A Phase 3 Randomized, Open-Label Study to Evaluate the Efficacy and Safety of Tobevibart+Elebsiran Combination Therapy in Participants with Chronic HDV Infection (ECLIPSE 1)

开始日期2025-05-29

申办/合作机构

Vir Biotechnology, Inc.

NCT06903338

/ Recruiting临床3期

A Phase 3 Randomized, Open-Label Study to Evaluate the Efficacy and Safety of Tobevibart + Elebsiran Combination Therapy in Participants With Chronic HDV Infection (ECLIPSE 1)

This is a multicenter, open label, randomized Phase 3 clinical study to evaluate the efficacy and safety of the combination of tobevibart + elebsiran for the treatment of chronic hepatitis delta in comparison to delayed treatment.

开始日期2025-03-12

申办/合作机构

Vir Biotechnology, Inc.

NCT06650852

/ Recruiting临床2期

A Phase 2 Multicenter, Randomized, Double-Blind Study to Evaluate the Efficacy and Safety of Combination Therapy of BRII-179, BRII-835 and Pegylated Interferon Alpha (PEG-IFNα) in Participants With Chronic Hepatitis B Virus (HBV) Infection (ENHANCE)

This Phase 2, randomized, double-blind study will evaluate the clinical efficacy and safety of the combination therapy of BRII-179, BRII-835, plus PEG-IFNα compared to PEG-IFNα in adult participants with chronic HBV infection without cirrhosis receiving neucloes(t)ide reverse transcriptase inhibitors (NRTIs) as background therapy.

开始日期2024-10-31

申办/合作机构

Brii Biosciences Ltd.

100 项与 Elebsiran 相关的临床结果

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100 项与 Elebsiran 相关的转化医学

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100 项与 Elebsiran 相关的专利（医药）

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项与 Elebsiran 相关的文献（医药）

2025-07-01·GASTROENTEROLOGY

The Impact of Hepatitis B Surface Antigen Reduction via Small Interfering RNA Treatment on Natural and Vaccine (BRII-179)-Induced Hepatitis B Virus-Specific Humoral and Cellular Immune Responses

Article

作者: Ma, Haiyan ; Tan, Ying ; Lee, Ariel ; Chen, Jieliang ; Bertoletti, Antonio ; Wang, Bing ; Zhu, Chong ; Lai-Hung Wong, Grace ; Douglas, Mark W ; Li, Dong ; Ji, Yun ; Chen, Xiaofei ; Yuen, Man-Fung ; Lv, Jianxiang ; Zhu, Qing ; Le Bert, Nina

BACKGROUND & AIMS:

The impact of hepatitis B surface antigen (HBsAg) reduction from small interfering RNA (siRNA) treatments on hepatitis B virus (HBV)-specific immunity of individuals with chronic hepatitis B (CHB) has not been adequately analyzed in humans. We conducted a phase 2a study treating CHB participants with nine 4-weekly doses of HBV-targeted siRNA elebsiran (BRII-835), either alone (n = 10) or in combination with a virus-like particle-based therapeutic vaccine (BRII-179) containing Pre-S1, Pre-S2, and S antigens, coadministered with (n = 39) or without (n = 41) interferon alfa.

METHODS:

We analyzed longitudinally for 72 weeks virologic, clinical, and immunologic parameters, including HBsAg, alanine aminotransferase, hepatitis B surface antibody (anti-HBs), the neutralizing activity of representative sera, and frequency and cytokine secretion ability of T cells specific for Pre-S1, Pre-S2, and S both directly ex vivo and after in vitro expansion.

RESULTS:

Combination therapy with elebsiran and BRII-179 was well tolerated. Although no sustained HBsAg seroclearance or notable difference in mean HBsAg reduction at the group level was observed, we detected marked heterogeneity in immunologic responses among groups. HBsAg reduction mediated by siRNA alone was associated with minimal HBV-specific immune response recovery. In contrast, combination of elebsiran with BRII-179 induced a significant modification of immune responses demonstrated by anti-HBs antibody production and an expansion of interleukin 2-producing helper T cells specific for Pre-S1/Pre-S2 antigens only. Importantly, anti-HBs antibodies persisted at ≥100 IU/L in ∼40% of the participants for at least 32 weeks after combined treatment. Moreover, the neutralizing ability of the anti-HBs-positive sera was associated with HBsAg reduction.

CONCLUSIONS:

siRNA-induced HBsAg reduction may contribute to the persistence and efficacy of the humoral arm of HBV-specific adaptive immunity in CHB participants receiving the therapeutic vaccine BRII-179.

CLINICALTRIALS:

gov number: NCT04749368.

