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Daplusiran/Tomligisiran
更新于：2025-05-19
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关联
16
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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10
项与 Daplusiran/Tomligisiran 相关的文献（医药）2025-03-01GUT
Long-term hepatitis B surface antigen response after finite treatment of ARC-520 or JNJ-3989
Article
作者: Wooddell, Christine I ; Mak, Lung Yi ; Lenz, Oliver ; Yuen, Man-Fung ; Biermer, Michael ; Hamilton, James ; Seto, Wai-Kay ; Mao, Xianhua ; Schluep, Thomas ; Davis, Heather L
Background and aims:
RNA interference has been extensively explored in patients with chronic hepatitis B (CHB) infection. We aimed to characterise the long-term efficacy of small interfering RNA (siRNA) on hepatitis B surface antigen (HBsAg) suppression.
Methods:
We prospectively followed up participants with CHB who received siRNA, either ARC-520 or JNJ-73763989 (JNJ-3989), in combination with nucleoside analogue (NUC) in our centre. Participants enrolled included 15 receiving 4 monthly injections of ARC-520, 38 receiving 3 injections of JNJ-3989 at 1, 2 or 4 weekly intervals and 5 receiving placebo in previous clinical trials. Serial blood sampling was performed according to the original protocols and on completion every 24 weeks until last follow-up (LFU) with mean duration of 52.5 months.
Results:
Among the 53 NUC+siRNA-treated participants (mean age 46.8, baseline HBsAg 3.08 log, 83% previously on NUC, 34% hepatitis B e antigen+), the proportion of patients achieving HBsAg seroclearance or <100 IU/mL at LFU was 1.9% and 32.1%, respectively, compared with 0% and 0% for placebo. Among siRNA-recipients, 48.5% and 5.0% of those with HBsAg <100 IU/mL and >100 IU/mL at nadir or ≤24 weeks from last dose could maintain or achieve HBsAg <100 IU/mL at LFU, respectively. Compared with placebo recipients, siRNA-recipients demonstrated faster overall annual decline of HBsAg (0.08 vs 0.21 log IU/mL/year) contributed predominantly by changes in the first year. Age was negatively correlated with HBsAg reduction at LFU (r=−0.427, p=0.001).
Conclusion:
Short-duration siRNA treatment suppressed HBsAg expression with a prolonged effect for up to 6 years in some participants.
2024-09-01Journal of hepatology
JNJ-73763989 and bersacapavir treatment in nucleos(t)ide analogue-suppressed patients with chronic hepatitis B: REEF-2
Article
作者: van Bömmel, Florian ; Jezorwski, John ; Lonjon-Domanec, Isabelle ; Beumont, Maria ; Lenz, Oliver ; Biermer, Michael ; Buti, Maria ; Mayer, Cristiana ; Kalmeijer, Ronald ; Lampertico, Pietro ; Verbinnen, Thierry ; Vanwolleghem, Thomas ; Kakuda, Thomas N ; Agarwal, Kosh ; Bourliere, Marc ; Muenz, Daniel ; Janczewska, Ewa
BACKGROUND & AIMS:
Functional cure for chronic hepatitis B (CHB) requires finite treatment. Two agents under investigation with the goal of achieving functional cure are the small-interfering RNA JNJ-73763989 (JNJ-3989) and the capsid assembly modulator JNJ-56136379 (JNJ-6379; bersacapavir).
METHODS:
REEF-2, a phase IIb, double-blind, placebo-controlled, randomized study, enrolled 130 nucleos(t)ide analogue (NA)-suppressed hepatitis B e-antigen (HBeAg)-negative patients with CHB who received JNJ-3989 (200 mg subcutaneously every 4 weeks) + JNJ-6379 (250 mg oral daily) + NA (oral daily; active arm) or placebos for JNJ-3989 and JNJ-6379 +active NA (control arm) for 48 weeks followed by 48 weeks off-treatment follow-up.
RESULTS:
At follow-up Week 24, no patients achieved the primary endpoint of functional cure (off-treatment hepatitis B surface antigen [HBsAg] seroclearance). No patients achieved functional cure at follow-up Week 48. There was a pronounced on-treatment reduction in mean HBsAg from baseline at Week 48 in the active arm vs. no decline in the control arm (1.89 vs. 0.06 log10 IU/ml; p = 0.001). At follow-up Week 48, reductions from baseline were >1 log10 IU/ml in 81.5% vs. 12.5% of patients in the active and control arms, respectively, and 38/81 (46.9%) patients in the active arm achieved HBsAg <100 IU/ml vs. 6/40 (15.0%) patients in the control arm. Off-treatment HBV DNA relapse and alanine aminotransferase increases were less frequent in the active arm with 7/77 (9.1%) and 11/41 (26.8%) patients in the active and control arms, respectively, restarting NAs during follow-up.
