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Abstract

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Appendix
  7. References
  8. Supporting Information

Mericitabine is a nucleoside analog polymerase inhibitor of hepatitis C virus (HCV). Treatment-naïve HCV genotype 1 or 4 patients were randomized to double-blind treatment with oral mericitabine at a dosage of 500 mg twice-daily (BID) for 12 weeks (A), 1,000 mg BID for 8 (B) or 12 weeks (C and D), or placebo BID for 12 weeks (E). All patients received pegylated interferon alpha-2a (Peg-IFNα-2a; 40 kD)/ribavirin (RBV) at standard doses for 24 or 48 weeks during and after mericitabine/placebo therapy. Patients in arms A-C who maintained a virologic response (VR) (HCV RNA <15 IU/mL) from weeks 4 to 22 stopped all treatment at week 24; all other patients (arms A-E) continued Peg-IFNα-2a/RBV to complete 48 weeks. The primary outcome was sustained VR (SVR) (HCV RNA <15 IU/mL after 24 weeks of untreated follow-up; SVR-24). VR rates were higher in arms A-D than in arm E at weeks 4 and 12 overall, in patients with and without cirrhosis and in patients with CC and non-CC IL28B genotypes. However, the overall SVR-24 rate in arms D (50.6%) and E (placebo, 51.2%) was similar and those in the response-guided therapy arms A, B, and C were lower (48.8%, 42.0%, and 32.9%, respectively). No viral breakthrough or mericitabine-resistance mutations (S282T) were observed during mericitabine therapy. Conclusion: Treatment with mericitabine plus Peg-IFNα-2a/RBV for 8 or 12 weeks provided potent suppression of HCV RNA, was well tolerated, and did not select resistant variants, but did not increase SVR rates, compared to placebo. IFN-free and IFN-containing trials of mericitabine of longer treatment duration are ongoing. (HEPATOLOGY 2013;58:524–537)

Abbreviations
AE

adverse event

BID

twice-daily

CHC

chronic hepatitis C

DAA

direct-acting antiviral

EC50

half-maximal effective concentration

eRVR

extended rapid virologic response

G

genotype

HCV

hepatitis C virus

ITT

intention to treat

LLOQ

lower limit of quantitation

Peg-IFNα-2a

pegylated interferon alpha-2a

PI

protease inhibitor

PK

pharmacokinetics

RBV

ribavirin

RGT

response-guided therapy

RVR

rapid virologic response

SVR

sustained virologic response

SVR-24

SVR after 24 weeks of untreated follow-up

VR

virologic response

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.[3] 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.[4] 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.[3] High rates of anemia were observed in clinical trials of both telaprevir and boceprevir, and rash was prevalent in studies of telaprevir.[4] These adverse effects were associated with treatment discontinuation in clinical trials and have negative implications for patient acceptability and treatment compliance in practice.[4]

Mericitabine is an investigational nucleoside analog polymerase inhibitor that terminates viral RNA chain elongation by inhibition of the HCV NS5B RNA polymerase.[10] The active site of the NS5B polymerase is highly conserved across all HCV genotypes, offering the potential of broad cross-genotype activity.[11]

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.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Appendix
  7. References
  8. Supporting Information
Trial Design

PROPEL, a phase IIb randomized, double-blind, active-controlled, parallel-group study, took place at 65 sites in North America, Europe, and Australia (http://www.clinicaltrials.gov. NCT00869661; funded by F. Hoffmann-La Roche Ltd). The study was conducted in accord with the Declaration of Helsinki, the protocol was approved by all institutional review boards at participating sites, and each patient provided informed consent.

Patients

Eligible participants were treatment-naïve males and females 18-65 years of age with HCV G1 or G4 infection of at least 6 months' duration, serum HCV RNA level of at least 50,000 IU/mL, liver biopsy consistent with CHC within 24 calendar months of first dose (36 months for patients with cirrhosis or incomplete/transition to cirrhosis, fibrosis stage 3-4), and no concomitant infection with hepatitis A or B viruses or human immunodeficiency virus. (Further details on eligibility and exclusion criteria provided in the Supporting Information.)

