主要目的：有效性：评估两种不同剂量的DAP/TOM持续24周序贯Bepirovirsen 300 mg每周一次（含负荷剂量）持续24周治疗，在慢性HBV感染受试者（接受NA治疗；基线HBsAg不设限的所有受试者）中实现功能性治愈的治疗效果。次要目的：有效性：评估两种不同剂量的DAP/TOM持续24周序贯Bepirovirsen 300 mg每周一次（含负荷剂量）持续24周治疗，在慢性HBV感染受试者（接受NA治疗且基线HBsAg>3000 IU/mL）中实现功能性治愈的治疗效果。有效性：评估两种不同剂量的DAP/TOM或安慰剂持续24周序贯Bepirovirsen 300 mg每周一次（含负荷剂量）持续24周治疗，在慢性HBV感染受试者（接受NA治疗且基线HBsAg≤3000 IU/mL）中实现功能性治愈的治疗效果。

开始日期2025-01-15

申办/合作机构

葛兰素史克（中国）投资有限公司

[+2]

NCT06537414

/ 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

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）

2025-03-01·Gut

Long-term hepatitis B surface antigen response after finite treatment of ARC-520 or JNJ-3989

Article

作者: Schluep, Thomas ; Lenz, Oliver ; Biermer, Michael ; Wooddell, Christine I ; Davis, Heather L ; Mao, Xianhua ; Hamilton, James ; Mak, Lung Yi ; Seto, Wai-Kay ; Yuen, Man-Fung

Background and aimsRNA 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.MethodsWe 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.ResultsAmong 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).ConclusionShort-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: Lampertico, Pietro ; Lenz, Oliver ; Verbinnen, Thierry ; Bourliere, Marc ; Mayer, Cristiana ; van Bömmel, Florian ; Janczewska, Ewa ; Biermer, Michael ; Vanwolleghem, Thomas ; Kakuda, Thomas N ; Beumont, Maria ; Buti, Maria ; Agarwal, Kosh ; Lonjon-Domanec, Isabelle ; Jezorwski, John ; Kalmeijer, Ronald ; Muenz, Daniel

BACKGROUND & AIMSFunctional 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).METHODSREEF-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.RESULTSAt 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.CONCLUSIONSFinite 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 IMPLICATIONSAchieving 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.CLINICALTRIALSGOV IDENTIFIERNCT04129554.

2023-09-01·The 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

作者: Jezorwski, John ; Tabak, Ömer Fehmi ; Tan, Soek Siam ; Van Vlierberghe, Hans ; Conway, Brian ; Kawaoka, Tomokazu ; Shukla, Umesh ; Gusev, Denis ; Nevens, Frederik ; Felizarta, Franco ; Crespo Garcia, Javier ; Nastri, Ana Catharina ; Inmaculada, Fernandez ; Janssen, Harry ; Kato, Naoya ; Lambrecht, Tom ; Halota, Waldemar ; Coffin, Carla ; Korenblat, Kevin ; Gitlin, Norman ; Sagalova, Olga ; Morozov, Viacheslav ; Biermer, Michael ; Bourgeois, Stefan ; Chan, Henry LY ; Jacobson, Ira ; Berak, Hanna ; Asahina, Yasuhiro ; Bourliere, Marc ; Raffi, Francois ; Akarca, Ulus Salih ; Suzuki, Yoshiyuki ; Ahn, SangHoon ; Asselah, Tarik ; Beumont, Maria ; Jacobson, Ira M ; Sperl, Jan ; Piratvisuth, Teerha ; Diago, Moises ; Forns, Xavier ; Kawabe, Naoto ; Yuen, Man-Fung ; Vanwolleghem, Thomas ; Kennedy, Patrick ; Leerapun, Apinya ; Notsumata, Kazuo ; Verbinnen, Thierry ; Kakuda, Thomas N ; Sabranski, Michael ; Shafran, Stephen ; Sulkowski, Mark ; Enomoto, Hirayuki ; Geyvandova, Natalia ; Urbanek, Petr ; Ramji, Alnoor ; Koji, Ogawa ; Kalmeijer, Ronald ; Andreone, Pietro ; Mohamed, Rosmawati ; Hejda, Vaclav ; Hlebowicz, Maria ; Lampertico, Pietro ; Yuen, Man Fung ; Mayer, Cristiana ; Wedemeyer, Heiner ; Hilgard, Gudrun ; Rojter, Sergio ; Tangkijvanich, Pisit ; Schulze zur Wiesch, Julian ; Bell, David ; Takehara, Tetsuo ; Plisek, Stanislav ; Janczewska, Ewa ; Kiew, Kuang Kiat ; Buti, Maria ; Lenz, Oliver ; Wong, Vincent Ws ; Nahass, Ronald ; Andreeva, Alla ; Forton, Daniel ; Yatsuhashi, Hiroshi ; Janssen, Harry L A ; Taliani, Gloria ; Gasiorowski, Jacek ; Bessonova, Elena ; Namisaki, Tadashi ; Paik, Seung Woon ; Lim, Young-Suk ; Tanwandee, Tawesak ; Calleja, Jose Luis ; Takaguchi, Koichi ; Brunetto, Maurizia Rossana ; Sprinzl, Kathrin ; van Boemmel, Florian ; Yilmaz, Gurdal ; Samuel, Didier ; Lacombe, Karine ; Guyader, Dominique ; Fujiwara, Kei ; Kurosaki, Masayuki ; Akova, Murat ; Romanova, Svetlana ; Agarwal, Kosh ; Zoulim, Fabien ; Osipenko, Marina ; Fung, Scott ; Yoon, Jung-Hwan ; Horsmans, Yves ; Idilman, Ramazan ; Lacerda, Marcus ; Stepanova, Tatiana ; Hilleret, Marie-Noelle ; Arasteh, Keikawus ; Guinard-Azadian, Carine ; Gankina, Natalia ; Yabushita, Kazuhisa ; Lee, Yeong Yeh ; Hou, Jin Lin

