Exposure-response Relationship of Filibuvir in HCV-infected Patients: Application to Dose Selection for Combination Therapy

Exposure-response Relationship of Filibuvir in HCV-infected Patients: Application to Dose Selection for Combination Therapy


Reported by Jules Levin
EASL Apr 14-18 2010 Vienna Austria

S. Neelakantan,1 V.S. Purohit,2 M. O'Gorman,1 J. Hammond,2 T.G. Tensfeldt1 1Primary Care, Pfizer, New London, CT, USA; 2Specialty Care, Pfizer, New London, CT, USA


ABSTRACT

Background and Aims: Filibuvir is a hepatitis C virus NS5B RNA-dependent RNA polymerase inhibitor currently in development for chronic hepatitis C. An exposure-response (ER) analysis of the results from two monotherapy studies in HCV infected patients was performed and utilised for Phase 2b dose selection in combination with standard of care (SOC, pegylated interferon/ribavarin).

Methods: Results from two Phase 1 studies were pooled for the analysis. Study 1 investigated the antiviral activity of oral filibuvir doses of 100, 300 and 450 mg BID and 300 mg TID or placebo, for 8 days in treatment naïve patients. In the second study, the antiviral activity of filibuvir 450 mg BID in treatment experienced patients dosed for 10 days and 700 mg BID in treatment naïve patients dosed for 3 days was evaluated. Filibuvir exposures achieved over 24 hours (AUC24) were utilised to inform the ER analysis of the maximum log change in viral load from baseline. The relationship was described by an inhibitory Emax model using a non-linear mixed effects model. Effects of food, baseline viral load (BVL) and genotype (1a/1b) on relevant model parameters were also evaluated. The antiviral response for a range of doses was simulated from the model.

Results: The ER data from 52 subjects were adequately described by the Emax model with Emax (95% CI)= -2.14 (-2.54, -2.02) IU/mL and AUC24, 50 (95% CI)=54176 (44606, 102006) ng·hr/mL. BVL was the only influential covariate which described the maximal response (Emax). The analysis indicated that doses in excess of 300 mg BID were expected to achieve at least 70% of Emax. Furthermore, filibuvir exposures resulting from doses greater than 600 mg BID produced responses close to Emax indicating that higher doses (>600 mg BID) are unlikely to provide additional efficacy.

Conclusions: Filibuvir exposures adequately described the maximum log change in viral load relative to baseline. The above analysis in conjunction with results from a Phase 2a study (200/300/500 mg BID + SOC, rapid viral response rates of 60-75%) suggests that filibuvir doses of 300 and 600 mg BID are expected to be efficacious when combined with SOC and will be further investigated in Phase 2b studies.

INTRODUCTION

Filibuvir is a potent and selective non-nucleoside inhibitor of the hepatitis C virus (HCV) non-structural (NS5B) RNA-dependent RNA polymerase enzyme. Filibuvir is in development for chronic HCV infection.

In-vitro data show that filibuvir is equipotent against HCV genotype 1a and 1b replicons, with an overall mean EC50 of 0.059 mM.1 Two monotherapy studies showed that filibuvir potently inhibited viral replication in a dose-dependent manner in treatment-naïve and -experienced patients with HCV genotype 1.

METHODS

Study design
Data from the following studies were pooled for analysis:
-- Study 1: Phase 1 randomised, double-blind, placebo-controlled, sequential doseescalation study of orally administered filibuvir doses of 100, 300 or 450 mg BID or 300 mg TID or placebo for 8 days in treatment-naïve patients.
--- Study 2: Phase 1 non-randomised, open-label, sequential group study of orally administered filibuvir doses of 450 mg BID for 10 days in treatment-experienced, or 700 mg BID for 3 days in treatment-naïve patients.


RESULTS

The inhibitory E max model adequately described the relationship between filibuvir exposures and maximum HCV RNA reduction (Figure 1) and confirmed the dose dependency of HCV RNA reduction (Figure 2).

The analysis suggested a plateau in the response for filibuvir monotherapy, and that increasing filibuvir doses beyond those tested is unlikely to produce greater HCV RNA reductions.

The log of baseline HCV RNA (normalised to 6) was identified as an influential covariate describing the Emax.


Effects of genotype [1a (n=32) vs 1b (n=20)] on the E max, E0 or the AUC24, 50 parameters (based on 95% CI including null value) were not detected.

However, given that these studies were not powered to detect such differences, further explorations of the covariate-parameter relationships will be performed as and when new data emerge.

The parameter estimates, their relative standard errors and the associated 95% CI are presented in Table 1.

Predicted distributions of log of mean exposures for various filibuvir doses are shown in Figure 3 with reference lines representing the log of model-predicted AUC24, 50 (solid red line) and AUC24, 90 values (solid blue line), along with their respective 95% CIs (dashed lines).

Figure 3. Boxplot of logarithm of predicted exposures (AUC24) for various filibuvir doses.

Visual inspection of the figure indicates that the filibuvir 300 mg BID dose (600 mg total daily dose) is expected to achieve exposures that would produce at least half the maximal response, while exposures following administration of filibuvir doses in excess of 600 mg BID (1200 mg total daily dose) will likely produce HCV RNA reductions close to the maximal response.

Table 2 shows the predicted median maximum change from baseline in log of HCV RNA reduction for the various total daily doses of filibuvir and associated 95% CIs.