Abstract
The RNA interference (RNAi) drug ARC-520 was shown to be effective in reducing serum hepatitis B virus (HBV) DNA, hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) in HBeAg-positive patients treated with a single dose of ARC-520 and daily nucleosidic analogue (entecavir). To provide insights into HBV dynamics under ARC-520 treatment and its efficacy in blocking HBV DNA, HBsAg, and HBeAg production we developed a multi-compartmental pharmacokinetic–pharamacodynamic model and calibrated it with frequent measured HBV kinetic data. We showed that the time-dependent single dose ARC-520 efficacies in blocking HBsAg and HBeAg are more than 96% effective around day 1, and slowly wane to 50% in 1–4 months. The combined single dose ARC-520 and entecavir effect on HBV DNA was constant over time, with efficacy of more than 99.8%. The observed continuous HBV DNA decline is entecavir mediated, the strong but transient HBsAg and HBeAg decays are ARC-520 mediated. The modeling framework may help assess ongoing RNAi drug development for hepatitis B virus infection.
Highlights
Treatment options for chronic hepatitis B virus (HBV) infections are limited to two main drug groups: pegylated interferon-α (IFN) and nucleos(t)ide analogues (NAs)[1,2,3]
We developed mathematical models that best reproduce observed HBV DNA, hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) kinetics following a single dose of ARC-520 in five HBeAg-positive patients from the Heparc-2001 study
We build on previous modeling work, consider the interaction between HBV DNA, HBsAg and HBeAg titers in the presence of a single dose RNA interference (RNAi)-based therapy, and use the model to run in silico experiments to predict individual contributions of different drug effects on the dynamics for HBsAg titers
Summary
Treatment options for chronic hepatitis B virus (HBV) infections are limited to two main drug groups: pegylated interferon-α (IFN) and nucleos(t)ide analogues (NAs)[1,2,3]. Experiments in mice and chimpanzees, and a phase II clinical study in patients (Heparc-2001) showed potential for ARC-520 induced HBeAg, HBsAg and HBV DNA titers reduction[17,20,21]. While ARC-520 has been terminated due to delivery-associated toxicity[20], overall results indicate that RNAi-based therapy has the potential of reducing HBsAg and inducing functional cure[16,21,22] regardless of the patient’s HBeAg status[23,24]. We build on previous modeling work, consider the interaction between HBV DNA, HBsAg and HBeAg titers in the presence of a single dose RNAi-based therapy, and use the model to run in silico experiments to predict individual contributions of different drug effects on the dynamics for HBsAg titers
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