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更新于：2026-06-26
Daplusiran/Tomligisiran
更新于：2026-06-26
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最高研发阶段临床2期 |
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关联
15
项与 Daplusiran/Tomligisiran 相关的临床试验NCT06537414
A Phase 2b, Multi-centre, Randomized, Partially Placebo-controlled, Double-blind Study to Investigate the Safety and Efficacy of Sequential Therapy With Daplusiran/Tomligisiran Followed by Bepirovirsen in Participants With Chronic Hepatitis B Virus on Background Nucleos(t)Ide Analogue Therapy (B-United)
NCT05275023
A Phase 2 Open-label Trial to Evaluate Safety, Efficacy, Tolerability, and Pharmacodynamics of a Combination of JNJ-73763989, Nucleos(t)Ide Analogs, and a PD-1 Inhibitor in Chronic Hepatitis B Patients
NCT05123599
A Phase 1b, Open-label, Single-arm, Multicenter Study to Assess Efficacy, Safety, and Tolerability of Treatment With JNJ-73763989, JNJ-64300535, and Nucleos(t)Ide Analogs in Virologically Suppressed, HBeAg-negative Participants With Chronic Hepatitis B Virus Infection
100 项与 Daplusiran/Tomligisiran 相关的临床结果
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100 项与 Daplusiran/Tomligisiran 相关的转化医学
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100 项与 Daplusiran/Tomligisiran 相关的专利（医药）
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12
项与 Daplusiran/Tomligisiran 相关的文献（医药）2026-05-01JOURNAL OF HEPATOLOGY
siRNA JNJ-73763989 decreases HBsAg and HDV RNA in NA-treated hepatitis D patients but may cause ALT flares
Article
作者: Akarca, Ulus Salih ; Gane, Ed ; Jezorwski, John ; Morozov, Viacheslav ; Yilmaz, Gurdal ; Wedemeyer, Heiner ; Buti, Maria ; Fehmi Tabak, Ömer ; Bakala, Adam ; Aleman, Soo ; Pehlivanov, Nonko ; Biermer, Michael ; Lampertico, Pietro ; Lenz, Oliver ; Verbinnen, Thierry ; Agarwal, Kosh ; Forns, Xavier ; Kakuda, Thomas N
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 log10 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) 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 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.
2026-05-01GUT
Peginterferon alpha-2a add-on to siRNA JNJ-73763989 in untreated patients with HBeAg-positive chronic hepatitis B virus (HBV) infection: the phase 2 REEF-IT study
Article
作者: Biermer, Michael ; Chuang, Wan-Long ; Buti, Maria ; Klyashtornyy, Vladislav ; Jezorwski, John ; Guinard-Azadian, Carine ; Verbinnen, Thierry ; Lenz, Oliver ; Asselah, Tarik ; Kakuda, Thomas Naoki ; Kurosaki, Masayuki ; Kennedy, Patrick T F ; Yilmaz, Gurdal ; Fung, Scott
Background:
In the hepatitis B e antigen positive (HBeAg+) chronic infection disease phase, approved treatments have limited effects on hepatitis B surface antigen (HBsAg) and HBeAg.
Objective:
The phase 2 REEF-IT study (
NCT04439539
) assessed safety, efficacy and pharmacokinetics of pegylated interferon-α2a (PegIFN-α2a) add-on to JNJ-73763989 (JNJ-3989)±bersacapavir+nucleos(t)ide analogues (NA) in not currently treated, HBeAg+chronic hepatitis B.
Design:
Participants received JNJ-3989 (200 mg every 4 weeks)+NA±bersacapavir (250 mg daily) for 36–52 weeks (induction) followed by 12 weeks of PegIFN-α2a (180 µg weekly) add-on. The primary endpoint was the proportion of participants with HBsAg seroclearance 24 weeks after stopping all treatment including NA. Changes in viral markers, safety and pharmacokinetics were assessed.
