Elebsiran

点击蓝字关注我们本期看点慢性乙型肝炎（HBV）仍是全球重大公共卫生问题。据世界卫生组织（WHO）统计，约3亿人感染HBV，每年因乙肝相关并发症死亡逾80万。我国HBV感染者约8600万，慢性肝炎患者约2,000–3,000万。目前的抗病毒治疗（核苷类药物和干扰素）虽能有效抑制病毒复制，但真正达到“临床治愈”（停药后HBsAg持续阴性）者不足10%。实现功能性治愈，即在停药后仍保持HBsAg阴转且病毒被免疫系统控制，对扭转乙肝长期肝损伤及预防肝癌具有重要意义。乙型肝炎功能性治愈的终极目标是通过有限疗程实现血清HBsAg持续阴性并维持病毒学抑制。相较于丙肝已经实现了治愈的可能，乙肝尚待治愈创新疗法的突破。本文聚焦反义寡核苷酸（ASO）疗法、RNA干扰（RNAi）疗法、治疗性疫苗与免疫调节、T细胞疗法的最新进展，探讨乙肝治愈的可能性。本期内容01国内企业创新动态02自体HBV特异性TCR-T细胞疗法SCG10103国际领先疗法快览04总结与展望 【01 国内企业创新动态】2025年7月，舶望制药和正大天晴相继宣布终止其已推进至临床Ⅱ期的慢性乙型肝炎治疗药物BW-20507、TQA3605片开发。主要理由为“临床试验策略调整”、“基于商业考虑”。正大天晴丨TQA3605TQA3605是正大天晴药业研发的一款衣壳抑制剂，目前处于II期临床。2025年7月25日，正大天晴主动终止了一项评估TQA3605片联合恩替卡韦治疗初治、HBeAg阳性慢性HBV感染者的疗效和安全性的II期临床试验（NCT06990776/CTR20251402），显示原因为企业基于商业考虑决定终止该项试验，与本品的安全性和有效性无关。至此，TQA3605还有一项II期试验和一项Ib/IIa期试验仍在进行中：这项II期试验（NCT06644417/CTR20243879）旨在评估TQA3605片联合NAs治疗LLV患者的有效性和安全性，目前还在招募中；Ib/IIa期试验（NCT06150014/CTR20233364）旨在评估TQA3605片单药或联合NAs治疗初治或经治慢乙肝患者的疗效和安全性，招募已完成。舶望制药BW‑20507最新进展2025年7月16日，舶望制药主动终止了评估BW-20507单药在慢乙肝患者中有效性和安全性的II期临床试验（CTR20251532），显示原因为临床策略调整。但2025年6月3日，CDE官网显示，舶望制药在研的针对慢性乙型肝炎病毒感染的创新产品BW-20507注射液拟纳入突破性治疗品种。BW-20507是一种靶向HBV 信使 RNA S 区域的小干扰 RNA（siRNA）分子。该药物在EASL 2025大会Late-Breaker（最新突破专题）公布的I/IIa期临床数据令人振奋：剂量依赖性HBsAg降低：患者皮下注射BW-20507（每4周一次，共3剂）后，200mg和400mg组最大HBsAg平均降幅可达2.9–3.2 log₁₀ IU/mL。HBsAg清除率：基线HBsAg＜1000 IU/mL的患者中，有56%（5/9例）在研究期内达到HBsAg清除。HBV DNA抑制：对于未使用核苷类似物（NA）的初治患者，也观察到强劲的HBV DNA抑制。安全耐受良好：所有剂量组均未见严重安全性问题，BW-20507展现出良好耐受性，为后续研究提供了基础。舶望团队指出，这些数据代表了慢乙肝功能性治愈研究的重要进展，仅用三剂BW-20507就有患者出现HBsAg消失，在其他siRNA单药中极为罕见，为乙肝患者带来了新希望。基于此结果，舶望计划2025年下半年启动BW-20507的IIb期临床研究：单药IIb预计于2025年第二季度启动，联合疗法IIb预计于第三季度启动，旨在进一步评估BW-20507实现功能性治愈的潜力。该进展不仅提升了国内HBV RNAi药物研发信心，也有望加速行业对功能性治愈路径的重视。浩博医药丨AHB-1372025年7月22日，浩博医药正式宣布，CDE已批准其核心候选药物 AHB-137 进入 III 期临床。AHB-137 是一种非偶联型反义寡核苷酸（ASO），靶向乙肝病毒（HBV）mRNA，可快速、深度降低 HBsAg，并诱导乙肝表面抗体（anti-HBs）血清转换，被寄望成为慢性乙型肝炎（CHB）“功能性治愈”的基石疗法。即将启动的 III 期研究是一项在中国开展的随机、双盲、多中心注册试验，计划招募超过 300 名正在接受核苷（酸）类似物（NA）抑制治疗的 HBeAg 阴性慢乙肝患者。受试者将以 2:1 比例随机分配至 AHB-137 300 mg 每周一次皮下注射 24 周或安慰剂组，主要终点为治疗结束时 HBsAg 持续低于 0.05 IU/mL 且 HBV DNA 低于 10 IU/mL；关键次要终点包括 HBsAg 血清学清除率、anti-HBs 阳转率、48 周随访的持久应答及安全性。研究预计 2026 年完成患者入组，2027 年递交上市申请。支撑 III 期启动的 IIb 期数据同样亮眼。2025 年 5 月公布的开放标签、随机、多中心 IIb 研究中，64 例 HBeAg 阴性患者被分配至 16 周或 24 周 300 mg 治疗组：•  24 周组 75%（24/32）达到主要终点，54% 实现 anti-HBs 血清转换；•  16 周组 66%（21/32）达到主要终点，33% 出现抗体；•  超过 80% 的应答者在 12 周内即实现 HBsAg 清除；•  ≥3 级不良事件发生率低于 10%，最常见为注射部位反应和轻度 ALT 升高，无严重药物相关不良事件或停药。挚盟医药丨ZM-H1505R2025 年 6 月 25 日，药物临床试验与信息公示平台披露，挚盟医药登记了其自主研发的 HBV 核衣壳抑制剂 ZM-H1505R（Canocapavir，科诺卡帕韦）用于慢性乙型肝炎治疗的首个 III 期临床试验，此前该药已获 CDE 突破性治疗药物认定。截图来源：药物临床试验与信息公示平台本次 III 期试验为多中心、随机、双盲、安慰剂对照及开放标签扩展试验，旨在评估 ZM-H1505R 联合核苷（酸）类似物（NAs）相较于 NAs 单药治疗，在至少接受 12 个月 NAs 单药治疗的慢性乙型肝炎患者中的疗效与安全性，计划国内入组 1300 人。主要研究终点是双盲期治疗 48 周时，两组达到完全病毒学应答（CVR，即 HBV DNA 定量 ≤10IU/mL）的受试者百分比差异。ZM-H1505R 作为 HBV 核衣壳抑制剂，能有效抑制 HBV 核衣壳形成，其全新化学骨架使其对 I、II 类 HBV 核衣壳抑制剂及核苷类药物耐药的突变病毒仍具良好抗病毒活性。腾盛博药BRII-179治疗性疫苗：BRII-179（VBI-2601）是一种基于病毒样颗粒的HBV疫苗，含有三种HBV包膜蛋白序列。