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更新于：2025-09-15

Daplusiran/Tomligisiran

更新于：2025-09-15

概要

概要

基本信息

药物类型

siRNA

别名

DAP/TOM、ARO-HBV、GSK-5637608

+ [4]

靶点

cccDNA

作用方式

抑制剂

作用机制

cccDNA抑制剂(乙肝cccDNA抑制剂)、RNA干扰

治疗领域

感染消化系统疾病

在研适应症

慢性乙型肝炎乙型肝炎

非在研适应症

慢性丁型肝炎

原研机构

Arrowhead Pharmaceuticals, Inc.

在研机构

Janssen Research & Development LLC

GSK Plc

Arrowhead Pharmaceuticals, Inc.

非在研机构

强生（中国）投资有限公司Janssen Sciences Ireland UC

西安杨森制药有限公司

权益机构

Arrowhead Pharmaceuticals, Inc.

Janssen Pharmaceuticals, Inc.

GSK Plc

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)临床2期

特殊审评-

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结构/序列

使用我们的RNA技术数据为新药研发加速。

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Sequence Code 316576694

当前序列信息引自: *****

Sequence Code 316576738

当前序列信息引自: *****

关联

项与 Daplusiran/Tomligisiran 相关的临床试验

NCT06537414

/ Active, not recruiting临床2期

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)

The study is intended to evaluate the efficacy and safety of 2 different doses of DAP/TOM followed by bepirovirsen in participants living with CHB on standard of care nucleos(t)ide analogue (NA) therapy. The study also aims to identify an optimal dose of DAP/TOM for sequenced therapy with bepirovirsen for further clinical development and to assess the contribution of DAP/TOM to the sequential regimen.

开始日期2024-11-11

申办/合作机构

GSK Plc

NCT05275023

/ Completed临床2期

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

The purpose of this study is to evaluate efficacy of the study intervention, based on hepatitis B surface antigen (HBsAg) levels at follow-up (FU) Week 24.

开始日期2022-06-30

申办/合作机构

Janssen Research & Development LLC

NCT05123599

/ Completed临床1期

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

The purpose of this study is to evaluate the efficacy of the study intervention based on hepatitis B surface antigen (HBsAg) levels.

开始日期2021-12-06

申办/合作机构

Janssen Research & Development LLC

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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项与 Daplusiran/Tomligisiran 相关的文献（医药）

2025-10-01·JHEP Reports

Peginterferon-alpha-2a add-on to treatment with siRNA JNJ-73763989 in virologically suppressed chronic hepatitis B: The phase II PENGUIN study

Article

作者: Kim, Gloria ; Hlebowicz, Maria ; Chang, Ting-Tsung ; Jezorwski, John ; Chuang, Wan-Long ; Bakala, Adam ; Gane, Edward ; Peng, Cheng-Yuan ; Pehlivanov, Nonko ; Biermer, Michael ; Lenz, Oliver ; Takehara, Tetsuo ; Asahina, Yasuhiro ; Verbinnen, Thierry ; Anastasiou, Zacharias ; Kalmeijer, Ronald ; Janczewska, Ewa ; Kakuda, Thomas N

Background & Aims:

Previous studies showed that combination treatment with short interfering RNA JNJ-73763989 (JNJ-3989) ± capsid assembly modulator bersacapavir (JNJ-56136379) and nucleos(t)ide analogs (NAs) was well tolerated by patients with chronic HBV (CHB), with JNJ-3989 dose-dependent reductions in viral markers, including HBsAg. The open-label, single-arm phase IIa PENGUIN study (NCT04667104) evaluated this regimen plus pegylated interferon alpha-2a (PegIFN-α2a) in patients with virologically suppressed CHB.

Methods:

Patients who were either HBeAg-positive or -negative virologically suppressed and taking NAs were included; all received JNJ-3989 ± bersacapavir for 24 weeks (some either did not start or discontinued bersacapavir as a result of protocol amendment) with PegIFN-α2a added during the final 12 weeks of treatment. The primary endpoint was the proportion of patients with ≥2 log₁₀ IU/ml HBsAg reduction from baseline at week 24 (W24). Safety, tolerability, and proportion of patients meeting predefined NA stopping criteria were assessed. After 24 weeks of treatment, NA was stopped when stopping criteria were met; all patients were followed for 48 weeks. Efficacy and safety endpoints were summarized using descriptive statistics.

Results:

In total, 48 patients (HBeAg positive, n = 11; HBeAg negative, n = 37) were enrolled; 47 reached follow-up week 48 (FUW48). Of the 48 patients, 31 (64.6%) achieved the primary endpoint; one achieved HBsAg seroclearance (<0.05 IU/ml) at both W24 and FUW48 after stopping NA. Mean HBsAg changes from baseline were -1.43, -2.18, and -0.71 log₁₀IU/ml at W12, W24, and FUW48, respectively. At W24, 15/48 (31.3%) patients met NA stopping criteria; 11/15 (73.3%) remained off NA by FUW48. One patient achieved functional cure at FUW48. Adverse events were consistent with known PegIFN-α2a safety profiles.

Conclusions:

Treatment with JNJ-3989 ± bersacapavir + NA and PegIFN-α2a was generally well tolerated. Most patients had pronounced HBsAg reductions from baseline, no additional benefit from PegIFN-α2a, and did not achieve functional cure.

Clinical Trials registration:

The study is registered at ClinicalTrials.gov (NCT04667104).

Impact and implications:

Previous studies with JNJ-73763989 (JNJ-3989) ± bersacapavir (JNJ-56136379) and nucleos(t)ide analogs (NAs) in patients with chronic hepatitis B (CHB) have demonstrated JNJ-3989 dose-dependent and robust reductions in viral markers; however, functional cure was only rarely achieved. The current study assessed whether the addition of pegylated interferon alpha-2a (PegIFN-α2a) to a JNJ-3989-based regimen after HBsAg levels were reduced would lead to further HBsAg declines and improved outcomes during off-treatment follow-up. Study results confirmed pronounced HBsAg reductions from baseline in virologically suppressed patients with HBeAg-positive or -negative CHB. However, the addition of PegIFN-α2a to JNJ-3989 ± bersacapavir and NA for the final 12 weeks of a 24-week treatment period did not appear to improve antiviral activity in the studied population. Studies in other CHB groups, including treatment-naïve, HBeAg-positive patients, could help elucidate whether this or other treatment regimens including JNJ-3989 and NA can lead to functional cure in a larger proportion of patients.

2025-03-01·GUT

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 ; Yuen, Man-Fung ; Lenz, Oliver ; 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.

