Elebsiran

【导读】本文基于中国乙肝疫苗（Hepatitis B Vaccine）三十余年普及历程与抗病毒药物市场数据的交叉分析，系统论证疫苗普及对乙肝类药物需求的结构性影响。文章核心发现：疫苗普及并非简单线性压缩药物市场，而是引发"新发病例持续下降"与"存量患者池先升后降"的剪刀差效应（Scissors Effect）。短期（2024-2035）诊断率提升、治疗率扩容与创新药物迭代将驱动市场高速增长；中长期（2035-2050）存量患者池达峰后缓慢萎缩；长期（2050+）疫苗保护队列成为社会主体，传统药物市场面临实质性衰退。本文为医药投融资决策提供基于流行病学变迁的产业分析框架。版本号：V1.0 | 发布日期：2026年7月26日一、中国乙肝疫苗普及时间线：从"高流行"到"低流行"的三十年1.1 关键政策节点与接种率演变中国乙肝疫苗的普及经历了四个关键阶段，每一步都深刻改变了流行病学格局：时间节点政策举措接种率变化流行病学意义1985年血浆源性乙肝疫苗获批上市极低（自费、高价）技术准备期1992年纳入儿童计划免疫管理（自费）首针22% → 三针30%政策启动期1994年与默克公司技术转让，国产重组疫苗量产价格大幅下降产能突破期2002年纳入国家免疫规划（EPI），疫苗免费首针71% → 三针70%普及加速期2005年完全免费接种（取消服务费）首针85% → 三针85%全面覆盖期2009-2011年15岁以下人群补种6800万人补种覆盖率大幅提升历史欠账清理期2015年孕产妇HBsAg筛查+新生儿联合免疫全国推广母婴阻断率>90%精准阻断期2020年出生时接种覆盖率96%，三针99.6%接近完全覆盖目标达成期 1.2 流行病学数据：疫苗效果的因果证据四次全国血清流行病学调查清晰展示了疫苗的惊人效果：1992年：全人群乙型肝炎表面抗原（HBsAg, Hepatitis B Surface Antigen）携带率 9.75%，5岁以下儿童 9.67%，全国约1.2亿携带者2006年：全人群降至 7.18%，5岁以下儿童降至 0.96%（降幅90%）2014年：全人群降至约 5.5%，5岁以下儿童 0.3%（降幅97%）2020年：全人群 5.86%，5岁以下儿童 0.30%，1-4岁儿童 0.30%关键洞察：5岁以下儿童HBsAg携带率从9.67%降至0.30%，降幅达97%。这一年龄组恰好是1992年后出生、全程受益于疫苗接种的队列，构成了最强的因果证据。 二、疫苗普及对乙肝药物市场的"剪刀差"效应分析2.1 核心逻辑：新发病例↓ vs 存量患者池↑→↓疫苗普及对药物市场的影响遵循以下传导机制： 疫苗高覆盖率 ↓母婴传播阻断 + 儿童期感染大幅减少 ↓新发病例数持续下降（长期↓） ↓ BUT: 存量患者池 = 历史累积感染者 - 自然减员（死亡/治愈） ↓ 短期（2020-2035）：存量池仍大 + 诊断率/治疗率提升 → 药物需求↑ 中期（2035-2050）：存量池达到峰值后缓慢下降 → 药物需求 plateau 长期（2050+）：存量池加速萎缩 + 新发病例极少 → 药物需求↓2.2 不同出生队列的"药物需求窗口"从队列分析视角，可以清晰识别四个截然不同的群体：出生队列疫苗接种情况慢性感染者规模当前年龄（2026年）药物需求窗口1980年前出生未接种疫苗~4500万人≥46岁当前核心需求群体，已进入肝硬化/肝癌高发期1981-1991年出生部分接种（自费期）~2800万人35-45岁中期核心需求群体，正处于抗病毒治疗黄金期1992-2001年出生计划免疫期~1500万人25-34岁远期需求群体，感染率已大幅下降2002年后出生全面免费接种~300万人≤24岁几乎无药物需求，感染率极低2.3 市场预测的"悖论"：为什么药物市场反而在增长？疫苗普及背景下，市场预测显示乙肝药物市场仍在快速增长，其根源在于三个叠加效应：（1）诊断率提升效应2020年全国血清学调查显示：HBsAg阳性者中仅59.78%知晓自身感染状态。约3000万人未诊断，其中约1700万符合抗病毒治疗标准。