JUMP-C: A randomized trial of mericitabine plus pegylated interferon alpha-2a/ribavirin for 24 weeks in treatment-naïve HCV genotype 1/4 patients


  • Potential conflict of interest: Paul Pockros–research support from Genentech/Roche, Vertex, Gilead, Bristol-Myers Squibb, Novartis, Abbott, Intercept, Boehringer Ingelheim, Janssen, Merck and Roche Molecular Diagnostics; consulting and advisory boards for Genentech/Roche, Vertex, Gilead, Bristol-Myers Squibb, Merck, Kadmon, Janssen and Roche Molecular Diagnostics; speaking honoraria from Genentech/Roche, Vertex and Merck. Donald Jensen–Consulting: Abbott, Bristol-Myers Squibb, Boehringer Ingelheim, Genentech/Roche, Tibotec/J&J, Astex, Biotica, Vertex, Gilead/Pharmasset, Inhibitex, Merck; Grants/contracts: research: Abbott, Bristol-Myers Squibb, Boehringer Ingelheim, Genentech/Roche, Tibotec/J&J; Other interests: Consensus Medical Communications, Clinical Care Options. Naoky Tsai–Grants: Roche, Beckman; Consulting and advisory arrangements: Roche. Speakers' bureau: Roche. Ryan Taylor–Grants: Roche; Speakers' bureau: Roche. Alnoor Ramji - Grants, consulting, advisory arrangements, and speakers' bureau: Gilead, Merck, Hoffmann, Vertex, and Janssen. Curtis Cooper–Grants: Roche, Merck, Vertex; Advisory arrangements: Roche, Merck; Speakers' bureau: Vertex. John M. Vierling–Advisory arrangements: Abbott, Bristol-Myers Squibb, Excalenz, Gilead, Globeimmune, HepQuant, Hyperion, Immuron, Janssen, Novartis, Roche, Schering (now Merck), Salix, Sundise, Vertex, HepaLife Technologies, Herbalife, Ocera; Speakers' bureau: Chronic Liver Diseases Foundation; Grants/contracts: research: Abbott, Bristol-Myers Squibb, Conatus, Excalenz, Gilead, Globeimmune, Hyperion, Idenix-Novartis, Ikaria, Intercept, Merck (formerly Schering), Mochida, Novartis, Ocera, Pfizer, Pharmasset, Roche, Sundise, Vertex, Zymogenetics. Marie Lou Munson–employee of Genentech. Ya-Chi Chen–employee of Roche. Isabel Najera–Stock ownership or equity: Roche; employee of Roche; Grants: Abbott, Bristol-Myers Squibb, Excalenz, Gilead, GlobeImmune, Hyperion, Roche, Merck, Sundise, Ocera, Vertex, Conatus, Idenix-Novartis, Ikaria, Intercept, Mochida, Novartis, Pfizer, Pharmasset, and Zymogenetics; Consulting and advisory arrangments: Abbott, Bristol-Myers Squibb, Excalenz, Gilead, GlobeImmune, Hyperion, Roche, Merck, Sundise, Ocera, Vertex, Salix, HepaLife Technologies, Herbalife, and Ocera. James Thommes–Medical Director at Genentech.

  • This research was funded by F. Hoffmann-La Roche Ltd. Support for third-party writing assistance for this manuscript was provided by F. Hoffmann-La Roche Ltd.

  • Additional JUMP-C Investigators are listed in the Appendix.