BACKGROUNDJNJ-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.METHODSThe 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.FINDINGSBetween 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.INTERPRETATIONAlthough 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.FUNDINGJanssen Research and Development.

项与 Daplusiran/Tomligisiran 相关的新闻（医药）

2025-02-05

·FierceBiotech

GSK drops one potential \'functional cure\' for hep B as it goes all-in on bepirovirsen

Hopes for GSK3528869 appeared to be dashed in December when GSK terminated a phase 1/2 chronic hepatitis B study.\n GSK is prioritizing development of its hepatitis B treatment bepirovirsen as the pharma ends work on another potential functional cure for the infectious disease.On a media call Wednesday morning to discuss her company\'s fourth-quarter and full-year earnings, CEO Emma Walmsley said that when it came to the British pharma’s infectious disease pipeline, “we\'re prioritizing development of bepirovirsen, our potential functional cure for hepatitis B.”The pharma licensed the antisense oligonucleotide from Ionis Pharmaceuticals for $25 million upfront in 2019 and is currently aiming for an approval decision by regulators for chronic hepatitis B next year. The reemphasis on bepirovirsen came as GSK disclosed this morning that it has discontinued work on GSK3528869. The company had been holding out hopes that the candidate could be another functional cure for the infection—meaning it reduces hepatitis B virus DNA and viral proteins to undetectable levels. This stands in contrast to currently available oral antiviral therapies, which only suppress the virus.But those hopes for GSK3528869 appeared to be dashed in December when GSK terminated a phase 1/2 chronic hepatitis B study after the therapeutic vaccine regimen failed to meet the efficacy endpoint. The study tested different dose levels and sequences—and included placebo—but the idea was to prime the immune system with a viral vector encoding hepatitis B protein antigens, boost the immune system with a different vaccine and administer adjuvants to enhance the response.At the time, the pharma still had another study of GSK3528869 listed as active on the federal trial database. That study was evaluating the effect of giving vaccines to prime and boost the immune system—and adjuvants to enhance the response—after patients have received GSK’s bepirovirsen. But GSK confirmed in its earnings documents (PDF) today that it won’t be taking GSK3528869 forward.GSK isn’t the only pharma to have struggled with hepatitis B candidates in the clinic. Roche axed phase 1 and 2 trials in a recent pipeline cull, while Altimmune dropped a drug candidate after phase 2 data disappointed, and Ascletis Pharma stopped a hepatitis B program after the asset flopped in another indication.While bepirovirsen is taking priority, GSK still has a number of other assets in clinical development for chronic hepatitis B, including the hepatitis B virus-targeted siRNA GSK5637608, the PAPD5/PAPD7 inhibitor GSK3965193 and the TLR8 agonist GSK5251738. GSK also disclosed this morning that it had removed a capsid protein inhibitor for HIV called VH4004280 from its phase 2 pipeline. The company still has another HIV capsid protein inhibitor in multiple clinical trials in the form of VH3739937.The final drug to be pulled is the phase 1-stage GSK2556286, which is designed to inhibit the intracellular growth of Mycobacterium tuberculosis. The pharma has other tuberculosis candidates in the clinic in the form of the leucyl t-RNA synthetase inhibitor ganfeborole, the ethionamide booster alpibectir and the serine beta lactamase inhibitor sanfetrinem cilexetil. When it came to M&A, Walmsley told journalists on the media call that the company “continues to add new opportunities through targeted business development.” She pointed to the acquisition of Boston-based cancer-focused biotech IDRx last month as “a good example of what we want to do here.”

$GSK drops one potential \'functional cure\' for hep B as it goes all-in on bepirovirsen$

