Continued therapy with ABI-H0731+NRTI results in sequential reduction/loss of HBV DNA, HBV RNA, HBeAg, HBcrAg and HBsAg in HBeAg positive patients

Abstract

Background: Standard of care nucleos(t)ide analogs (NrtI) are effective in chronic HBV (CHB) infection, but achieve low rates of sustained responses off therapy. The combination of the HBV Core Inhibitor ABI-H0731 (731) with a NrtI has demonstrated potent antiviral activity in prior clinical studies and is being evaluated in a long-term treatment study. Methods: Studies ABI-H0731-201 and ABI-H0731-202 were 24-wk double-blind, placebo (Pbo)-controlled studies in CHB patients (pts). After 24 wks of treatment, pts could enter the openlabel extension study ABI-H0731-211 and receive 731+NrtI for up to an additional 52 wks. The study diagram summarizes study design, patient flow and monitored parameters. This interim report summarizes data for HBeAg+ pts only. Results: Final Wk 24 results confirmed greater mean log10 declines in HBV DNA (5.27 vs 3.99; p=0.017) and RNA (2.34 vs 0.61; p<0.001) are achieved with 731+ETV vs ETV in Study 202. By Wk 24 in Study 201, the proportion of pts on 731+NrtI vs NrtI achieving DNA “TND” was 69% vs 0% (p<0.001), and the proportion of pts achieving RNA <35 U/mL whose baseline RNA ≥ 35 U/mL was 52% vs 0% (p=0.0013) respectively. There are 64 HBeAg+ pts currently on treatment in Study 211, having received an overall treatment duration of ≥32 wks. Among the 27 HBeAg+ pts receiving 731+NrtI in Study 201, 41% (11/27) have now achieved DNA TND along with RNA <35 U/mL and HBeAg <1 IU/mL. At their last timepoint, Study 202 (Rx naïve) pts now in Study 211 (n=22) have demonstrated mean DNA and RNA declines of 6.1 and 3.0 logs, respectively, with observed mean log changes of ≥0.6 for HBeAg (11 pts ≥0.5, 4 pts ≥1.0), >0.8 log for HBcrAg (7 pts ≥1.0, 3 pts ≥2.0) and ≥0.4 log for HBsAg (7 pts ≥0.5, 3 pts ≥1.0). When, administered in combination with NrtI for up to 1 year, 731 has been well-tolerated, with only mild/moderate adverse events and lab abnormalities, and only a single discontinuation due to a Grade 1 rash. Conclusion: ABIH0731 continues to exhibit a favorable safety and tolerability profile in pts treated for up to 1 yr. The combination of 731+NrtI results in faster, deeper declines in HBV DNA and RNA than NrtI alone, as well as subsequent declines in the surrogate markers of cccDNA (pgRNA, HBeAg and HBcrAg) predictive of cccDNA pool depletion, and HBsAg. The emergent data supports the continued development of ABI-H0731. Updated safety and efficacy data will be presented.