2024-09-01·Journal 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 ; Lonjon-Domanec, Isabelle ; Jezorwski, John ; 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.

项与 Daplusiran/Tomligisiran 相关的新闻（医药）

2025-07-13

·抗体圈

siRNA药物开发的三个“E”挑战

摘要：siRNA治疗方法已获得广泛关注，目前已有六种siRNA获准用于临床应用。尽管它们被研究用于治疗代谢、心血管、传染性和罕见遗传疾病，以及癌症和中枢神经系统（CNS）疾病，但依然存在几个药物可用性挑战。在这里，我们提供有关这些挑战的深入讨论，包括靶向积累和细胞摄取（‘进入’）、内溶酶体逃逸（‘逃逸’）以及体内药效表现（‘疗效’）——这三个‘E’挑战，同时也阐明siRNA药物开发。此外，我们提出几种有前景的策略，这些策略在促进siRNA治疗药物临床转化方面具有巨大潜力，包括探索多样的配体-siRNA结合物、扩大潜在疾病靶点，以及开掘新的修饰几何形状，以及开发组合疗法。文章亮点：1.理论上，siRNA能够靶向任何感兴趣的基因，潜在地解决那些对小分子和蛋白质而言‘无法药物化’的疾病靶标。2.目前，已有六种siRNA治疗药物获得临床使用批准，以及大约20种其他候选药物已进入临床研究的后期阶段。3.靶向累积和细胞摄取（进入）、内溶酶体逃逸（逃避）以及体内药理学性能（疗效）（三个‘E’挑战）是siRNA药物开发中最关键的瓶颈。4.配体缀合的siRNA是有前景的平台，已经在强健的肝外递送方面取得了突破。复杂且适当的化学修饰可能会在siRNA方式的稳定性和长期疗效方面带来惊人的突破。【NO.1】siRNA治疗的蓬勃发展从制药历史的角度来看，小分子药物作为最早开发和应用的治疗方式，享用了超过一个世纪的使用，而蛋白质和抗体相对较晚出现，并且研究了将近半个世纪。尽管核酸分子作为一种新型治疗方法的发展时间较短（20-30年），但它们已经引起了制药行业的显著全球关注，成为第三种最显著的治疗方式。核酸药物仍在快速探索和开发中，特别是在RNAi领域，其广泛而深远的治疗潜力日益显现。考虑到这一点，我们相信即将到来的时期将是核酸的一个关键时代，既扩大了治疗选择的范围，也为该领域提供了新可能性。与传统的小分子药物和抗体相比，siRNA（见词汇表）具有丰富的疾病靶点、高开发成功率、短开发时间、强大且持久的疗效，以及平台化模式的卓越特征。目前，六种siRNA药物（patisiran、givosiran、lumasiran、inclisiran、vutrisiran和Rivfloza）已成功商业化。尽管siRNA药物在临床实践中的应用前景广泛，但其开发面临关键挑战，包括靶向积累和细胞摄取（进入）、内溶酶体逃逸（逃逸）和体内药效（疗效）（三大“E”挑战）。在本文中，我们阐述了siRNA治疗的当前状态和未来前景，概括了该领域所遇到的关键挑战，并提出了一系列应对策略。通过提供广泛的见解和灵感，本文旨在为科学和制药界提供有价值的指导。【NO.2】siRNA疗法的最新研究和开发状态近年来，siRNA疗法在多个候选药物的前临床和临床研究开发中显示出了巨大的潜力。截至2023年8月，全球范围内有15种在临床二期或后期阶段的研究siRNA药物（表1），涵盖广泛的治疗领域，包括罕见疾病和遗传性疾病，并扩展到常见疾病。主要制药公司已扩大其研究重点，以涵盖代谢性疾病、心血管疾病、乙型肝炎和癌症等常见病。例如，ALN-AGT（NCT04936035i，NCT05103332ii，随机）目前正在开发中，用于治疗高血压，并已进入二期临床试验。Olpasiran（NCT05581303iii，随机）旨在治疗动脉粥样硬化斑块，正在进行三期研究。SLN360（NCT05537571iv，随机）是一种降脂siRNA，已进入二期研究。RBD1016（NCT05961098v，随机）是一种用于治疗乙型肝炎的N-乙酰半乳糖胺（GalNAc）结合siRNA，将在欧洲开始二期试验。STP705和STP707由两种siRNA组成，靶向转化生长因子β1（TGF-β1）和环氧合酶2（COX-2），并以肽纳米粒（PNPs）形式制备。STP705局部施用到病变组织中，以治疗原位鳞状细胞癌（isSCC）（NCT04844983vi，二期，随机）和基底细胞癌（BCC）（NCT04669808vii，二期，非随机），而STP707（NCT05037149viii，一期，非随机）则通过静脉注射到身体中，用于治疗几种实体瘤和纤维化肝病，例如原发性硬化性胆管炎（PSC）。表1.选定的商业化或晚期研究的siRNA疗法从产品管道的角度来看，siRNA疗法的一个显著突破在于其扩展到肝外疾病，包括小分子药物和抗体药物一直未能涉足的领域，如中枢神经系统疾病。ALN-APP（NCT05231785ix，第一阶段，随机）是一种经椎管内给药的siRNA，靶向淀粉样前体蛋白（APPs），用于治疗阿尔茨海默病（AD）和脑淀粉样血管病（CAA）。最近，ALN-APP的第一阶段研究在单药剂量递增试验中获得了积极的中期结果。ARO-SOD1（NCT05949294xi，第一阶段，随机）是一种针对中枢神经系统内超氧化物歧化酶1（SOD1）的研究性siRNA，可能用于治疗由SOD1突变引起的肌萎缩侧索硬化症（ALS），目前正在进行第一阶段研究。此外，临床开发的RNAi疗法正在向将siRNA递送到其他组织（如眼睛、肌肉、肺部和脂肪）迈进。Tivanisiran（SYL1001）（NCT03108664xii，NCT04819269xiii，随机）目前正在进行第三阶段临床研究，以治疗干眼症。ARO-DUX4（第一/第二阶段）用于治疗面肩肱肌营养不良（FSHD）已提交临床试验。ARO-MUC5AC（NCT05292950xv，第一阶段，随机）、ARO-RAGE（NCT05276570xvi，第一阶段，随机）和ARO-MMP7（NCT05537025xvii，第一/二a阶段，随机）目前正在研究用于治疗肺部疾病。值得注意的是，siRNA的给药频率已经实现了历史性的突破。siRNA的增强稳定性修饰使其能够在体内持久抑制基因和治疗效果，同时避免潜在的序列依赖性非特异性效果。例如，Leqvio在头三个月只需给药两次，随后每六个月治疗一次，以有效管理原发性高胆固醇血症或混合性脂质异常。