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PHARMACOKINETICS/PHARMACODYNAMICS (PK/PD) OF COMBINATION RG7227 AND RG7128 THERAPY FROM INFORM-1 DEMONSTRATES SIMILAR EARLY HCV VIRAL DYNAMICS WHEN RG7227 IS COMBINED WITH EITHER PEG-IFN/RIBAVIRIN (SOC) OR RG7128
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Reported by Jules Levin
AASLD Nov 2 2009 Boston, MA
P.N. Morcos1, R. Kulkarni1, D. Ipe1, J. Tran1, W. Bradford2, S. Seiwert2, B. Symonds3, E.J. Gane4, S.K. Roberts5, N.S. Shulman1, P.F. Smith11Roche, Palo Alto, CA, USA, 2InterMune, Inc., Brisbane, CA, USA, 3Pharmasset, Inc., Princeton, NJ, USA, 4Auckland Clinical Studies, Auckland, New Zealand, 5The Alfred, Melbourne, VIC, Australia
Background:
INFORM-1 is evaluating a nucleoside polymerase inhibitor (RG7128) and protease inhibitor (RG7227; ITMN-191) in combination, offering the potential for a potent, all oral, interferon-free regimen with a high barrier to resistance. In vitro HCV replicon experiments demonstrate that the combination of RG7128 and RG7227 is additive, without cross resistance, and the addition of RG7128 prevents the emergence of RG7227 resistance.1 The INFORM-1 clinical study has confirmed that a twice-daily combination of RG7128 and RG7227 results in significant reductions in HCV RNA, without the emergence of resistance.
Objective: To evaluate and compare the PK/PD relationships for RG7227 when combined with either RG7128 or standard of care (SOC).
Methods:
The PK/PD and viral kinetics of patients receiving RG7227 in combination with either a) RG7128 (INFORM-1) or b) SOC PEG-IFN/RBV (NSHC-0032) were evaluated.
Study design:
INFORM-1 was a randomized, double-blind, placebo controlled, dose ranging study of RG7128 and RG7227 in adult patients with chronic hepatitis C (CHC) genotype 1.
Treatment-naive (Cohorts A-D, and G), -experienced (Cohort E), or null responder (Cohort F) patients were randomized to escalating doses of RG7128 (500 or 1000 mg bid) and RG7227 (100 or 200 mg tid or 600 or 900 mg bid) for 13 days. Frequent on-treatment samples were taken to assess the pharmacokinetics and viral kinetics of the combination.
The study designs of INFORM-1 and NSHC-003 were generally similar; SOC treatment was initiated 24 hours prior to the first dose of R7227 in NSHC-003.
Pharmacokinetic/Pharmacodynamic and statistical methods
Concentration-response relationships were evaluated using nonlinear regression with an Emax-type model. A bi-phasic mixed effects model was used to describe the viral kinetic profiles. The individual parameter estimates were then used to compute alpha phase half-life, length of alpha phase and the slope of the beta phase.
Results
Treatment with RG7128 + RG7227 resulted in potent viral suppression with median reductions in HCV RNA ranging from 4.8 to 5.2 log10 at the higher dose cohorts.3 No resistance has been detected by phenotypic analysis or by population sequencing and clonal analysis.4
Exposure-Response Relationships
Cmin concentrations appear to be the pharmacodynamically linked variable for RG7227 antiviral activity. The relationship between RG7227 average Cmin (Cminavg), defined as the mean Cmin for each patient across all PK sampling days, and log10 HCV RNA change from baseline is shown in Figure 1.
Figure 1: Fitted antiviral response in treatment naive patients receiving RG7128 + RG7227
The PK/PD of RG7227 is similar when combined with either RG7128 or SOC: Emax (95% CI) and EC50 for a) RG7227 + RG7128 was 5.4 (4.99-5.85) log10 and 0.08 (0.04-0.13) ng/mL, respectively; and for b) RG7227 + SOC was 5.2 (4.74-5.60) log10 and 0.03 (-0.05-0.10) ng/mL, respectively.
As shown in Figure 1, all patients with an RG7227 Cmin avg > 0.5 ng/mL achieved significant decreases in HCV RNA (median ∼5.0 log10) by end of DAA treatment, irrespective of RG7128 dose. At RG7227 Cmin avg < 0.5 ng/mL, it appears that the higher RG7128 dose (1000 mg) may be beneficial. Patients with an RG7227 Cmin avg < 0.5 ng/mL achieved a median -3.6 log10 reduction in HCV RNA from baseline with 500 mg RG7128, compared to a -4.7 log10 reduction with 1000 mg.
Viral Kinetics
RG7227 demonstrated similar early viral kinetic profiles when administered in combination with either 1000 mg RG7128 or SOC (Figure 2).
Figure 2: Viral kinetic profile of 900 mg bid RG7227 plus either SOC or 1000 mg bid RG7128 in naive or null responders
Similar alpha phase VK profiles were observed with RG7227 added to either RG7128 or SOC (∼3.5 logs in the first 48hr); both regimens provide highly potent inhibition of viral production. Differences in study designs between INFORM-1 and NSHC-003 (24h induction with SOC in NSHC-003) complicate direct comparisons of the alpha phase between these two studies.
The combination of RG7227 + RG7128 displayed similar beta phase viral kinetic slopes compared to RG7227 + SOC, suggesting that the IFN-free small molecule combination has potent direct antiviral activity and similarly contributes to the clearance of infected hepatocytes (Table 1).
If combination with a nucleoside analogue such as RG7128 can prevent emergence of protease inhibitor resistance over longer treatment periods, treatment with RG7227 + RG7128 (with or without ribavirin) may result in a sustained virological response (SVR) in CHC.
Table 1: Median (MAD^) alpha-half-life, length of alpha phase, beta-phase slopes and % undetectable for RG7227 added to either RG7128 or S OC
References
1. Najera I, McCown M, Leveque V, et al. Silibinin inhibits HCV replication in vitro. J Hepatol 2009: 50 (Suppl 1): S346
2. Zeuzem S, Sulkowski M, Lawitz E, et al. Efficacy and safety of albinterferon alfa-2b in combination with ribavirin in treatment-naive, chronic hepatitis C genotype 1 (CHC G1) patients. J Hepatol 2009: 50 (Suppl 1): S377
3. Gane EJ, Roberts SK, Stedman CA, et al. Combination Therapy With A Nucleoside Polymerase (R7128) And Protease (R7227/ITMN-191) Inhibitor In HCV:Safety, Pharmacokinetics, And Virologic Results From INFORM-1. Hepatology 2009; 50 (4; Suppl 1):394A-395A
4. Pogam S, Chhabra M, Ali, S, et al. Combination therapy with nucleoside polymerase (RG7128) and protease (RG7227) inhibitors in genotype 1 HCV infected patients: interim resistance analysis of INFORM-1 cohorts A-D. Hepatology 2009; 50 (4; Suppl 1):1037A
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