随着国家筛查项目推进，大量"沉默患者"被激活进入诊疗体系。（2）治疗率提升效应符合治疗标准的患者中，仅17.33%（约300万人）正在接受治疗。2022版《慢性乙型肝炎防治指南》大幅放宽治疗指征：从"丙氨酸氨基转移酶（ALT, Alanine Aminotransferase）异常+病毒载量高"扩展至"HBV DNA阳性+年龄>30岁即建议治疗"，预计治疗人群从约1000万扩展至约3000万。（3）创新药物替代效应传统核苷（酸）类似物（Nucleos(t)ide Analogues, NAs）受国家药品集中采购影响价格大幅下降，但功能性治愈方向的新药（小干扰RNA/siRNA、核心蛋白抑制剂/Core Protein Inhibitors、治疗性疫苗/Therapeutic Vaccines）正在密集研发。新药单价远高于传统药物，形成"量价齐升"格局。三、市场规模预测：短期增长 vs 长期萎缩的博弈3.1 当前市场格局（2024年）指标数据中国乙肝抗病毒药物市场规模约123.4亿元人民币核苷（酸）类似物市场~100.2亿元（占比81%）创新药物市场~23.2亿元（占比19%）在治患者数~300万人潜在治疗人群~1700万人3.2 未来十年预测（2024-2034）市场将呈现"总量增长、结构剧变"的特征：年份总市场规模核苷（酸）类似物创新药物复合增速2024123.4亿100.2亿23.2亿—2030~380亿~142亿~238亿20.1%2034770.4亿181.0亿589.4亿20.1%关键发现：核苷（酸）类似物市场复合年增长率（CAGR, Compound Annual Growth Rate）仅6.1%，而创新药物市场CAGR超过30%。这意味着市场增长完全由创新药物驱动，传统药物市场实际上在"以价换量"中萎缩。3.3 恩替卡韦（ETV, Entecavir）的"陨落"：集采+疫苗双重挤压恩替卡韦（ETV）是观察传统药物市场趋势的绝佳案例：年份全国医院销售额同比变化关键事件2017~85亿元—集采前峰值2018~78亿元-8%4+7集采启动2019~45亿元-42%全国扩围集采2020~28亿元-38%全部执行中标价2021~22亿元-21%持续萎缩2022~18亿元-18%—202314.99亿元-17%较峰值下降82%ETV销售额暴跌的启示：传统核苷（酸）类似物面临"三重挤压"——集采导致单价暴跌（降幅90%+）、疫苗普及导致新患者减少、患者向丙酚替诺福韦（TAF, Tenofovir Alafenamide）/富马酸替诺福韦二吡呋酯（TDF, Tenofovir Disoproxil Fumarate）等新一代药物转移。四、疫苗因素对药物市场影响的量化分析4.1 直接影响：新发病例减少对新增药物需求的抑制根据流行病学模型估算：1992-2020年：疫苗接种预防了超过4000万人感染乙型肝炎病毒（HBV, Hepatitis B Virus），避免了700万人死于乙肝相关疾病若无疫苗接种：当前慢性感染者将从~7500万增至~1.1亿，药物需求增加约47%年度新发病例：已从1992年的约150万例降至2020年的约10万例以下（降幅>93%）4.2 间接影响：患者结构变化对药物选择的影响疫苗普及改变了患者人群的年龄和疾病阶段分布：维度疫苗前时代（1992年前）疫苗后时代（2020年后）主要感染途径母婴传播（70%+）母婴传播（<10%）+ 成人高危行为慢性化率新生儿90% → 儿童30%成人<10%患者年龄结构年轻化（大量儿童/青少年）老龄化（核心人群35-55岁）疾病阶段分布早期慢性肝炎为主肝硬化/肝癌比例上升治疗目标长期抑制病毒功能性治愈 + 肝癌预防对药物研发的影响：成人感染慢性化率低 → 急性期治疗需求减少；存量患者老龄化 → 肝癌辅助治疗、联合用药需求增加；功能性治愈成为终极目标 → 创新药物研发投入加大。