2025-06-01·JHEP Reports

Therapy with murinized tobevibart and elebsiran is efficacious in a liver-chimeric mouse model of HDV infection

Article

作者: Terrell, Ashley N ; Lempp, Florian A ; Zhou, Jiayi ; Puschnik, Andreas S ; Corti, Davide ; Rocha, Evelyn ; Kaiser, Hannah ; Purcell, Lisa A

Background & Aims:

Chronic hepatitis delta virus (HDV) infection represents the most severe form of viral hepatitis. HDV is a satellite virus of hepatitis B virus (HBV) and depends on the hepatitis B surface antigen (HBsAg) for envelopment and viral entry. Tobevibart (VIR-3434) is an investigational monoclonal antibody targeting the antigenic loop of HBsAg. Elebsiran (VIR-2218) is an investigational RNAi therapeutic targeting a highly conserved region within the HBV genome. The aim of this study was to investigate the antiviral effect of tobevibart and elebsiran on HDV infection in preclinical models.

Methods:

In vitro antiviral activity was determined in an HBV/HDV coinfection model in primary human hepatocytes (PHHs) or Huh7-NTCP cells. The in vivo efficacy of a murinized version of tobevibart alone or in combination with elebsiran was evaluated in HBV/HDV-coinfected liver-chimeric mice.

Results:

Elebsiran treatment reduced levels of secreted HBsAg and infectious HDV with picomolar potency. Tobevibart exhibited pan-genotypic neutralizing activity against all tested HDV genotypes with EC₅₀ ranging from 1.1 to 4.6 ng/ml. Combination treatment with tobevibart and elebsiran reduced infectious HDV levels in HBV/HDV-coinfected PHHs in an additive manner. In vivo, compared to vehicle, treatment with elebsiran, murinized tobevibart, or their combination significantly decreased HDV RNA serum levels by 0.7 log (p <0.0001), 1.6 log (p = 0.0034) and 2.1 log (p = 0.0002), respectively (measured at day 14 for elebsiran or day 21 for murinized tobevibart and the combination). HBsAg serum levels were reduced by 0.6 log (p <0.0001), 2.0 log (p <0.0001) and 2.8 log (p <0.0001), respectively.

Conclusions:

Tobevibart and elebsiran exert potent antiviral activity as single agents and in combination. The data support the clinical development of tobevibart and elebsiran for the treatment of patients with chronic HDV infection.

Impact and implications:

Chronic hepatitis delta is the most severe form of viral hepatitis and is associated with rapid progression of liver-related diseases and a high risk of hepatocellular carcinoma development. To date, there are only limited treatment options available. Tobevibart and elebsiran are currently being evaluated in clinical trials for the treatment of HDV (phase III) and for the treatment of HBV (phase II). The current study demonstrates that tobevibart and elebsiran are efficacious in preclinical models of HBV/HDV coinfection, supporting their clinical development.

2024-12-01·Lancet Gastroenterology & Hepatology

VIR-2218 (elebsiran) plus pegylated interferon-alfa-2a in participants with chronic hepatitis B virus infection: a phase 2 study

Article

作者: Lim, Tien-Huey ; Yuen, Man-Fung ; Gane, Edward ; Cloutier, Daniel ; Yoon, Ki Tae ; Gupta, Sneha V ; Arizpe, Andre ; Lim, Young-Suk ; Mao, Shenghua ; Heo, Jeong ; Thanawala, Vaidehi ; Cathcart, Andrea L ; Tak, Won Young ; Hwang, Carey ; Tangkijvanich, Pisit

BACKGROUND:

Chronic hepatitis B virus (HBV) remains a global concern, with current treatments achieving low rates of HBsAg seroclearance. VIR-2218 (elebsiran), a small interfering RNA agent against HBV transcripts, reduces HBsAg concentrations. We aimed to evaluate the safety and antiviral activity of VIR-2218 with and without pegylated interferon-alpha-2a treatment in participants with chronic HBV.

METHODS:

This open-label, phase 2 study was conducted at 23 sites in six countries (New Zealand, Australia, Hong Kong, Thailand, South Korea, and Malaysia). Adults (aged 18-65 years) with chronic HBV infection without cirrhosis and with HBsAg more than 50 IU/mL and HBV DNA less than 90 IU/mL who were on continued nucleoside or nucleotide reverse transcriptase inhibitor (NRTI) therapy for 2 months or longer were eligible. Participants were enrolled into one of six cohorts to receive VIR-2218 200 mg subcutaneously every 4 weeks, with or without 180 μg subcutaneous pegylated interferon-alfa-2a once per week. Cohort 1 received six doses of VIR-2218 (total 20 weeks); cohort 2 received six doses of VIR-2218 starting at day 1, plus 12 doses of pegylated interferon-alfa-2a starting at week 12 (total 24 weeks); cohort 3 received six doses of VIR-2218 and 24 doses of pegylated interferon-alfa-2a (total 24 weeks); cohort 4 received six doses of VIR-2218 and up to 48 doses of pegylated interferon-alfa-2a (total 48 weeks); cohort 5 received up to 13 doses of VIR-2218 and up to 44 doses of pegylated interferon-alfa-2a (total 48 weeks); and cohort 6 received three doses of VIR-2218 and 12 doses of pegylated interferon-alfa-2a (total 12 weeks). The primary endpoints were the incidence of adverse events and clinical assessments (including results of laboratory tests). Secondary endpoints were the mean maximum reduction of serum HBsAg at any timepoint; the proportion of participants with serum HBsAg seroclearance at any timepoint and for more than 6 months after the end of treatment; and the proportion of participants with anti-HBs seroconversion at any timepoint. For patients who were HBeAg-positive, we also assessed the proportion with HBeAg seroclearance or anti-HBe seroconversion at any timepoint. This study is registered with ClinicalTrials.gov, NCT03672188, and is ongoing.

