EASL 2012: [SLIDES] INTERFERON-FREE TREATMENT WITH A COMBINATION OF MERICITABINE AND DANOPREVIR/R WITH OR WITHOUT RIBAVIRIN IN TREATMENT-NAIVE HCV GENOTYPE 1-INFECTED PATIENTS

E.J. Gane,1 P. Pockros,2 S. Zeuzem,3 P. Marcellin,4 A. Shikhman,5 C. Bernaards,6 E. Yetzer,6 N.S. Shulman,6 X. Tong,5 I. Nájera,5 A. Bertasso,5 J. Hammond,5 S. Stancic5

1Auckland Clinical Studies, Auckland, New Zealand; 2Scripps Clinic and Scripps Translational Science Institute, La Jolla, CA, USA; 3J. W. Goethe University Hospital, Theodor-Stern-Kai, Frankfurt, Germany; 4Hôpital Beaujon, Clichy, France; 5Roche, Nutley, NJ, USA;
6Genentech, South San Francisco, CA, USA

INTRODUCTION

• The hepatitis C treatment landscape is rapidly evolving. The recent regulatory approval of first-generation protease inhibitors has resulted in a new standard of care for genotype 1 patients, consisting of peginterferon alfa/ribavirin (RBV) in combination with telaprevir or boceprevir, with sustained virological response (SVR) rates of 68–75% achievable in treatment naive patients.[1-3]
• However, safety and tolerability remain suboptimal. The benefits of adding one direct-acting antiviral agent (DAA) to peginterferon alfa/RBV remain limited due to the underlying safety and tolerability issues associated with interferon-based treatment.
• An all-oral, interferon-free DAA combination treatment would fill an unmet medical need and potentially further change the treatment paradigm.[4]
• Two DAAs currently in phase II clinical development are mericitabine (MCB) and danoprevir (DNV; RG7227).
• MCB is a selective and non-cytotoxic hepatitis C virus (HCV) polymerase inhibitor which is active against all HCV genotypes and has a high barrier to resistance.[5-7]
• DNV is a potent, macrocyclic, HCV protease inhibitor that has equipotent activity against HCV genotypes 1, 4 and 6 in vitro.[8,9]
• The phase I INFORM-1 study demonstrated that treatment with a combination of these two DAAs for 13 days resulted in significant reductions in HCV RNA in both treatment-naive and prior null responders and was well tolerated.[4]
• Co-administration of ritonavir with lower doses of DNV has since been shown to decrease the overall exposure of DNV while maintaining potent antiviral activity.[10]
• The phase IIb INFORM-SVR study is investigating the safety and efficacy of response-guided treatment with MCB in combination with ritonavir-boosted DNV (DNVr) with and without RBV for 12 or 24 weeks in treatment naive patients with genotype (G) 1 chronic HCV infection.
• Here, results from a 12-week post-treatment interim analysis of the INFORM-SVR study are presented.

METHODS

• INFORM-SVR is an ongoing, randomised, multicentre, double blind, parallel group phase IIb study. Eligible patients are treatment-naive, chronic HCV G1-infected adults (≥18 years of age) with F0–F2 fibrosis.
• Patients were randomised (1:1) to receive a combination of MCB (1000 mg bid) and DNVr (100 mg/100 mg bid) plus either RBV (1000/1200 mg daily) (Arm A) or placebo (Arm B) for 12 or 24 weeks (Figure 1).
• In both arms, patients achieving an early extended rapid virological response (eRVR2, defined as unquantifiable HCV RNA [<43 IU/mL]) between week 2 to week 8, and with undetectable HCV RNA [<15 IU/mL] at week 10, were re-randomised (1:1) at week 12 to either discontinue treatment (total therapy duration: 12 weeks) or continue the assigned regimen until week 24 (total therapy duration: 24 weeks).
• HCV RNA was measured using Roche COBAS® AmpliPrep/ COBAS TaqMan® HCV Test with a lower limit of detection of 15 IU/mL and a lower limit of quantification of 43 IU/mL.
• The primary outcome of the trial was SVR24.
• Resistance monitoring was performed in patients who experienced breakthrough, partial response, non-response or relapse through sequencing (population and clonal) of target genes.

