Short interfering RNA JNJ-3989 combination therapy in chronic hepatitis B shows potent reduction of all viral markers but no correlate was identified for HBsAg reduction and baseline factors

Abstract

Background and aims: Short RNA interference (siRNA) therapy with JNJ-3989 includes both S and X triggers which silence all HBV RNA ranscripts. In AROHBV1001 (phase 2a; NCT03365947), JNJ-3989 (3 monthly doses 25–400 mg) + a nucleos (t)ide analogue (NA) demonstrated antiviral activity in patients (pts) with chronic hepatitis B (CHB). Here we assessed baseline factors associated with HBsAg reduction and compared the effect of JNJ-3989 against the viral markers HBsAg, HBeAg, HBcrAg and HBV RNA. Method: Data from NA experienced or naïve, HBeAg ± ve CHB pts who received 3 s.c. JNJ-3989 doses (days 1, 27, 57) of 100 (n = 8), 200 (n = 8), 300 (n = 16) or 400 mg (n = 8) were used. Pts started/ continued with an NA on day 1 and continued throughout the study to Day 392. HBsAg, HBeAg, HBV RNA, HBcrAg was assessed using standard assays. Results: Treatment with JNJ-3989 + an NA resulted in mean (range) HBsAg reductions from baseline at nadir of 1.93 (0.73, 3.84) log10 IU/ ml with 39/40 pts (98%) achieving >1log10 IU/ml reduction. Baseline HBsAg levels and other viral markers, treatment status (naïve vs NA suppressed) and BMI had no impact on HBsAg reduction. A trend for greater reduction in HBsAg was seen in HBeAg +ve vs HBeAg -ve pts mainly driven by a few (n = 4) HBeAg +ve females who showed the greatest HBsAg response (>2.5 reduction at nadir). Impact of race IL28B status could not be assessed since the majority of pts were Asians with IL28B CC genotype. HBV genotype had no impact on HBsAg reduction but a limited number of pts had data available. Pronounced reductions in HBeAg, HBcrAg and HBV RNA were observed, although HBeAg and HBcrAg reductions were generally smaller than for HBsAg. In pts with baseline levels >1log above LLOQ of the respective marker, the mean (SE, N) reduction at day 113 for HBeAg were −1.47 (0.12, 12) vs −2.12 (0.21, 12) for HBsAg, for HBcrAg −1.20 (0.17, 18) vs −1.97 (0.16, 18) for HBsAg, and −1.93 (0.14, 21) for HBV RNA vs −1.86 (0.15, 21) for HBsAg. Generally, the reductions of the different markers correlated within pts, but individual differences were observed. Conclusion: JNJ-3989 (100–400 mg, Q4W) achieved potent reduction of all viral markers, with trends for more pronounced reductions in HBsAg than other markers, and in HBeAg +ve compared to HBeAg -ve pts. Reductions in HBeAg, HBcrAg and HBV RNA generally correlated with reductions in HBsAg. These findings are being evaluated in larger Phase 2b studies with JNJ-3989 + NA in CHB pts.