Wei Gao (1), Faye Zhang (1), Kyle Baron (2), Matthew Riggs (2), Matthew L. Rizk (1), Wendy W. Yeh (3), Mike Robertson (3)
(1) Quantitative Pharmacology and Pharmacometrics, PPDM, Merck & Co., Inc., Kenilworth, NJ, USA, (2) Metrum Research Group, LLC, (3) Clinical Research, Merck & Co., Inc., Kenilworth, NJ, USA
Objectives: Grazoprevir (GZR, a protease inhibitor), uprifosbuvir (UPR, a NS5B inhibitor) and ruzasvir (RZR, a NS5A inhibitor) are direct acting antiviral agents for treatment of chronic HCV infection. Efficacy of these agents was tested as monotherapy in Phase 1 studies or as combination therapy in Phase 2 studies[1,2]. A semi-mechanistic viral dynamic model was developed to translate the viral kinetics data obtained from the short term monotherapy studies to the clinical outcomes after long term combination therapy.
Methods: Plasma HCV RNA time courses during and after treatment were collected in the monotherapy studies: 10 to 800 mg once daily (QD) of GZR for 10 days, 10 to 450 mg of UPR as single dose or QD for 7 days, or 10 to 120 mg QD of RZR for 5 days. In Phase 2 trials, the combination regimen of 100 mg GZR, 450 mg UPR and 60 mg RZR for 8, 12 or 16 weeks was evaluated. The HCV RNA data were collected at various time points from day 1 to end of treatment and the clinical efficacy endpoint was SVR12 rate, the proportion of subjects achieving sustained virologic response 12 weeks after the end of all study therapy.
The viral dynamics model was developed based on the previously published two strain model [3]. Uninfected cells were assumed to be infected with HCV (either wild-type or mutant) and new virus was produced from infected cells (either wild-type or mutant) which would go on to infect other uninfected cells. The drug effect was characterized as inhibiting the viral load production and/or increasing the infected cell death rate. Specifically, the effects of GZR and RZR were driven by the plasma concentrations while the effect of UPR was driven via an effect compartment. The model was simultaneously fit to all monotherapy data from each regimen component and parameters describing the viral dynamics system and drug effects were estimated.
The model was then used to simulate the clinical efficacy of combination therapy. The effect of HCV genotype (GT) and the presence of baseline resistance-associated substitutions (RASs) were also accounted for in the model.
Results: The maximum HCV RNA reduction following short term monotherapies ranged from nearly no reduction to ~4.5 log10 IU/mL reduction from baseline. The semi-mechanistic viral dynamics model described the HCV viral kinetics following monotherapy adequately. In Ph2 studies, HCV RNA in the majority of patients was below the limit of quantification at week 4. After including the combinational drug effect, simulated HCV RNA time courses agreed well with the observations from Ph2 studies. SVR12 rates in Ph2 studies ranged from 78% to 100%, varying between treatment duration, HCV GTs and presence of baseline RASs. After accounting for these baseline characteristics, the model was able to predict SVR12 rates reasonably well for each treatment arm.
Conclusions: By incorporating our current knowledge of HCV viral dynamics, baseline patient characteristic and pharmacodynamic data from short term Phase 1 monotherapy studies, the viral dynamics model was able to successfully predict the clinical efficacy outcomes in long term HCV combination therapy studies. This model can be used to predict efficacy of the described combination regimen under conditions that were not studied clinically and could potentially provide a framework for extrapolation to other combination regimens.
References:
[1] Gane EJ, Pianko S, Roberts SK, Thompson AJ, Zeuzem S, Zuckerman E, et al. Safety and efficacy of an 8-week regimen of grazoprevir plus ruzasvir plus uprifosbuvir compared with grazoprevir plus elbasvir plus uprifosbuvir in participants without cirrhosis infected with hepatitis C virus genotypes 1, 2, or 3 (C-CREST-1 and C-CREST-2, part A): two randomised, phase 2, open-label trials. Lancet Gastroenterol Hepatol. 2017 Nov;2(11):805–13.
[2] Lawitz E, Buti M, Vierling JM, Almasio PL, Bruno S, Ruane PJ, et al. Safety and efficacy of a fixed-dose combination regimen of grazoprevir, ruzasvir, and uprifosbuvir with or without ribavirin in participants with and without cirrhosis with chronic hepatitis C virus genotype 1, 2, or 3 infection (C-CREST-1 and C-CREST-2, part B): two randomised, phase 2, open-label trials. Lancet Gastroenterol Hepatol. 2017 Nov;2(11):814–23.
[3] Nguyen T, Guedj J. HCV Kinetic Models and Their Implications in Drug Development. CPT Pharmacometrics Syst Pharmacol. 2015 Apr 1;4(4):231–42.
Reference: PAGE 27 (2018) Abstr 8552 [www.page-meeting.org/?abstract=8552]
Poster: Drug/Disease Modelling - Infection