Figure 1: INFORM-SVR study design

Arm A (12 week option) and Arm B (both 12 and 24 week options) stopped prematurely at different times due to unexpectedly high relapse rates. eRVR2: extended rapid virologic response; HCV RNA unquantifiable (<43 IU/mL) between week 2 and 8 and undetectable (<15 IU/ml) at week 10. Continue if HCV RNA quantifiable between week 2 and week 8 (≥43 IU/mL) but <43 IU/mL at week 10, or, HCV RNA <43 IU/mL between week 2 and 8 and <43 IU/mL but ≥15 IU/mL at week 10. Patients with virologic failure (confirmed rebound or <2 log drop after 1 month of treatment) discontinued treatment. Patients with quantifiable virus at week 10 stopped treatment at week 12.

RESULTS

Patients

• A total of 169 patients were randomised to treatment (Arm A n=83; Arm B n=86) and received at least one dose of study medication.
• Demographics were balanced between arms (Table 1).

Table 1: Baseline characteristics of the study population

ALT = alanine aminotransferase; BMI = body mass index; DNVr = ritonavir-boosted danoprevir; MCB = mericitabine; RBV = ribavirin.

• Randomisation to 12 weeks of treatment in Arm A and to the whole of Arm B was stopped prematurely due to high relapse rates, and patients in Arm B were offered follow-on with peginterferon alfa-2a (40KD)/RBV therapy.
• As a result, only 20/169 patients were randomised to 12 weeks of treatment (Arm A n=17; Arm B n=3) and thus, for efficacy analyses, Arm A (24 weeks of treatment), is the key group analysed here (n=66).

Efficacy

• Among patients randomised to Arm A for 24 weeks (n=66), two patients were excluded from the present efficacy analysis; one patient discontinued for reasons other than virological breakthrough or an adverse event (AE) and one patient was lost to follow-up.
• The efficacy population thus consisted of 64 patients who received MCB combined with DNVr and RBV for 24 weeks; 43 patients with HCV G1a and 21 with HCV G1b.
• SVR12 rates for G1a and G1b patients receiving 24 weeks of MCB plus DNVr and RBV treatment are presented in Figure 2.
  ——O verall, 41% of patients achieved SVR12 (26/64; 95% CI 28–53). However, SVR12 rates were considerably higher among patients with HCV G1b (71%; 95% CI 50–92) compared with patients with G1a infection (26%; 95% CI 12–39)
  ——W hen SVR12 rates were stratified according to IL28B genotype (CC and non-CC), 32% of patients with IL28B CC genotype, and 44% with non-CC genotype achieved SVR12
  —— I n G1a patients, SVR12 rates were similar irrespective of IL28B genotype. However, in G1b patients the number of IL28B CC patients was too small (n=4) to allow a meaningful comparison to patients with IL28B non-CC genotype.
• Among patients in Arm A treated with MCB combined with DNVr and RBV for 24 weeks, 60.5% (26/43) of HCV G1a-infected patients achieved an eRVR2 compared to 47.6% (10/21) of patients with HCV G1b infection.
• Among the patients achieving an eRVR2, 31% (8/26) of G1a and 80% (8/10) G1b achieved an SVR (Figure 3).

Figure 2: SVR12 rates in patients receiving 24 weeks MCB + DNVr + RBV
(Arm A) by HCV genotype and IL28B genotype

G = HCV genotype; DNVr = ritonavir-boosted danoprevir; MCB = mericitabine; RBV = ribavirin; SVR12 = sustained virological response after 12 weeks of untreated follow-up

Figure 3: SVR12 rates according to eRVR2 status and HCV genotype in patients randomised to MCB + DNVr + RBV for 24 weeks (Arm A)

G = HCV genotype; DNVr = ritonavir-boosted danoprevir; eRVR = extended rapid virological response; MCB = mericitabine; RBV = ribavirin; SVR12 = sustained virological response after 12 weeks of untreated follow-up.

Breakthrough rates

• In total, among all patients who received at least one dose of study medication, 26 patients experienced breakthrough: 8 in Arm A (8/83; 9.6%) and 18 in Arm B (18/86; 20.9%).
• When evaluated by HCV genotype, breakthrough rates were higher among HCV G1a patients (Arm A: 6/56; 11%; Arm B: 15/57; 26%) compared to G1b patients (Arm A: 2/27; 7%; Arm B: 3/29; 10%).
• DNV resistance mutations were detected by population sequencing in 25 patients at virological breakthrough; sequencing could not be performed in one G1a patient due to low viral load.
  ——The NS3 R155K amino acid change was the only known DNV resistance mutation detected at the population level in 16 patients (14 G1a, two G1b)
  ——R155K + V36M/A was observed in five G1a patients
  ——D168T was observed in one G1b patient
  ——D168E + V36V/G was observed in one G1b patient
  ——One patient (GT1a) had a dual resistant virus to MCB and DNV, bearing substitutions NS5B S282T and NS3 R155K
  ——R155K/Q was observed in one G1b-infected patient
• The dual resistant virus reverted to wild type by week 12 of follow-up (T282S at week 8 and K155R at week 12); clonal sequencing and/or ultra-deep pyrosequencing analyses are ongoing.