CONCLUSIONS:
Finite 48-week treatment with JNJ-3989 + JNJ-6379 + NA resulted in fewer and less severe post-treatment HBV DNA increases and alanine aminotransferase flares, and a higher proportion of patients with off-treatment HBV DNA suppression, with or without HBsAg suppression, but did not result in functional cure.
IMPACT AND IMPLICATIONS:
Achieving a functional cure from chronic hepatitis B (CHB) with finite treatments is a major unmet medical need. The current study assessed the rate of functional cure and clinical outcome after controlled nucleos(t)ide analogue (NA) withdrawal in patients with low levels of HBsAg induced by 48 weeks of treatment with the small-interfering RNA JNJ-3989 and the capsid assembly modulator JNJ-6379 plus NA vs. patients who only received NA treatment. Though functional cure was not achieved by any patient in either arm, the 48-week treatment regimen of JNJ-3989, JNJ-6379, and NA did result in more patients achieving pronounced reductions in HBsAg, with clinically meaningful reductions maintained for up to 48 weeks off all treatments, as well as fewer off-treatment HBV DNA increases and alanine aminotransferase flares. These findings provide valuable insights for future studies investigating potential finite treatment options, while the reported efficacy and safety outcomes may be of interest to healthcare providers making treatment decisions for patients with NA-suppressed HBeAg-negative CHB.
CLINICALTRIALS:
GOV IDENTIFIER:
NCT04129554.
2023-09-01The lancet. Gastroenterology & hepatology
Efficacy and safety of the siRNA JNJ-73763989 and the capsid assembly modulator JNJ-56136379 (bersacapavir) with nucleos(t)ide analogues for the treatment of chronic hepatitis B virus infection (REEF-1): a multicentre, double-blind, active-controlled, randomised, phase 2b trial
Article
BACKGROUND:
JNJ-73763989 (JNJ-3989), a small interfering RNA, targets all hepatitis B virus (HBV) RNAs, reducing all HBV proteins. JNJ-56136379 (JNJ-6379; also known as bersacapavir), a capsid assembly modulator, inhibits HBV replication. We aimed to evaluate the efficacy (ie, antiviral activity) and safety of these therapeutics in combination with nucleos(t)ide analogues in patients with chronic hepatitis B.
METHODS:
The REEF-1 multicentre, double-blind, active-controlled, randomised, phase 2b study was done at 108 hospitals or outpatient centres across 19 countries in Asia, Europe, and North and South America. We included patients aged 18-65 years with chronic hepatitis B (defined as HBsAg positivity at screening and at least 6 months before screening or alternative markers of chronicity [eg, HBV DNA]), including those not currently treated, virologically suppressed, HBeAg positive, and HBeAg negative. Patients were randomly assigned (1:1:2:2:2:2) via permuted block randomisation according to a computer-generated schedule to receive oral nucleos(t)ide analogues once per day plus placebo (control group); oral JNJ-6379 250 mg daily plus nucleos(t)ide analogues (JNJ-6379 dual group); nucleos(t)ide analogues plus subcutaneously injected JNJ-3989 at doses of 40 mg (JNJ-3989 dual 40 mg group), 100 mg (JNJ-3989 dual 100 mg group), or 200 mg (JNJ-3989 dual 200 mg group) every 4 weeks; or JNJ-6379 250 mg plus JNJ-3989 100 mg every 4 weeks plus nucleos(t)ide analogues (triple group) for 48 weeks followed by a follow-up phase. An interactive web response system provided concealed treatment allocation, and investigators remained masked to the intervention groups until the primary analysis at week 48. The primary endpoint was the proportion of patients meeting predefined nucleos(t)ide analogue-stopping criteria (alanine aminotransferase <3 × upper limit of normal, HBV DNA below the lower limit of quantitation, HBeAg negative, and HBsAg <10 IU/mL) at week 48. All patients who received at least one dose of study drug were included in the analysis population used for primary efficacy assessment, excluding those who withdrew because of COVID-19-related reasons, withdrew before week 44, or had no efficacy data (ie, the modified intention-to-treat population). Safety was assessed in all participants who received at least one dose of study drugs. This trial is registered with ClinicalTrials.gov, NCT03982186. The study has been completed.