腾盛近日公布的ENSURE II期（NCT05970289）队列4数据显示，该疫苗可用于精准富集有望达成治愈的患者：完成BRII-179疫苗免疫的患者中，先前对疫苗产生乙肝表面抗体的“应答者”在后续标准治疗结束时HBsAg清除率高达55.6%（10/18），而未应答患者仅10.0%（1/10）。这表明BRII-179可作为功能性治愈疗程的“预测工具”，帮助选择更易获益的目标人群。其他队列数据显示，BRII-835（VIR-2218）siRNA联合干扰素治疗组的最终HBsAg清除率也明显优于干扰素单用组。这些结果凸显了疫苗+基因沉默联合策略的优势。歌礼药业ASC22免疫调节单抗：ASC22（恩沃利单抗）为皮下注射PD-L1单抗，可恢复乙肝患者T细胞功能。据Ascletis公布的IIb期扩展队列结果，在基线HBsAg≤100 IU/mL的患者中，联合核苷类似物治疗后有42.9%的患者实现了持续HBsAg清除。这一潜力说明ASC22可作为免疫调节治疗组件，帮助一部分低抗原负荷患者获得功能性治愈。【02 自体HBV特异性TCR-T细胞疗法SCG101】SCG Cell Therapy公司开发的SCG101是一款自体T细胞受体（TCR）T细胞疗法，通过精准识别HBsAg表位，选择性靶向并清除HBV感染肝细胞及相关癌变细胞。SCG101 作用机制在2025年欧洲肝脏研究协会大会（EASL）上公布了1期临床（NCT06617000）关键数据，整理如下：抗病毒活性17例晚期HBV相关HCC患者单次输注后，94%在28天内HBsAg下降1.0–4.6 log₁₀，并在长达1年内持续保持≤100 IU/mL；23.5%实现HBsAg丢失。抗肿瘤活性47%患者出现可测量的肿瘤缩小，中位总生存期（OS）尚未达到，显示出持久生存获益潜力。安全性与耐受性仅94%出现短暂ALT升高，且14天内恢复；可管理的不良事件包括细胞因子释放综合征、中性粒细胞减少及血小板减少，均可逆且可控。临床意义与未来SCG101在多次预处理的重症患者群体中，首次实现了持续HBsAg清除与肿瘤缩小双重疗效，填补了HBV相关HCC免疫治疗领域的空白。随着后续剂量探索与Ⅱ/Ⅲ期研究推进，SCG101有望为晚期肝癌患者带来全新、潜在功能性治愈方案。02 国际领先疗法快览 Bepirovirsen：首个申报上市的HBV ASO疗法在乙肝治疗领域，葛兰素史克（GSK）与Ionis Pharmaceuticals联合开发的Bepirovirsen备受瞩目。图源：威斯康星大学麦迪逊分校分子病毒研究所Bepirovirsen（GSK3228836）是一种靶向HBV全基因组mRNA的反义寡核苷酸，通过降解病毒转录本同时激活先天免疫通路，从而双重抑制HBV复制与清除HBsAg。Ⅱ期临床（B-Clear/B-Sure）：约30%患者在24周治疗后实现HBsAg丢失，且多数受试者在停药后继续维持低病毒载量。Ⅲ期规划：GSK已启动B-WellⅢ期项目，计划于2026年在美国、中国、欧洲和日本等主要市场提交上市申请，力争成为全球首个获批的乙肝功能性治愈药物GSK。监管加速：美国FDA已于2024年2月授予Bepirovirsen快速通道（Fast Track）资格，以加速其开发与审评进程。RG6346：RNAi疗法的先驱RG6346是罗氏与Dicerna合作开发的GalXC™平台下RNAi候选药，靶向HBV S基因mRNA，通过靶向降解抑制HBsAg表达与病毒复制。临床进展：自2021年起，RG6346已在多国开展Ⅱ期组合疗法试验，联用核苷（酸）类似物显示出良好耐受性和持久的HBsAg降低效果；中国Ⅱ期研究同步推进，彰显了在亚洲高流行区的开发重视度。作用机制优势：RNAi疗法能特异性沉默HBV mRNA，减少cccDNA转录产物，为功能性治愈提供关键辅助手段。上述案例说明，目前国内外均趋向联合治疗策略，将RNA干扰、免疫激活（疫苗、抗体）和传统抑制药物结合，以提高治愈率。实现理想的功能性治愈路线图需要多种方法协同作用（例如siRNA降低抗原负荷+疫苗或TCR细胞激活免疫+CI恢复T细胞功能），预期未来更多此类组合疗法将临床验证。04 总结与展望当前HBV功能性治愈研究已形成多路径并进的格局：除了前述RNA干扰和免疫疗法，精准T细胞疗法、免疫检查点抑制、B细胞抗体疗法等也在同步探索。综合已公布的创新疗法数据，可以预见未来几年功能性治愈方案将转向“组合拳”模式。正如WHO数据所示，对全球3亿HBV感染者而言，仅控制病毒已不足以根治流行病，功能性治愈的实现意义重大。通过RNAi降低病毒抗原、疫苗或TCR疗法激活免疫、加上免疫恢复剂，我们有望大幅提高治愈率。专家认为，随着这些新疗法成功推动，HBV“治愈时代”并非遥远梦想，而将给全球公共卫生带来深远影响。细致的患者筛选和精准用药策略也将成为关键，帮助更多患者摆脱长期用药，享受真正意义上的功能性治愈。乙肝功能性治愈的突破不仅将改善全球数亿患者的生活质量，还可能推动乙肝领域在诺贝尔生理学或医学奖上获得认可。正如2020年丙型肝炎病毒的发现者荣获诺贝尔奖一样，乙肝领域的重大突破同样值得期待。 ★

SAN FRANCISCO--(BUSINESS WIRE)--Vir Biotechnology, Inc. (Nasdaq: VIR) today announced the enrollment of the first participant in the ECLIPSE 2 Phase 3 clinical trial, which is designed to compare the combination of tobevibart and elebsiran to continued bulevirtide monotherapy in participants with chronic hepatitis delta (CHD) who have not achieved undetectable hepatitis delta virus (HDV) RNA despite bulevirtide treatment. ECLIPSE 2 is one of three trials in Vir Biotechnology’s registrational ECLIPSE program for CHD, which was initiated in March 2025. ECLIPSE 2 is designed to provide the registrational efficacy and safety data needed for potential submission to global regulatory agencies, including agencies in the U.S. and Europe. “Patients