4.3 长期展望（2050年后）：药物市场的"终极萎缩"当1992年后出生的"疫苗保护队列"成为社会主体时：新发病例：趋近于零（仅残余母婴传播失败案例和成人高危感染）存量患者：1980年前出生队列自然减员完成，剩余患者<500万药物需求：核苷（酸）类似物市场可能萎缩至<50亿元创新药物：仅保留功能性治愈药物（如果有的话）和肝癌辅助治疗五、对药品市场预测的核心结论与投资建议5.1 核心结论维度结论疫苗影响是否成立完全成立，但影响是结构性的而非简单的线性递减短期影响（2024-2035）疫苗因素被"诊断率提升+治疗率提升+创新药物"三重增长对冲，市场仍将高速增长中期影响（2035-2050）存量患者池达到峰值后缓慢下降，市场进入平台期长期影响（2050+）疫苗保护队列成为主体，药物市场将面临实质性萎缩结构影响传统核苷（酸）类似物市场已见顶下滑，创新药物（功能性治愈）是唯一的增长引擎5.2 对投资决策的建议第一，避免重仓传统核苷（酸）类似物仿制药。 ETV、TDF等已进入"量价双杀"通道，市场规模持续萎缩。第二，关注功能性治愈创新药管线。 重点跟踪siRNA类药物（如VIR-2218）、核心蛋白抑制剂（如Vebicorvir）、HBsAg分泌抑制剂、治疗性疫苗等方向。第三，布局肝癌辅助治疗市场。 随着存量患者老龄化，HBV相关肝细胞癌（HCC, Hepatocellular Carcinoma）发病率将在2035年前维持高位，索拉非尼（Sorafenib）、仑伐替尼（Lenvatinib）、免疫检查点抑制剂（Immune Checkpoint Inhibitors）等需求稳定。第四，警惕"2035年拐点"。 当1980年前出生队列（最大感染队列）进入高龄期，药物需求可能出现断崖式下跌。【结语】乙肝疫苗普及对药物市场的影响，是一场跨越半个世纪的流行病学变迁与产业演进的宏大叙事。它揭示了一个深刻的产业规律：公共卫生干预措施（疫苗接种）对下游治疗市场的压缩效应，并非即时显现，而是通过"队列更替"机制在数十年间逐步释放。对于医药投融资决策者而言，理解这一时间滞后效应（Time-lag Effect）至关重要——当前市场的繁荣（存量释放+渗透率提升）不应掩盖长期的结构性衰退风险。唯有将流行病学变迁纳入产业分析框架，才能在创新药物的结构性增长与传统药物的周期性衰退之间，做出精准的投资判断。【免责声明】本文所载内容仅供学术研究与产业分析参考，不构成任何投资建议、医疗建议或商业决策依据。文中涉及的市场规模预测、流行病学数据及药物研发进展均基于公开可获取的权威资料整理分析，作者已尽合理审慎义务进行核实，但不对数据的绝对准确性与完整性作出任何明示或暗示的保证。医药产业具有高度不确定性，药物研发存在临床失败、监管审批受阻、市场竞争格局变化等风险，投资者应独立判断并自行承担决策风险。本文观点仅代表作者个人学术分析，不代表任何机构立场。如需引用本文内容，请注明出处并确保符合学术规范。对于因使用本文信息而产生的任何直接或间接损失，作者及相关方不承担任何法律责任。

编者按：刚刚过去的7月28日是2026年世界肝炎日，乙型肝炎病毒（HBV）感染这一全球重大公共卫生问题值得关注。据世界卫生组织数据，2024年全球约有2.87亿慢性乙肝或丙肝感染者。为达到世界卫生组织制定的“2030年消除病毒性肝炎”目标，帮助更多乙肝患者实现功能性治愈，科学家正努力探索新兴治疗策略。其中，反义寡核苷酸（ASO）与小干扰RNA（siRNA）等小核酸药物以全新的作用机制和积极的早期临床研究疗效，为乙肝的功能性治愈带来突破性进展。作为全球医药创新的赋能者，药明康德一直以来依托“一体化、端到端”的CRDMO赋能平台，助力全球合作伙伴，推进乙肝等各类疾病的创新疗法开发，加速造福病患。 对于广大慢性乙型肝炎患者而言，乙型肝炎表面抗原（HBsAg）转阴不仅是检查报告上的一行结果，而可能说明身体的免疫系统开始能“自己盯着”乙肝病毒，不再完全依赖药物压制。临床上将这种状态称为“功能性治愈”，即HBsAg转阴且HBV DNA低于定量检测下限，并持续至治疗结束后24周。 目前，国际指南推荐的乙肝抗病毒药物为核苷（酸）类似物（NAs）和/或聚乙二醇干扰素α（PEG-IFNα）。