Patients were recruited in two cohorts: Cohort 1 included the first 100 enrolled patients, with a vanguard of 25 patients reaching week 4 of treatment before the remaining 75 patients were enrolled. Once all patients in cohort 1 reached week 12 of treatment, the data monitoring committee approved enrollment of the remainder of the study population (cohort 2; n = 324).

Treatment

Patients were randomized to double-blind treatment with mericitabine (Genentech, South San Francisco, CA) at 500 or 1,000 mg orally twice-daily (BID) or matching placebo together with Peg-IFNα-2a (PEGASYS; Roche, Basel, Switzerland) 180 μg subcutaneously once-weekly and oral RBV (COPEGUS; Roche) at a dosage of 1,000 mg (body weight: <75 kg) or 1,200 mg (body weight: ≥75 kg) daily in two divided doses (morning and evening) (Fig. 1). Mericitabine and RBV were taken together BID (morning and evening) with food (within 15 minutes before or within 1 hour after a meal). All patients were to receive study treatment for 24-48 weeks, with treatment-free follow-up of 24 weeks (Fig. 1). Patients in arms A, B, and C who achieved a rapid virologic response (RVR; defined as undetectable HCV RNA at week 4) and had undetectable HCV RNA through week 22 (extended RVR; eRVR) stopped all treatment at week 24. This applied to patients with and without cirrhosis. Patients without an eRVR received Peg-IFNα-2a/RBV for a total duration of 48 weeks.

image

Figure 1. Study design.

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Randomization was stratified by geographical region. The randomization sequence was generated centrally by the sponsor and incorporated into double-blind labeling. See the Supporting Information for further details on randomization.

Patients who did not demonstrate virologic response (VR) by week 12 (VR defined as ≥2 log10 reduction in HCV RNA from baseline) or who had detectable HCV RNA at week 24 were required to discontinue treatment. Mericitabine was discontinued subsequent to any serious adverse event (AE), development of treatment-emergent renal abnormalities, sustained hypertension, progressive rash of moderate intensity or greater, any confirmed clinically significant grade 4 laboratory abnormality, or a confirmed lymphocyte count <350 cells/mm3.

Investigators were allowed to make dose adjustments according to protocol-specified criteria for adverse effects considered possibly related to Peg-IFNα-2a or RBV, including laboratory abnormalities and changes in vital signs.

Outcomes

Serum HCV RNA concentration was determined at baseline and at weeks 1, 2, 4, 6, 8, 10, 12, 14, 18, 24, 30, 36, 42, and 48 of treatment and at weeks 4, 12, and 24 of follow-up. HCV RNA was extracted using the Roche COBAS AmpliPrep (CAP) and analyzed with the Roche COBAS TaqMan HCV Test version 1.0 (lower limit of detection: 15 IU/mL; lower limit of quantification [LLOQ]: 43 IU/mL) (Roche Diagnostics, Indianapolis, IN). The primary outcome was SVR, defined as undetectable HCV RNA 24 weeks after the last dose of study medication. Patients without HCV RNA measurements at the end of the 24-week treatment-free follow-up period were considered nonresponders.

Secondary efficacy endpoints included VRs (defined as HCV RNA <15 IU/mL) at clinic visits and at the last dose of study medication (end of treatment) as well as relapse (defined as detection of HCV RNA in a patient who had an end-of-treatment response [HCV RNA undetectable at end of treatment]). Only patients with an end-of-treatment response were included in calculations of relapse.

Patients were assessed at baseline before treatment, with subsequent assessments at weeks 1 and 2 and biweekly thereafter during treatment. Follow-up visits took place 4, 12, and 24 weeks after the last dose of study medication. Assessments included AE, laboratory tests, electrocardiogram readings, and monitoring for ophthalmological events. 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. Samples for pharmacokinetics (PK) and resistance monitoring were obtained at scheduled time points during the study.

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

Samples from patients who experienced viral breakthrough, nonresponse, or partial response during treatment with mericitabine plus Peg-IFNα-2a/RBV or relapse were evaluated genotypically by sequencing and phenotypically by drug-susceptibility testing. Viral breakthrough was defined as a sustained increase in HCV RNA level of ≥1 log10 above nadir before the end of treatment with mericitabine (≥2 consecutive measurements), where nadir was a ≥0.5 log10 decrease from baseline, or where HCV RNA becomes quantifiable (≥43 IU/mL; ≥2 consecutive measurements) having been previously undetectable (<15 IU/mL; ≥2 consecutive measurements). Nonresponse was defined as a decline in serum HCV RNA level of <0.5 log10 after 2 weeks of mericitabine treatment. Partial response was defined as an initial decline in serum HCV RNA of ≥0.5 log10 from baseline, followed by stabilization (>2 consecutive viral load measurements within 0.5 log10 of nadir), while on mericitabine treatment and/or serum HCV RNA level ≥1,000 IU/mL at the end of mericitabine dosing of at least 4 weeks' duration.

PK

Exposure to RO4995855 (parent drug of mericitabine) was determined at week 4 of treatment. Plasma samples were collected from a subset of patients at 0.5 hours predose and at 0.5, 1, 2, 3, 4, 6-8, and 12 hours postdose (before the evening dose of mericitabine and RBV) at week 4. Plasma concentrations of RO4995855 were determined by a validated liquid chromatography/tandem mass spectrometry method (PharmaNet USA, Inc., Princeton, NJ). The LLOQ for RO4995855 was 10.0 ng/mL. Plasma concentration data were analyzed by noncompartmental methods using WinNonlin (Professional version 5.2.1; Pharsight Corporation, Mountain View, CA). The maximum observed plasma concentration (Cmax) and the area under the plasma concentration-time curve from 0 to the end of the dosing interval (AUCtau) were calculated for each patient.

Statistical Analyses

No formal statistical hypothesis testing was performed; therefore, sample size per treatment group was not derived to control the probability of type I error or to provide sufficient statistical power. Further details of statistical methods are provided in the Supporting Information.

All randomized patients and those who received at least one dose of study medication comprised 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 comprised the safety population.

Subgroup analyses of efficacy and safety data stratified by pretreatment fibrosis stage were conducted. An ad-hoc exploratory analysis of efficacy stratified by IL28B status was performed for patients who participated in biomarker sampling procedures.

Results

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Appendix
  7. References
  8. Supporting Information
Patient Disposition and Baseline Characteristics

The first patient was screened in March 2009, and the last patient completed follow-up in July 2011. A total of 621 patients were screened, 424 were randomized, and 408 received at least one dose of study medication and were included in the ITT population (407 patients had a postbaseline safety assessment and comprised the safety population) (Fig. 2).

image

Figure 2. Patient disposition.

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One hundred and thirty-nine patients (34.1%) prematurely withdrew from the study during treatment (Fig. 2). The majority of these patients (n = 116; 83.5%) withdrew for nonsafety reasons. The most common reason for withdrawal was lack of efficacy (n = 87 of 116; 75.0%). All such withdrawals for futility occurred after the end of mericitabine/placebo treatment at week 12. Overall, 22 patients refused treatment, with the majority (n = 11) randomized to arm D.

Study arms were generally well balanced with no major disparity between mericitabine and placebo groups (Table 1). Overall, the majority of patients were male (56%-71%), white (85%-89%), and infected with HCV G1a (55%-69%). Within each arm the majority of patients were without cirrhosis (72%-79%), and approximately 10% of patients had stage F4 fibrosis. Among the subset of patients in whom the host IL28B genotype was determined, the majority had a non-CC genotype (69%-80%).

Table 1. Baseline Patient Demographics and Disease Characteristics
 A MCB 500 mg 12 weeks RVR-guided N = 80B MCB 1,000 mg 8 weeks RVR-guided N = 81C MCB 1,000 mg 12 weeks RVR-guided N = 82D MCB 1,000 mg 12 weeks Non-RVR-guided N = 81E Placebo Plus Peg-IFNα-2a/RBV 48 weeks N = 84
  1. Abbreviations: MCB, mericitabine; SD, standard deviation; BMI, body mass index; ALT, alanine transaminase.

Male, n (%)45 (56)48 (59)58 (71)53 (65)51 (61)
Race, n (%)     
White70 (88)69 (85)70 (85)71 (88)75 (89)
Black8 (10)9 (11)9 (11)6 (7)3 (4)
Other2 (3)3 (4)3 (4)4 (5)6 (7)
Hispanic, n (%)8 (10)5 (6)6 (7)7 (9)9 (11)
Mean age, years (range)47 (18-62)47 (23-62)47 (21-65)48 (23-60)48 (22-65)
Mean weight, kg (± SD)81.1 (15.2)79.1 (13.9)77.3 (12.3)79.6 (13.6)77.8 (14.6)
Mean BMI, kg/m2 (± SD)27.9 (4.3)27.1 (4.0)26.1 (3.8)26.9 (3.8)26.2 (3.9)
Median creatinine clearance, mL/min (range)115.0 (71.0-205.0)110.0 (75.0-318.0)113.0 (51.0-244.0)117.0 (80.0-172.0)115.5 (64.0-218.0)
HCV genotype, n (%)     
1a44 (55)51 (63)50 (61)56 (69)52 (62)
1b28 (35)26 (32)26 (32)22 (27)25 (30)
48 (10)4 (5)6 (7)3 (4)7 (8)
Mean HCV RNA, log10 IU/mL (± SD)6.4 (0.7)6.4 (0.7)6.5 (0.5)6.5 (0.6)6.4 (0.7)
Mean HCV RNA level, IU/mL, n (%)     
<400,00010 (13)12 (15)3 (4)7 (9)13 (15)
400,000-<800,0003 (4)6 (7)6 (7)6 (7)5 (6)
≥800,00067 (84)63 (78)73 (89)68 (84)66 (79)
Mean ALT, U/L (± SD)112.4 (83.8)105.4 (67.4)104.6 (63.7)109.9 (85.6)123.2 (126.7)
Cirrhosis or incomplete/transition to cirrhosis17 (21)18 (22)18 (22)23 (28)19 (23)
Noncirrhotic63 (79)63 (78)64 (78)58 (72)65 (77)
Fibrosis stage, n (%)     
F38 (10)11 (14)9 (11)14 (17)11 (13)
F49 (11)7 (9)9 (11)8 (10)8 (10)
 N = 49N = 49N = 46N = 55N = 46
Host IL28B genotype     
CC, n (%)15 (31)12 (24)13 (28)11 (20)12 (26)
Non-CC, n (%)34 (69)37 (76)33 (72)44 (80)34 (74)
Efficacy

Across all mericitabine-treatment arms (A-D), VRs ranged from 38.8% to 63.0% at week 4 and from 67.9% to 86.6% at week 12. In comparison, VRs were lower at weeks 4 (17.9%) and 12 (48.8%) in the placebo control group (Fig. 3). At week 24, the VRs ranged from 70.4% to 76.3% across mericitabine treatment arms and was 72.6% in the placebo arm.

image

Figure 3. Overall VR and relapse rates.

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The SVR-24 (SVR after 24 weeks of untreated follow-up) rate was 50.6% in arm D among patients who received mericitabine 1,000 mg BID for 12 weeks followed by 36 weeks of treatment with Peg-IFNα-2a/RBV and was 51.2% in the placebo control arm (Fig. 3). Relapse rates were 29.3% (arm D) and 31.1% (placebo control arm).

eRVR was achieved by 59.8% and 56.8% of patients randomized to 12 weeks of treatment with mericitabine 1,000 mg BID in arms C and D, respectively. eRVR rate was lower in patients randomized to a lower dose of mericitabine in arm A (38.8%) or a shorter duration of mericitabine treatment in arm B (53.1%). In contrast, the eRVR rate was 17.9% in the placebo control group.