疫苗临床2期并购寡核苷酸siRNA

2025-01-06

·药智网

由罕见病到慢病到肿瘤，小核酸开启新药研发第三次浪潮

前言小核酸药物，即寡核苷酸药物，是由十几个到几十个核苷酸串联组成的短链核酸，主要通过碱基互补配对原则作用于细胞内的pre-mRNA或mRNA，通过调控蛋白质的表达，从而实现治疗疾病的目的。小核酸药物从转录后水平进行治疗，攻克难以成药的特殊蛋白靶点，具备治疗“不可成药”疾病的潜力，有望成为继小分子药物、抗体药物之后的现代新药第三次浪潮的引领者。分类与作用机制广义的小核酸药物包括反义寡核苷酸（ASO）、小干扰核酸（siRNA）、微小RNA（miRNA）、核酸适配体（Aptamer）、小激活RNA（saRNA）、向导RNA（sgRNA）等。已获批和在研的核酸药物以ASO和siRNA、Aptamer为主。小核酸药物主要类型及作用机制[1] 分类 ASO siRNA miRNA Aptamer 长度 13-30个核苷酸 21-25个碱基对约22个核苷酸 20-100个核苷酸单双链单链双链单链单链靶点 mRNA、miRNA、Pre-mRNA mRNA mRNA protein 作用位点细胞核、细胞质细胞质细胞质细胞外作用机制抑制/降解mRNA，剪接调控、上调蛋白质翻译切割 mRNA 抑制/降解mRNA 功能抑制来源：文献检索，药智咨询整理小核酸药物相比现有疗法优势显著小核酸药物相比现有的小分子和抗体药物，具有靶点筛选快、治疗领域更广、安全性更高、疗效更久、研发成功率高等优点。继而，随着未来研发技术的不断进步，小核酸药物有望成为继小分子和抗体之后具有颠覆性的新主流疗法。小核酸药物和小分子药物、抗体药物对比[1] 类别小核酸药物小分子药物抗体药物分子量中（＞7kDa）小（＜500da）大（＞150kDa）靶点丰富度高中低作用类型碱基互补配对静电力吸附蛋白相互作用特异性强中强半衰期长（以月计）短（以小时计）中（以周计）免疫原性低低中-高基因污染风险无无无生产成本中低高新产品早期设计时间数周数月数月新产品开发难度较低中高给药方式主要静脉注射首选口服首选静脉或皮下安全性/毒性已上市药物常见不良反应：肝肾毒性和超敏反应脱靶效应、潜在毒性免疫不良反应来源：文献检索，药智咨询整理参考小核酸领域头部企业Alnylam的研发成功率，从临床I期到III期的累计转化率达到66.7%，相比靶向药（10.3%）和医药行业整体的研发成功率（5.7%）整整高6-12倍。Alnylam公司超高的临床转化率与小核酸药物本身的特性，还有整体小核酸行业技术平台的通用延展性强密不可分。图1 Alnylam RNAi药物和靶向药研发成功率对比[2] 来源：AInylam Pharmaceuticals官网全球已上市小核酸药物概览目前，全球已有21款小核酸药物获批上市，包括13款ASO药物、6款siRNA药物和2款核酸适配体药物。其中，遗传罕见病是目前获批最多的适应症类别，共有16款药物针对遗传罕见病，3款针对眼科疾病，1款针对心血管疾病，1款针对血液肿瘤并发症，可见小核酸药物的临床应用正在逐渐探索罕见病以外的疾病领域。靶点差异性较大，但递送系统主要为GalNAc。原研公司主要为 Ionis 、Alynlam、Sarepta等，上市药物共占比78.9%。值得关注的是，2024年上市的Geron公司研发的Rytelo（imetelstat），用于治疗低危骨髓增生异常综合征患者的输血依赖性贫血，这款基于寡核苷酸的药物是首个获得 FDA 批准的端粒酶抑制剂，也是端粒酶自1984年被发现以来的首款靶向疗法。Imetelstat的上市，充分验证了该技术路径的可行性，开创了小核酸药物研发的新市场。全球已上市小核酸药物注：*代表已退市来源：截至2025.01.02，药智数据，药智咨询整理罕见病—慢病—肿瘤在研管线概览据药智数据统计，全球小核酸药物在研管线共739条，从管线的适应症来看，排名前五的疾病依次是肿瘤（24%）、遗传病 (22%)、感觉器官疾病 (13%)、心血管系统疾病 (12%) 、消化代谢性疾病（9%）。此外，小核酸药物也在皮肤病、血液病、泌尿、感染等多个领域布局。图2 全球小核酸药物在研适应症分布来源：截至2025.01.02，药智数据，药智咨询整理 1、遗传性罕见病：从无药可治到临床进展迅速遗传性罕见病通常由基因突变导致，致病靶点明确便于小核酸设计，同时罕见病多“无药可治”可以加速进行临床以及罕见病对药物安全性耐受度较高等，因此小核酸药物在罕见病适应症上率先突破。已经获批上市的小核酸药物针对的罕见病适应症就有7种，涉及16个产品（表3），3个产品申请上市，10个产品处于临床III期（表4），相对于其他疾病领域，小核酸药物在罕见病领域研发进展迅速。全球在研罕见病小核酸药物（临床后期）来源：截至2025.01.02，药智数据，药智咨询整理 2、慢病领域在研管线梳理 Alnylam/诺华共同开发的Leqvio是首款且目前唯一一款用于降低低密度脂蛋白胆固醇（LDL-C）的siRNA药物，相继于2021年和2023年在美国和中国上市，突破了小核酸药物应用于罕见病的局限，首次成功进军慢性病领域，极具里程碑意义。目前有多款小核酸药物正在被开发用于高血脂、动脉粥样硬化、高血压、传染性肝病等慢病的治疗，一场全新的慢病治疗药物研发竞赛已开启。高血脂及动脉粥样硬化：高血脂、动脉粥样硬化是常见的脂代谢异常疾病。肝脏是脂代谢的重要路径，转运内源性甘油三酯和胆固醇的脂蛋白在肝脏合作，刺激肝脏脂蛋白合成因子会导致血脂升高；因此擅长肝靶向的小核酸药物在降血脂方面展现出良好的治疗前景。近年新兴降脂治疗靶点不断涌现[3]，包括载脂蛋白C（ApoC）、脂蛋白a（Lp(a)）、血管生成素样蛋白（ANGPTL）等，目前已有3款新产品已进入临床III期，临床试验数据均展现出较好的降脂效果。