目前，全球有超过100家公司从事siRNA领域，其中大约30家公司专注于siRNA药物开发。根据Informa Pharma Intelligence的生物追踪记录，目前大约有200种基于siRNA/RNAi的药物正在进行临床前和临床研究。自2016年以来，共有14种siRNA和反义寡核苷酸（ASO）获得批准商业化。此外，寡核苷酸治疗领域在并购方面也见证了显著活动。近年来，在心血管和代谢疾病、神经系统疾病和乙型肝炎等领域有一些值得注意的许可协议。代表性的siRNA递送平台包括脂质纳米颗粒（LNP）、GalNAc-siRNA偶联物（GalAheadTM、PDoV-GalNAc等）、GEMINI、™TRiM™、PNP、RIBO-GalSTAR®和RIBO-OncoSTAR，而IKARIA™的建立是为了开发长效siRNA。【NO.3】siRNA临床研究的瓶颈尽管siRNA药物研究取得了重大进展，但仍存在一些需要克服的关键挑战。具体来说，三个“E”挑战（进入、逃逸、疗效）是限制siRNA临床翻译和应用的三个关键问题。图1.限制siRNA临床翻译和应用的三个“E”挑战3.1进入挑战：靶向积累和细胞摄取第一个挑战是在靶器官/组织中实现siRNA的高效富集并有效内化到靶细胞中（图1A）。由于它们的大尺寸和阴离子电荷，未修饰的裸siRNA显示出低生物利用度，半衰期短至几分钟。纳米载体封装的siRNA通常与血清蛋白结合，导致网状上皮系统（RES）摄取和吞噬清除。此外，siRNA可被血浆、组织和细胞质中存在的核酸酶或磷酸酶快速降解。全身清除后，siRNA必须穿过毛细血管的内皮才能进入组织，由于广泛的粘附和紧密连接，这尤其具有挑战性。尽管siRNA可能被动地积累在肝脏或肿瘤组织等多孔部位，但将这些治疗剂输送到优先吸收这些分子的器官以外的身体其他部位，以及血液-脑屏障（BBB）和血液-视网膜屏障等屏障的有效穿越，仍然面临巨大的挑战。3.2逃逸激发试验：内体和溶酶体逃逸第二个挑战是如何实现有效的内体和溶酶体逃逸。虽然siRNA可以通过内吞作用进入细胞，但只有不到1%的siRNA可以从内吞作用中逃逸，被动siRNA逃逸率低于0.01%。去唾液酸糖蛋白受体（ASGPR）是一个明显的例外，其肝细胞表达水平约为500000或更高，循环时间不到20分钟。足够的GalNAc-siRNA偶联物可以在肝细胞的细胞质中积累，以在治疗期间达到治疗水平。虽然这为未来基于RNAi的肝脏治疗靶向带来了希望，但siRNA逃逸对于其他类型的细胞来说仍然是一个未解决的问题。大多数表面受体的表达范围为10000–100000或更短，受体回收时间大约或超过90分钟（图1B）。由于细胞质和内体中siRNA的降解，观察到在任何给定时刻，只有极小的内吞GalNAc-siRNA偶联物存在于体内细胞质中。值得注意的是，虽然内体包埋的RNA治疗药物起到了作用，从而维持了较长的单剂量反应持续时间，但这一优势被很大一部分无法穿透细胞质的内吞RNA治疗药物所抵消。因此，虽然内体的释放确实是抑制RNA疗法在人类疾病治疗中更广泛应用的主要障碍，但值得注意的是，需要有一种平衡，以在一定程度上维持贮存效应，确保长时间的持续反应。迄今为止，试图使用改良的pH敏感性、离子穿透剂、氯喹样溶酶体试剂、成孔肽如蜂毒肽、十二烷基磷酸胆碱（DPC）和/或GalNAc偶联的蜂毒肽样肽（NAG-MLP）来增强内体逃逸，但尚未完全解决细胞毒性与内体逃逸增加之间的关系。3.3疗效挑战：体内药物性能第三个挑战是要求良好的体内稳定性、持久效果和安全性。使用病毒载体进行体内核酸递送有一些毒副作用和目前主要限于临床前研究。化学合成的载体系统，如阳离子脂质和大多数无机纳米颗粒，可在体内诱导细胞凋亡和炎症。给药系统还必须确保生产、质量控制和运输的便利性，以实现大规模临床应用。此外，目前RNA药物临床前研究中广泛使用的小鼠模型并不是毒性评价模型，因为从小鼠模型获得的RNA剂量反应关系不能直接应用于人类。非灵长类动物模型通常缺乏与人类的基因组序列的足够重叠来预测药效学效应，因此有必要扩大非人灵长类动物（NHP）模型的使用，或者作为潜在的选择，扩大与疾病相关的类器官的使用。未经修饰的寡核苷酸通常在体内不稳定，并且很容易被血液中的核酸酶降解。此外，外源寡核苷酸可能在体内显示免疫原性并引起免疫反应。随着技术的突破，化学修饰【例如，对硫代磷酸盐（PS）骨架、核糖和链末端的修饰】已被广泛用于增强siRNA的稳定性，减少/消除脱靶效应和免疫原性，从而提高siRNA的“功效”（图1C）。通过复杂的修饰，siRNA已成功实现99%的基因沉默并在体内持续存在，允许低剂量季度、半年甚至每年给药。化学修饰的进化史及其对siRNA功效的影响是一个令人着迷的研究领域，值得进一步全面探索。然而，尽管取得了这些可喜的成就，但仍存在一些挑战。例如，修饰诱导的稳定性和特异性增强可能会降低沉默活性或引起意想不到的不良反应（图1D）。此外，在临床前和临床研究中，都需要仔细评估siRNA的免疫原性和毒性（包括脱靶诱导毒性）。更重要的是，一系列专利家族对siRNA药物开发的知识产权格局做出了重大贡献。例如，WO2016028649概述了一种几何结构，该几何结构将siRNA的两条链的修饰划分为由核苷酸计数的特定范围定义的不同区域，从而提供每个区域的修饰单体的化学结构或物理化学性质。WO2013074974描述了一种dsRNA双链体，其基序由一条或两条链中三个连续核苷酸上的三个相同修饰组成，特别是在切割位点附近。此外，WO2018185241重点介绍了反义链5'端2位和14位核苷酸的修饰策略，以及正义链上的核苷酸，对应于反义链的11、13、11和13或11-13位。这些专利对siRNA药物开发构成了重大障碍，必然需要该领域的其他实体建立独特的技术。【NO.4】克服三个“E”挑战的有前途的策略为了应对这些挑战并推动siRNA疗法的发展，几种有前途的策略或方法值得探索。图2.克服三个“E”挑战的有前途的方法4.1开发新型化学修饰优化化学修饰是提高siRNA稳定性、特异性、安全性和生物利用度的重要方向。这包括开发新的化学修饰单体、修饰模式和RNAi触发结构（图2A-C）。传统的siRNA修饰主要涉及2′-O-甲基化（2′-OMe）、2′-氟脱氧核糖核苷酸（2′-F）和PS，而新型修饰单体和修饰模式的开发将进一步完善siRNA的药代动力学和安全性。例如，已经开发了新型单体，如乙二醇核酸（GNA）和5′-（E）-乙烯基膦酸盐[5′-（E）-VP]（图2B），新型修饰模式，如增强稳定化学（ESC）plus（ESC+）（图2A），以及新型RNAi触发结构，如小环状干扰RNA（sciRNA）、不对称siRNA和二价siRNA支架（图2C）。此外，现在可以使用算法实现siRNA的设计和修饰。例如，Alnylam已经开发了几代siRNA设计，包括部分修饰的标准模板化学（STC）、ESC、高级ESC、ESC+和IKARIA™。几种ESC+偶联物目前正处于临床流程中。在专利方面，新型单体、图案和结构的发展可以为新来者提供绕过现有知识产权的空间。此外，业务合作期间的开放许可协议可以为其他公司提供使用siRNA技术的机会，促进其普及和商业化。4.2建立独特的递送系统虽然LNP、聚合物、无机纳米颗粒和外泌体等各种纳米材料已被开发为siRNA载体，但它们的负载能力、稳定性、安全性和有效性仍然存在局限性。未来的基础研究应侧重于优化这些载体的物理化学性质，并使用独特的靶向配体或化学部分特异性结合患病细胞的表面标志物/受体。siRNA可以与配体共价连接以形成配体-siRNA偶联物，这可以降低循环中的清除率并增强靶向积累和细胞摄取，从而调节其药代动力学和药效学特征。这些配体包括小分子、脂质[如胆固醇、2′-O-十六烷基（C16）、各种脂肪酸]、肽（如RGD衍生物、H2009.1、A20FMDV2、胱氨酸结肽）、适配体、抗体、蛋白质（如centyrin）、糖类（如GalNAc）和非编码RNA（ncRNA）（图2D）。与纳米颗粒相比，配体偶联物通常体积小，易于大规模合成，并具有明显的药代动力学特性。与脂肪酸等脂质部分结合可以改变肝外组织中的积累，从而能够在包括CNS、心脏、肺和肌肉在内的多种组织中进行基因调控。抗体和细胞表面受体之间的特异性相互作用可能能够递送到其他技术无法到达的特定组织和/或细胞亚群。单剂量的TfR1抗体（αTfR1）与siRNA偶联，在小鼠和猴子中产生超过75%的mRNA减少，骨骼肌和心脏（横纹）肌的沉默最严重，而其他主要器官的沉默活动最少或没有。siRNA治疗药物还可以与阳离子肽部分（如细胞穿透肽和Endo-Porter）连接，有效穿透组织屏障和细胞膜。此外，siRNA和内体逃逸增强佐剂的组合可能是将配体偶联的siRNA递送至非肝组织的可行策略。4.3扩大疾病目标siRNA技术主要用于目标蛋白质编码基因。然而，最近的研究表明，ncRNA，如长ncRNA（lncRNA），在各种疾病中起着重要作用（图2E）。因此，开发能够有效调节ncRNA表达的新型RNA靶向技术可能为疾病治疗提供更广泛的机会。此外，探索编码和ncRNA之间的相互作用，例如竞争性内源性RNA（ceRNA）网络，可能会为疾病机制提供新的见解，并实现更有效的治疗干预。除了在mRNA水平调节基因表达外，siRNA技术还可以靶向表观遗传修饰，例如DNA甲基化或组蛋白修饰，这些修饰在疾病的发展和发展中起着至关重要的作用。通过调节表观遗传标记，有可能重编程基因表达模式并逆转疾病表型。4.4探索联合疗法利用双靶向方法或将siRNA与其他治疗药物（如化疗药物、抗体或免疫调节剂）联合使用，有望增强疗效、克服耐药性和减少脱靶效应。这些策略可能为治疗以前无法治愈的疾病创造新的机会。例如，正在实施一种涉及VIR-2218（GalNAc-siRNA偶联物，也称为ALNHBV02）和聚乙二醇-干扰素α(PEG-IFN-α)的联合治疗，旨在实现乙型肝炎的功能性治愈。siRNAJNJ-73763989（JNJ-3989）加核苷（t）类似物（NA）用于评估有/没有衣壳组装调节剂JNJ-56136379（JNJ-6379）的慢性乙型肝炎患者的治疗效果。此外，pozelimab（补体C5靶向抗体）和cemdisiran（一种GalNAc-siRNA偶联物）正在联合用于治疗重症肌无力和阵发性睡眠性血红蛋白尿症（PNH）。此外，正在进行Empaveli（一种环肽）和siRNA组合的临床前研究，这可能会降低Empaveli的治疗频率和/或提高治疗效果。【NO.5】总结和未来展望我们正在见证RNA药物治疗新时代的到来。RNA疗法基于一个强大且多功能的平台，该平台在解决未满足的临床需求方面具有几乎无限的潜力。因此，RNA疗法注定会改变许多疾病的护理标准。随着第六种siRNA药物Rivfloza的获批，未来几年肯定会有更多的siRNA疗法出现。在成功建立用于肝细胞递送的最先进的GalNAc-siRNA偶联物后，肝外递送技术的探索将成为该领域的下一个前沿领域（参见临床医生专区）。与肝脏相比，将RNAi分子递送到靶向非肝脏疾病的挑战要大得多。配体-siRNA偶联物必须以足够的速率在靶细胞中积累以实现沉默。此外，避免同时进行肾脏和网状内皮清除、增强外渗和组织渗透、增加货物内化受体低表达细胞类型的摄取、改善内体逃逸以及支持强效和安全治疗效果等几个因素需要进行珠子处理以实现令人满意的沉默。为了将siRNA的适用性扩大到肝脏组织之外，至关重要的是：（i）识别或确定可以促进有效内化的独特受体;（ii）提出具体的筛选或勘探策略;（iii）设计并鉴定用于稳健递送和持续基因沉默的新型配体;（iv）选择与特定疾病有关的遗传或临床可行的靶基因。如果在临床条件下肝外递送变得可行且稳健，则狩猎RNAi疗法的领域可能会显着扩大。此外，在siRNA的开发中，与化学制造和控制（CMC）以及药物注册政策相关的问题会显著影响新药营销。siRNA的CMC面临多重挑战，包括单体供应、质量控制、能力建设、杂质表征和分离纯化。在药品注册政策方面，目前还缺乏统一的国际标准。建议通过加强科学研究、提高透明度以及修订法规和政策来确保临床试验的安全性和有效性。此外，目前siRNA的主要扩展方向是在慢性疾病领域，如高胆固醇血症、高甘油三酯血症、高血压、高脂蛋白胆固醇（a）[Lp（a）]心血管疾病、非酒精性脂肪性肝炎（NASH）和乙型肝炎。未来siRNA药物开发的突破性方向包括递送至CNS、眼睛、肌肉、肺和脂肪组织和肿瘤。这为siRNA治疗留下了相当大的市场空间。尽管存在挑战（参见悬而未决的问题），但siRNA代表了一种有前途的方式，有可能彻底改变各种疾病的治疗。为了应对与高效和安全递送、内体逃逸、体内功效相关的挑战，其他方面则需要跨多个领域的持续创新和合作。可以肯定的是，经过不懈的努力，这些挑战将继续被规避，并最终迎来进一步的重大突破。识别微信二维码，添加抗体圈小编，符合条件者即可加入抗体圈微信群！请注明：姓名+研究方向！本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

