RNA interference therapy with ARC-520 Injection results in long term off-therapy antigen reductions in treatment naïve, HBeAg positive and negative patients with chronic HBV

Abstract

Background and Aims: ARC-520 Injection (ARC), a RNA interference drug, targets cccDNA-derived mRNA in chronic hepatitis B patients (CHB).We previously reported HBsAg reduction and safety in a multidose extension study. Here we report additional antigen reductions observed off-therapy during a 6-month follow-up period. Method: 8 CHB (5 HBeAg-neg, 3 HBeAg-pos) received up to 9 doses of 4 mg/kg ARC once every 4 weeks with daily entecavir (ETV). Treatment naïve CHB who previously received a single IV dose of 4 mg/kg ARC and started daily ETV on the same day were eligible. Viral DNA and antigen knockdown (KD) were measured at regular intervals [qHBsAg, HB core-related antigen (qHBcrAg) in all, qHBeAg in HBeAg-pos]. Patients continued their daily ETV post ARC and were followed for an additional 6 months. Results: Patients received ETV for 34 to 44weeks after a single dose of ARC before receiving the first ARC dose of the multi-dose extension. After a single dose of ARC, qHBsAg in 3 of 3 HBeAg-pos and 1 of 5 HBeAg-neg remained below baseline. Multi-dose re-challenge resulted in additional qHBsAg KD in all CHB. Two of three HBeAgpos and one of five HBeAg-neg had mild ALT elevations post ARC which coincided with additional antigen reductions. In the HBeAgpos, mean HBsAg reduction w as 3.0 log and max reduction 4.6log with one patient achieving an HBsAg level of 1 IU/ml. This patient seroconverted for HBeAg post ARC with mean HBeAg reduction of 2.8 log and max reduction of 4.2 log to LLOQ. Mean HBcrAg reductionwas 3.4 log with max reduction of 6.1log in HBeAg-pos. In HBeAg-neg, mean HBsAg KD was 1.0 log and maximum was 2.1 log, HBcrAg reduction was 0.7 log in the only patient positive for this marker. Conclusion: (1) Consistent with our previous reports, ARC was more active in HBeAg-pos, presumably due to more cccDNA-driven antigen production in treatment naïve HBeAg-pos and a higher fraction of qHBsAg from integrated DNA in HBeAg-neg. (2) Mild ALT elevations off ARC therapy coincided with additional antigen reductions in 2/3 HBeAg-pos and 1/5 HBeAg-neg. (3) Antigen reduction through RNAi in combination with oral ETV may lead to sustained control of CHB off-therapy.