表5 全球在研脂代谢异常小核酸药物管线梳理（临床后期）药品类别药品名称靶点适应症研发单位全球最高阶段 siRNA ARO-APOC3 ApoC-III 高甘油三酯血症 Arrowhead 临床Ⅲ期 (2024-09-04) Lepodisiran Sodium ASGPR; Lp(a) 动脉粥样硬化性心血管疾病 Dicerna；礼来临床Ⅲ期 (2024-02-27) 奥帕司兰 olpasiran (突破性治疗) Lp(a) 动脉粥样硬化性心血管疾病 Arrowhead；安进临床Ⅲ期 (2022-10-12) ASO 佩拉卡生 pelacarsen(突破性治疗) ASGPR; Apo(a) 动脉粥样硬化性心血管疾病 Akcea；诺华临床Ⅲ期 (2024-04-24) 来源：截至2025.01.02，药智数据，药智咨询整理高血压：从上游靶点高效/长效控制血压高血压是一种常见慢性病，也是心血管疾病的主要危险因素，常见致病通路是肾素-血管紧张素-醛固酮系统（RAAS）。而AGT（Angiotensinogen，血管紧张素原）位于RAAS通路最上游，由肝脏合成，抑制后可降低高血压。Alnylam和Ionis针对AGT均有所布局（Zilebesiran 、IONIS-AGT-LRx），目前全球也只有这两款产品进入临床II期。表6 全球在研高血压小核酸药物管线梳理公司 Alny lam lonis 产品名称 Zilebesiran 1ONIS-AGT-LRx 技术路径 GaINAc-siRNA ESC+ Gen2+LICA-ASO 临床进展 Ph2 Ph2 靶点 AGT AGT 适应症 HTN HTN 用法用量 <800mg sc q3M 80mg sc qM 有效性 SBP CFB>10mmHg (单次注射剂量≥200mg) SBP CFB:-8 vs -2 mmHg DBP CFB:-1 vs 4 mmHg 来源：截至2025.01.02，药智数据，药智咨询整理乙肝：以小核酸为基石多药联用，冲刺功能性治愈慢性乙型肝炎一直是全球重大公共卫生问题，亟待得到有效治疗，功能性治愈是目前临床慢乙肝治疗的短期目标。国内外指南中主流抗乙肝病毒（HBV）治疗分为两类[4]：一类是干扰素，另一类就是核苷与核苷酸类似物，统称为NAs，作用机制是降低HBsAg水平同时激活自身免疫系统抗病毒反应。相比之下，RNA干扰（RNAi）疗法能在更上游阻断HBV复制，并且在临床试验中显著降低HBsAg水平，具备作为基石疗法冲刺乙肝功能性治愈的潜力。表7 全球在研慢乙肝小核酸药物管线梳理公司 lonis/GSK Alnylam/VIR/腾盛博药 Arrowhead /J&J Dicerna/Roche Arbutus/齐鲁制药产品名称 Bepirovirsen/GSK836 VIR-2218 JNJ-3989 RG6346/DCR-HBVS AB-729 技术路径 ASO GaINAc-siRNA ESC+ GaINAc-siRNA Ga INAc-siRNA GaINAc-siRNA 临床进展 Ph3 Ph2 Ph2b Ph2 Ph2 靶点 HBx保守基因序列 HBx保守基因序列 HBx保守基因序列 HBx保守基因序列 HBx保守基因序列适应症 HBV HBV HBV HBV HBV 临床数据给药第24周病毒学响应率：28%(w/NA)、29%(w/o NA)。停药后24周HBV DNA转阴比例降至10% VIR-2218+PEG-IFNa给药第48周病毒学响应率：31% VIR-2218+VIR-3434结束给药HBsAg较基线下降≥2 log10 给药第48周病毒学相应率：19.1%(200mg +NA） HBsAg降幅达到1.6~1.9log10 HBsAg降幅达到1.9~2.2log10 来源：截至2025.01.02，药智数据，药智咨询整理 3、肿瘤：治疗机理丰富，与现有疗法形成协同效应行业发展早期，众多海外小核酸企业均有布局肿瘤适应症，但当时的化学修饰和递送系统发展尚不成熟，药物进入体内后难以到达病灶，靶点/适应症选择不理想，单一靶点由于肿瘤异质性无法对肿瘤细胞完全清除，导致临床效果不佳，有多个管线处在终止/暂停状态。但考虑到RNAi疗法可特异性靶向多个基因干涉肿瘤细胞的增殖、血管生成、转移、化疗抗性或影响肿瘤微环境等从而治疗肿瘤，治疗机理丰富，目前仍有企业在多方尝试通过RNAi疗法与现有肿瘤疗法的联合治疗，形成良好的协同效应。目前，暂无针对肿瘤的小核酸药物上市，排除已终止管线，有2款产品进入临床III期，有10款产品进入临床II期。国内企业如：圣诺生物、海昶生物走在前列，展现出较强的小核酸药物创新能力。表8 全球在研肿瘤小核酸药物管线梳理来源：截至2025.01.02，药智数据，药智咨询整理 3款新药2025年有望获批（Plozasiran、Donidalorsen与Fitusiran） Plozasiran Plozasiran（ARO-APOC3）作为一款由Arrowhead Pharmaceuticals/维亚臻研发的靶向APOC3基因的潜在“first-in-class”RNAi疗法，适应症主要针对家族性乳糜微粒血症综合征 (FCS)与高甘油三酯血症等。相对传统小分子降脂药物，Plozasiran所在的核酸类降脂疗法领域，一方面在作用上更长效，持久降低胆固醇的特性有助于在一定程度上简化患者血脂管理；另一方面，近80%的三酸甘油脂水平中位数减少与83%的急性胰腺炎发生率降低在有效性方面也有明显区别于其他疗法。根据cortellis预测，Pelacarsen 2030年销售额有望突破6.67亿美元。 Donidalorsen Donidalorsen作为一款由Ionis设计的潜在“first-in-class”的RNA反义寡核苷酸配体偶联（LICA）药物，适应症为遗传性血管性水肿(HAE)。