siRNA临床研究

2025-06-17

·PRNewswire

Chronic Hepatitis B Market--The US to Have the Lion's Share Among the 7MM, Predicts DelveInsight

The chronic hepatitis B market size is predicted to surge owing to the increasing prevalence of the disease globally and rising awareness about early diagnosis and treatment. Advances in antiviral therapies and the development of novel treatment options are fueling market expansion. LAS VEGAS, June 17, 2025 /PRNewswire/ -- Hepatitis B is the most widespread serious liver infection globally, caused by the hepatitis B virus (HBV), which targets and damages the liver. Millions of individuals worldwide are affected by chronic hepatitis B. The virus spreads through contact with infected blood and bodily fluids, including transmission via unprotected sex, sharing of contaminated needles, use of illegal drugs, and exposure to unsterilized medical equipment. In most cases, hepatitis B resolves on its own within 1 to 2 months. However, if the infection persists beyond six months, it can become chronic, potentially leading to ongoing liver inflammation, cirrhosis (liver scarring), liver cancer, or liver failure. As of 2024, around 5 million people across the 7MM were living with chronic hepatitis B. Among these, 85% had compensated liver function, while the remaining 15% had progressed to decompensated liver disease. Currently, there is no definitive cure for hepatitis B. Antiviral medications and interferon injections can help manage the disease by reducing viral activity and easing symptoms, but they do not eliminate the virus entirely. If the infection persists beyond six months, it is classified as chronic, making patients eligible for drug therapy, particularly those with active liver disease. Learn more about the chronic hepatitis B virus market @ New Treatment for Chronic Hepatitis B The US FDA has approved seven medications for treatment: two injectable interferons and five oral antiviral drugs. These treatments must be taken daily and work by suppressing viral replication, thereby reducing liver inflammation and potential damage. VEMLIDY (tenofovir alafenamide), developed by Gilead Sciences, is an innovative, targeted prodrug of tenofovir formulated as an oral tablet. In March 2024, Gilead announced that the FDA had approved a supplemental New Drug Application (sNDA) for VEMLIDY 25 mg, allowing its once-daily use in pediatric patients aged 6 years and older and weighing at least 25 kg who have chronic hepatitis B (CHB) infection with compensated liver disease. Earlier, in November 2022, the FDA approved the same 25 mg dose for once-daily use in children aged 12 and above with CHB and compensated liver disease. The initial FDA approval came in November 2016 for adult patients with CHB and compensated liver function. In January 2017, Gilead announced that the European Commission (EC) had granted marketing authorization for VEMLIDY 25 mg to treat CHB in adults and adolescents aged 12 and older who weigh at least 35 kg. Additionally, in December 2016, Japan's Ministry of Health, Labour and Welfare (MHLW) approved VEMLIDY for the treatment of chronic hepatitis B in patients showing active viral replication and abnormal liver function. Find out more on FDA-approved chronic hepatitis B drugs @ Chronic Hepatitis B (CHB) Market The chronic hepatitis B treatment drug market is continuously evolving. Several pharma companies are evaluating their lead assets in different phases of development. Many potential therapies are being investigated to manage chronic hepatitis B. Some of the drugs in the pipeline include Imdusiran (AB-729) (Arbutus Biopharma), GSK3228836 (bepirovirsen) (GlaxoSmithKline), Tobevibart (VIR-3434) + elebsiran (VIR-2218) ± PEG-IFN-a (Vir Biotechnology), and others. Even though it is too soon to comment on the above-mentioned promising candidate to enter the market during the forecast period (2025–2034), it is safe to assume that the future of this market is bright. Discover which therapies are expected to grab major chronic hepatitis B treatment drug market @ Chronic Hepatitis B Market Report Daplusiran (also known as tomligisiran, formerly JNJ-3989/GSK5637608) is an experimental siRNA-based therapy targeting hepatitis B virus (HBV). It is being studied in combination with bepirovirsen in a sequential regimen for adult patients with chronic hepatitis B who are non-cirrhotic and receiving nucleos(t)ide analogue (NA) therapy. In October 2023, GSK and Arrowhead Pharmaceuticals announced an agreement with Janssen Pharmaceuticals to acquire the exclusive global rights to further develop and commercialize JNJ-3989. Janssen had originally licensed the drug (then called ARO-HBV) from Arrowhead in 2018. Imdusiran is an RNA interference (RNAi) therapy designed to suppress all HBV