Understanding the antiviral effects of RNAi-based therapy in HBeAg-positive chronic hepatitis B infection

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.

Lipid-Based Nanoparticles in the Clinic and Clinical Trials: From Cancer Nanomedicine to COVID-19 Vaccines

“…ARC-520 formulated from interference RNA, which can reduce all RNA transcripts derived from covalently closed circular DNA that leads to reduce viral antigens and hepatitis B virus DNA. However, ARC-520 was terminated due to delivery-associated toxicity [112]. Currently, Dicerna Pharmaceuticals, Inc. has developed LNPs with siRNA (named as DCR-HBVS) targeting the mRNA for the hepatitis B surface antigen (HbsAg) for treatment of chronic hepatitis B.…”

Transaminase Elevations during Treatment of Chronic Hepatitis B Infection: Safety Considerations and Role in Achieving Functional Cure

“…The specificity and activity of both these classes of oligonucleotides is strictly dependent on the perfect homology between the single-stranded (antisense) or double-stranded (RNAi) oligonucleotide and the target region of the mRNA. While in vivo data have been consistent with this mechanism, clinical studies with a variety of these compounds have indicated that off-target stimulation of innate immunity is playing a role in the clinical responses observed [ 9 , 145 ]. Limited data are available from ongoing trials with these compounds.…”

A Mathematical Model for Early HBV and -HDV Kinetics during Anti-HDV Treatment

“…Both the variables and all of the parameters of the model are shown in Table 3. We keep the number of infected cells, I 0 , constant, i.e., ignoring the dynamics of infected cells, such as infection of susceptible cells and/or infected cell proliferation and/or death (assuming a long-infected cell life-span as previously performed [16,17]). Treatment is assumed to solely block HDV production rate p 1 by (1 − ε), where 0 ≤ ε ≤ 1 represents its efficacy.…”