其设计思路为通过精确靶向以沉默前激肽释放酶（PKK）的表达，中断导致HAE攻击的通路。 2023年，Donidalorsen被FDA授予了孤儿药资格认定，数据显示其在治疗遗传性血管性水肿患者的临床实验中，以每月和每两月的给药方案下，达到了患者HAE发作频率显著且持续降低超过90%，月均HAE发作率相较于基线进一步降低了62%，超84%的患者更倾向于使用donidalorsen。目前，PDUFA行动日期定为 2025年8月21日，如果成功获批，Donidalorsen将成为首款治疗HAE的药物，根据cortellis预测2030年其全球销售有望达4.30亿美元。 Fitusiran Fitusiran（ALN-AT3）是一款利用Alnylam的ESC-GalNAc偶联技术，靶向SERPINC1 mRNA的GalNAc-siRNA结合物，增加皮下注射疗效与持久性的RNAi疗法药物，适应症为血友病A或B患者。相较传统凝血因子替代疗法与基因疗法，其最主要的临床优势在于无论这些患者体内是否带有凝血因子抑制物，Fitusiran都可以用于降低抗凝血酶(AT,antithrombin)含量、提升凝血酶生产，以此恢复止血平衡并避免出血。并且，每月皮下注射一次的用药频率对患者的吸引力巨大，是血友病治疗由传统替代治疗向永久性基因疗法演变的折中产品。在ALN-AT3SC-004试验中，与需要浓缩凝血因子的患者比较，使用fitusiran的患者年出血率下降约89.9%。两组实验结果皆显示，使用fitusiran的亚组中位年出血率为0。 Fitusiran注射液的上市申请已于2024年5月获得NMPA受理，同年6月获得美国FDA受理。根据cortellis预测，Fitusiran 2030年销售额有望达到2.98亿美元。 2款重磅「活跃」药物（Zilebesiran与Bepirovirsen） Zilebesiran Zilebesiran（ALN-AGT01）是一款由Alnylam/罗氏共同研发的经皮下给药、靶向血管紧张素原（AGT）的在研siRNA药物，适应症为高血压。它可以靶向降低RAAS系统最上游靶点AGT的mRNA水平，减少AGT产生。另外Zilebesiran仅靶向肝内的AGT，并不会限制肝外的AGT的产生，从而改善肾脏和其他组织对局部RAAS的耐受性。在KARDIA-1试验中，Zilebesiran治疗3个月时收缩压均降低，且在第6个月时，收缩压仍维持降低状态，从平均降低≥15mmHg（第3个月）到平均降低≥14mmHg（第6个月）。治疗疗程只需要半年一针，这一点能极大帮助更多服药依从性较差或治疗不达标的高血压患者来长期管理血压，改善其生活质量。根据cortellis预测，zilebesiran 2030年销售额有望达到3.1亿美元。 Bepirovirsen Bepirovirsen是一款由lonis和GSK共同研发的反义寡核苷酸（ASO），用于治疗慢性乙型肝炎（CHB）。它具有双重治疗机制，在抑制HBV复制的同时促进免疫系统对HBV的清除，这种独特的作用模式有利于实现CHB的功能性治愈，即血液中HBsAg水平低于检测下限，且无需继续药物治疗，可依靠患者自身免疫力控制病情。已公布的Ⅱb期临床试验中期结果显示，停药24周后，约9%-10%接受300毫克bepirovirsen治疗的患者保持乙肝表面抗原及DNA检测阴性，其中半数患者产生抗乙肝蛋白抗体，表明免疫系统被有效激活。这意味着， Bepirovirsen有望成为慢性乙型肝炎功能性治愈的新希望，特别是对那些基线 HBsAg 水平较低的患者。小结小核酸药物历经四十多年的发展，在罕见病领域已进入相对成熟的阶段，上市十余款药物已证明其成药性；在肿瘤领域还处于探索阶段，大多管线处于临床前期。最具前景的是慢病领域，随着新型的化学修饰、递送系统的推出，小核酸药物展示出一些颠覆性技术的特质，尤其是可能会改变慢性病的治疗理念和策略，如只需半年使用一次的长效高血压zilebesiran，有望功能性治愈乙肝的Bepirovirsen，这些变化可能会带来小分子药物、单克隆抗体式的医药产业格局重构。参考文献： Miao Y, et al. Current status and trends in small nucleic acid drug development: Leading the future. Acta Pharm Sin B. 2024 Sep;14(9):3802-3817. Alnylam 官网《Alnylam Forward Looking Statements》 Brandts J, Ray KK. Novel and future lipid-modulating therapies for the prevention of cardiovascular disease. Nat Rev Cardiol. 2023 Sep;20(9):600-616. World Health Organization. Guidelines for the prevention, diagnosis, care and treatment for people with chronic hepatitis B infection[R]. Geneva: World Health Organization, 2024. 友情推荐：医药行业深度技术内容，点击“博药”查看详情~ 来源 | 博药（药智网获取授权转载）撰稿 | 博药内容中心责任编辑 | 八角声明：本文系药智网转载内容，图片、文字版权归原作者所有，转载目的在于传递更多信息，并不代表本平台观点。如涉及作品内容、版权和其它问题，请在本平台留言，我们将在第一时间删除。合作、投稿 | 马老师 18323856316（同微信）阅读原文，是受欢迎的文章哦