viral proteins and antigens, including HBsAg, which is believed to be critical for restoring the immune system's ability to fight the virus. It uses Arbutus' proprietary GalNAc-conjugated delivery platform to specifically target liver cells (hepatocytes), allowing for subcutaneous administration. Arbutus plans to launch a Phase IIb clinical trial in the first half of 2025 to evaluate imdusiran in combination with interferon (IFN) and NA therapy. Discover more about drugs for chronic hepatitis B in development @ Chronic Hepatitis B Clinical Trials The anticipated launch of these emerging therapies for chronic hepatitis B are poised to transform the market landscape in the coming years. As these cutting-edge therapies continue to mature and gain regulatory approval, they are expected to reshape the chronic hepatitis B market landscape, offering new standards of care and unlocking opportunities for medical innovation and economic growth. DelveInsight estimates that the market size for chronic hepatitis B is expected to grow at a significant CAGR by 2034. In 2024, the United States dominated the CHB market among the 7MM, capturing approximately 72% of the total market share. The market size of chronic hepatitis B is expected to grow due to several factors, including rising global prevalence of hepatitis B virus infection and increasing awareness about the disease. Advances in antiviral therapies and growing screening initiatives also boost market growth by enabling early diagnosis and improved disease management. DelveInsight's latest published market report, titled as Chronic Hepatitis B Market Insight, Epidemiology, and Market Forecast – 2034 , will help you to discover which market leader is going to capture the largest market share. The report provides comprehensive insights into the chronic hepatitis B country-specific treatment guidelines, patient pool analysis, and epidemiology forecast to help understand the key opportunities and assess the market's underlying potential. The chronic hepatitis B market report proffers epidemiological analysis for the study period 2020–2034 in the 7MM segmented into: Total Prevalent Cases of Chronic Hepatitis B Total Diagnosed Cases of Chronic Hepatitis B Chronic Hepatitis B Cases by Age Group Chronic Hepatitis B Cases by Gender Treated Cases of Chronic Hepatitis B Chronic Hepatitis B Cases by Impact on Liver The report provides an edge while developing business strategies by understanding trends shaping and driving the 7MM chronic hepatitis B market. Highlights include: 10-year Forecast 7MM Analysis Epidemiology-based Market Forecasting Historical and Forecasted Market Analysis upto 2034 Emerging Drug Market Uptake Peak Sales Analysis Key Cross Competition Analysis Industry Expert's Opinion Access and Reimbursement Download this chronic hepatitis B market report to assess the epidemiology forecasts, understand the patient journeys, know KOLs' opinions about the upcoming treatment paradigms, and determine the factors contributing to the shift in the chronic hepatitis B market. Also, stay abreast of the mitigating factors to improve your market position in the chronic hepatitis B therapeutic space. Related Reports Chronic Hepatitis B Epidemiology Chronic Hepatitis B Epidemiology Forecast – 2034 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, and the CHB epidemiology trends. Chronic Hepatitis B Pipeline Chronic Hepatitis B Pipeline Insight – 2025 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key CHB companies, including Vedanta Biosciences, Gilead Sciences, Dong-A ST Co, Assembly Biosciences, Arbutus Biopharma, Vir Biotechnology, Antios Therapeutics, Ascletis Pharmaceuticals, Shanghai HEP Pharmaceutical, Romark Laboratories, Qilu Pharmaceutical, Golden Biotechnology, Sunshine Lake Pharma, Ascentage Pharma, GlaxoSmithKline, Janssen Sciences, Henlix, Enyo Pharma, Tasly Tianjin Biopharmaceutical, Brii Biosciences, Vaxine Pty Ltd, Vaccitech Limited, Zhejiang Palo Alto Pharmaceuticals, Suzhou Ribo Life Science, PharmaEssentia, Nucorion Pharmaceuticals, Jiangsu HengRui Medicine, Enanta Pharmaceuticals, Chong Kun Dang Pharmaceutical, Guangzhou Lupeng Pharmaceutical, VenatoRx Pharmaceuticals, Zhimeng Biopharm, among others. Hepatitis A Market Hepatitis A Market Insights, Epidemiology, and Market Forecast – 2034 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key hepatitis A companies, including Boryung Pharmaceutical, Cadila Healthcare, Indian Immunologicals, Biological E Limited, among others. Hepatitis C Market Hepatitis C Market Insights, Epidemiology, and Market Forecast – 2034 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key hepatitis C companies, including AbbVie, Gilead Sciences, Atea Pharmaceuticals, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

