characteristics and overrides, to some extent, the negative impact of advanced fibrosis and IL28B genotype on the activity of Peg-IFN.
Although mericitabine increased on-treatment RVR and eRVR rates, compared to the placebo arm, VRs were not maintained after discontinuation of mericitabine at weeks 8 or 12 in study arms A-D. Moreover, VRs increased over time in the placebo control arm such that VRs were similar in all five treatment groups at week 24 and at the end of all therapy.
Mericitabine had a favorable safety profile and was well tolerated in the present study. The AE burden associated with Peg-IFNα-2a/RBV was not increased by the addition of mericitabine. The number of AEs was similar across the study arms. Importantly, renal function did not appear to be altered during or after 12 weeks of mericitabine therapy. Two patients experienced increases in serum creatinine, with an accompanying decrease in creatinine clearance during the trial. Only one of these occurred during treatment with mericitabine, but the increase was not sustained and all other serum creatinine measurements in this patient were in the order of the patient's pretreatment sample. In the second patient, an increase in serum creatinine occurred 12 weeks after completion of mericitabine.
Mericitabine demonstrated a high barrier to resistance. Viral breakthrough was not observed during mericitabine therapy and partial responses occurred predominantly among patients receiving low-dose or 8-week mericitabine therapy. Only 1 patient assigned to mericitabine 1,000 mg BID for 12 weeks experienced a partial response. The in vitro–identified NS5B S282T resistance mutation was not detected in any baseline or on-treatment samples collected from any patient with breakthrough or partial response during mericitabine therapy, breakthrough during Peg-IFNα-2a/RBV therapy, or relapse after the end of therapy. There was wide variation in SVR and relapse rates across arms A-D overall and especially in the subgroups of patients with difficult-to-cure characteristics (cirrhosis and non-CC IL28B genotype). However, the wide variation in SVR and relapse rates across groups A-D cannot be explained on the basis of PK variability, because PK data show that mean exposure to the parent drug (RO4995855) at week 4 was consistent across the mericitabine 1,000 mg dosage groups (arms B-D) and was approximately twice that in the mericitabine 500 mg dosage group (arm A). A more plausible explanation for these SVR differences between mericitabine arms includes the variation in dose and duration of mericitabine between treatment groups and the utilization of a RGT strategy in selected arms.
When the trial was designed, it was expected that higher on-treatment VRs achieved during the first 12 weeks of treatment would translate into higher SVR rates. However, early VRs were frequently lost after cessation of 12 weeks of mericitabine treatment. The final SVR-24 rates in arm D and in the placebo control arm (E) were 51%. Relapse rates in these two groups were also very similar (approximately 30%). These were the only two treatment groups in which all patients received a total duration of 48 weeks of treatment with Peg-IFNα-2a/RBV. An RGT strategy was evaluated in arms A-C. The pattern of SVR and relapse rates in these groups is a reflection of the dose and duration of treatment with mericitabine, resulting eRVR rates, and number of patients with an eRVR who were assigned to abbreviated therapy. The higher dose of mericitabine (1,000 mg) produced a higher eRVR rate in groups B (53.1%) and C (59.8%) than the lower dose (500 mg) used in group A (38.8%). Similarly, longer duration of treatment with mericitabine in arm C (12 weeks) produced a higher eRVR rate in group C than shorter duration of treatment (8 weeks) in group B. The higher eRVR rate in group C resulted in a higher proportion of patients being assigned to abbreviated treatment (24 weeks) than in groups A or B. The abbreviated regimen was insufficient to sustain an off-treatment response (SVR) in many patients, especially those with difficult-to-cure characteristics, such as cirrhosis or a non-CC genotype. Virologic breakthrough was observed in some patients during dual Peg-IFNα-2a/RBV therapy after completion of mericitabine therapy. Collectively, these observations can explain the progressively lower overall SVR rates and progressively higher relapse rates in groups A, B, and C, when compared to group D, and the generally poor performance of these regimens in patients with difficult-to-cure characteristics.
The lack of correlation between on-treatment VR and SVR is puzzling, given the consistently high barrier to resistance shown by mericitabine. Mericitabine is a prodrug that is converted to a pyrimidine (cytidine) nucleoside analog, which, in turn, is taken up by hepatocytes and sequentially phosphorylated to form the active chain terminator. When given as monotherapy, mericitabine is associated with a relatively slow first-phase decline in HCV RNA that extends throughout at least 14 days, likely because the first phosphorylation step is thought to be rate limiting in the production of the active triphosphate species. This slow onset of activation as the triphosphate may explain the lack of sustained efficacy observed with only 12 weeks of mericitabine therapy in this trial. Indeed, another investigational pyrimidine nucleotide analog inhibitor (sofosbuvir), that is formulated as a uridine monophosphate, bypasses the first phosphorylation reaction and has been shown to have more-rapid early-phase kinetics and produce high SVR rates (90%) when administered for 12 weeks together with Peg-IFNα-2a/RBV.
If the rate of activation of mericitabine is critical to achieving an SVR, then one might expect longer treatment durations to offset the slower onset of action of the drug and to be more efficacious. Indeed, a significant increase in SVR-24, compared to a control group, was observed when mericitabine was administered with Peg-IFNα-2a/RBV for 24 weeks in JUMP-C. This result is particularly striking, because more than 60% of mericitabine-treated patients in JUMP-C stopped all treatment after only 24 weeks, compared to the control group, in which all patients received 48 weeks of treatment with Peg-IFNα-2a (40 kD) plus RBV alone.