  • See Editorial on Page 488


Mericitabine is a selective nucleoside analog inhibitor of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase, with activity across all HCV genotypes. Treatment-naïve patients infected with HCV genotype 1 or 4 were randomized to 24 weeks of double-blind treatment with either mericitabine 1,000 mg (N = 81) or placebo (N = 85) twice-daily (BID) in combination with pegylated interferon alpha-2a (Peg-IFNα-2a)/ribavirin (RBV). Patients randomized to mericitabine with HCV RNA <15 IU/mL from week 4 to 22 (extended rapid virologic response; eRVR) stopped all treatment at week 24; all other patients continued Peg-IFNα-2a/RBV to complete 48 weeks of treatment. The primary efficacy endpoint was sustained virologic response (SVR; HCV RNA <15 IU/mL after 24 weeks of treatment-free follow-up). SVR was achieved in 56.8% (95% confidence interval [CI]: 45.9-67.0) of mericitabine-treated patients and 36.5% (95% CI: 27.0-47.1) of placebo-treated patients (Δ = 20.3%; 95% CI 5.5-35.2). SVR rates were higher in mericitabine- than placebo-treated patients when subdivided by IL28B genotype (CC, 77.8% versus 56.0%; non-CC, 44.1% versus 16.2%) and hepatic fibrosis (noncirrhotic, 63.3% versus 41.9%; cirrhotic, 38.1% versus 21.7%). Overall relapse rates were 27.7% and 32.0% in mericitabine- and placebo-treated patients, respectively. No evidence of NS5B S282T-variant virus or phenotypic resistance to mericitabine was observed in the one patient who experienced partial response. No S282T variants were detected in any baseline samples. The safety profile of mericitabine was similar to that of, and fewer patients in the mericitabine than in the placebo group discontinued treatment for safety reasons. Conclusion: A 24-week response-guided combination regimen of mericitabine 1,000 mg BID plus Peg-IFNα-2a/RBV is well tolerated and more effective than a standard 48-week course of Peg-IFNα-2a/RBV. (HEPATOLOGY 2013;58:514–523)


adverse events




chronic hepatitis C


confidence interval


direct-acting antiviral


extended rapid virologic response


hepatitis C virus


intention to treat


interactive voice response system


lower limit of detection


pegylated interferon alpha-2a




severe adverse events


sustained virologic response


upper limit of normal


virologic response

Treatment for chronic hepatitis C virus (HCV) infection is evolving rapidly. The first direct-acting antiviral (DAA) agents for HCV, protease inhibitors, were approved in 2011 and have changed the standard of care for patients with HCV genotype 1 infection.[1] A number of other agents from several different pharmacological classes are currently in late-phase development. The HCV protease inhibitors, boceprevir and telaprevir, significantly increase sustained virologic response (SVR) rates for patients with genotype 1 infection, including previous nonresponders to peginterferon Peg-IFN/RBV.[2] However, boceprevir and telaprevir increase the safety burden on patients.[7, 8] For example, real-life experience with telaprevir and boceprevir from an interim analysis of the French CUPIC (Compassionate Use of Protease Inhibitors in viral C Cirrhosis) study indicated that among patients with at least 16 weeks of treatment with boceprevir or telaprevir, patients with cirrhosis have higher rates of severe adverse events (SAEs; 38.4% and 48.6%, respectively) and higher rates of discontinuation as a result of SAEs (7.4% and 14.5%, respectively) than were experienced in phase III trials.[2, 9] Furthermore, boceprevir and telaprevir increase dosing complexity and are metabolized by cytochrome P450 isoenzymes, which expose patients to a large number of potentially clinically significant pharmacokinetic drug-drug interactions.10

Thus, there is an ongoing need for new agents with different pharmacological properties to optimize treatment for chronic hepatitis C (CHC). Polymerase inhibitors are drugs that inhibit the NS5B RNA-dependent RNA polymerase of HCV. Polymerase inhibitors fall into two distinctive groups: nucleoside/nucleotide inhibitors and non-nucleoside inhibitors. Nucleoside/nucleotide inhibitors are analogs of natural substrates that bind to the active site of the viral polymerase and act as RNA chain terminators. The active site of the polymerase is highly conserved[11]; thus, viruses with mutations that disrupt the function of the active site tend to be replication impaired.[12, 13] Nucleoside polymerase inhibitors are active across all HCV genotypes and, for those with a resistance profile that occurs through the S282T mutation, have a high barrier to resistance.[13]

In contrast, non-nucleoside inhibitors bind to several allosteric sites and induce conformational changes in the polymerase. The antiviral activity of non-nucleoside inhibitors is influenced by HCV genotype and subtype and these drugs vary in the extent to which they select for resistant variants.[18, 19]

Mericitabine is being evaluated in combination with Peg-IFNα-2a/RBV, with the HCV protease inhibitor, danoprevir, in a dual oral IFN-free regimen as well as in a quadruple combination regimen with Peg-IFNα-2a/RBV and danoprevir.[20]

Treatment with mericitabine plus Peg-IFNα-2a/RBV for up to 12 weeks in a phase IIb clinical trial increased on-treatment virologic response (VR) rates and was safe and well tolerated, but did not increase SVR rates, when compared with Peg-IFNα-2a/RBV.[25] The aim of the present trial (JUMP-C) was to evaluate the efficacy and safety of 24 weeks of response-guided therapy with mericitabine plus Peg-IFNα-2a/RBV in treatment-naïve patients with HCV genotype 1 or 4 infection.