Safety

• Treatment with MCB in combination with DNVr and RBV was safe and well tolerated and no safety concerns were identified (Tables 2 and 3).
• No serious AEs were reported during treatment in Arm A.
• No Grade 4 laboratory abnormalities were reported (Table 2).

Table 2: Adverse events and laboratory abnormalities

AE = adverse event; ALT = alanine aminotransferase; ANC = absolute neutrophil count;
AST = aspartate aminotransferase; DNVr = ritonavir-boosted danoprevir; MCB = mericitabine;
RBV = ribavirin.
* SAE due to multiple myeloma at 63 days after last dose
† discontinuation was due to oropharyngeal discomfort

Table 3. Most common adverse events (≥10%)*

DNVr = ritonavir-boosted danoprevir; MCB = mericitabine; RBV = ribavirin.
* Includes mild, moderate and severe AEs

CONCLUSIONS

• In G1b patients, 24 weeks of MCB in combination with DNVr and RBV yielded an  SVR12 rate of 71%, while in G1a patients the SVR12 rate was 26%.
• Higher SVR12 rates were reported among patients who were rapid responders, i.e. those who achieved an eRVR2. Among patients with an eRVR2, 80% with G1b and 31% with G1a achieved SVR12.
• IL28B genotype (CC and non-CC) appeared to have less impact on SVR12 rates relative to differences observed between HCV G1a and G1b patients.
• Among patients not receiving RBV, breakthrough rates were higher indicating that RBV still plays an important role in preventing viral breakthrough.
• All patients with a confirmed viral breakthrough showed DNV-resistant variants, while only one patient showed the NS5B S282T polymerase mutation associated with resistance to MCB.
• Combination of MCB, DNVr and RBV is safe and well tolerated, resulting in no significant cytopenias, no treatment-emergent alanine aminotransferase elevations or any new signals with combination therapy.
• In view of its promising efficacy in G1b patients (>70%) and its good tolerability and safety profile, this interferon-free regimen warrants further study.

References

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2. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364: 2405–16

3. Sherman K, Flamm SL, Afdhal NH, et al. Response-Guided Telaprevir Combination Treatment for Hepatitis C Virus Infection. N Engl J Med 2011; 365: 1014–1024

4. Gane EJ, Roberts SK, Stedman CA, et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose escalation trial. Lancet 2010; 376: 1467–75

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6. Leveque V, Fung A, Le Pogam S. et al. Nucleoside analog R7128, a prodrug of PSI-6130, shows inhibition potency across HCV genotypes 1-6 in vitro. Poster P-215 presented at the 16th International Symposium on Hepatitis C Virus and Related Viruses, Nice, France; 2009. Poster 215

7. Reddy R, Rodriguez-Torres M, Gane E, et al. Antiviral activity, pharmacokinetics, safety, and tolerability of R7128, a novel nucleoside HCV RNA polymerase inhibitor, following multiple, ascending, oral doses in patients with HCV genotype 1 infection who have failed prior interferon therapy. Hepatology 2007; 46(4 suppl): 862A

8. Gottwein JM, Scheel TK, Jensen TB, et al. Differential efficacy of protease inhibitors against HCV genotypes 2a, 3a, 5a, and 6a NS3/4A protease recombinant viruses. Gastroenterology 2011;141: 1067–79

9. Imhof I, Simmonds P. Genotype differences in susceptibility and resistance development of hepatitis C virus to protease inhibitors telaprevir (VX-950) and danoprevir (ITMN-191). Hepatology 2011; 53: 1090–9

10. Gane EJ, Rouzier R, Stedman C, et al. Antiviral activity, safety, and pharmacokinetics of danoprevir/ritonavir plus PEG-IFN a-2a/RBV in hepatitis C patients. J Hepatol 2011; 55: 972–9

Presented at the International Liver CongressTM 2012 [47th Annual Meeting of the European Association for the Study of the Liver (EASL)], April 18-22, Barcelona, Spain
This research was funded by Roche
Support for third-party writing assistance for this presentation was provided by F. Hoffmann-La Roche Ltd.

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