上市批准引进/卖出临床2期

2025-05-19

·同写意

20年折戟，MNC的“天坑”困局

同写意年度巨献！！7月25-26日，邀您相聚金鸡湖畔，与5000人一起为中国医药创新“同写意”代谢功能障碍相关脂肪性肝炎（MASH）是脂肪性肝病（SLD）的严重形式，全球约25%的成年人患有脂肪肝，其中20%-30%会进展为MASH，患者基数超3亿人。若未及时干预，MASH可发展为肝硬化、肝癌，甚至需肝移植。据Frost & Sullivan预测，到2030年全球MASH药物市场规模将达322亿美元，中国市场规模亦有望突破355亿元人民币。图片来源：方正证劵-中国生物制药-港股公司深度报告：全面转型创新进入收获期BD&MA+国际化打开全新战略空间）2024年，Madrigal的口服小分子药物Rezdiffra（Resmetirom）获FDA加速批准，成为40年来首个MASH治疗药物，首年销售额即达1.8亿美元。Rezdiffra通过激活肝脏甲状腺激素受体β（THR-β）调节脂质代谢，临床Ⅲ期数据显示，治疗组肝纤维化改善率达26%，显著优于安慰剂组的14%。正是这一突破点燃了行业的信心，MASH从“研发黑洞”迈向商业化蓝海。TONACEA0120年折戟MNC的“天坑”困局MASH致病机制异常复杂，涉及脂肪堆积、炎症、纤维化等多环节，且缺乏可靠生物标志物。FDA要求药物需通过肝穿刺活检验证“纤维化改善且MASH不恶化”的双终点，导致临床开发成本高、周期长。近二十年来，MASH研发失利超过90%。强生、默沙东、礼来等跨国药企的20余条管线折戟。默沙东的MK-3655（GLP-1/GCGR双靶点）因疗效不足终止、诺和诺德的司美格鲁肽（GLP-1单靶点）在Ⅱ期试验中未能显著改善纤维化、吉利德的ACC抑制剂Selonsertib因Ⅲ期失败黯然退场... ...幸存者寥寥，更加让想要入局MASH领域的药企望而却步。TONACEA02GSK以身入局5月14日，GSK宣布以12亿美元预付款收购Boston Pharmaceuticals的FGF21类似物Efimosfermin，里程碑金额高达8亿美元。Efimosfermin已完成Ⅱ期试验，计划进入Ⅲ期临床，主要针对MASH和酒精性肝病（ALD）。Efimosfermin通过蛋白改造延长半衰期，实现每月一次皮下注射（同类药物需每周给药）达到每月一次给药的“潜在同类最佳”，并且其Ⅱ期数据显示，45.2%患者肝纤维化改善≥1阶段，显著优于安慰剂组的20.6%还能同步降低甘油三酯和血糖，契合MASH患者常伴代谢综合征的特点。GSK在肝病领域已有siRNA疗法GSK’990（针对特定患者亚群），未来或探索与Efimosfermin联用，覆盖更广泛人群。此外，GSK这次的快速决策也凸显了其战略灵活性——就在收购前一天，GSK因临床数据不佳终止了TIGIT抗体Belrestotug的研发（耗资6.25亿美元），迅速将资源转向MASH赛道。TONACEA03MASH的蓝海是砸出来的MASH长期以来缺乏有效治疗手段，患者需依赖生活方式干预或肝移植，但全球患者基数庞大（中国预计2030年达3.15亿）。2024年可以说是MASH领域的元年。2024年3月，Madrigal的Resmetirom（THR-β激动剂）获FDA批准，定价4.74万美元/年，成为40年来首个MASH药物，标志着市场正式开启。MNC们也通过BD交易抢占先机。诺华收购信瑞诺医药扩充肾病管线（含MASH相关药物Iptacopan）、罗氏与锐格医药达成8.5亿美元合作开发CDK抑制剂、GSK、诺华等剥离非核心业务（如仿制药板块），集中资源投入代谢性疾病领域。2018年强生与Arrowhead的合作共同开发和推广乙肝RNAi疗法ARO-HBV。然而2023年2月，强生决定退回在研的siRNA药物权益给Arrowhead。MASH可能给强生也造成了不小的“心理阴影”，截至2024年底，强生已经没有MASH的管线。同样在2018年默沙东与NGM Biopharmaceuticals合作开发的MASH产品MK-3655，也因为疗效问题在2023年终止了研发。2019年吉利德支付1500万美元首付款用于和韩国Yuhan公司同开发用于治疗MASH所致的晚期纤维化的新治疗方案，然后吉利德接连败退，最后宣布于去年10月份宣布已终止与韩国生物技术公司Yuhan就两种MASH疗法的合作和许可协议。2020年默沙东又以8.6亿美元从韩美制药购买了Efinopegdutide在韩国地区以外的全球开发、生产和商业化独家许可权，然而Efinopegdutide在此之前还被强生买下过，但是强生在2019年7月选择终止合作并退回了Efinopegdutide的全球权益。......虽然MASH赛道有的药企节节败退，但是Rezdiffra的上市验证了THR-β靶点的成药性，也让市场看到了可能性。如今，已有4加药企的产品已推进到临床II期阶段，分别是Terns Pharmaceuticals的TERN-501、Viking Therapeutics的VK2809（Ⅱb期纤维化改善率57.1%）、国内歌礼制药的ASC41（肝脂降幅达68.2%）以及海思科的HSK31679。诺和诺德、礼来等也凭借GLP-1药物在肥胖症市场的优势，正探索其在MASH的延伸价值。例如，司美格鲁肽联合GIP激动剂可增强减重与代谢改善效果。国内正大天晴的拉尼兰诺（PPAR激动剂）、海思科的HSK31679（THR-β激动剂）以及恒瑞、中国生物制药等亦在加速布局。Rezdiffra的成功和GSK的入局都在不断证明着MAS赛道的价值所在。MASH市场的蓝海亦是药企们一步一个脚印砸出来的。靶点的选择（如FGF21的长效优势）、临床设计的优化（如非侵入性诊断替代肝活检）和联合疗法探索，将成为破局的关键所在。— 未来展望 —“高投入、高风险、高回报”可以说是最适合MASH赛道的概括。尽管前景光明，但MASH研发仍需面对高失败率、漫长周期和激烈竞争。MASH的蓝海市场由资本与技术共同“砸开”，而那些具备差异化数据或成本优势的企业，才能在百亿市场中分得蛋糕。

临床3期siRNA临床2期加速审批

100 项与 Daplusiran/Tomligisiran 相关的药物交易

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研发状态

10 条进展最快的记录,

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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	Janssen Research & Development LLC	2020-09-28
慢性丁型肝炎	临床2期	美国	强生（中国）投资有限公司	2020-09-28
慢性丁型肝炎	临床2期	日本	强生（中国）投资有限公司	2020-09-28
慢性丁型肝炎	临床2期	日本	Janssen Research & Development LLC	2020-09-28
慢性丁型肝炎	临床2期	澳大利亚	强生（中国）投资有限公司	2020-09-28
慢性丁型肝炎	临床2期	澳大利亚	Janssen Research & Development LLC	2020-09-28
慢性丁型肝炎	临床2期	巴西	强生（中国）投资有限公司	2020-09-28
慢性丁型肝炎	临床2期	巴西	Janssen Research & Development LLC	2020-09-28
慢性丁型肝炎	临床2期	法国	强生（中国）投资有限公司	2020-09-28
慢性丁型肝炎	临床2期	法国	Janssen Research & Development LLC	2020-09-28