Patients and Methods

Trial Design

JUMP-C was a phase IIb, randomized, double-blind, parallel-group study in treatment-naïve patients with HCV genotype 1 or 4 infection (clinicaltrials.gov NCT01057667). The study was conducted at 25 sites in the United States and Canada. The study was conducted in accord with the Declaration of Helsinki, the protocol was approved by an institutional review board, and each patient provided informed consent.


Treatment-naïve adults 18 to 70 years of age with CHC of at least 6 months' duration, a serum HCV RNA titer of at least 50,000 IU/mL (COBAS AmpliPrep/ COBAS TaqMan HCV Test; lower limit of detection [LLOD] = 15 IU/mL), and HCV genotype 1 or 4 infection were eligible for the study. Patients were required to have had a liver biopsy within the previous 24 months (36 months in patients with cirrhosis/bridging fibrosis). Patients with compensated cirrhosis (Child-Pugh grade A) or transition to cirrhosis were required to have had an abdominal ultrasound, computerized tomography scan, magnetic resonance imaging scan demonstrating the absence of evidence of hepatocellular carcinoma (within 2 months before randomization), and a serum alpha-fetoprotein level <100 ng/mL. Exclusion criteria are listed in the Supporting Appendix.


Patients were randomized in a 1:1 ratio (Fig. 1) to receive either oral mericitabine (Genentech, San Francisco, CA) 1,000 mg or matching placebo twice-daily (BID) in combination with Peg-IFNα-2a (40 kD) (PEGASYS; Roche, Basel, Switzerland) 180 μg subcutaneously once-weekly and oral RBV (COPEGUS; Roche) at a dosage of 1,000 (body weight: <75 kg) or 1,200 mg/day (body weight: ≥75 kg) in two divided doses. Mericitabine and RBV were taken together BID with food.

Figure 1.

Study design.

All patients in the mericitabine group received study treatment for 24 or 48 weeks, followed by a treatment-free period of 24 weeks. Patients with an extended rapid virologic response (eRVR), defined as undetectable HCV RNA from week 4 through 22, were assigned to complete 24 weeks of treatment with the three-drug regimen; patients without an eRVR were assigned to 48 weeks of treatment (24 weeks with the three-drug regimen followed by 24 weeks of treatment with Peg-IFNα-2a [40 kD]/RBV). All patients in the placebo control group received study treatment for 48 weeks, with a treatment-free follow-up period of 24 weeks.

Patients were required to discontinue all study treatment if they did not experience a ≥2-log10 drop in HCV RNA by week 12 or had detectable HCV RNA (COBAS AmpliPrep/COBAS TaqMan HCV Test; LLOD = 15 IU/mL) at week 24.

Patients were randomized by an interactive voice response system (IVRS). Randomization was centralized and stratified by cirrhotic status (cirrhosis/transition to cirrhosis versus no cirrhosis/transition to cirrhosis) and creatinine clearance (no more than 20% of the patients enrolled were to have an estimated creatinine clearance >70 to ≤80 mL/min calculated by Cockcroft-Gault's formula). A computer-generated randomization list was maintained by the sponsor, and neither study personnel nor investigators had access to the list. Double blinding was achieved through the use of matching placebo tablets. Investigators were advised by IVRS at week 24 as to whether a patient was to stop treatment (mericitabine-treated patients with an eRVR) or continue to week 48 (mericitabine-treated patients without an eRVR and all placebo-treated patients).

Criteria for discontinuing or modifying the treatment regimen are listed in the Supporting Appendix.

Use of hematopoietic growth factors to manage hematologic adverse events (AEs) or laboratory abnormalities was allowed, but not encouraged.


