Journal of hepatology · 2026
siRNA JNJ-73763989 decreases HBsAg and HDV RNA in NA-treated hepatitis D patients but may cause ALT flares.
СтатьяРандомизированное исследованиеКлиническое исследование II фазыНазвание и аннотация: Перевод в очереди
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Wedemeyer Heiner, Gane Ed, Agarwal Kosh, Tabak Ömer Fehmi, Forns Xavier, Akarca Ulus Salih, Morozov Viacheslav, Aleman Soo, Buti Maria, Yilmaz Gurdal, Lampertico Pietro, Jezorwski John, Kakuda Thomas N, Bakala Adam, Pehlivanov Nonko, Verbinnen Thierry, Lenz Oliver, Biermer Michael
Аннотация
BACKGROUND & AIMS: HDV requires HBsAg for viral assembly. The siRNA JNJ-73763989 (JNJ-3989) targets all HBV transcripts and reduces HBsAg in patients with chronic hepatitis B. We evaluated whether HBsAg reduction with JNJ-3989 leads to a decline in HDV RNA and ALT in patients with chronic hepatitis D (CHD).
METHODS: REEF-D, a two-part, phase II, 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 subcutaneously every 4 weeks) + nucleos(t)ide analogue (NA) for 144 weeks (active arm, n = 17) or for 96 weeks after 52 weeks of placebo + NA (deferred treatment arm, n = 5). During the 48-week follow-up period, NA therapy was continued. The primary endpoint was achievement of a ≥2 log10 IU/ml reduction of HDV RNA from baseline (or <LLOQ) and normal ALT at treatment week (TW) 48.
RESULTS: The primary endpoint was achieved by 4/17 (24%) participants in the active arm and 0/5 in the deferred treatment 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) log10 IU/ml vs. 0.07 (0.04) log10 IU/ml for HBsAg and 1.52 (0.38) log10 IU/ml vs. 0.23 (0.15) log10 IU/ml for HDV RNA in active and deferred treatment arms, respectively. Four of five participants in the control arm rolled-over to JNJ-3989 at TW52 including two experiencing subsequent ALT elevations. No ALT elevations were seen in the seven 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).
GOV IDENTIFIER: NCT04535544 IMPACT AND IMPLICATIONS: In the REEF-D study of patients with chronic hepatitis D, the reduction of 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 chronic hepatitis D.
METHODS: REEF-D, a two-part, phase II, 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 subcutaneously every 4 weeks) + nucleos(t)ide analogue (NA) for 144 weeks (active arm, n = 17) or for 96 weeks after 52 weeks of placebo + NA (deferred treatment arm, n = 5). During the 48-week follow-up period, NA therapy was continued. The primary endpoint was achievement of a ≥2 log10 IU/ml reduction of HDV RNA from baseline (or <LLOQ) and normal ALT at treatment week (TW) 48.
RESULTS: The primary endpoint was achieved by 4/17 (24%) participants in the active arm and 0/5 in the deferred treatment 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) log10 IU/ml vs. 0.07 (0.04) log10 IU/ml for HBsAg and 1.52 (0.38) log10 IU/ml vs. 0.23 (0.15) log10 IU/ml for HDV RNA in active and deferred treatment arms, respectively. Four of five participants in the control arm rolled-over to JNJ-3989 at TW52 including two experiencing subsequent ALT elevations. No ALT elevations were seen in the seven 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).
GOV IDENTIFIER: NCT04535544 IMPACT AND IMPLICATIONS: In the REEF-D study of patients with chronic hepatitis D, the reduction of 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 chronic hepatitis D.