siRNA JNJ-73763989 decreases HBsAg and HDV RNA in NA-treated hepatitis D patients but may cause ALT flares

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Background & Aims HDV requires HBsAg for viral assembly. The siRNA JNJ-73763989 (JNJ-3989) targets all HBV transcripts and reduces HBsAg in CHB patients. We evaluated whether HBsAg reduction with JNJ-3989 leads to decline of HDV RNA and ALT in patients with chronic hepatitis D (CHD). Methods REEF-D, a 2-part, phase 2, randomized, double-blind, placebo-controlled study, enrolled 22 adults with CHD in Part-1. Participants were randomized 4:1 to receive JNJ-3989 (100 mg SC every 4 weeks) + NA for 144 weeks (active arm, n=17) or for 96 weeks after 52 weeks of placebo + NA (deferred treatment arm, n=5). During 48 weeks of follow-up NA was continued. The primary endpoint was achievement of ≥2 log 10 IU/mL reduction of HDV RNA from baseline (or Results The primary endpoint was achieved by 4/17 (24%) in the active arm and 0/5 in the control arm. ALT elevations leading to treatment discontinuation occurred in 12/17 (71%) active-arm participants. Among those on JNJ-3989 treatment at TW48 (n=9) mean (SE) reductions from baseline were 1.75 (0.29) log 10 IU/mL vs 0.07 (0.04) log 10 IU/mL for HBsAg and 1.52 (0.38) log 10 IU/mL vs. 0.23 (0.15) log 10 IU/mL for HDV RNA in active and control arms, respectively. 4/5 participants in the control arm rolled-over to JNJ-3989 at TW52 including 2 experiencing subsequent ALT elevations. No ALT elevations were seen in the 7 participants with screening-HBsAg <10,000 IU/mL. Conclusion This is the first study showing that the HBsAg-targeting siRNA JNJ-3989 can reduce HDV RNA and HBsAg in patients with CHD. Unexpected ALT elevations were seen in 14 of 21 (67%) participants receiving JNJ-3989 (immediate or deferred). Impact and Implications In the REEF-D study of patients with chronic hepatitis D (CHD), the reduction of hepatitis B surface antigen (HBsAg) with the HBsAg targeting siRNA JNJ-73763989 (JNJ-3989) led to HDV RNA decline, and in some participants, to prolonged HDV RNA suppression. Participants with high HBsAg levels (>10,000 IU/mL) at screening experienced unexpected ALT elevations, sometimes severe, with a return to baseline levels after discontinuation of JNJ-3989. Both HDV RNA reduction and ALT elevation are critical observations for a better understanding of HDV biology and the interplay between viral antigens and the infected hepatocyte. Despite the low sample size and majority of participants not completing the planned treatment course, these findings are important for caregivers and researchers developing novel treatment strategies for patients with CHD. ClinicalTrials.gov Identifier: NCT04535544

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