Serum HCV RNA concentration was determined at baseline and at weeks 1, 2, 4, 8, 16, 20, 22, 24, 36, 42, and 48 of treatment and at weeks 4, 12, and 24 of treatment-free follow-up using the Roche COBAS TaqMan HCV Test (detection limit: 15 IU/mL) (Roche Diagnostics, Indianapolis, IN). Investigators and patients were blinded to HCV RNA test results.

The primary efficacy endpoint was SVR defined as undetectable HCV RNA (<15 IU/mL) 24 weeks after the last dose of study medication. Other secondary efficacy endpoints included undetectable HCV RNA at weeks 4, 12, 24, 36, 48, and 60. Relapse was defined as detection of HCV RNA in a patient who had an end-of-treatment response (undetectable HCV RNA at end of treatment). Only patients with an end-of-treatment response were included in calculations of relapse.

Whole blood samples were taken from patients who consented to the optional sampling for the Roche Clinical Repository. IL28B rs12979860 genotype was determined by real-time TaqMan polymerase chain reaction and results were reported as CC and non-CC (CT and TT combined).

Drug Resistance Monitoring

Blood samples were collected for resistance monitoring from all patients. Population and clonal sequencing was performed as well as phenotypic drug susceptibility evaluation for samples from patients meeting resistance monitoring criteria, including those who experienced viral breakthrough, nonresponse, or partial response during treatment with mericitabine plus Peg-IFNα-2a/RBV. Viral breakthrough was defined as a sustained increase in HCV RNA level of >1 log10 from nadir before the end of treatment with mericitabine where nadir is ≥0.5 log10 decrease from baseline, or reversion of HCV RNA from undetectable (≥15 IU/mL) for ≥2 consecutive measurements to quantifiable (≥43 IU/mL) for ≥2 consecutive measurements. Nonresponse was defined as a decline in serum HCV RNA level of <0.5 log10 by the end of mericitabine treatment of 2 weeks' duration. Partial response was defined as a serum HCV RNA level ≥1,000 IU/mL at the end of at least 4 weeks of mericitabine dosing or an initial decline in serum HCV RNA of >0.5 log10 from baseline followed by stabilization. Baseline samples from all patients were sequenced spanning the NS5B polymerase coding region.

Safety assessments included AEs and laboratory tests. Because a renal safety signal was detected in preclinical studies in monkeys, the renal safety of mericitabine was a particular focus of the safety analysis.

Sample Size and Statistical Analysis

The study protocol did not specify any formal statistical hypothesis testing, and the planned enrollment of 80 patients per treatment group was based on convenience. Also, for 80 patients per treatment group, the 95% confidence limits are approximately ±9% to ±11% around binomial proportions observed from 20% to 50%. The 95% confidence intervals (CIs) for the individual patient VR rates were calculated by Wilson's score method without continuity correction. All patients who were randomized and who received at least one dose of study medication were included in the intention-to-treat (ITT) population. All patients who received at least one dose of study medication and had at least one postbaseline safety assessment were included in the safety analysis.

Logistic regression analyses were used to explore associations between SVR and pretreatment variables and between relapse and pretreatment variables in patients with an eRVR (see Supporting Appendix).


Patient Disposition and Baseline Characteristics

The first patient was enrolled on January 26, 2010, and the last patient completed follow-up on October 10, 2011. A total of 228 patients were enrolled and 168 randomized at 25 study centers in the United States and Canada. Of those randomized, 166 patients (98.9%) received at least one dose of study medication and were included in the ITT population (Fig. 2).

Figure 2.

Patient disposition.

A total of 59 patients (35.6%) were prematurely withdrawn during study treatment (Fig. 2). The majority of these (67.8%) were for nonsafety reasons. Discontinuations resulting from lack of efficacy were more frequent in the placebo group than in the mericitabine group (26 versus 7 patients, respectively).

Both groups were generally well balanced with regard to demographics and baseline disease characteristics (Table 1). The majority of patients were infected with HCV genotype 1a (62% in the mericitabine-treated group and 80% in the placebo group). Overall, approximately 25% of patients had transition to cirrhosis/cirrhosis at baseline (26% in the mericitabine-treated group versus 27% in the placebo group). From the subset of patients who had IL28B data available, a similar proportion of patients in each group had a non-CC IL28B genotype (65% and 60% in the mericitabine and placebo treatment groups, respectively).