FINDINGS:
Between Aug 1, 2019, and April 26, 2022, 470 patients (310 [66%] male and 244 [52%] White) were randomly assigned: 45 to the control group, 48 to the JNJ-6379 dual group, 93 to the JNJ-3989 dual 40 mg group, 93 to the JNJ-3989 dual 100 mg group, 96 to the JNJ-3989 dual 200 mg group, and 95 to the triple group. At week 48, five (5%; 90% CI 2-11) of 91 patients in the JNJ-3989 dual 40 mg group, 15 (16%; 10-24) of 92 in the JNJ-3989 dual 100 mg group, 18 (19%; 13-27) of 94 in the JNJ-3989 dual 200 mg group, eight (9%; 4-15) of 94 in the triple group, and one (2%; 0-10) of 45 in the control group met nucleos(t)ide analogue stopping criteria. No patients in the JNJ-6379 dual group met stopping criteria. 38 (81%) patients who met nucleos(t)ide analogue-stopping criteria at week 48 were virologically suppressed and HBeAg negative at baseline. Ten (2%) of 470 patients had serious adverse events during the treatment phase, and two patients (one each from the JNJ-3989 dual 200 mg group [exercise-related rhabdomyolysis] and the triple group [increase in ALT or AST]) had serious adverse events related to study treatment. During follow-up, 12 (3%) of 460 patients had a serious adverse event; one (<1%), a gastric ulcer, was considered to be related to nucleos(t)ide analogues and occurred in a patient from the JNJ-3989 dual 200 mg group. 29 (6%) of 460 patients in the treatment phase and in ten (2%) of 460 patients in the follow-up phase had grade 3 or 4 adverse events. Five (1%) of 470 patients discontinued treatment due to adverse events, and there were no deaths.
INTERPRETATION:
Although treatment with JNJ-3989 led to a dose-dependent response for meeting nucleos(t)ide analogue-stopping criteria, it rarely led to HBsAg seroclearance. However, most patients treated with JNJ-3989 had clinically meaningful reductions in HBsAg that might contribute to a liver environment conducive to better immune control and, in turn, might improve the response to immune-modulating therapies.
FUNDING:
Janssen Research and Development.
54
项与 Daplusiran/Tomligisiran 相关的新闻（医药）2025-05-19
·同写意
临床3期siRNA临床2期加速审批
2025-05-15
并购引进/卖出临床2期
2025-05-08
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siRNA临床2期寡核苷酸核酸药物临床1期
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 | 37 | JNJ-73763989 (JNJ-3989)+Nivolumab (JNJ-73763989 (JNJ-3989) + Nivolumab (1 Infusion) + NA) | 鹹廠壓齋醖壓糧衊鬱簾 = 廠淵遞艱範壓觸餘選積 鬱願繭遞顧廠醖選醖遞 (蓋憲遞網廠鹽醖廠遞遞, 餘醖顧壓壓鹽餘蓋淵夢 ~ 鹹憲窪鬱膚鹹齋範積積) 更多 | - | 2025-02-10 | ||