FINDINGS:

Between July 2, 2020, and Nov 2, 2021, 124 individuals were screened for eligibility, 84 of whom were enrolled (15 in cohort 1, 15 in cohort 2, 18 in cohort 3, 18 in cohort 4, 13 in cohort 5, and five in cohort 6). Participants were predominantly HBeAg-negative, Asian, and male (66 [79%] participants were male and 18 [21%] were female). Most treatment emergent adverse events were grades 1-2. Three (20%) participants in cohort 1, four (27%) in cohort 2, eight (44%) in cohort 3, seven (39%) in cohort 4, six (46%) in cohort 5, and two (40%) in cohort 6 reported treatment-emergent adverse events related to VIR-2218. 12 (80%) participants in cohort 2, 12 (67%) in cohort 3, 14 (78%) in cohort 4, 13 (100%) in cohort 5, and three (60%) in cohort 6 reported treatment-emergent adverse events related to pegylated interferon-alfa-2a. Two (13%) participants in cohort 1 had elevations in alanine aminotransferase, compared with 13 (87%) participants in cohort 2, 15 (83%) in cohort 3, 17 (94%) in cohort 4, 11 (85%) in cohort 5, and three (60%) in cohort 6. The mean maximum change from baseline at any timepoint in HBsAg concentration was -2·0 log₁₀ IU/mL (95% CI -2·1 to -1·8) in cohort 1, -2·2 log₁₀ IU/mL (-2·5 to -1·8) in cohort 2, -2·5 log₁₀ IU/mL (-2·8 to -2·1) in cohort 3, -2·4 log₁₀ IU/mL (-3·1 to -1·8) in cohort 4, -3·0 log₁₀ IU/mL (-3·7 to -2·3) in cohort 5, and -1·7 log₁₀ IU/mL (-2·1 to -1·4) in cohort 6. 11 participants (one in cohort 2, one in cohort 3, five in cohort 4, and four in cohort 5) receiving VIR-2218 plus pegylated interferon-alfa-2a had HBsAg seroclearance at any timepoint. Of these, ten (91%; one in cohort 2, five in cohort 4, and four in cohort 5) had anti-HBs seropositivity. Six participants (one in cohort 2, three in cohort 4, and two in cohort 5) had sustained HBsAg seroclearance through to 24 weeks after the end of treatment. No participants receiving VIR-2218 monotherapy (cohort 1) or VIR-2218 plus pegylated interferon-alfa-2a 12-week regimen (cohort 6) had HBsAg seroclearance. 12 (42%) of 26 participants (one of four in cohort 1, two of six in cohort 2, four of seven in cohort 3, four of six in cohort 4, and one of three in cohort 5) who were HBeAg positive at baseline had HBeAg seroclearance or anti-HBe seroconversion.

INTERPRETATION:

The results of this phase 2 study support further development of VIR-2218 as a potential therapy for patients with chronic HBV infection. Additional clinical trials of VIR-2218 with and without pegylated interferon-alfa-2a in combination with an HBsAg-targeting monoclonal antibody are ongoing.

FUNDING:

Vir Biotechnology.