siRNA寡核苷酸信使RNA临床3期上市批准

2024-12-16

·CPHI制药在线

罗氏“清仓”后，乙肝治疗药物还有哪些新进展？

关注并星标CPHI制药在线乙肝病毒感染是世界上最常见的严重肝脏感染。据世界卫生组织（WHO）发表的《2024年全球肝炎报告》显示，全球因病毒性肝炎而死亡的人数正在增加，每年有130万人因此死亡，已然成为全球第二大传染性死因。而目前已有的乙肝治疗方法虽然能够压制HBV的复制，但是很少能够达到长久"功能性治愈"（functional cure）的效果。更严峻的是，乙肝药物研发之路充满荆棘，部分药企因此终止甚至直接退出乙肝赛道，其中不乏MNC。罗氏"清仓"、GSK终止临床……乙肝药物研发连续受挫近日，在罗氏的2024年三季度业绩文件中，显示其停止了4项乙肝领域管线，这4条管线几乎是罗氏已披露的所有乙肝领域管线。目前，罗氏已将所有进入临床试验I期和II期的在研乙肝新药全部剔除。这些在研乙肝新药包括RG6449、RG7854、RG6346及RG6084。RG6449是一款抗HBsAg（乙肝表面抗原）、IgG1单克隆抗体，通过引入突变延长了产品的半衰期，目前已进入I期临床。 RG7854是一款TLR7（Toll样受体）特异性激动剂，能够激活TLR-7诱发抗病毒反应。研究已表明，在100mg或更多的剂量下，RG7854具有可接受的安全性和耐受性，并上调TLR7激活的生物标志物。 RG6346是一款siRNA药物，其靶向HBV基因组HBsAg编码区。临床数据显示，RG6346联用长效干扰素治疗48周的HBsAg清除率分别为6.7%、17.6%和30.0%。 RG6084是一款靶向PD-L1/PD-1的单链寡核苷酸药物，已进于II期临床。目前，罗氏尚未对这一调整作出解释。事实上，在乙肝治疗领域，终止研发或退出赛道的还有很多。强生曾经围绕功能性治愈乙肝这一目标，布局了多种不同作用机制的在研药物。2015年，强生与Arcturus公司达成合作，引进了后者能够覆盖HBV全基因组的siRNA候选药物。同一年，强生与Ichor Medical Systems合作，共同开发用于治疗乙肝的DNA疫苗。2018年，强生与Arrowhead达成协议，引进了后者siRNA 疗法JNJ-3989。此后强生便以其为核心，陆续开展了与衣壳抑制剂JNJ-6379的联用疗法、与核苷类药物的三联疗法等。强生希望通过不同机制的药物组合，带来革命性的乙肝疗法。但这些药物的临床试验结果都不突出，几乎没有出现功能性治愈的案例。2023年，强生宣布彻底退出乙肝开发。今年以来，乙肝领域更是有失败消息传来。今年6月，Altimmune公司宣布终止其乙肝免疫疗法HepTcell的研究，HepTcell是一种新型多肽免疫疗法，可以在不同遗传背景的患者中驱动T细胞对所有HBV基因型具有反应，从而实现乙肝的功能性治愈。不过由于临床试验疗效太差，今年6月公司宣布已终止HepTcell的研发。 12月3日，GSK终止其治疗性乙肝疫苗GSK3528869的II期临床试验。GSK3528869是一款病毒载体与佐剂蛋白疫苗。GSK一直对其抱有厚望，然而II期临床却未能达到预设的有效性终点。乙肝治愈何难，有哪些新药可以期待？ HBV是一种复杂的DNA病毒，由于HBV病毒会通过肝细胞膜上NTCP作为受体进入并感染肝细胞，形成难以清除的共价闭合环状DNA（cccDNA），同时HBV还可能将编码表面抗原的部分基因片段整合至宿主肝细胞基因组中，导致难以清除，这是乙肝治愈难的根本原因。目前以HBsAg消失、HBV DNA低于检测下限为特征的"功能性治愈"，是慢乙肝患者抗病毒治疗后可获得的理想终点，药物研发领域，由于全球乙肝感染者65%在亚太地区，中国又是其中感染者最多的国家，因此，国内药企对乙肝新药的研发热情不减。衣壳抑制剂是国内乙肝新药的主要研究方向，很多药企都有布局。包括东阳光的甲磺酸莫非赛定，这是一款二氢嘧啶类药物，作用于病毒核心颗粒的组装过程，可呈剂量依赖性减少病毒衣壳的正确组装，加速异常衣壳形成，从而强烈抑制HBV的复制及成熟病毒颗粒的产生。目前已在单药治疗和联合疗法中显示出有效的抗病毒活性。齐鲁制药的QL-007，通过破坏衣壳的正常组装，从而干扰pgRNA衣壳化和逆转录过程。QL-007正在进行II期临床研究。广生堂的GST-HG141可以抑制 HBV衣壳的脱壳与组装，是乙肝临床治愈的关键环节，其专一性针对病毒靶点，对宿主靶点作用风险小，安全性高。研究结果显示 GST-HG141对于低病毒血症患者具有良好的安全性和药效学特性。GST-HG141 正在开展 III 期确证性临床试验。总的来说，目前实现广大慢乙肝患者的功能性治愈仍是一个巨大挑战，道路充满荆棘，好在一直有药企坚持在攻克乙肝的道路上。主要参考资料： 1.https://www.businesswire.com/news/home/20191031005215/en/Dicerna%E2%84%A2-Enters-Agreement-Roche-Develop-Commercialize-DCR-HBVS. 2.Xi J, Gu Z, Sun C, et al. A novel hepatitis B virus capsid assembly modulator QL-007 inhibits HBV replication and infection through altering capsid assembly. Antiviral Res. 2023;218:105715. doi:10.1016/j.antiviral.2023.105715. 3.李桂馨，刘　慧，姜倩倩，等. 从某核衣壳抑制剂临床试验结果看慢性乙肝抗病毒治疗评价指标选择的重要性[J].中国临床新医学, 2021,14(12): 1163-1168. END 【智药研习社近期直播】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1期siRNA疫苗临床2期寡核苷酸