living with chronic hepatitis delta, a known cause of liver cancer, are waiting for effective options to change the course of their disease." “Patients living with chronic hepatitis delta, a known cause of liver cancer, are waiting for effective options to change the course of their disease,” said Marianne De Backer, M.Sc., Ph.D., MBA, Chief Executive Officer, Vir Biotechnology. “We are excited about the rapid progress of our ECLIPSE program, which demonstrates our unwavering commitment to deliver a highly effective treatment for people living with chronic hepatitis delta.” “We are encouraged by the transformational potential of tobevibart and elebsiran to rapidly drive the hepatitis delta virus to undetectable levels, as demonstrated by compelling data from our Phase 2 SOLSTICE clinical trial. We remain focused on advancing this investigational combination for chronic hepatitis delta with utmost urgency,” said Mark Eisner, M.D., M.P.H., Executive Vice President and Chief Medical Officer, Vir Biotechnology. CHD is the most severe form of chronic viral hepatitis,1 with people living with the disease rapidly progressing to cirrhosis, liver failure2 and liver-related death.1 There are currently no approved treatments in the U.S., and options are limited in the European Union and globally. The objective of therapy is to eliminate the virus. Tobevibart in combination with elebsiran offers the potential to achieve this by tackling the viral lifecycle through multiple mechanisms. The significant unmet need in CHD and the potential for tobevibart and elebsiran to provide a much-needed treatment option has been recognized by the U.S. Food and Drug Administration (FDA) with Breakthrough Therapy and Fast Track designations, and by the European Medicines Agency (EMA) with Priority Medicines (PRIME) and orphan drug designations. About the ECLIPSE Registrational Program ECLIPSE is a registrational program to evaluate the safety and efficacy of tobevibart in combination with elebsiran in patients with chronic hepatitis delta (CHD). ECLIPSE includes three randomized, controlled trials designed to evaluate the combination therapy in comparison to deferred treatment or bulevirtide. ECLIPSE 1 (NCT06903338), a Phase 3 trial evaluating the safety and efficacy of tobevibart in combination with elebsiran compared to deferred treatment in the U.S. or other regions where bulevirtide use is limited, is currently recruiting. ECLIPSE 2 is a Phase 3 trial that will evaluate the efficacy and safety of switching to tobevibart and elebsiran in people with CHD who have not achieved viral suppression with bulevirtide therapy. ECLIPSE 1 and 2 are designed to provide the registrational efficacy and safety data needed for potential submission to global regulatory agencies. ECLIPSE 3 is a Phase 2b head-to-head trial to evaluate tobevibart and elebsiran compared with bulevirtide in