Overall, SVR-24 rates in the RGT arms (A-C) ranged from 32.9% to 48.8% and overall relapse rates ranged from 33.9% to 51.8% (Fig. 3). SVR-24 rates among patients who achieved an eRVR and discontinued treatment at week 24 in arms A, B, and C were 61.3%, 62.8%, and 40.8%, respectively, which were higher than those in patients who did not achieve an eRVR and received 48 weeks of treatment (40.8%, 18.4%, and 21.2%, respectively). Relapse rates among patients who achieved an eRVR and discontinued treatment at week 24 in arms A, B, and C were 36.7%, 37.2%, and 57.4%. In comparison, relapse rates among patients who did not achieve an eRVR and who were assigned to 48 weeks of treatment were 31.0%, 41.7%, and 22.2%, respectively.

The pattern of VR rates in patients without and with cirrhosis were consistent with overall results. In both subgroups, VRs at weeks 4 and 12 were higher in each of the mericitabine treatment arms than in the placebo arm (Fig. 4A,B). Among patients treated with mericitabine 1,000 mg/day in arms B, C, and D, 64.1%-69.0% of patients without cirrhosis and 47.8%-55.6% of patients with cirrhosis achieved an RVR at week 4. In contrast, an RVR was achieved by 21.5% of patients without cirrhosis and 5.3% of patients with cirrhosis in the placebo control arm.

image

Figure 4. VR and relapse rates in patients without cirrhosis (A) and (B) patients with cirrhosis.

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SVR-24 rates in patients without and with cirrhosis treated with mericitabine 1,000 mg in arm D were 56.9% and 30.4%, respectively, and 46.2% and 47.4%, respectively, in the placebo control arm (Fig. 4A,B). Relapse rates in patients without and with cirrhosis were 26.1% and 41.7%, respectively, in group D and 31.3% and 30.8%, respectively, in the placebo control arm.

IL28B genotype was available for 245 of 408 patients (60.0%; Table 1). Among patients treated with mericitabine 1,000 mg BID in arms B, C, and D, an RVR was achieved by 83.3%-100% of CC patients (Fig. 5A) and 45.9%-54.5% of non-CC patients (Fig. 5B). In comparison, an RVR was achieved by 25.0% and 8.8% of CC and non-CC patients, respectively, in the placebo control arm.

image

Figure 5. VR and relapse rates by IL28B genotype: CC (A) and non-CC (B).

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SVR-24 and relapse rates in arm D were 90.9% and 0% among CC patients (Fig. 5A) and 29.5% and 51.9% among non-CC patients (Fig. 5B). In comparison, SVR-24 and relapse rates in the placebo control arm were 58.3% and 41.7% among CC patients (Fig. 5A) and 41.2% and 36.4% among non-CC patients (Fig. 5B). Patients treated with mericitabine in the RGT arms (B and C) had lower SVR rates and higher relapse rates than patients in arm D. This reflects the shorter duration of therapy in patients with an eRVR in arms B and C.

Of 21 G4 patients randomized to treatment with mericitabine in arms A-D, 14 achieved an SVR, including 7 of 9 patients who received mericitabine 1,000 mg BID for 12 weeks in arms C and D. In addition, 3 of 7 G4 patients in the placebo control arm achieved an SVR.

PK

Mean exposure to RO4995855 (Cmax and AUCtau) at week 4 was comparable in patients treated with mericitabine 1,000 mg BID in arms B, C, and D and was slightly less than 2-fold greater in the pooled group of patients treated with mericitabine 1,000 mg BID than in those treated with 500 mg BID in arm A (see Supporting Table 1).

Resistance Monitoring

No patient experienced viral breakthrough during treatment with mericitabine plus Peg-IFNα-2a/RBV. Eleven patients with HCV G1 infection experienced a partial response with an HCV RNA level above 1,000 IU/mL at the end of mericitabine treatment (5 who received mericitabine 500 mg twice for 12 weeks, 5 who received mericitabine 1,000 mg BID for 8 weeks, and 1 who was treated with mericitabine 1,000 mg BID for 12 weeks). Sequence analysis of the entire NS5B coding region in these 11 patients did not detect the S282T mutation or other common amino acid changes that could be involved with resistance to mericitabine. Moreover, there was also no increase in the half-maximal effective concentration (EC50) of mericitabine in on-treatment samples, compared with baseline samples.