Table 1. Baseline Patient Demographics and Disease Characteristics
 Mericitabine Plus Peg-IFNα-2a/RBV (N = 81)Placebo Plus Peg-IFNα-2a/RBV (N = 85)
  1. Abbreviations: SD, standard deviation; BMI, body mass index.
Male, n (%)51 (63.0)67 (78.8)
Race, n (%)  
White63 (77.8)69 (81.2)
Black10 (12.4)8 (9.4)
Other8 (9.9)8 (9.4)
Hispanic, n (%)10 (12.4)9 (10.6)
Mean age, years (± SD)49.7 (10.4)48.2 (9.8)
Mean weight, kg (± SD)82.3 (14.8)84.8 (16.0)
Mean BMI, kg/m2 (± SD)27.6 (4.2)27.7 (4.0)
Mean creatinine clearance, mL/min (± SD)116.6 (30.7)120.3 (31.7)
HCV genotype, n (%)  
1a50 (61.7)68 (80.0)
1b24 (29.6)17 (20)
1 (indeterminate)2 (2.5)0
45 (6.2)0
Mean HCV RNA, log10 IU/mL (± SD)6.6 ± 0.76.5 ± 0.6
Mean HCV RNA level, IU/mL, n (%)  
<400,0009 (11.1)6 (7.1)
400,000-<800,0002 (2.5)8 (9.4)
≥800,00070 (86.4)71 (83.5)
Fibrosis status, n (%)  
No cirrhosis60 (74.1)62 (72.9)
Cirrhosis/transition to cirrhosis21 (25.9)23 (27.1)
Host IL28B genotypeN = 52N = 62
CC, n (%)18 (34.6)25 (40.3)
Non-CC, n (%)34 (65.4)37 (59.7)


Treatment with mericitabine plus Peg-IFNα-2a/RBV was associated with consistently higher VR rates, compared to treatment with placebo plus Peg-IFNα-2a/RBV during treatment and follow-up (Fig. 3). A higher percentage of patients achieved the primary efficacy endpoint (SVR) after treatment with mericitabine than placebo (56.8%, 95% CI: 45.9-67.0, versus 36.5%, 95% CI 27.0-47.1, respectively, Δ = 20.3%, 95% CI 5.5-35.2).

Figure 3.

VR over time.

Treatment with mericitabine was also associated with consistently higher on-treatment VR rates and SVR rates when patients were grouped according to cirrhosis status (Fig. 4A) and host IL28B genotype (CC or non-CC) (Fig. 4B).

Figure 4.

VR (HCV RNA <15 IU/mL) stratified by cirrhosis status or IL28B genotype.

In a logistic regression analysis, HCV subtype (1a versus 1b) was not associated with SVR in the overall population (P = 0.953) or in the subset of patients with known host IL28B genotype (P = 0.900).

An eRVR was achieved by 49 patients (60.5%) in the mericitabine group and 11 in the placebo group (12.9%). SVR rates among these individuals were 73.5% and 100.0%, respectively, and relapse rates were 21.3% (10 of 47) and 0% (0 of 11), respectively. Among non-eRVR patients, SVR rates were 31.3% in the mericitabine group and 27.0% in the placebo group.

The overall relapse rate was 27.7% in mericitabine-treated patients and 32.0% in placebo-treated patients (Fig. 5). Among patients without cirrhosis, relapse rates were lower than in the overall study population (19.1% and 30.0% in patients treated with mericitabine and placebo, respectively), and among patients with transition to cirrhosis/cirrhosis, relapse rates were higher than in the overall population (50.0% and 40.0% in patients treated with mericitabine and placebo, respectively). The greatest difference in relapse rates was observed in patients with a non-CC host IL28B genotype, among whom relapse rates were 38.5% in mericitabine-treated patients and 62.5% in placebo-treated patients (Fig. 5). In a logistic regression analysis, older age and higher weight were the two most important factors associated with relapse in patients with an eRVR who discontinued all therapy at week 24. Further analyses indicated that neither age nor weight was associated with trough concentrations of mericitabine (data not shown).

Figure 5.

Relapse rates overall and stratified by cirrhosis status or host IL28B genotype.