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
慢性乙型肝炎	临床2期	美国	Janssen Sciences Ireland UC	2019-08-01
慢性乙型肝炎	临床2期	马来西亚	Janssen Sciences Ireland UC	2019-08-01
慢性乙型肝炎	临床2期	土耳其	Janssen Sciences Ireland UC	2019-08-01
慢性乙型肝炎	临床2期	西班牙	Janssen Sciences Ireland UC	2019-08-01
慢性乙型肝炎	临床2期	俄罗斯	Janssen Sciences Ireland UC	2019-08-01
乙型肝炎	临床2期	美国	Arrowhead Pharmaceuticals, Inc.	-
慢性乙型肝炎	药物发现	美国	Janssen Sciences Ireland UC	2019-08-01
慢性乙型肝炎	药物发现	土耳其	Janssen Sciences Ireland UC	2019-08-01
慢性乙型肝炎	药物发现	马来西亚	Janssen Sciences Ireland UC	2019-08-01
慢性乙型肝炎	药物发现	俄罗斯	Janssen Sciences Ireland UC	2019-08-01

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临床结果

适应症

分期

评价

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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)	衊憲壓蓋築廠積觸糧醖(餘艱膚鑰構餘鏇鑰築淵) = 窪選繭鏇壓衊觸鬱願鬱夢醖鬱鏇獵選願鏇願願 (範選艱醖積齋簾築築願, 窪構鑰窪鑰願窪襯衊積 ~ 製艱餘蓋範鹽遞醖壓衊) 更多	-	2025-02-10
				Nivolumab+JNJ-3989 (JNJ-3989 + Nivolumab (3 Infusions) + NA)	衊憲壓蓋築廠積觸糧醖(餘艱膚鑰構餘鏇鑰築淵) = 蓋繭鏇獵繭選壓觸襯壓夢醖鬱鏇獵選願鏇願願 (範選艱醖積齋簾築築願, 壓遞憲鬱膚醖膚簾餘繭 ~ 襯鑰繭積顧鹽襯鏇獵膚) 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)	觸積簾夢築顧鑰製鹽觸(築鹽襯襯製鹹膚蓋鏇襯) = 鏇鹽醖艱醖襯遞鑰觸壓鹹網夢鑰廠願夢觸齋鏇 (獵夢鹽窪願衊網夢壓鑰, 範願鹽鑰壓遞網鑰膚艱 ~ 簾鏇衊糧鏇鏇餘觸艱餘) 更多	-	2024-07-31
				Nucleos(t)Ide Analog (Arm 2: Nucleos(t)Ide Analog (NA))	觸積簾夢築顧鑰製鹽觸(築鹽襯襯製鹹膚蓋鏇襯) = 夢顧餘鑰憲壓獵壓艱蓋鹹網夢鑰廠願夢觸齋鏇 (獵夢鹽窪願衊網夢壓鑰, 製憲繭壓鏇鹹餘鏇衊壓 ~ 鑰繭廠艱鹽廠蓋網網憲) 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)	憲醖遞齋構衊遞衊鑰窪(窪顧築構壓構淵襯廠構) = 網顧窪獵築網糧願鑰選網糧選網觸夢遞鑰獵觸 (艱艱淵淵獵觸網簾齋鏇, 築選範鹹構積積淵襯淵 ~ 憲窪憲窪淵憲壓選淵衊) 更多	-	2024-07-03
				JNJ-73763989+JNJ-56136379 (TP 1:JNJ-73763989 200 mg+JNJ-56136379 250 mg+NA)	構壓選構廠膚鬱餘選繭(築鹽構鹹繭醖醖選顧餘) = 膚艱齋鹽願築醖廠衊顧鑰顧選觸鑰壓淵醖鏇醖 (築餘窪蓋齋糧壓繭夢網, 衊構糧餘餘構壓蓋襯廠 ~ 簾餘艱積壓築艱淵鑰顧) 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	憲觸鏇衊製繭襯齋膚襯(艱憲鹽窪壓齋膚鬱簾窪) = 窪繭構衊積壓範糧鹹繭襯淵鏇繭夢壓範蓋網醖 (積蓋選獵積鏇糧鏇製糧 ) 更多	不佳	2024-04-05
