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Roche Polymerase Nuc Mericitabine, study results reported from JUMP-C
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Below is the just published study of mericitabine+peg/rbv, but its important to realize that mericitabine like other HCV drugs although they are being studied initially in combination with peg/rbv, they will not be used that way as we get close to IFN-free therapy, the beginning of this era being very close now. Roche is studying now mericitabine in a 4-drug all oral IFN-free regimen containing their protease danoprevir, their non-nuc ANA598, mericitabine (a 2-log+ drug) and RBV. The study is called the ANNAPURNA Study, it started last Spring, here are links to data reported for all these Roche drugs:
4 Oral Drug IFN-Free Roche HCV Regimens Studies, Treatment Naïve or Null Responders: setrobuvir (non-nuc)+mericitabine (nuc)+danoprevir/r (protease)+rbv. ANNAPURNA Study...http://www.natap.org/2012/HCV/090412_01.htm
AASLD: Up to 100% SVR4 rates with ritonavir-boosted danoprevir (DNVr), mericitabine and ribavirin with or without peginterferon alfa-2a (40KD) in HCV genotype 1-infected partial and null responders: results from the MATTERHORN study- (11/13/12)
AASLD: Safety and efficacy of ritonavir-boosted danoprevir (DNVr), peginterferon alfa-2a (40KD), and ribavirin with or without mericitabine in HCV genotype 1-infected treatment-experienced patients with advanced hepatic fibrosis: the MATTERHORN study- (11/13/12)
JUMP-C: A randomized trial of mericitabine plus peginterferon alfa-2a/ribavirin for 24 weeks in treatment-naive HCV genotype 1/4 patients
Hepatology
Accepted manuscript online: 28 JAN 2013
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record
Paul J. Pockros,1 Donald Jensen,2 Naoky Tsai,3 Ryan Taylor,4 Alnoor Ramji,5 Curtis Cooper,6 Rolland Dickson,7 Alan Tice,8 Rohit Kulkarni,9 John M. Vierling,10 Marie Lou Munson,9 Ya-Chi Chen,11 Isabel Najera,11 and James Thommes9 on behalf of the JUMP-C Investigators*
Abstract
Mericitabine is a selective nucleoside analog inhibitor of the HCV NS5B RNA-dependent RNA polymerase, with activity across all HCV genotypes. Treatment-naive 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 in combination with peginterferon alfa-2a/ribavirin. Patients randomized to mericitabine with HCV RNA<15 IU/mL from week 4-22 (extended rapid virologic response RVR [eRVR]) stopped all treatment at week 24; all other patients continued peginterferon alfa-2a/ribavirin 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% 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%, CI 5.5-35.2%). SVR rates were higher in mericitabine- than placebo-treated patients when subdivided by IL28B genotype (CC, 77.8% vs. 56.0%; non-CC, 44.1% vs. 16.2%) and hepatic fibrosis (noncirrhotic, 63.3% vs. 41.9%; cirrhotic, 38.1% vs. 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 placebo 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 twice daily plus peginterferon alfa-2a/ribavirin is well tolerated and more effective than a standard 48-week course of peginterferon alfa-2a/ribavirin.
Introduction
Treatment for chronic hepatitis C virus (HCV) infection is evolving rapidly. The first direct-acting antiviral 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 now 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 non-responders to peginterferon/ribavirin.(2-6) 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 (38.4% and 48.6%, respectively) and higher rates of discontinuation due to severe adverse events (7.4% and 14.5%, respectively) than were experienced in phase 3 trials.(2-6, 9) Furthermore, boceprevir and telaprevir increase the 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. 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.(13-17)
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 peginterferon alfa-2a/ribavirin, with the HCV protease inhibitor danoprevir in a dual oral interferon-free regimen, and in a quadruple combination regimen with peginterferon alfa-2a/ribavirin and danoprevir.(20-24) Treatment with mericitabine plus peginterferon alfa-2a/ribavirin for up to 12 weeks in a phase 2b clinical trial increased on-treatment virologic response rates and was safe and well tolerated, but did not increase SVR rates when compared with peginterferon alfa-2a/ribavirin.(25) The objective of the present trial (JUMP-C) was to evaluate the efficacy and safety of 24 weeks of response-guided therapy with mericitabine plus peginterferon alfa-2a/ribavirin in treatment-naive patients with HCV genotype 1 or 4 infection.
Results
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 intention-to-treat population (Fig. 2). A total of 59 patients (35.6%) were prematurely withdrawn during study treatment (Fig. 2). The majority of these (67.8%) were for non-safety reasons. Discontinuations due to lack of efficacy were more frequent in the placebo group than in the mericitabine group (26 vs. 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).
Efficacy
Treatment with mericitabine plus peginterferon alfa-2a/ribavirin was associated with consistently higher virologic response rates compared with treatment with placebo plus peginterferon alfa-2a/ribavirin 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%, CI 45.9-67.0%, vs. 36.5%, CI 27.0-47.1%, respectively, M = 20.3%, CI 5.5-35.2%).