Resistance Monitoring

The in vitro–identified mericitabine NS5B resistance mutation, S282T, was not detected in baseline samples from any patient (samples from 160 of 161 genotype 1 patients and 3 of 5 genotype 4 patients were successfully amplified).

A total of 31 patients met the criteria for resistance monitoring: One patient (genotype 1b) had a partial response during mericitabine therapy; 9 (5 genotype 1a and 4 genotype 1b) experienced breakthrough during treatment with Peg-IFNα-2a/RBV; 16 (9 genotype 1a, 6 genotype 1b, and 1 genotype 4) relapsed after completing 48 weeks of therapy; and 5 (4 genotype 1a and 1 genotype 1b) discontinued treatment between weeks 4 and 12.

The NS5B region was successfully sequenced in samples obtained from 30 of these 31 patients. The S282T mutation was not detected in any sample from the 30 patients. Phenotypic characterization was performed in samples from 14 patients, including the patient with a partial response while on mericitabine, 5 who experienced breakthrough during treatment with Peg-IFNα-2a/RBV, and 8 who experienced relapse. Three common nonpolymorphic amino acid changes (D61D/G, A112A/T, and D559D/N) were detected in samples obtained from these 30 patients, but none of these mutations conferred resistance to mericitabine. In the 1 patient with a partial response during treatment with mericitabine, mixtures of wild-type and mutants at residues L159F, I262V, and L320F were identified in on-treatment and follow-up samples. For each patient, the 50% effective concentration values for mericitabine in on-treatment and follow-up samples remained within 2-fold of the respective baseline samples.


The safety profile of mericitabine did not differ greatly from that of placebo. The nature and incidence of AEs and laboratory abnormalities were typical of those associated with Peg-IFNα-2a/RBV. No new safety concerns were identified. The most frequent AEs were fatigue, headache, and nausea, with a similar incidence in both treatment groups (Table 2).

Table 2. Summary of AEs and Laboratory Abnormalities
 Mericitabine Plus Peg-IFNα-2a/RBV (N = 81)Placebo Plus Peg-IFNα-2a/RBV (N = 85)
  1. aAEs that were reported in ≥20% of patients in at least one treatment group.
  2. bDefined as <60 mL/min or ≥35% decrease from baseline.
  3. cMarked increase in urine protein/creatinine ratio was defined as >1% and >200% increase from baseline; last or replicated value.
  4. Abbreviation: BUN, blood urea nitrogen.
Patients with SAEs, n (%)5 (6.2)3 (3.5%)
SAEs, n64
Incidence of individual AEs,a n (%)  
Fatigue58 (72)58 (68)
Headache42 (52)38 (45)
Nausea33 (41)34 (40)
Chills31 (38)33 (39)
Insomnia31 (38)28 (33)
Decreased appetite25 (31)22 (26)
Myalgia24 (30)24 (28)
Pyrexia20 (25)27 (32)
Irritability21 (26)25 (29)
Rash17 (21)28 (33)
Pruritus15 (19)28 (33)
Cough17 (21)22 (26)
Arthralgia18 (22)21 (25)
Dizziness19 (23)20 (24)
Diarrhea18 (22)20 (24)
Alopecia14 (17)17 (20)
Laboratory abnormalities, n (%)  
Neutrophils <0.5 × 109 cells/L1 (1)5 (6)
Hemoglobin <8.5 g/dL1 (1)1 (1)
Platelets <20 × 109 cells/L00
Lymphocytes <0.35 × 109 cells/L4 (5)4 (5)
Decreased creatinine clearanceb2 (2)1 (1)
Serum creatinine >2 × ULN1 (1)0
BUN >2 × ULN00
Urine protein/creatinine ratio ≥0.52 (2)0
Marked increase in urine protein/creatinine ratioc00
Dose modifications for AEs, n (%)  
Mericitabine4 (5)0
Peg-IFNα-2a7 (9)4 (5)
RBV15 (19)13 (15)
Dose modifications for laboratory abnormalities, n (%)  
Anemia1 (1)0
Neutropenia8 (10)9 (11)
Thrombocytopenia2 (2)3 (4)
Anemia11 (14)13 (15)
Other laboratory abnormality02 (2)

Fewer patients in the mericitabine plus Peg-IFNα-2a/RBV group discontinued treatment for safety reasons (n = 6 versus n = 13 in the placebo plus Peg-IFNα-2a/RBV group, respectively).