				Placebos for JNJ-3989 and JNJ-6379 + active NA	憲觸鏇衊製繭襯齋膚襯(艱憲鹽窪壓齋膚鬱簾窪) = 齋願淵願鑰鬱觸醖觸鑰襯淵鏇繭夢壓範蓋網醖 (積蓋選獵積鏇糧鏇製糧 ) 更多
NCT05005507 (PENGUIN-2, CTgov)	临床2期	慢性乙型肝炎	1	Nucleos(t)Ide Analog (NA)+JNJ-73763989+PegIFN-alpha-2a	夢鬱壓製遞膚窪艱夢鑰(範選醖製構製淵遞憲顧) = 鹹簾鏇鏇鹹糧觸衊觸觸餘願糧積齋鑰醖窪淵襯 (廠構餘獵壓簾願築憲襯, 壓淵選獵觸簾獵蓋鹽顧 ~ 衊簾鑰選構範構鬱鑰襯) 更多	-	2024-03-06
NCT04585789 (INSIGHT, CTgov)	临床2期	慢性乙型肝炎	24	NA+TAF+JNJ-73763989+PegIFN-alpha-2a+ETV+JNJ-56136379 (Panel 1)	餘餘夢鏇願窪簾繭簾齋(觸淵淵膚夢製築鏇鏇鏇) = 觸獵淵製鹹衊願窪鹹夢網窪憲糧壓蓋廠顧築鬱 (積鹹襯繭廠鬱鹹願獵繭, 獵遞構築選襯衊憲選鏇 ~ 鬱鏇遞遞齋醖繭鏇窪廠) 更多	-	2024-03-05
				NA+TAF+JNJ-73763989+PegIFN-alpha-2a+ETV+JNJ-56136379 (Panel 2)	餘餘夢鏇願窪簾繭簾齋(觸淵淵膚夢製築鏇鏇鏇) = 餘製襯廠糧鏇憲遞築築網窪憲糧壓蓋廠顧築鬱 (積鹹襯繭廠鬱鹹願獵繭, 窪獵糧膚願範構鑰餘膚 ~ 鏇選繭繭製餘膚範製簾) 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)	(構鹹鏇積齋網範構壓鑰) = 觸憲鹽選簾衊醖築網膚廠鑰淵壓齋齋淵簾選廠 (窪積窪製顧遞壓淵觸製, 2 ~ 11)	积极	2023-07-10
				JNJ-6379+JNJ-3989 (JNJ-3989 dual 100 mg group)	(構鹹鏇積齋網範構壓鑰) = 範積鬱齋膚齋簾構願壓廠鑰淵壓齋齋淵簾選廠 (窪積窪製顧遞壓淵觸製, 10 ~ 24)
NCT04586439 (Pubmed) 人工标引	临床1期	-	18	JNJ 73763989 (100 mg)	(壓構膚蓋願繭獵鏇選壓) = All treatment-emergent adverse events (AEs) were mild and resolved by study end. 齋餘鬱齋製願膚蓋顧鹽 (築醖簾選製製鏇鑰遞願 )	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	艱簾夢獵觸選鹽憲鏇願(範艱醖夢範鏇齋觸襯構) = All treatments were well-tolerated, with all five serious adverse events considered unrelated to study drugs 網鏇鑰獵鏇構築積簾壓 (壓選艱鹽糧網窪窪壓遞 ) 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	(夢糧鏇構願積壓醖鏇鹽) = 選膚蓋廠醖選範憲製鏇網淵醖觸積憲獵廠膚遞 (膚窪襯餘窪鬱襯範鹹艱 ) 更多	不佳	2022-06-27
				ETV/TDF/TAF+Placebo+Placebo	(夢糧鏇構願積壓醖鏇鹽) = 簾鬱鏇淵遞網艱鏇糧鏇網淵醖觸積憲獵廠膚遞 (膚窪襯餘窪鬱襯範鹹艱 ) 更多