NAs治疗下可实现持续的HBV DNA抑制，改善肝组织病理学，并减少终末期肝病的发生，且现有的NAs加用PEG-IFNα联合治疗在特定的优势人群可有一定的功能性治愈率。 但仅HBV DNA持续抑制尚不能完全满足临床需求，接受NAs长期治疗的人群仍有肝细胞癌发生的风险。此外，NAs通常需要长期甚至终身使用。现有研究显示，在初治乙肝患者中，NAs单药或联合PEG-IFNα治疗后的HBsAg血清学清除率通常仅为0%～9%。 因此，开发新的治疗方法进一步提高HBsAg血清转阴率，促进HBV感染达到功能性治愈，仍是全球迫切需要解决的难题。 图片来源：123RF 小核酸药物为乙肝功能性治愈带来希望 共价闭合环状DNA（cccDNA）持续存在、整合型HBV DNA的转录和表达，以及机体免疫反应功能失调是导致HBV感染持续存在的主要原因。因此，要实现乙肝的功能性治愈需采取双重策略：抑制病毒复制并恢复宿主免疫系统功能。 基于这一认识，目前乙肝治疗方式主要为两类：一类是直接抗病毒机制，抑制HBV生命周期的不同关键阶段，如钠-牛磺胆酸共转运蛋白抑制剂（针对HBV进入）、核酸聚合物、siRNA等小核酸类药物（针对病毒复制及病毒蛋白表达）等；另一类是间接免疫调节策略，恢复或提高宿主HBV特异性免疫应答。 在这些策略中，小核酸新药治疗过程中HBsAg水平下降及HBsAg转阴率尤为突出，特别是反义寡核苷酸和小干扰RNA的研发进展较快，在帮助患者实现乙肝功能性治愈方面展示出很大的潜力。据公开数据显示，截至2026年6月，处于活跃研发状态的在研ASO和siRNA乙肝药物共有23款。 ▲小核酸药物作用机制（图片来源：参考文献[1]） ASO药物是一类人工合成的单链寡核苷酸，主要是通过碱基互补配对原则靶向HBV mRNA或者mRNA前体，来抑制病毒蛋白的产生。 siRNA则是一类双链短RNA，主要是通过靶向HBV转录的mRNA，对其进行降解，阻止相关蛋白如HBsAg、乙型肝炎e抗原（HBeAg）等的合成，抑制病毒颗粒的产生，来达到抗病毒的目的。 化学修饰和递送系统的突破，提升乙肝功能性治愈可能性 尽管小核酸类药物在治疗乙肝方面前景可期，但其从研发迈向临床的过程仍面临多重挑战。例如，面对复杂的生理环境，如何防止药物被核酸酶快速降解，从而维持有效的血药浓度与作用时间？如何克服生物膜屏障，实现药物向靶组织的精准递送与胞内释放？ 近年来，化学修饰与递送系统两大技术的突破，成为解决上述难题、推动乙肝寡核苷酸药物成功研发的关键所在。 化学修饰 小核酸药物由三种基本结构组分构成：磷酸基团、糖环和碱基。对这些组分进行化学修饰已成为提升寡核苷酸药物稳定性、疗效和安全性的核心策略。 磷酸骨架与糖环的结构改造是提升稳定性的基石。在磷酸骨架方面，硫代磷酸酯（PS）修饰是目前应用尤为广泛的技术，即通过用一个硫原子取代磷酸二酯键中的非桥接氧原子。这种修饰不仅有效降低了分子的亲水性，显著增强了其对核酸酶降解的抵抗力，还能增加寡核苷酸与血浆蛋白的结合率，从而改善药物的药代动力学性质。 在糖环修饰方面，如2'-O-甲氧乙基（2'-MOE）修饰、锁核酸及其甲基化衍生物等，进一步增强了耐核酸酶性能，大幅提高了与靶RNA的结合亲和力，并能精细调节药物与胞内蛋白的相互作用。 在碱基修饰中，胞嘧啶的5-甲基化是常见的策略，不仅能提升寡核苷酸与靶mRNA的杂交稳定性，还能降低潜在的免疫原性毒副作用。 通常，小核酸药物可能采用多种化学修饰的组合性策略。以bepirovirsen研发为例，其采用缺口嵌合体（gapmer）结构，其序列首尾各5个核苷酸经2'-MOE修饰，中间的脱氧核苷酸区域则整体经硫代磷酸酯修饰。这种双重修饰策略可增强对核酸酶的稳定性、提高与血浆蛋白的结合，并降低肾脏清除率。 递送策略 尽管化学修饰显著提高了寡核苷酸的抗核酸酶降解能力，并有助于降低非特异性免疫刺激，但其成药性仍面临巨大的生理屏障：寡核苷酸分子量大、亲水性强且携带高负电荷，难以跨越细胞膜；此外，裸露的序列缺乏组织特异性，易产生非靶向分布。