Fifty-six patients experienced viral breakthrough after discontinuation of mericitabine and during ongoing Peg-IFNα-2a/RBV therapy (6 of these patients were partial responders during mericitabine treatment). Sequencing data for 35 of 56 patients showed no S282T mutation or any common amino acid changes across patients. Phenotypic analysis of samples from 6 of 56 patients showed no evidence of an increase in EC50 value of mericitabine over baseline.

In total, 88 patients relapsed after end of treatment, and sequencing analysis was performed on samples from 44 of these patients. Once again, neither the S282T mutation nor any common amino acid changes across patients were detected and there was no increase in EC50 value of mericitabine over baseline in 21 patients whose samples underwent phenotypic analysis.

Safety

The safety profile of patients in the mericitabine-containing arms did not differ substantially from patients who received placebo, and no new safety concerns were identified. The most frequent AEs in each treatment group were headache and fatigue (Table 2). AEs occurred with a similar incidence across all treatment. Laboratory findings for hematologic and renal parameters were generally similar across treatment groups (Table 3) as was mean serum creatinine and creatinine clearance (Supporting Figs. 1 and 2). Two patients in arm C had isolated marked increases in serum creatinine and marked decreases in creatinine clearance. A 49-year-old male patient had a serum creatinine value of 203 μmol/L at study week 2 (estimated creatinine clearance: 43 mL/min). All other values before and after this time point ranged from 71 to 80 μmol/L. A 54-year-old male patient had a serum creatinine value of 327 μmol/L (estimated creatinine clearance: 28 mL/min) at study week 24, at which point Peg-IFNα-2a/RBV treatment was stopped. Serum creatinine declined in this individual and was 115 μmol/L at the end of follow-up, with an estimated creatinine clearance of 75 mL/min.

Table 2. Summary of AEs
 A MCB 500 mg 12 weeks RVR-guided N = 79B MCB 1,000 mg 8 weeks RVR-guided N = 81C MCB 1,000 mg 12 weeks RVR-guided N = 82D MCB 1,000 mg 12 weeks Non-RVR-guided N = 81E Placebo Plus Peg-IFNα-2a/RBV 48 weeks N = 84
  1. Abbreviations: AE, adverse event; MCB, mericitabine; SAE, serious adverse event.

Patients with at least one AE, n (%)79 (100)81 (100)80 (98)81 (100)84 (100)
Mild78 (99)79 (97)76 (93)76 (94)82 (98)
Moderate52 (66)51 (63)58 (71)60 (74)65 (76)
Severe5 (6)8 (10)12 (15)11 (14)8 (10)
Life-threatening1 (1)1 (1)2 (2)1 (1)4 (5)
Patients with at least one SAE, n (%)5 (6)6 (7)9 (11)5 (6)7 (8)
Patients with AEs leading to withdrawal of study drug, n (%)     
MCB/placebo1 (1)3 (4)1 (1)4 (5)5 (6)
Peg-IFNα-2a3 (4)2 (2)2 (2)9 (11)7 (8)
RBV3 (4)2 (2)2 (2)9 (11)7 (8)
AEs occurring in ≥20% of patients, n (%)
Headache44 (56)41 (51)43 (52)42 (52)43 (51)
Fatigue36 (46)39 (48)30 (37)39 (48)45 (54)
Nausea25 (32)32 (40)24 (29)26 (32)26 (31)
Insomnia21 (27)19 (23)26 (32)27 (33)29 (35)
Pruritus26 (33)26 (32)24 (29)12 (15)28 (33)
Myalgia22 (28)20 (25)25 (30)26 (32)21 (25)
Chills25 (32)22 (27)22 (27)19 (23)19 (23)
Pyrexia15 (19)19 (23)26 (32)18 (22)23 (27)
Diarrhea19 (24)17 (21)20 (24)19 (23)17 (20)
Decreased appetite18 (23)21 (26)11 (13)16 (20)25 (30)
Rash17 (22)21 (26)15 (18)16 (20)16 (19)
Alopecia14 (18)17 (21)7 (9)25 (31)19 (23)
Asthenia17 (22)13 (16)16 (20)16 (20)20 (24)
Arthralgia21 (27)14 (17)10 (12)14 (17)19 (23)
Cough16 (20)15 (19)18 (22)12 (15)15 (18)
Irritability9 (11)15 (19)14 (17)16 (20)22 (26)
Dry skin18 (23)11 (14)14 (17)15 (19)16 (19)
Depression10 (13)18 (22)17 (21)10 (12)15 (18)
Table 3. Summary of Laboratory Abnormalities
n (%)A MCB 500 mg 12 weeks RVR-guided N = 79B MCB 1,000 mg 8 weeks RVR-guided N = 81C MCB 1,000 mg 12 weeks RVR-guided N = 82D MCB 1,000 mg 12 weeks Non-RVR-guided N = 81E Placebo Plus Peg-IFNα-2a/RBV 48 weeks N = 84
  1. MCB, mericitabine; ULN, upper limit of normal; BUN, blood urea nitrate.