Results:
49/54 (91%) enrolled participants completed the study; 52% were male, with mean age of 33.6 years. No participant achieved the primary endpoint; one met NA completion criteria. 11/54 (20.4%) participants achieved HBsAg seroclearance at least once, 6 of them maintained it until Follow-up Week 48 (FUW48). Overall mean (SE) change from baseline in HBsAg of –2.85 (0.13), –3.61 (0.18) and –2.63 (0.26)log
10
IU/mL were observed at end of induction, end of treatment and FUW48. 16/53 (30.2%) participants reached HBeAg seroclearance at least once; 12 maintained it until FUW48. Similar proportions of participants experienced an adverse event (AE) during induction (83.3%), PegIFN-α2a add-on (85.7%) and follow-up (64.7%). There were no deaths or serious AEs; two participants discontinued PegIFN-α2a.
Conclusions:
In this population, adding PegIFN-α2a increased HBsAg declines after reductions by JNJ-3989; 20.4% achieved HBsAg seroclearance at least once. Treatment was generally safe with acceptable tolerability.
Trial registration number:
NCT04439539
.
2025-12-01JHEP Reports
Viral sequence analysis of chronic hepatitis B patients treated with the siRNA JNJ-73763989 in phase II clinical trials
Article
作者: De Meyer, Sandra ; Augustyns, Ilse ; Jezorwski, John ; Grant, Craig ; Verbinnen, Thierry ; Yuen, Man-Fung ; Lenz, Oliver ; Agarwal, Kosh ; Lathouwers, Erkki ; Biermer, Michael
Background & Aims:
JNJ-73763989 (JNJ-3989) is a small-interfering RNA composed of two triggers targeting the HBsAg and HBx protein open reading frame, designed to target all HBV RNAs for degradation. JNJ-3989 + nucleos(t)ide analogue (NA) treatment dose-dependently reduced chronic hepatitis B (CHB) viral antigens. Viral sequence changes in the JNJ-3989 S-/X-trigger target regions were evaluated at baseline, on-treatment, and in patients with virologic relapse (VR) after discontinuation of all treatment in REEF-1 (NCT03982186) and REEF-2 (NCT0412954) studies.
Methods:
HBV DNA/RNA was extracted from plasma samples, and the HBV genome was sequenced using next-generation sequencing. Nucleotide variants were defined as changes vs. the universal HBV reference sequence (read frequency >15%).
Results:
Baseline polymorphisms in the JNJ-3989 target region complementary to positions 2-18 of the S-/X-trigger were present in 10.1% and 2.4% of not currently treated patients, respectively, with no relevant impact on JNJ-3989-induced HBsAg decline. Variants at X-trigger target region positions of interest (POI) were more frequently observed off treatment in JNJ-3989-treated virologically suppressed (VS) patients with VR vs. NA-control arm VS patients with VR (55.8% vs. 5.7%, respectively). Variants at S-trigger POI were observed off treatment in 32.1% and 19.4% of JNJ-3989- and NA-control treated VS patients with VR, respectively. Off-treatment HBsAg kinetics did not differ between JNJ-3989-treated patients with and without variants in S-/X-trigger target POI during VR.
Conclusion:
Baseline sequence polymorphisms did not impact JNJ-3989 treatment response. JNJ-3989-treated patients who experienced VR post-treatment had variants in the X-trigger target region during VR, but not at baseline or on-treatment, suggesting that X-trigger variants developed off treatment in JNJ-3989-treated patients. The presence of these variants did not impact off-treatment HBsAg kinetics.
ClinicalTrialgov Identifiers:
NCT03982186 and NCT0412954.
Impact and implications:
Small-interfering RNA (siRNA) therapy with JNJ-3989 in patients with chronic hepatitis B induces potent, dose-dependent reductions in viral antigens, though the magnitude of decline varies among individuals. Baseline nucleotide polymorphisms in JNJ-3989 trigger target regions did not account for variability in HBsAg or HBeAg responses. Substitutions in siRNA trigger target regions were frequently detected during and after virologic relapse in JNJ-3989-treated patients, confirming antiviral target engagement. However, the emergence of these variants did not affect off-treatment HBsAg or HBV DNA kinetics. This study provides the first comprehensive clinical virology analysis of siRNA-based therapy in HBV infection, offering insights relevant to the broader development of antiviral siRNA therapeutics. The clinical significance of X-trigger substitutions for potential re-treatment with JNJ-3989 or other HBV-targeting siRNAs remains to be determined.ClinicalTrial.gov Identifiers: NCT03982186 and NCT0412954.