The incidence of Peg-IFNα-2a and RBV dose adjustments for laboratory abnormalities occurred with similar frequency in the two treatment groups (Table 2).

In total, 8 patients (4.8%) experienced SAEs: 5 patients in the mericitabine group (6.2%) and 3 in the placebo group (3.5%) (Table 2). One mericitabine-treated patient experienced a transient increase in serum creatinine to greater than 2 times the upper limit of normal (ULN) 11 weeks after the last dose of mericitabine. The abnormality was not replicated in subsequent tests and was not considered to be clinically significant.


This study demonstrates that response-guided treatment with the combination of 24 weeks of treatment with mericitabine plus Peg-IFNα-2a/RBV for 24 or 48 weeks is safe and is associated with a 20% higher SVR rate than that achieved in patients randomized to placebo plus Peg-IFNα-2a/RBV (56.8% versus 36.5%). Moreover, when compared to placebo, mericitabine produced higher SVR rates among patients, irrespective of cirrhosis status and host IL28B genotype (i.e., CC or non-CC). SVR rates were higher and relapse rates similar in patients with an IL28B CC genotype treated with mericitabine, most of whom received only 24 weeks of treatment, compared to placebo-treated patients, all of whom received 48 weeks of treatment.

VR rates at weeks 4 and 12 in the present study were similar to those reported in the PROPEL study,[25] in which mericitabine was administered for up to 12 weeks with Peg-IFNα-2a/RBV. However, SVR rates were not improved with the addition of 8 or 12 weeks of mericitabine treatment in the PROPEL study. In contrast, 24 weeks of mericitabine administered with Peg-IFNα-2a/RBV in a response-guided strategy increased SVR rates, relative to the control group, in the JUMP-C study. The difference in SVR rates can be explained by a comparative analysis of relapse rates. Among patients who received response-guided therapy with mericitabine in JUMP-C, the overall relapse rate was 28%. In contrast, the relapse rate was 52% in patients who received response-guided therapy with mericitabine at a dosage of 1,000 mg BID for 12 weeks in the PROPEL study. When the analysis is restricted to patients who achieved an eRVR and stopped all therapy at week 24 in either study, the relapse rate was lower in the present study (22%) and higher in the PROPEL study (57%).[25]

Although the overall relapse rates were similar in both the mericitabine and placebo control groups in JUMP-C, relapse rates varied by patient subgroups. Among patients treated with mericitabine, relapse rates were lowest in patients without cirrhosis (F0-F2) and in those with a host IL28B CC genotype and highest in patients with transition to cirrhosis/cirrhosis and in those with non-CC genotypes. Nonetheless, relapse rates in mericitabine-treated patients who achieved an eRVR and completed 24 weeks of treatment are higher than one might expect, when compared with the results of studies of other DAA agents that employed a response-guided therapy strategy.[3] In an attempt to explain these comparatively high relapse rates in patients who achieved an eRVR, a regression analysis was used to explore predictors of relapse. In these analyses, increased age (≥50 years) and body weight (≥85 kg) were associated with relapse in patients with an eRVR. Further analyses revealed no effect of age or weight on mericitabine exposure, suggesting that the comparatively high relapse rates in patients who achieved an eRVR are not driven by difference in exposure. However, both age and weight are known to influence the effectiveness of Peg-IFN/RBV therapy, suggesting that responsiveness to Peg-IFN strongly influences viral clearance during virologic suppression associated with mericitabine. Mericitabine-treated patients with an IL28B CC genotype had the highest end-of-treatment response rate (100%), but more than 20% of these individuals experienced virologic relapse. This phenomenon may be related to IFN responsiveness and overall treatment duration. Most of the genotype CC patients in the mericitabine-treatment group received 24 weeks of Peg-IFNα-2a/RBV therapy, whereas CC patients in the placebo group received a full 48-week course of Peg-IFNα-2a/RBV therapy, but had a similar relapse rate. This suggests that mericitabine acts primarily by inhibiting viral replication, rather than by preventing relapse.