  2. a

    Defined as creatinine clearance <60 mL/min or a ≥35% drop from baseline.

  3. b

    Protocol-defined marked laboratory abnormality.

  4. c

    Defined as any occurrence of a urine protein/creatinine ratio ≥0.5.

  5. d

    Defined as a urine protein/creatinine ratio ≥1.0 and >200% increase from baseline; last or replicated value.

Neutrophils <0.5 × 109/L1 (1)4 (5)3 (4)3 (4)5 (6)
Hemoglobin <8.5 g/dL1 (1)0 (0)3 (4)0 (0)1 (1)
Platelets <20 × 109/L0 (0)0 (0)0 (0)0 (0)0 (0)
Lymphocytes <0.35 × 109/L1 (1)5 (6)4 (5)4 (5)2 (2)
Decreased creatinine clearancea1 (1)2 (2)5 (6)1 (1)1 (1)
Serum creatinine >2 × ULN0 (0)0 (0)1 (1)0 (0)0 (0)
BUN >2 × ULN0 (0)0 (0)0 (0)0 (0)0 (0)
Serum phosphate >1.60b mmol/L0 (0)1 (1)3 (4)0 (0)5 (6)
Urine protein/creatinine ratio ≥0.5c7 (9)3 (4)6 (7)1 (1)3 (4)
Urine protein/creatinine ratio (high)d0 (0)0 (0)0 (0)0 (0)0 (0)

In total, 23 patients (5.6%) withdrew from the study because of AEs associated with Peg-IFNα-2a or RBV, and 14 (3.4%) withdrew from treatment because of AEs associated with mericitabine or placebo (5%) (Table 2). There were no withdrawals from the study for AEs involving renal or hematologic disorders.

A total of 37 serious AEs occurred in 32 patients; these were distributed evenly across the five treatment groups (Table 2). Psychiatric events were the most frequent serious AE, occurring in 5 patients overall (2 each in arms C and D and 1 in the placebo control group). No serious AEs for cytopenia, renal disorders, or rash were reported. One death occurred during the study: a completed suicide during untreated follow-up (on study day 276; all treatment had been completed on study day 168) by a 54-year-old female patient with a history of depression and anxiety who was receiving ongoing treatment with escitalopram and who had received mericitabine 1,000 mg BID. The death was considered possibly related to Peg-IFNα-2a treatment in the opinion of the investigator.

Discussion

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Appendix
  7. References
  8. Supporting Information

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,[12] likely because the first phosphorylation step is thought to be rate limiting in the production of the active triphosphate species.[13] 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,[14] 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.[15]

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.[16] 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.[16]

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.[17] 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.[16]

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.

Appendix

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Appendix
  7. References
  8. Supporting Information

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.

References

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Appendix
  7. References
  8. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Appendix
  7. References
  8. Supporting Information

Additional Supporting Information may be found in the online version of this article.

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hep26274-sup-0002-suppfig2.tif3395KSupporting Information Figure 2
hep26274-sup-0003-suppinfo1.doc30KSupporting Information
hep26274-sup-0004-suppinfo2.doc24KSupporting Information
hep26274-sup-0005-supptable.doc31KSupporting Information Tables

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