100 项与 Daplusiran/Tomligisiran 相关的药物交易
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研发状态
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 慢性丁型肝炎 | 临床2期 | 美国 | 2020-09-28 | |
| 慢性丁型肝炎 | 临床2期 | 美国 | 2020-09-28 | |
| 慢性丁型肝炎 | 临床2期 | 日本 | 2020-09-28 | |
| 慢性丁型肝炎 | 临床2期 | 日本 | 2020-09-28 | |
| 慢性丁型肝炎 | 临床2期 | 澳大利亚 | 2020-09-28 | |
| 慢性丁型肝炎 | 临床2期 | 澳大利亚 | 2020-09-28 | |
| 慢性丁型肝炎 | 临床2期 | 巴西 | 2020-09-28 | |
| 慢性丁型肝炎 | 临床2期 | 巴西 | 2020-09-28 | |
| 慢性丁型肝炎 | 临床2期 | 法国 | 2020-09-28 | |
| 慢性丁型肝炎 | 临床2期 | 法国 | 2020-09-28 |
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临床结果
临床结果
适应症
分期
评价
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临床2期 | 22 | JNJ-3989 + NA (Chronic Hepatitis D) | 廠鏇鏇觸願廠鹽遞簾醖(鹽選網艱憲繭網築築壓) = 願顧膚壓築鑰糧糧築構 鏇襯顧繭簾廠膚網鹹醖 (憲範鑰鬱網鏇繭窪襯壓 ) 更多 | 积极 | 2026-05-01 | ||
placebo + NA | 鏇醖願淵鹹築膚窪鹽鬱(憲繭範遞壓遞廠遞襯艱) = 齋繭觸壓選築鹹淵壓鹹 衊壓淵窪襯醖蓋獵膚糧 (積廠壓壓壓鏇鹽願範糧, 0.04) 更多 | ||||||
临床2期 | 慢性乙型肝炎 HBsAg | HBx protein open reading frame | HBV RNAs | 479 | JNJ-3989 + nucleos(t)ide analogue (NA) | 簾膚醖窪衊願網願餘糧(繭簾願顧繭淵憲窪夢餘) = 積齋夢鏇鹹築繭鹹選製 鹽積鏇遞鹽餘憲艱齋糧 (觸鏇構獵範蓋壓顧憲鑰 ) 更多 | 积极 | 2025-12-01 | |
临床2期 | 54 | 鹽範衊簾鹹壓衊憲窪醖(齋淵顧繭觸網範齋餘鬱) = 襯餘鏇鏇齋衊鹹窪鬱壓 齋餘襯壓衊窪製獵鹹鹹 (壓醖窪顧夢糧獵齋鏇醖 ) 更多 | 积极 | 2025-11-04 | |||
临床2期 | 48 | JNJ-3989 ± bersacapavir + NA + PegIFN-α2a (HBeAg-positive + HBeAg-negative) | 鹽鏇繭構淵糧鬱積憲簾(簾繭衊艱製憲鹽餘製窪) = 糧獵鏇夢範積網廠製艱 襯選蓋簾壓壓積網齋鹽 (膚鬱網醖築獵選選醖鹽 ) | 不佳 | 2025-10-01 | ||
临床2期 | 37 | JNJ-73763989 (JNJ-3989)+Nivolumab (JNJ-73763989 (JNJ-3989) + Nivolumab (1 Infusion) + NA) | 鬱餘積憲願壓鏇鏇願鹹 = 襯淵齋餘遞範糧範獵餘 網窪窪壓鏇選觸衊範遞 (鬱淵膚鏇積範鏇製膚醖, 範憲蓋鏇淵壓顧窪築憲 ~ 糧顧鬱齋選顧憲遞顧鏇) 更多 | - | 2025-02-10 | ||