234

项与 Elebsiran 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

2025-06-05

·CPHI制药在线

收藏 | 现有管线与上市RNA疗法汇总

关注并星标CPHI制药在线RNA疗法正迅速成为现代医学中最具变革性的治疗策略之一。从反义寡核苷酸（ASO）和小干扰RNA（siRNA）等精准调控基因表达的工具，到mRNA疫苗和肿瘤免疫疗法等前沿应用，RNA技术已在多个疾病领域展现出巨大潜力。近年来，随着递送系统、生物偶联技术和修饰化学的不断进步，RNA疗法的临床管线迅速扩展，涵盖了罕见病、神经系统疾病、代谢性疾病以及肿瘤等多个领域。目前，RNA疗法的临床开发全景涵盖了ASO、siRNA、mRNA、核酸适体（aptamer）等主要技术路径，在不同适应症中布局广泛，关键企业的研发动态频繁，已获批上市的代表性药物不断涌现。本文总结了现有管线和上市的 RNA疗法，将这一新兴领域的开发全景呈现出来。1. ASO类 RNA资产梳理 1.1 I期ASO资产 • Praxis ASO资产：Elsunersen（PRAX-222）靶点：SCN2A基因适应症：由SCN2A基因的功能获得性突变引起的早发性SCN2A发育性和癫痫性脑病。 • PYC Therapeutics ASO资产：VP-001 靶点：PRPF31基因适应症：由PRPF31基因突变引起的视网膜色素变性11型 ASO资产：PYC-001 靶点：OPA1基因适应症：由OPA1基因突变引起的常染色体显性视神经萎缩（ADOA） ASO资产：PYC-003 靶点：PKD1基因适应症：常染色体显性多囊肾病（ADPKD） • Bio-Path Holdings ASO资产：BP1002（Liposomal Grb2 ASO）适应症：急性髓性白血病（AML）、B细胞淋巴瘤（B-cell lymphoma）技术特点：使用独特的中性脂质体递送系统（DNAbilize® Platform）递送ASO。1.2 II期ASO资产 • Stoke Therapeutics ASO资产：Zorevunersen（STK-001）靶点：SCN1A基因适应症：Dravet综合征（一种严重癫痫） ASO资产：STK-002 靶点：OPA1基因适应症：常染色体显性视神经萎缩（ADOA） • Entrada Therapeutics ASO资产：ENTR-601-44 适应症：Duchenne肌营养不良（DMD）靶点：DMD中的Exon 44跳跃技术特点：使用Entrada独有的分子穿透技术（Endosomal Escape Vehicle, EEV）提高细胞内递送效率。 ASO资产：ENTR-601-45 靶点：DMD基因的外显子45（Exon 45）适应症：适用于外显子45跳跃的杜氏肌营养不良症（DMD）患者 • Dyne Therapeutics ASO资产：DYNE-251 适应症：Duchenne肌营养不良（DMD），针对DMD中的Exon 51跳跃。技术特点：使用抗体-寡核苷酸结合平台（FORCE platform）进行肌肉组织特异性递送。 ASO资产：DYNE-101 适应症：肌强直性营养不良症1型（DM1）靶点：DMPK基因的异常CTG重复序列 • Ribomic ASO资产：Umedaptanib Pegol（原RBM-007，严格来说是核酸适体aptamer，而不是典型ASO) 靶点：FGF2（成纤维细胞生长因子2）。适应症：湿性年龄相关性黄斑变性（wAMD），软骨发育不全症 • Wave Life Sciences ASO资产： WVE-N531：DMD（杜氏肌营养不良症）治疗，靶向Exon 53跳跃 WVE-003：亨廷顿舞蹈症（Huntington's Disease, HD），靶向HTT基因突变 • PepGen ASO资产：PGN-EDO51 适应症：Duchenne肌营养不良（DMD）技术特点：结合增强型细胞穿透肽（Enhanced Delivery Oligonucleotide, EDO）技术，提高ASO进入肌肉细胞的效率。 