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临床结果

适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT05275023 (OCTOPUS-1, CTgov)	临床2期	慢性乙型肝炎	37	JNJ-73763989 (JNJ-3989)+Nivolumab (JNJ-73763989 (JNJ-3989) + Nivolumab (1 Infusion) + NA)	淵構願顧壓網衊築糧顧 = 夢鹽衊壓夢壓窪鏇顧繭獵膚簾範襯餘鏇齋窪齋 (鹹夢鏇憲積艱窪夢醖簾, 憲遞夢衊選遞膚夢顧觸 ~ 窪鏇襯願網鹹蓋築淵餘) 更多	-	2025-02-10
				JNJ-3989+Nivolumab (JNJ-3989 + Nivolumab (3 Infusions) + NA)	淵構願顧壓網衊築糧顧 = 鏇願夢壓願鏇艱醖顧顧獵膚簾範襯餘鏇齋窪齋 (鹹夢鏇憲積艱窪夢醖簾, 膚構網夢簾餘範製鏇衊 ~ 顧壓獵齋獵艱夢獵憲鏇) 更多
NCT04129554 (REEF-2, CTgov)	临床2期	慢性乙型肝炎	130	JNJ-73763989+JNJ-56136379 (Arm 1: JNJ-73763989 (200 Milligrams [mg])+JNJ-56136379 (250 mg)+NA)	鏇餘鬱憲製繭壓壓範鬱 = 鬱鬱顧選蓋憲鹹遞鏇糧淵壓鹽簾壓鹽艱糧衊壓 (夢醖繭簾廠鹽鹽夢窪簾, 鏇夢淵衊積糧觸襯顧積 ~ 鬱獵鑰齋蓋衊鬱鑰範鏇) 更多	-	2024-07-31
				Nucleos(t)Ide Analog (Arm 2: Nucleos(t)Ide Analog (NA))	鏇餘鬱憲製繭壓壓範鬱 = 願積糧繭鬱鹹衊網鏇鬱淵壓鹽簾壓鹽艱糧衊壓 (夢醖繭簾廠鹽鹽夢窪簾, 製鏇範築顧積鹹醖餘網 ~ 鹹廠願簾選憲顧範夢顧) 更多
NCT04667104 (PENGUIN, CTgov)	临床2期	慢性乙型肝炎	48	JNJ-3989+PegIFN-alpha2a+JNJ-6379 (TP 2:JNJ-3989 200 mg+JNJ-6379 250 mg+PegIFN-alpha2a 180 mcg+NA)	蓋遞遞淵鏇遞選醖範顧 = 糧糧鏇醖遞醖簾艱構膚膚網膚淵廠蓋範鬱鏇製 (網範廠憲遞艱膚醖襯壓, 餘遞鑰鬱簾鬱膚鏇窪糧 ~ 壓艱糧簾膚顧觸蓋遞憲) 更多	-	2024-07-03
				JNJ-73763989+JNJ-56136379 (TP 1:JNJ-73763989 200 mg+JNJ-56136379 250 mg+NA)	憲願淵遞簾醖蓋鹹淵鹹 = 壓齋鹹築構構遞遞鬱齋構糧鑰鑰獵窪鬱選衊窪 (廠憲淵餘窪糧鹽襯膚獵, 襯願選廠齋選餘網構積 ~ 蓋鑰鹽鏇築膚獵簾餘艱) 更多
NCT04129554 (REEF-2, Pubmed) 人工标引	临床2期	慢性乙型肝炎 Hepatitis B e-antigen (HBeAg)-negative \| HBsAg	130	JNJ-73763989-6JNJ-56136379	鹽艱廠觸觸憲窪襯餘構(範壓窪夢蓋願鏇鹽觸餘) = 鹽淵淵製淵鏇鹹鑰廠衊觸顧鑰醖餘獵積鏇觸糧 (廠鬱膚壓鹽鬱衊鏇艱鹹 ) 更多	不佳	2024-04-05
				Placebos for JNJ-3989 and JNJ-6379 + active NA	鹽艱廠觸觸憲窪襯餘構(範壓窪夢蓋願鏇鹽觸餘) = 憲願顧範餘鬱鬱衊餘齋觸顧鑰醖餘獵積鏇觸糧 (廠鬱膚壓鹽鬱衊鏇艱鹹 ) 更多
NCT05005507 (PENGUIN-2, CTgov)	临床2期	慢性乙型肝炎	1	JNJ-73763989+PegIFN-alpha-2a	鬱獵鏇膚窪壓鑰顧淵範 = 壓膚鏇憲夢選製廠製憲憲鹹壓構鑰醖簾構簾廠 (夢鑰襯鹽繭築網構獵鏇, 觸衊獵獵艱積廠蓋獵鑰 ~ 餘構鬱觸網膚獵獵網鬱) 更多	-	2024-03-06
NCT04585789 (INSIGHT, CTgov)	临床2期	慢性乙型肝炎	24	NA+TAF+JNJ-3989+PegIFN-alpha-2a+JNJ-6379+ETV (Panel 1)	遞鹽範窪糧夢構築衊鬱(選廠獵積艱願鹹廠齋廠) = 積網窪憲襯鑰觸鬱衊網艱鬱膚餘選範鹹膚簾醖 (鏇壓蓋淵網簾廠糧製餘, 範淵獵鑰窪膚鹽觸築醖 ~ 餘構淵獵憲繭積範網鏇) 更多	-	2024-03-05
				PegIN-alpha2a+TAF+JNJ-3989+PegIFN-alpha-2a+JNJ-6379+ETV (Panel 2)	遞鹽範窪糧夢構築衊鬱(選廠獵積艱願鹹廠齋廠) = 觸壓廠醖壓壓範廠壓顧艱鬱膚餘選範鹹膚簾醖 (鏇壓蓋淵網簾廠糧製餘, 淵窪製鑰窪糧廠糧鑰築 ~ 積鹽窪鹹鑰範夢簾鏇觸) 更多
NCT03982186 (REEF-1, Pubmed) 人工标引	临床2期	慢性乙型肝炎一线	470	JNJ-6379+JNJ-3989 (JNJ-3989 dual 40 mg group)	艱願繭鏇艱繭選鏇齋選(鹽鏇範鬱艱襯醖鹽積糧) = 窪網構觸鹹夢鏇蓋選襯糧願顧蓋網廠簾糧壓襯 (襯願顧醖淵鬱廠鏇願壓, 2 ~ 11)	积极	2023-07-10
				JNJ-6379+JNJ-3989 (JNJ-3989 dual 100 mg group)	艱願繭鏇艱繭選鏇齋選(鹽鏇範鬱艱襯醖鹽積糧) = 糧觸憲鏇廠鏇淵淵積艱糧願顧蓋網廠簾糧壓襯 (襯願顧醖淵鬱廠鏇願壓, 10 ~ 24)
NCT04586439 (Pubmed) 人工标引	临床1期	-	18	JNJ 73763989 (100 mg)	鹽鬱築簾膚遞餘製廠鬱(鑰鬱鏇糧淵齋糧築鏇膚) = All treatment-emergent adverse events (AEs) were mild and resolved by study end. 醖襯蓋願齋淵鑰蓋網網 (顧簾壓繭顧糧膚觸齋蓋 )	积极	2022-11-22
				JNJ 73763989 (200 mg)
NCT03365947 (Pubmed)	临床2期	慢性乙型肝炎	114	JNJ-3989 plus nucleos(t)ide analogue	製鹽鏇窪糧衊憲範廠夢(餘壓鑰艱觸鬱憲網鬱繭) = All treatments were well-tolerated, with all five serious adverse events considered unrelated to study drugs 夢鹽觸壓網積餘蓋淵膚 (憲憲夢廠鏇繭鹽蓋鹽簾 ) 更多	积极	2022-07-20
				JNJ-3989 Q4W plus JNJ-6379 plus nucleos(t)ide analogue
NCT04129554 (REEF-2, Corporate Publications) 人工标引	临床2期	慢性乙型肝炎 HBeAg Negative	130	ETV/TDF/TAF+JNJ 73763989+JNJ 56136379	齋選製選繭艱築繭構鏇(獵夢蓋鑰築夢窪構壓壓) = 襯壓築蓋積齋鹹顧構築繭齋製獵選選顧蓋簾醖 (範觸鏇淵廠衊憲廠簾膚 ) 更多	不佳	2022-06-27
				ETV/TDF/TAF+Placebo+Placebo	齋選製選繭艱築繭構鏇(獵夢蓋鑰築夢窪構壓壓) = 鹹淵遞構觸製鹽選餘鹹繭齋製獵選選顧蓋簾醖 (範觸鏇淵廠衊憲廠簾膚 ) 更多