Nivolumab+JNJ-3989 (JNJ-3989 + Nivolumab (3 Infusions) + NA) | 鹹廠壓齋醖壓糧衊鬱簾 = 獵蓋鹽顧淵選構壓鹹鹽 鬱願繭遞顧廠醖選醖遞 (蓋憲遞網廠鹽醖廠遞遞, 繭觸鹽製繭鬱糧構鹹構 ~ 鹽簾廠遞簾壓範構淵憲) 更多 | ||||||
临床2期 | 130 | (Arm 1: JNJ-73763989 (200 Milligrams [mg])+JNJ-56136379 (250 mg)+NA) | 觸衊襯鹹觸繭膚夢廠鑰 = 窪衊齋廠醖網觸糧艱遞 遞襯窪齋夢積顧窪選窪 (憲獵繭選遞顧網窪範構, 選簾遞構壓糧選構簾繭 ~ 膚鹽襯繭構膚醖獵製遞) 更多 | - | 2024-07-31 | ||
Nucleos(t)Ide Analog (Arm 2: Nucleos(t)Ide Analog (NA)) | 觸衊襯鹹觸繭膚夢廠鑰 = 壓網蓋窪遞衊繭壓鹹築 遞襯窪齋夢積顧窪選窪 (憲獵繭選遞顧網窪範構, 築鏇廠顧淵鹹餘襯壓艱 ~ 構夢廠齋觸網鏇築範壓) 更多 | ||||||
临床2期 | 48 | (TP 2:JNJ-3989 200 mg+JNJ-6379 250 mg+PegIFN-alpha2a 180 mcg+NA) | 鏇廠遞淵憲廠網鑰願顧 = 鹹鹽鏇遞鏇膚鏇衊糧夢 選醖製選鬱鑰繭壓壓淵 (繭夢構鹽鹹糧觸醖窪壓, 遞艱網膚遞構糧網網顧 ~ 積夢築衊窪築網鹹壓製) 更多 | - | 2024-07-03 | ||
JNJ-73763989+JNJ-56136379 (TP 1:JNJ-73763989 200 mg+JNJ-56136379 250 mg+NA) | 積糧夢鏇淵繭築餘製鏇 = 積蓋糧壓衊獵遞構製繭 繭餘積鹹願廠網糧製醖 (顧鹽獵選範鏇憲範鑰鹹, 簾衊顧糧鹹製糧艱繭衊 ~ 鬱築齋積襯網鏇鹽鬱餘) 更多 | ||||||
临床2期 | 慢性乙型肝炎 Hepatitis B e-antigen (HBeAg)-negative | HBsAg | 130 | 鹽繭築製觸願膚獵夢憲(鏇餘壓鏇選窪餘願齋繭) = 襯艱繭醖淵願鹽築襯艱 糧鹽繭願蓋顧蓋憲範鬱 (窪鑰夢艱獵築醖顧壓簾 ) 更多 | 不佳 | 2024-04-05 | ||
Placebos for JNJ-3989 and JNJ-6379 + active NA | 鹽繭築製觸願膚獵夢憲(鏇餘壓鏇選窪餘願齋繭) = 選繭選選糧窪顧艱鬱糧 糧鹽繭願蓋顧蓋憲範鬱 (窪鑰夢艱獵築醖顧壓簾 ) 更多 | ||||||
临床2期 | 1 | JNJ-73763989+PegIFN-alpha-2a | 廠窪遞淵醖餘選鏇範觸 = 鑰獵鬱壓觸網膚淵鹹齋 築鏇繭網選簾製獵觸鏇 (壓願蓋構構鹽齋範願鹹, 觸壓顧顧蓋鹹鏇範醖廠 ~ 襯範蓋壓夢膚膚壓鹹製) 更多 | - | 2024-03-06 | ||
临床2期 | 24 | (Panel 1) | 鏇範範窪製艱艱鹽選獵(鑰壓顧餘衊憲鹽夢壓願) = 網鏇繭糧衊廠鹹淵積淵 壓窪鑰糧鬱築衊夢鹹艱 (鹹積窪網醖壓糧窪鬱襯, 鏇願簾艱憲製獵簾壓顧 ~ 製製憲齋顧範製糧簾網) 更多 | - | 2024-03-05 | ||
(Panel 2) | 鏇範範窪製艱艱鹽選獵(鑰壓顧餘衊憲鹽夢壓願) = 鹹製膚廠憲齋製鑰構網 壓窪鑰糧鬱築衊夢鹹艱 (鹹積窪網醖壓糧窪鬱襯, 廠鹹夢壓鑰網蓋餘簾網 ~ 簾鑰遞願願齋願餘糧築) 更多 | ||||||
临床2期 | 慢性乙型肝炎 一线 | 470 | 窪顧獵鹽鬱壓鑰鏇淵構(遞衊齋構醖廠衊鑰網積) = 餘廠鹽憲蓋積鏇鬱網襯 鹽鹽衊製廠糧餘醖醖鹽 (憲鹹夢顧範襯齋艱窪衊, 2 ~ 11) | 积极 | 2023-07-10 | ||
窪顧獵鹽鬱壓鑰鏇淵構(遞衊齋構醖廠衊鑰網積) = 鹹製夢窪觸選蓋糧觸窪 鹽鹽衊製廠糧餘醖醖鹽 (憲鹹夢顧範襯齋艱窪衊, 10 ~ 24) | |||||||
临床1期 | - | 18 | (100 mg) | 願觸窪夢鹹艱顧顧鹽糧(鑰鹽糧窪壓遞簾繭醖觸) = All treatment-emergent adverse events (AEs) were mild and resolved by study end. 齋鏇膚艱廠淵繭襯憲網 (鏇簾餘壓齋鑰構選積選 ) | 积极 | 2022-11-22 | |
(200 mg) | |||||||
临床2期 | 114 | JNJ-3989 plus nucleos(t)ide analogue | 構齋艱壓膚壓鏇廠蓋製(糧簾簾鬱餘壓製憲衊夢) = All treatments were well-tolerated, with all five serious adverse events considered unrelated to study drugs 艱鑰鹹糧膚鏇繭積網膚 (簾鏇觸齋衊膚醖鹹築醖 ) 更多 | 积极 | 2022-07-20 | ||
临床2期 | 慢性乙型肝炎 HBeAg Negative | 130 | 網壓壓鏇獵蓋醖膚選遞(鬱餘糧觸淵積獵壓廠鬱) = 淵網憲鹽壓鏇築獵襯廠 鹹艱積觸簾襯廠遞鑰鏇 (艱遞憲鹹遞糧獵繭遞鏇 ) 更多 | 不佳 | 2022-06-27 | ||
ETV/TDF/TAF+Placebo+Placebo | 網壓壓鏇獵蓋醖膚選遞(鬱餘糧觸淵積獵壓廠鬱) = 廠製淵廠廠糧壓淵網繭 鹹艱積觸簾襯廠遞鑰鏇 (艱遞憲鹹遞糧獵繭遞鏇 ) 更多 |
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