ASO资产：PGN-EDODM1 靶点：DMPK基因的异常CUG重复序列适应症：肌强直性营养不良症1型（DM1） • 罗氏 ASO资产：Tominersen（RG6042）靶点：Huntingtin（HTT）基因适应症：亨廷顿病（Huntington's Disease, HD） ASO资产：IONIS-FB-LRx（RO7434656 / RG6299）靶点：补体因子B（Factor B）适应症：IgA肾病（IgAN） • Ultragenyx ASO资产：GTX-102 靶点：UBE3A-AS（UBE3A反义转录本）适应症：天使综合征（Angelman Syndrome）1.3 ASO类3期资产 • Oncotelic Therapeutics ASO资产：OT-101（也叫Trabedersen）靶点：转化生长因子β2（TGF-β2）适应症：胶质母细胞瘤（GBM）、胰腺癌、恶性黑色素瘤机制：抑制TGF-β2，有望减轻肿瘤免疫抑制，增强抗肿瘤免疫反应 • 阿斯利康 ASO资产：ION449（亦称AZD8233），与Ionis合作开发的ASO疗法靶点：PCSK9（一种影响低密度脂蛋白胆固醇LDL-C水平的蛋白质）适应症：高胆固醇血症（hypercholesterolemia）备注：主要竞争对手包括小分子抑制剂和PCSK9单抗（如Repatha、Praluent） • GSK ASO资产：bepirovirsen 靶点：乙型肝炎病毒（HBV）的前基因组RNA和mRNA 适应症：慢性乙型肝炎（chronic hepatitis B, CHB），通过抑制HBV基因表达，帮助病毒清除或实现功能性治愈（functional cure）。 • 诺华 ASO资产：Pelacarsen 靶点：LPA基因（编码脂蛋白(a)）作用机制：Pelacarsen通过抑制LPA基因的mRNA，降低血液中脂蛋白(a)(Lp(a))水平，从而降低心血管疾病风险。Lp(a)是目前被认为的重要但尚无针对性治疗手段的心血管风险因子。适应症：主要用于治疗动脉粥样硬化性心血管疾病高危患者中，血脂异常（特别是Lp(a)升高）的情况。临床阶段：正在进行III期临床试验（Lp(a)HORIZON）。Pelacarsen可能成为首个专门针对Lp(a)升高治疗获批的药物。1.4 ASO类上市药物 • 渤健 Spinraza（nusinersen）靶点：SMN2前体mRNA（促进功能性SMN蛋白表达）适应症：脊髓性肌萎缩症（SMA）获批时间：2016年12月（美国FDA批准）备注：全球首个获批的SMA治疗药物。由Ionis开发，Biogen负责商业化。 • Sarepta Therapeutics Exondys 51（eteplirsen）靶点：DMD基因的Exon 51 适应症：Duchenne肌营养不良（DMD）获批时间：2016年9月（FDA加速批准） Vyondys 53（golodirsen）靶点：DMD基因的Exon 53 适应症：DMD 获批时间：2019年12月 Amondys 45（casimersen）靶点：DMD基因的Exon 45 适应症：DMD 获批时间：2021年2月（FDA加速批准） • Ionis Pharmaceuticals Tegsedi（inotersen）靶点：TTR（转甲状腺素蛋白）适应症：遗传性转甲状腺素蛋白淀粉样变性多发性神经病（hATTR-PN）获批时间：2018年10月（FDA，EMA批准） Waylivra（volanesorsen）靶点：APOC3（载脂蛋白C-III）适应症：家族性乳糜微粒血症综合征（FCS）获批时间：2019年5月（欧洲EMA批准；未获美国FDA批准） • NS Pharma Viltepso（viltolarsen）靶点：DMD基因的Exon 53 适应症：Duchenne肌营养不良（DMD）获批时间：2020年8月（FDA加速批准）2.RNAi类 RNA资产2.1 I期RNAi资产 • Aligos Therapeutics RNAi资产：ALG-125755 靶点：乙型肝炎病毒（HBV）RNA 适应症：慢性乙型肝炎（CHB） • Regulus Therapeutics RNAi资产：RGLS8429 靶点：microRNA-17（miR-17家族）适应症：常染色体显性多囊肾病（ADPKD） • Phio Pharmaceuticals RNAi资产：PH-762 靶点：程序性死亡受体1（PD-1）适应症：癌症免疫疗法（通过下调T细胞表面PD-1，增强免疫杀伤）技术特点：采用其自有的INTASYL✓平台，优化了siRNA的稳定性和局部递送。 • TransCode Therapeutics RNAi资产：VIR-2218 TTX-MC138 靶点：microRNA-10b（miR-10b）适应症：针对转移性实体肿瘤（如乳腺癌、胰腺癌、脑肿瘤等）技术特点：使用纳米颗粒系统高效递送siRNA药物，特别适合针对深部转移灶。