bulevirtide-naïve patients, and it is designed to provide important supportive data to help establish access and reimbursement in key markets. ECLIPSE 2 plans to enroll participants in regions where bulevirtide is approved for the treatment of CHD. Participants who fail to achieve virologic suppression (defined as failure to achieve HDV RNA TND) after a minimum 24 weeks of bulevirtide treatment will be randomized 2:1 to switch to the combination of tobevibart and elebsiran or continue receiving bulevirtide. The primary endpoint in ECLIPSE 2 measures HDV RNA at the lower limit of quantification target not detected, HDV RNA TND (defined as HDV RNA = 0 IU/mL), at Week 24. About Tobevibart and Elebsiran Tobevibart is an investigational broadly neutralizing monoclonal antibody targeting the hepatitis B surface antigen (HBsAg). It is designed to inhibit the entry of hepatitis B and hepatitis delta viruses into hepatocytes and to reduce the level of circulating viral and subviral particles in the blood. Tobevibart was identified using Vir Biotechnology’s proprietary monoclonal antibody discovery platform. The Fc domain has been engineered to increase immune engagement and clearance of HBsAg immune complexes and incorporates Xencor’s Xtend™ technology to extend half-life. Tobevibart is administered subcutaneously, and it is currently in clinical development for the treatment of patients with chronic hepatitis delta. Elebsiran is an investigational hepatitis B virus-targeting small interfering ribonucleic acid (siRNA) discovered by Alnylam Pharmaceuticals, Inc. It is designed to degrade hepatitis B virus RNA transcripts and limit the production of hepatitis B surface antigen. Current data indicate that it has the potential to have direct antiviral activity against hepatitis B virus and hepatitis delta virus. Elebsiran is administered subcutaneously, and it is currently in clinical development for the treatment of patients with chronic hepatitis delta. About Vir Biotechnology, Inc. Vir Biotechnology, Inc., is a clinical-stage biopharmaceutical company focused on powering the immune system to transform lives by discovering and developing medicines for serious infectious diseases and cancer. Its clinical-stage portfolio includes programs for chronic hepatitis delta and multiple dual-masked T-cell engagers across validated targets in solid tumor indications. Vir Biotechnology also has a preclinical portfolio of programs across a range of infectious diseases and oncologic malignancies. Vir Biotechnology routinely posts information that may be important to investors on its website. References: 1 WHO Hepatitis Delta Factsheet – Hepatitis D (who.int), accessed June 2025 2 CDC What is Hepatitis D - FAQ | CDC, accessed June 2025 Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as “should,” “could,” “may,” “might,” “will,” “plan,” “potential,” “aim,” “expect,” “anticipate,” “promising” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements. Forward-looking statements contained in this press release include, but are not limited to, statements regarding: the therapeutic potential of the combination of tobevibart and elebsiran to treat CHD and Vir Biotechnology’s belief that it can be a highly effective and transformative treatment option for these patients; Vir Biotechnology’s clinical development plans and expectations for the ECLIPSE Phase 3 registrational program, including protocols for and enrollment into ongoing and planned clinical studies, target endpoints and data readouts; Vir Biotechnology’s strategy and plans; and any assumptions underlying any of the foregoing. Many factors may cause differences between current expectations and actual results, including, without limitation: unexpected safety or efficacy data or results observed during clinical studies or in data readouts, including the occurrence of adverse safety events; risks of unexpected costs, delays or other unexpected hurdles; challenges in accessing manufacturing capacity; clinical site activation rates or clinical enrollment rates that are lower than expected; the timing and outcome of Vir Biotechnology’s planned interactions with regulatory authorities, as well as general difficulties in obtaining any necessary regulatory approvals; successful development and/or commercialization of alternative product candidates by Vir Biotechnology’s competitors, as well as changes in expected or existing competition; geopolitical changes or other external factors; and unexpected litigation or other disputes. In light of these risks and uncertainties, the events or circumstances referred to in the forward-looking statements may not occur. Drug development and commercialization involve a high degree of risk, and only a small number of research and development programs result in commercialization of a product. Results in early-stage clinical studies may not be indicative of full results or results from later stage or larger scale clinical studies and do not ensure regulatory approval. The actual results may vary from the anticipated results, and the variations may be material. You are cautioned not to place undue reliance on any scientific data presented or these forward-looking statements, which are based on Vir Biotechnology’s available information, expectations and assumptions as of the date of this press release. Other factors that may cause Vir Biotechnology’s actual results to differ from those expressed or implied in the forward-looking statements in this press release are discussed in Vir Biotechnology’s filings with the U.S. Securities and Exchange Commission, including the section titled “Risk Factors” contained therein. Except as required by law, Vir Biotechnology assumes no obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise.