Towards Model-Based Drug Development of New Therapeutics for Hepatitis C Virus
Rong Deng, Brinda Emu, William Capra, Jin Y. Jin
Genentech, Inc., South San Francisco, CA, US
Objectives: The FDA "critical path" document characterizes model-based drug development (MBDD) as the development and application of pharmaco-statistical models of drug efficacy and safety from preclinical and clinical data to improve drug development knowledge, management and decision-making. One of the frequent and well established applications of MBDD is utilization of mathematical models of disease progression to test different study designs in silico via clinical trial simulations. In the past few years, MBDD has been a unique and useful tool to inform drug development strategy and decision-making in various therapeutic areas, such as metabolic, neurological, and cardio-vascular diseases, and we believe it can be similarly useful in infectious diseases.
Methods: The life cycle of Hepatitis C virus (HCV) has been studied extensively in the past decade, from which mathematical models have been developed to quantitatively describe both viral dynamics as well as existing and potential therapeutic interventions. The models have also been well validated against the rich clinical data of patient viral load reduction upon receiving the standard of care (SOC)( ribavirin+ peginterferon). We propose to utilize and modify these models to assist the design of clinical trials of an HCV entry inhibitor by testing different input clinical parameters (choice of antiviral therapy, viral load, known characteristics of patient population), to inform selection of virologic endpoints, sample size, and patient population.
Results: We have developed and validated a modified HCV dynamic model that incorporates resistance to SOC and use of an HCV entry inhibitor for treatment. This model suggests HCV entry inhibition may increase cure rate and decrease treatment duration when combined with current SOC or direct-acting antiviral agents, with or without interferon. In additional, an HCV entry inhibitor is likely to show larger added benefits in patients not responding well to SOC. Based on the model, a phase I study is proposed in HCV patients, regardless of baseline viral load, designed to show evidence of viral load decline, and the PKPD relationship of a novel HCV entry inhibitor.
Conclusions: MBDD has been successfully applied to develop a study design for HCV in the early drug development stage.