Treatment with mericitabine was also associated with consistently higher on-treatment virologic response rates and SVR rates when patients were grouped according to cirrhosis status (Fig. 4A) and host IL28B genotype (CC or non-CC) (Fig. 4B). In a logistic regression analysis HCV subtype (1a vs. 1b) was not associated with SVR in the overall population (P = 0.953) or in the sub-set 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 patients in the placebo group (12.9%). SVR rates among these individuals were 73.5% and 100.0%, respectively, and relapse rates were 21.3% (10/47) and 0% (0/11), 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 the 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 the 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).
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 three of five 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; nine patients (five genotype 1a, four genotype 1b) experienced breakthrough during treatment with peginterferon alfa-2a/ribavirin; 16 patients (nine genotype 1a, six genotype 1b, one genotype 4) relapsed after completing 48 weeks of therapy; and five patients (four genotype 1a, one 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, five patients who experienced breakthrough during treatment with peginterferon alfa-2a/ribavirin and eight patients who experienced relapse. Three common non-polymorphic 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 one 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 EC50 values for mericitabine in ontreatment and follow-up samples remained within 2-fold of the respective baseline samples.
Safety
The safety profile of mericitabine did not differ greatly from that of placebo. The nature and incidence of adverse events and laboratory abnormalities were typical of those associated with peginterferon alfa-2a/ribavirin. No new safety concerns were identified. The most frequent adverse events were fatigue, headache and nausea, with a similar incidence in both treatment groups (Table 2).
Fewer patients in the mericitabine plus peginterferon alfa-2a/ribavirin group discontinued treatment for safety reasons (n = 6 vs. n = 13 in the placebo plus peginterferon alfa-2a/ribavirin group, respectively).
The incidence of peginterferon alfa-2a and ribavirin dose adjustments for laboratory abnormalities occurred with similar frequency in the two treatment groups (Table 2). In total, eight patients (4.8%) experienced serious adverse events: five patients in the mericitabine group (6.2%) and three patients 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 11 weeks after the last dose of mericitabine. The abnormality was not replicated in subsequent tests and was not considered to be clinically significant.
Discussion
This study demonstrates that response-guided treatment with the combination of 24 weeks of treatment with mericitabine plus peginterferon alfa-2a/ribavirin 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 peginterferon alfa-2a/ribavirin (56.8% vs. 36.5%). Moreover, when compared with 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.
The virologic response 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 peginterferon alfa-2a/ribavirin. 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 peginterferon alfa-2a/ribavirin 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 twice daily 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 non-cirrhotic patients (F0-2) 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 direct-acting antiviral agents that employed a response-guided therapy strategy.(3-5) 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 peginterferon/ribavirin therapy, suggesting that responsiveness to peginterferon 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 interferon responsiveness and overall treatment duration. Most of the genotype CC patients in the mericitabine-treatment group received 24 weeks of peginterferon alfa-2a/ribavirin therapy, whereas CC patients in the placebo group received a full 48-week course of peginterferon alfa-2a/ribavirin 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 peginterferon alfa-2a/ribavirin. The spectrum and severity of adverse events was similar in the two treatment groups. No novel adverse effects were observed, and mericitabine treatment did not exacerbate any known adverse events of peginterferon alfa-2a/ribavirin. Indeed, fewe rpatients discontinued treatment with mericitabine than placebo. There was also no evidence that mericitabine has an additive effect on laboratory abnormalities associated with peginterferon/ribavirin, 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 non-response 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 followon treatment with peginterferon alfa-2a/ribavirin 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 ribavirin, the most common resistant mutations accompanying treatment failure were associated with danoprevir (R155K, V36M/A, and D168T)(28). In that study, only one 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 peginterferon alfa-2a/ribavirin 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, peginterferon alfa-2a and ribavirin produces higher SVR12 rates and lower relapse rates than the triple combination of ritonavir-boosted danoprevir plus peginterferon alfa-2a/ribavirin in patients with a prior partial response to peginterferon/ribavirin.(29)
In conclusion, when administered for 24 weeks at a dosage of 1,000 mg twice daily as part of a response-guided combination with peginterferon alfa-2a/ribavirin, mericitabine produced higher SVR rates than a standard 48-week course of peginterferon alfa-2a/ribavirin and was extremely well tolerated, without any documented antiviral resistance. Despite these results, recent favorable results achieved with all-oral direct-acting antiviral combination regimens suggest that future development scenarios for mericitabine will need to include combinations with other direct-acting antiviral agents. The high barrier to resistance, and the good tolerability and safety profile, make mericitabine potentially useful in combination with other direct-acting antivirals 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 interferon-free combinations with protease inhibitors and non-nucleoside polymerase inhibitors, and in a quadruple combination regimen with a protease inhibitor and peginterferon/ribavirin in the most difficult-to-treat populations.
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