Journal
SCIENTIFIC REPORTS
Volume 11, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41598-020-80594-6
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Funding
- National Science Foundation [1813011]
- NIH [R01AI144112, R01AI146917]
- Direct For Mathematical & Physical Scien
- Division Of Mathematical Sciences [1813011] Funding Source: National Science Foundation
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The RNA interference drug ARC-520 has shown significant efficacy in reducing HBV DNA, HBeAg, and HBsAg levels in patients, with a more than 96% efficacy in blocking HBsAg and HBeAg at the start of treatment, gradually decreasing to around 50% within 1-4 months. The combined use of ARC-520 and entecavir maintained a consistent efficacy of over 99.8% in reducing HBV DNA levels, with entecavir mediating continuous decline in HBV DNA and ARC-520 mediating strong but temporary reductions in HBsAg and HBeAg. The developed modeling framework could aid in assessing the development of RNAi drugs for HBV infection.
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.
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