Mericitabine was well tolerated when administered for 24 weeks in combination with Peg-IFNα-2a/RBV. The spectrum and severity of AEs was similar in the two treatment groups. No novel adverse effects were observed, and mericitabine treatment did not exacerbate any known AEs of Peg-IFNα-2a/RBV. Indeed, fewer patients discontinued treatment with mericitabine than placebo. There was also no evidence that mericitabine has an additive effect on laboratory abnormalities associated with Peg-IFNα-2a/RBV, such as neutropenia, thrombocytopenia, or anemia. Mericitabine treatment did not alter renal function, as assessed by creatinine clearance. No patients experienced a virologic breakthrough or nonresponse while on treatment with mericitabine, and no evidence of genotypic or phenotypic resistance to mericitabine was observed during the study. The variant that confers resistance to mericitabine (NS5B S282T) was not detected in any sample collected from any patient at baseline, during mericitabine treatment, during follow-on treatment with Peg-IFNα-2a/RBV, or during untreated follow-up. This is consistent with observations in other studies of mericitabine resistance.[26, 27]

Furthermore, in a study of all-oral regimens with mericitabine with danoprevir, with and without RBV, the most common resistant mutations accompanying treatment failure were associated with danoprevir (R155K, V36M/A, and D168T).[28] In that study, only 1 genotype 1a patient with treatment failure was shown to select a viral isolate with dual resistance to both mericitabine and danoprevir, containing mutations in NS5b (S282T) and NS3 (R155K).[28] Taken together, the low incidence of the S282T mutation in studies of mericitabine in all-oral regimens and in combination with Peg-IFNα-2a/RBV show that virus containing the S282T amino acid substitution has low fitness and that mericitabine has a high barrier to resistance. Preliminary data from an ongoing trial shows that the quadruple combination of mericitabine, ritonavir-boosted danoprevir, Peg-IFNα-2a, and RBV produces higher SVR12 rates and lower relapse rates than the triple combination of ritonavir-boosted danoprevir plus Peg-IFNα-2a/RBV in patients with a previous partial response to Peg-IFN/RBV.[29]

In conclusion, when administered for 24 weeks at a dosage of 1,000 mg BID as part of a response-guided combination with Peg-IFNα-2a/RBV, mericitabine produced higher SVR rates than a standard 48-week course of Peg-IFNα-2a/RBV and was extremely well tolerated, without any documented antiviral resistance. Despite these results, recent favorable results achieved with all-oral DAA combination regimens suggest that future development scenarios for mericitabine will need to include combinations with other DAA agents. The high barrier to resistance, and the good tolerability and safety profile, make mericitabine potentially useful in combination with other DAAs that have a lower barrier to resistance and may be more potent. Ongoing studies will provide data on the efficacy and safety of mericitabine in various IFN-free combinations with protease inhibitors and non-nucleoside polymerase inhibitors as well as in a quadruple combination regimen with a protease inhibitor and Peg-IFN/RBV in the most difficult-to-treat populations.


In addition to the authors, the JUMP-C Investigators include the following: F. Anderson, Liver and Intestinal Research Center, Vancouver, British Columbia, Canada; S. Arora, University of New Mexico, Albuquerque, NM; N. Bräu, James J. Peters Veterans Affair Medical Center, Bronx, NY; B. Freilich, Kansas City Research Institute, Kansas City, MO; M. Galambos, Digestive Healthcare of Georgia, Atlanta, GA; E. Godofsky, Bach and Godofsky Infectious Diseases, Bradenton, FL; I. Jacobson, Cornell University, Cornell, NY; K. Kaita, University of Manitoba, Winnipeg, Manitoba, Canada; P.Y. Kwo, Indiana University Hospital, Indianapolis, IN; S.S. Lee, University of Calgary, Calgary, Alberta, Canada; P. Marotta, London Health Sciences Center, University of Western Ontario, London, Ontario, Canada; A. Min, Beth Israel Medical Center, Boston, MA; M. Porayko, Vanderbilt University Medical Center, Nashville, TN; K.R. Reddy, University of Pennsylvania, Philadelphia, PA; R.A. Rubin, Digestive Healthcare of Georgia, Atlanta, GA; J. Strohecker, Columbia Gastroenterology Associates, Columbia, SC; E. Tam, Liver and Intestinal Research Center, Vancouver, British Columbia, Canada.