One potential limitation of this study is the lack of stratification by HCV G1 subtype (1a, 1b) and the lack of evaluation of VRs by HCV G1 subtype. SVR rates have been shown to be higher in patients infected with HCV G1b than G1a when treated with a PI-containing regimen, likely because of differences in the barrier to resistance between these two subtypes. However, this does not appear to be an issue that affects mericitabine treatment, because SVR rates did not differ by HCV G1 subtype in JUMP-C, where patients received mericitabine plus Peg-IFNα-2a/RBV for 24 weeks.
In conclusion, the results of this study demonstrate that the combination of mericitabine plus Peg-IFNα-2a/RBV increases on-treatment VRs and has a high barrier to resistance and a favorable safety and tolerability profile in treatment-naïve patients with HCV G1 or G4 infection. However, when dosed at 1,000 mg BID for 12 weeks in combination with a 48-week Peg-IFNα-2a/RBV regimen, mericitabine did not increase SVR rates or decrease relapse rates.
In addition to the authors, the PROPEL Investigators include the following: K. Agarwal, Institute of Liver Studies, King's College Hospital, London, UK; P. Andreone, University of Bologna, Bologna, Italy; Y. Benhamou, Hôpital Pitié Salpétrière, Paris, France; T. Berg, Sektion Hepatologie, Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Universitätsklinikum Leipzig, Leipzig, Germany; J. Bloomer, University of Alabama at Birmingham, Birmingham, AL; J.-P. Bronowicki, INSERM U954, Centre Hospitalier Universitaire de Nancy, Université de Lorraine, Lorraine, France; M.R. Brunetto, Azienda Ospedaliero Universitaria Pisana, Pisana, Italy; S. Bruno, Internal Medicine and Liver Unit, Azienda Ospedaliera Fatebenefratelli e Oftalmico, Milano, Italy; J.L. Calleja, Hospital Universitario Puerta de Hierro, Madrid, Spain; M.A. Castro Iglesias, Hospital Universitario de A Coruña, A Coruña, Spain; W. Cheng, Royal Perth Hospital, Perth, Australia; A. Ciancio, Azienda Ospedaliera San Giovanni, Rome, Italy; V. Clark, Shands at the University of Florida, Gainesville, FL; D. Crawford, The University of Queensland, Greenslopes Hospital, Brisbane, Australia; V. de Lédinghen, Haut Lévêque Hospital, University Hospital of Bordeaux, Bordeaux, France; P. Desmond, St Vincent's Hospital, Melbourne, Australia; M. Diago, Hospital General De Valencia, Valencia, Spain; N. Dikopoulos, Universitaetsklinik Ulm, Ulm, Germany; B. Freilich, Kansas City Research Institute, Kansas City, KS; E. Godofsky, Bach and Godofsky Infectious Diseases, Bradenton, FL; T. Hassanein, University of California, San Diego Medical Center, San Diego, CA; C. Hézode, Hôpital Henri Mondor, Université Paris-Est, Créteil, Paris, France; I. Jacobson, Cornell University, New York, NY; D.M. Klass, Universitaetsklinik Ulm, Ulm, Germany; A. Kuo, University of California, San Diego Medical Center, San Diego, CA; S.S. Lee, University of Calgary, Calgary, Alberta, Canada; B. Leggett, Royal Brisbane and Women's Hosptial, University of Queensland, Brisbane, Australia; G.A. Macdonald, Princess Alexandra Hospital, Queensland, Australia; G. MacQuillan, Sir Charles Gairdner Hospital, University of Western Australia, Perth, Australia; P. Marotta, London Health Sciences Center, University of Western Ontario, London, Ontario, Canada; R. Planas Vila, Hospital Germans Trias i Pujol, CIBERehd, Barcelona, Spain; S. Pol, Université Paris Descartes; APHP, Unité d'Hépatologie, Hôpital Cochin; INSERM U-1016, Institut Cochin, Paris, France; A. Ramji, University of British Columbia, Vancouver, British Columbia, Canada; J.W.F. Rasenack, Universitätsklinikum Freiburg, Freiburg, Germany; V. Ratziu, Hôpital Pitié Salpétrière, Paris, France; S. Roberts, Department of Medicine, Monash University, Alfred Hosptial, Melbourne, Australia; M. Romero-Gómez, Hospital Universitario Nuestra Señora de Valme, Sevilla, Spain; W. Rosenberg, UCL Institute of Liver and Digestive Health, Division of Medicine, University College London, London, UK; L. Rossaro, University of California Davis Medical Center, Sacramento, CA; F.J. Salmeron, Hospital Clinico De Granada, Granada, Spain; J.M. Sánchez-Tapias, Hospital Clínic, Barcelona, Spain; A.J. Sanyal, McGuire VA Medical Center and Virginia Commonwealth University School of Medicine, Richmond, VA; A. Scuteri, Università Degli Studi Di Bologna, Bologna, Italy; T. Sepe, Thomas E. Sepe, MD, Inc., Providence, RI; A. Sheikh, Gastrointestinal Specialists of Georgia, Marietta, GA; M. Sherman, Toronto General Hospital, Toronto, Ontario, Canada; G.L. Simon, George Washington University Medical Center, Washington, DC; J. Slim, Saint Michael's Medical Center, Newark, NJ; J.P. Smith, The Penn State Hershey Medical Center, Hershey, PA; R. Solà, Hospital del Mar, IMIM, Universitat Autónoma de Barcelona, Barcelona, Spain; S.I. Strasser, Royal Prince Alfred Hospital, Sydney, Australia; J. Strohecker, Columbia Gastroenterology Associates, Columbia, SC; M. Sulkowski, Johns Hopkins University School of Medicine, Baltimore, MD; A. Tran, Hôpital de L'Archet, Nice, France; B. Willems, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada; E. Yoshida, University of British Columbia, Vancouver, British Columbia, Canada; R. Zachoval, Ludwig-Maximilians Universität Munich, Munich, Germany; J.-P. Zarski, Hôpital Albert Michallon, Grenoble, France.