2.2 II期RNAi资产 • Arbutus Biopharma RNAi资产：AB-729 靶点：乙型肝炎病毒（HBV）表面抗原（HBsAg）适应症：慢性乙型肝炎（CHB）备注：AB-729是Arbutus当前最重要的核心资产之一。 • OliX Pharmaceuticals RNAi资产：OLX703A 靶点：HBV病毒相关RNA 适应症：慢性乙型肝炎（CHB）机制：抑制HBV病毒蛋白表达 • Silence Therapeutics RNAi资产：SLN360 靶点：LPA基因（编码脂蛋白Lp(a)）适应症：高脂蛋白(a)血症（Lp(a)过高相关的心血管疾病）机制：通过降低血液中Lp(a)水平，减少动脉粥样硬化风险。备注：SLN360是Silence在心血管RNA疗法领域的主力项目。 • Sirnaomics RNAi资产：STP705 靶点：双靶点siRNA药物，靶向TGF-β1和COX-2。适应症：瘢痕治疗（皮肤纤维化）、非黑色素瘤皮肤癌（如基底细胞癌、鳞状细胞癌）机制：抑制纤维化、降低肿瘤微环境免疫抑制。备注：Sirnaomics的特点是双靶点siRNA联合递送。 • GSK RNAi资产：GSK4532990 靶点：靶向HSD17B13基因适应症：代谢功能障碍相关脂肪性肝炎（MASH） • 礼来 RNAi项目：LY3561774 靶点：SERPINA1基因适应症：α1-抗胰蛋白酶缺乏症（AATD）机制：降低异常α1-抗胰蛋白酶（AAT）积聚 • VIR Biotechnology RNAi项目：VIR-2218 靶点： HBV RNA 适应症：慢性乙型肝炎（CHB）。机制：抑制HBV表面抗原表达 • 罗氏 RNAi资产：Zilebesiran 靶点：肝脏表达的血管紧张素原（AGT）基因。适应症：高血压，特别是高心血管风险患者。2.3 III期RNAi资产 • Arrowhead Pharmaceuticals RNAi资产：ARO-APOC3 靶点：APOC3（载脂蛋白C-III），适应症：高甘油三酯血症和罕见脂代谢异常 • 武田 RNAi资产：Fazirsiran 靶点：SERPINA1（编码α1-抗胰蛋白酶）适应症：α1-抗胰蛋白酶缺乏症（AATD）引起的肝病 • 安进 RNAi资产：Olpasiran 靶点：LPA基因（脂蛋白(a)）适应症：高脂蛋白(a)血症及其引发的心血管疾病风险备注：这是一款非常重磅的RNAi项目，对心血管领域意义重大。 • Avidity Biosciences RNAi资产：AOC 1001 靶点：DMPK基因（导致肌强直性营养不良症1型DM1）适应症：肌强直性营养不良症1型（DM1）技术特点：AOC（Antibody Oligonucleotide Conjugate，抗体-寡核苷酸偶联体），用于肌肉靶向递送siRNA。 • 赛诺菲 RNAi资产：Fitusiran 靶点：AT（抗凝血酶）适应症：血友病A或B患者的出血预防 • VIR Biotechnology RNAi资产：VIR-2218 靶点：HBV RNA 适应症：慢性乙型肝炎（CHB）2.4 上市RNAi资产 • Alnylam Pharmaceuticals Alnylam是全球RNAi疗法先锋，拥有最多已上市RNAi药物。 Onpattro（Patisiran）靶点：TTR 适应症：遗传性转甲状腺素蛋白淀粉样变性引起的多发性神经病（hATTR-PN）批准情况：2018年FDA/EMA批准 Givlaari（Givosiran）靶点：ALAS1 适应症：急性肝卟啉症（AHP）批准情况：2019年FDA/EMA批准 Oxlumo（Lumasiran）靶点：HAO1 适应症：原发性高草酸尿症1型（PH1）批准情况：2020年FDA/EMA批准 Amvuttra（Vutrisiran）靶点：TTR 适应症：遗传性转甲状腺素蛋白淀粉样变性引起的多发性神经病（hATTR-PN）（长效皮下注射版）批准情况：2022年FDA批准 • 诺华 RNAi资产：Leqvio（Inclisiran）靶点：PCSK9 适应症：高胆固醇血症，动脉粥样硬化性心血管疾病风险降低批准情况：2020年欧洲EMA批准；2021年底美国FDA批准 • 诺和诺德 RNAi资产：Rivfloza (nedosiran) 靶点：肝脏中乳酸脱氢酶（LDH）mRNA 适应症：治疗9岁及以上、肾功能相对良好的原发性高草酸尿症1型（PH1）患者。