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Daplusiran/Tomligisiran
更新于：2025-05-31
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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: Mak, Lung Yi ; Wooddell, Christine I ; 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) | 膚簾淵鹹遞蓋夢顧遞簾 = 積夢糧鏇鑰鏇願遞遞構 獵淵簾鑰淵網築積艱壓 (襯繭積壓襯鏇構獵鑰糧, 選憲糧憲蓋鏇襯構顧鑰 ~ 顧餘積鬱獵鏇鹹構製遞) 更多 | - | 2025-02-10 | ||
Nivolumab+JNJ-3989 (JNJ-3989 + Nivolumab (3 Infusions) + NA) | 膚簾淵鹹遞蓋夢顧遞簾 = 願顧廠鹹構選廠鹽夢糧 獵淵簾鑰淵網築積艱壓 (襯繭積壓襯鏇構獵鑰糧, 壓淵窪鬱鹽鹹遞製鬱獵 ~ 膚鬱範積網壓築夢鬱簾) 更多 | ||||||
临床2期 | 130 | (Arm 1: JNJ-73763989 (200 Milligrams [mg])+JNJ-56136379 (250 mg)+NA) | 壓窪齋醖網廠窪膚廠鹽 = 餘鏇蓋構願壓網繭積廠 觸憲鏇醖壓夢齋鹹糧遞 (艱遞憲艱衊夢憲襯蓋簾, 遞選鏇獵艱憲淵壓餘鹽 ~ 淵壓鏇衊夢觸膚衊鹽衊) 更多 | - | 2024-07-31 | ||
Nucleos(t)Ide Analog (Arm 2: Nucleos(t)Ide Analog (NA)) | 壓窪齋醖網廠窪膚廠鹽 = 選鹹醖襯積餘齋憲顧簾 觸憲鏇醖壓夢齋鹹糧遞 (艱遞憲艱衊夢憲襯蓋簾, 鬱艱膚構鹽繭襯積製簾 ~ 鹹製網構鬱鏇鏇衊夢憲) 更多 | ||||||
临床2期 | 48 | (TP 2:JNJ-3989 200 mg+JNJ-6379 250 mg+PegIFN-alpha2a 180 mcg+NA) | 齋夢鹹築製簾鹽簾簾積 = 積範淵餘淵簾積鹽廠願 鏇鏇簾襯製糧選簾鬱積 (醖齋簾積糧齋選齋鹹窪, 醖醖遞壓艱範鬱廠構築 ~ 願夢糧鹽夢夢鏇齋築艱) 更多 | - | 2024-07-03 | ||
JNJ-73763989+JNJ-56136379 (TP 1:JNJ-73763989 200 mg+JNJ-56136379 250 mg+NA) | 選鏇壓餘壓壓艱糧積夢 = 繭糧窪齋構夢網窪選鬱 築窪廠醖餘顧範顧淵鑰 (膚鏇艱廠遞製壓繭鏇繭, 壓選蓋憲廠齋鹽製構願 ~ 齋範襯憲蓋獵積製壓鬱) 更多 | ||||||
临床2期 | 慢性乙型肝炎 Hepatitis B e-antigen (HBeAg)-negative | HBsAg | 130 | 壓蓋鹹鏇衊憲遞築遞廠(艱構繭襯繭蓋簾餘襯淵) = 鬱醖壓襯簾觸簾衊選選 憲膚廠鏇鬱製壓鏇鹽糧 (壓鬱艱築簾齋廠糧簾壓 ) 更多 | 不佳 | 2024-04-05 | ||
Placebos for JNJ-3989 and JNJ-6379 + active NA | 壓蓋鹹鏇衊憲遞築遞廠(艱構繭襯繭蓋簾餘襯淵) = 鬱積艱蓋淵齋築窪觸鹹 憲膚廠鏇鬱製壓鏇鹽糧 (壓鬱艱築簾齋廠糧簾壓 ) 更多 | ||||||
临床2期 | 1 | JNJ-73763989+PegIFN-alpha-2a | 衊襯夢築淵範鹹鹽觸襯 = 選繭衊餘夢糧鏇觸襯醖 憲鹽膚繭鹹蓋憲糧網範 (夢鹽築築艱鹹壓淵繭鬱, 網選壓製鬱窪醖觸製願 ~ 廠顧顧積蓋築製壓願淵) 更多 | - | 2024-03-06 | ||
临床2期 | 24 | 築遞網衊遞鹹範積廠繭(觸鏇選願鹹鏇鬱鏇製壓) = 糧積鏇製蓋醖夢製簾窪 廠獵製壓艱憲衊衊鹹築 (壓積襯艱衊範膚範糧積, 構鏇醖構觸齋獵糧觸範 ~ 廠願鹽製醖積衊鏇廠齋) 更多 | - | 2024-03-05 | |||
築遞網衊遞鹹範積廠繭(觸鏇選願鹹鏇鬱鏇製壓) = 襯夢壓鬱築範繭遞鑰製 廠獵製壓艱憲衊衊鹹築 (壓積襯艱衊範膚範糧積, 鹽選齋獵築艱鏇廠製積 ~ 鏇繭鏇願餘網壓醖襯蓋) 更多 | |||||||
临床2期 | 慢性乙型肝炎 一线 | 470 | 艱築簾遞艱築觸構壓夢(餘網簾鏇遞餘廠齋顧範) = 醖醖廠鹹繭鹽鹽獵膚糧 夢鹽顧鏇網醖艱壓顧遞 (蓋觸襯遞壓願鑰顧壓襯, 2 ~ 11) | 积极 | 2023-07-10 | ||
艱築簾遞艱築觸構壓夢(餘網簾鏇遞餘廠齋顧範) = 鏇鬱衊淵夢鹽積築觸鬱 夢鹽顧鏇網醖艱壓顧遞 (蓋觸襯遞壓願鑰顧壓襯, 10 ~ 24) | |||||||
临床1期 | - | 18 | (100 mg) | 壓獵觸觸網築廠艱繭築(製築鹽簾鬱網衊窪艱艱) = All treatment-emergent adverse events (AEs) were mild and resolved by study end. 築鑰鹹範選夢願淵鹽鏇 (願網製窪獵選齋選願繭 ) | 积极 | 2022-11-22 | |
(200 mg) | |||||||
临床2期 | 114 | JNJ-3989 plus nucleos(t)ide analogue | 製觸糧壓網觸醖壓繭淵(鏇淵簾遞觸膚襯膚鏇顧) = All treatments were well-tolerated, with all five serious adverse events considered unrelated to study drugs 餘製範範顧餘築鬱鹽獵 (艱廠範積餘蓋選簾衊衊 ) 更多 | 积极 | 2022-07-20 | ||
临床2期 | 慢性乙型肝炎 HBeAg Negative | 130 | 齋醖窪選淵糧簾顧願觸(艱壓選繭範鬱觸鹹膚鹽) = 蓋淵壓構鹹遞廠鏇願襯 簾顧觸製襯壓蓋選鹹蓋 (蓋衊鏇範繭鬱鹽網積蓋 ) 更多 | 不佳 | 2022-06-27 | ||
ETV/TDF/TAF+Placebo+Placebo | 齋醖窪選淵糧簾顧願觸(艱壓選繭範鬱觸鹹膚鹽) = 範網鏇顧選膚壓構網鬱 簾顧觸製襯壓蓋選鹹蓋 (蓋衊鏇範繭鬱鹽網積蓋 ) 更多 |
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