Nivolumab+JNJ-3989 (JNJ-3989 + Nivolumab (3 Infusions) + NA) | 鬱餘積憲願壓鏇鏇願鹹 = 齋蓋選醖鏇製糧壓繭選 網窪窪壓鏇選觸衊範遞 (鬱淵膚鏇積範鏇製膚醖, 遞夢衊窪齋壓製糧鬱膚 ~ 選簾糧顧廠夢觸齋觸簾) 更多 | ||||||
临床2期 | 130 | (Arm 1: JNJ-73763989 (200 Milligrams [mg])+JNJ-56136379 (250 mg)+NA) | 遞鹹襯鏇鬱遞夢積築廠 = 鑰顧鬱範選膚遞襯憲鹽 蓋願繭簾憲鏇構糧範鬱 (憲憲蓋廠蓋糧壓壓襯觸, 鏇觸衊築醖鬱遞構構鹽 ~ 襯願衊膚範齋憲願觸製) 更多 | - | 2024-07-31 | ||
Nucleos(t)Ide Analog (Arm 2: Nucleos(t)Ide Analog (NA)) | 遞鹹襯鏇鬱遞夢積築廠 = 鹹蓋鹽顧鹽齋鏇網繭膚 蓋願繭簾憲鏇構糧範鬱 (憲憲蓋廠蓋糧壓壓襯觸, 餘餘夢獵餘鑰醖憲願獵 ~ 鬱網夢觸獵遞製齋壓壓) 更多 | ||||||
临床2期 | 48 | (TP 2:JNJ-3989 200 mg+JNJ-6379 250 mg+PegIFN-alpha2a 180 mcg+NA) | 艱網簾範築壓艱範鏇選 = 糧膚齋獵積壓製鹹鬱襯 構構範蓋鏇蓋構鑰鬱膚 (憲蓋襯構鏇簾壓衊繭廠, 鹽積築夢廠製積蓋襯鏇 ~ 艱餘積鹽淵網艱膚範獵) 更多 | - | 2024-07-03 | ||
JNJ-73763989+JNJ-56136379 (TP 1:JNJ-73763989 200 mg+JNJ-56136379 250 mg+NA) | 製鏇範鹽衊餘簾鬱鬱鹽 = 繭艱構觸觸淵廠餘夢齋 顧蓋廠鏇繭廠醖壓壓齋 (醖顧餘鹽蓋顧鹽艱廠糧, 觸齋鹹醖網鑰衊蓋膚夢 ~ 網簾顧繭願齋製膚糧廠) 更多 | ||||||
临床2期 | 慢性乙型肝炎 Hepatitis B e-antigen (HBeAg)-negative | HBsAg | 130 | 築鹹壓壓膚製構廠餘醖(製簾繭醖窪艱齋範鏇淵) = 憲製願淵鏇衊糧糧蓋糧 構夢構獵憲網糧構繭鏇 (襯簾糧夢遞網齋襯構遞 ) 更多 | 不佳 | 2024-04-05 | ||
Placebos for JNJ-3989 and JNJ-6379 + active NA | 築鹹壓壓膚製構廠餘醖(製簾繭醖窪艱齋範鏇淵) = 齋積範積憲遞餘壓夢衊 構夢構獵憲網糧構繭鏇 (襯簾糧夢遞網齋襯構遞 ) 更多 | ||||||
临床2期 | 1 | 積繭夢淵鹹廠鏇艱壓願 = 齋觸獵鏇淵顧壓選夢夢 築醖夢積製鹹艱廠鬱膚 (襯簾繭構齋齋獵觸鏇窪, 繭蓋壓鹽顧糧願選鹽鹽 ~ 獵繭窪觸鬱窪衊鬱顧獵) 更多 | - | 2024-03-06 | |||
临床2期 | 24 | 壓網選鹽範廠網壓廠鑰(繭鑰願膚艱蓋積膚築淵) = 網醖顧窪壓製廠鏇獵顧 築鑰構憲鑰鹽鏇壓積齋 (夢鬱衊鏇願憲鬱簾艱積, 鹽餘觸壓憲積鹹遞廠膚 ~ 淵膚憲構築獵鏇繭獵糧) 更多 | - | 2024-03-05 | |||
壓網選鹽範廠網壓廠鑰(繭鑰願膚艱蓋積膚築淵) = 鏇製獵夢壓膚窪糧齋蓋 築鑰構憲鑰鹽鏇壓積齋 (夢鬱衊鏇願憲鬱簾艱積, 艱衊構觸築網遞憲壓餘 ~ 襯鹽鬱衊鬱夢簾膚簾製) 更多 |
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