作用机制：抑制LDH蛋白表达，减少草酸过度生成，缓解PH1疾病过程，减少肾脏损害风险。批准情况：2023年9月29日FDA正式批准Rivfloza上市。成为继Alnylam的Oxlumo（Lumasiran）之后，全球第二款获批用于PH1治疗的RNAi药物。3.mRNA类 RNA药物资产3.1 1期mRNA资产 • 赛诺菲 SP0237: 季节性流感 mRNA 疫苗适应症：针对 A/H3N2 毒株的季节性流感。 SP0256 – RSV mRNA 疫苗（老年人群）适应症：用于预防老年人群中的呼吸道合胞病毒（RSV）感染。 SP0268 – mRNA 痤疮疫苗适应症：针对痤疮（Acne）的 mRNA 疫苗。 SP0291 – 多价呼吸道病毒 mRNA 疫苗适应症：针对 RSV、人类偏肺病毒（hMPV）和副流感病毒 3 型（PIV3）的组合疫苗，主要用于老年人群。沙眼衣原体（Chlamydia）mRNA 疫苗候选适应症：预防沙眼衣原体感染，主要针对 18 至 29 岁的成人。 • Vertex mRNA资产：VX-522：用于囊性纤维化（CF）的mRNA疗法靶点：CFTR基因（囊性纤维化跨膜电导调节因子）。适应症：无法通过CFTR调节剂治疗的CF（囊性纤维化）患者，尤其是那些由于CFTR基因突变导致CFTR蛋白缺失的患者。作用机制：VX-522是一种mRNA疗法，通过脂质纳米颗粒（LNP）递送CFTR mRNA至肺部细胞，促使其合成功能性CFTR蛋白，从而恢复氯离子通道的功能。3.2 II期mRNA资产 • Gritstone Bio GRANITE（GRT-C901/GRT-R902）个体化肿瘤新抗原疫苗，采用腺病毒（ChAd68）和自扩增mRNA（samRNA）组成的异源prime-boost策略。适应症：用于治疗转移性微卫星稳定型结直肠癌（MSS-CRC）。 CORAL 基于自扩增mRNA（samRNA）的COVID-19疫苗，诱导广泛且持久的中和抗体和T细胞免疫反应。 • CureVac/GSK 季节性流感mRNA疫苗候选该疫苗候选基于CureVac的第二代mRNA平台，针对流感病毒株，包括A型和B型毒株。 COVID-19 mRNA疫苗候选CV0601和CV0701 CV0601为单价疫苗，编码Omicron BA.4/5变异株的刺突蛋白；CV0701为二价疫苗，编码Omicron BA.4/5变异株和原始SARS-CoV-2毒株的刺突蛋白。3.3 III期mRNA资产 • 第一三共 DS-5670a（原始毒株单价疫苗）适应症：Covid-19疫苗，作为加强针用于已完成初始疫苗接种的成人和老年人。 DS-5670a/b（原始毒株与Omicron BA.4/5二价疫苗）适应症：Covid-19疫苗，作为加强针用于12岁及以上已完成初始疫苗接种的人群。 DS-5670d（Omicron XBB.1.5单价疫苗）适应症：Covid-19疫苗，作为季节性加强针用于12岁及以上人群，包括未接种疫苗者。 • 默沙东 mRNA资产：V940（mRNA-4157）类型：肿瘤疫苗（个体化mRNA疫苗）适应症：手术切除后的高风险黑色素瘤患者辅助治疗靶点：个体化新抗原（根据患者肿瘤突变特异设计）3.4上市mRNA资产 • Arcturus Therapeutics mRNA资产：KOSTAIVE（ARCT-154 / Zapomeran）类型：自扩增mRNA（sa-mRNA）疫苗适应症：用于预防COVID-19，适用于18岁及以上人群靶点：SARS-CoV-2病毒刺突蛋白（Spike protein） • BioNTech/辉瑞 Comirnaty 类型：mRNA疫苗适应症：用于预防COVID-19，适用于6个月及以上人群靶点：SARS-CoV-2病毒刺突蛋白（Spike protein）获批时间：✓2020年12月获得FDA紧急使用授权，2021年8月获得美国FDA完全批准 • 莫德纳 Spikevax 类型：mRNA疫苗适应症：用于预防COVID-19，适用于6个月及以上人群靶点：SARS-CoV-2病毒刺突蛋白（Spike protein）获批时间：2020年12月18日，美国FDA授予紧急使用授权；2022年1月31日，获得FDA完全批准Ref. TD Cowen. Pharmaceuticals’ websitesEND【企业推荐】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

临床2期寡核苷酸上市批准信使RNA临床1期

100 项与 Elebsiran 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3期	-	Vir Biotechnology, Inc.	2025-03-13
丁型肝炎	临床3期	美国	Vir Biotechnology, Inc.	2025-03-12
丁型肝炎	临床3期	加拿大	Vir Biotechnology, Inc.	2025-03-12
丁型肝炎	临床3期	摩尔多瓦	Vir Biotechnology, Inc.	2025-03-12
丁型肝炎	临床3期	新西兰	Vir Biotechnology, Inc.	2025-03-12
丁型肝炎	临床3期	罗马尼亚	Vir Biotechnology, Inc.	2025-03-12
丁型肝炎	临床3期	乌克兰	Vir Biotechnology, Inc.	2025-03-12
丁型肝炎	临床3期	英国	Vir Biotechnology, Inc.	2025-03-12
慢性乙型肝炎	临床2期	美国	Vir Biotechnology, Inc.	2020-07-03
慢性乙型肝炎	临床2期	美国	Alnylam Pharmaceuticals, Inc.	2020-07-03

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临床结果

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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


NCT04856085 (MARCH, Company_Website) 人工标引	临床2期	慢性乙型肝炎	83	Tobevibart + Elebsiran	製鹽鹽遞範製積鑰繭繭(範鹽鑰積鏇衊製襯顧觸) = 鹹觸繭齋鑰鏇醖觸鹽鏇醖齋鑰鬱構衊選觸鹹壓 (夢蓋網鏇繭觸窪鏇衊襯 ) 更多	积极	2025-05-09
				Tobevibart + Elebsiran + PEG-IFNα	製鹽鹽遞範製積鑰繭繭(範鹽鑰積鏇衊製襯顧觸) = 範願夢鏇淵醖構築簾艱醖齋鑰鬱構衊選觸鹹壓 (夢蓋網鏇繭觸窪鏇衊襯 ) 更多
NCT05970289 (ENSURE, PipelineReview) 人工标引	临床2期	慢性乙型肝炎	31	Elebsiran + PEG-IFNα (Cohort 4)	衊繭膚築鏇製廠窪壓窪(簾遞選願觸選壓糧鹹網) = 糧觸壓餘艱膚窪壓鹹襯齋網鹽網願衊獵願選選 (鏇構醖範壓構醖壓簾窪 )	积极	2025-03-31
				Elebsiran + PEG-IFNα (Cohort 4 + BRII-179 responders)	衊繭膚築鏇製廠窪壓窪(簾遞選願觸選壓糧鹹網) = 願餘窪鹹淵製鏇鑰糧積齋網鹽網願衊獵願選選 (鏇構醖範壓構醖壓簾窪 )
NCT03672188 (Pubmed \| Lancet Gastroenterol Hepatol)	临床1/2期	慢性乙型肝炎	-	VIR-2218 200 mg + Pegylated interferon-alfa-2a	鑰醖遞夢窪襯遞鑰窪艱(糧獵膚構築鹽願構積構) = 20% in cohort 1, 27% in cohort 2, 44% in cohort 3, 39% in cohort 4, 46% in cohort 5, 40% in cohort 6 蓋襯顧衊繭範構廠蓋觸 (願簾鏇鑰廠顧膚構鹹憲 ) 更多	-	2024-12-01
NCT05970289 (ENSURE, NEWS) 人工标引	临床2期	乙型肝炎	-	Elebsiran 200 mg+PEG-IFNα	蓋製蓋簾選鏇鬱選鏇獵(範網壓膚鑰積襯廠餘觸) = 齋壓夢廠築築築衊艱艱觸繭夢構鏇遞餘窪範製 (鹹鑰網餘窪夢廠願繭範 ) 更多	积极	2024-11-19
				Elebsiran 100mg+PEG-IFNα	蓋製蓋簾選鏇鬱選鏇獵(範網壓膚鑰積襯廠餘觸) = 艱襯鏇繭繭齋齋夢築夢觸繭夢構鏇遞餘窪範製 (鹹鑰網餘窪夢廠願繭範 ) 更多
NCT04507269 (CTgov)	临床2期	慢性乙型肝炎	21	VIR-2218 (Part 1: VIR-2218 50 mg)	構範餘繭積艱願範範顧 = 艱壓選夢願築齋鑰壓選觸遞觸獵夢憲艱鹽窪夢 (範製蓋襯齋顧製顧齋選, 襯廠艱膚觸鑰艱鏇鑰願 ~ 築網醖範構齋夢願鑰獵) 更多	-	2024-08-26
				VIR-2218 (Part 1: VIR-2218 100 mg)	構範餘繭積艱願範範顧 = 膚膚鏇夢鹹餘蓋遞蓋選觸遞觸獵夢憲艱鹽窪夢 (範製蓋襯齋顧製顧齋選, 顧獵蓋蓋鬱積遞選願壓 ~ 艱顧願簾憲廠鑰襯鹽膚) 更多
NCT03672188 \| NCT02826018 (Pubmed \| J Hepatol)	临床1/2期	慢性乙型肝炎	-	VIR-2218	網糧窪醖選淵網鑰襯壓(鹽蓋觸觸鹹鬱範構願遞) = 鏇餘蓋壓糧遞遞餘衊鑰觸顧夢憲醖選製獵艱網 (糧獵蓋鑰觸繭醖遞範壓 )	-	2023-06-06
GlobeNewswire 人工标引	临床2期	乙型肝炎	-	VIR-2218VIR-2218 (six-dose regimen of VIR-2218)	鏇夢顧餘憲餘憲糧鏇膚(鏇網衊鏇鏇艱襯醖膚餘) = all participants achieving a >1 log10 IU/mL reduction during the trial. 齋鏇淵鑰範構製觸憲遞 (積鏇窪構獵蓋衊網選憲 ) 更多	积极	2022-06-25
				VIR-2218VIR-2218 (two-dose regimen of VIR-2218)
EASL2021	临床2期	慢性乙型肝炎	27	VIR-2218 alone	衊顧築遞壓艱繭蓋憲構(製製衊憲衊蓋淵淵衊夢) = Some participants receiving Peg-IFNa and VIR-2218 combination experienced asymptomatic ALT elevations (grade 2 – 3) concurrent with HBsAg decline ( ≥ 1 log 10 IU/ ml). ALT elevations were not associated with functional changes of the liver (bilirubin, PT or INR). No serious AEs have been reported. 簾鏇艱鑰艱選網衊製鑰 (淵壓醖製積淵憲夢網構 )	-	2021-06-23
				VIR-2218 + Peg-IFNa
EASL2020	临床2期	慢性乙型肝炎	24	VIR-2218 20 mg	餘艱艱醖選廠獵襯鑰淵(鬱簾獵鏇築築糧範簾夢) = No clinically significant ALTelevations were observed 窪壓醖願壓糧鬱願壓鏇 (顧網憲鹹製鹹鬱鹽鹽齋 ) 更多	-	2020-08-27
				VIR-2218 50 mg