因此，开发高效的递送系统成为解决细胞摄取低下和靶向精准度不足的关键，是降低继发性脱靶效应、释放药物临床潜力的必经之路。 N-乙酰半乳糖胺（GalNAc）是目前针对肝细胞递送的有利工具。由于其对肝细胞表面高表达的去唾液酸糖蛋白受体（ASGPR）具有很高亲和力，GalNAc偶联物可通过受体介导的内吞作用实现高效的肝脏特异性摄取，具有结构简单、安全性高的优势。 脂质纳米颗粒（LNP）是临床应用成熟的载体之一，一般为直径约100 nm的自组装结构。其利用可电离脂质通过静电作用包裹带负电荷的核酸，并可通过表面修饰优化药代动力学及靶向能力，成为肝脏及肝外递送的重要工具。 在寡核苷酸药物研发快速发展的背景下，从序列设计到功能验证的系统化能力对于提升研发效率与成功率至关重要。药明康德生物学业务平台（WuXi Biology）构建了覆盖设计、筛选、评价与转化研究的一体化寡核苷酸药物发现平台，可为合作伙伴提供端到端的寡核苷酸研发支持。平台依托自主建立的in silico序列设计体系，可综合考虑脱靶风险、跨物种活性、序列特征等多维参数，实现候选寡核苷酸的高效设计与优选；结合超过1500种细胞资源及多类型细胞模型开展高通量体外筛选与功能评估，快速识别具备高敲降效率与良好特异性的候选分子。 在安全性与机制研究方面，平台整合RNA转录组分析、免疫原性与细胞毒性检测，实现对脱靶效应与安全风险的系统评估。在递送方面，除了肝靶向的GalNAc以外，平台也支持肝外递送工具的发现，包括抗体、多肽等，优化偶联位点和药物-抗体比（DAR）提升递送效率，支持多维度对抗体偶联，多肽偶联和脂质偶联的寡核苷酸进行体内外评价。同时，通过多给药途径的体内PK/PD研究及安全性评估，可验证寡核苷酸药物在疾病模型中的药效与早期毒性信号。整体而言，WuXi Biology通过跨学科整合与标准化流程，将寡核苷酸设计与优化、递送、安全性评估与药效评价紧密衔接，有效降低早期研发风险，加速创新寡核苷酸疗法迈向临床阶段。 新兴疗法为乙肝功能性治愈带来更多可能 有限疗程的小核酸药物虽能降低HBsAg，但是否能恢复针对HBV和感染细胞的宿主免疫应答并诱导HBsAg长久血清清除仍有待探索，单一直接抑制策略可能难以达到功能性治愈。因此，联合免疫治疗、表观遗传编辑疗法、体内基因编辑疗法等新兴策略将成为未来慢性HBV感染治疗的新趋势。 治疗性疫苗联合其他抗病毒或免疫调节治疗 HBV候选免疫疗法BRII-179由腾盛博药和VBI Vaccines共同开发。发表于《自然-医学》（Nature Medicine）的ENSURE的2期临床试验探索性分析结果显示，既往接受过siRNA药物elebsiran与BRII‑179（一种潜在“first-in-class”的Pre-S1/Pre-S2/S治疗性疫苗）联合治疗的慢性乙肝患者，采用elebsiran联合PEG-IFNα方案治疗后，抗HBs应答者的HBsAg清除比例为57.9%（11/19），高于无抗HBs应答者的16.7%（2/12），提示“先筛选或诱导免疫应答，再给予组合治疗”可能成为未来的治疗方向。 表观遗传编辑疗法 TUNE-401是一款潜在“first-in-class”的表观遗传沉默剂，利用Tune Therapeutics的多功能、模块化TEMPO平台所开发，旨在表观遗传水平上沉默靶向整合入宿主细胞的乙肝病毒DNA和cccDNA，不涉及切割或编辑DNA。在2026年欧洲肝脏研究协会（EASL）年会上，Tune Therapeutics公布的TUNE-401 1b/2a期研究数据表明，治疗后多项HBV生物标志物均显示出持久且剂量依赖性的抑制，在特定剂量组中，100%的患者出现HBV相关生物标志物下降，提示对cccDNA的直接沉默作用。单次用药后，抑制时间最长可持续至17个月。 图片来源：123RF 体内基因编辑疗法 Precision BioSciences的PBGENE-HBV代表着基因编辑方向的探索。该疗法旨在通过编辑cccDNA和整合HBV DNA，从更接近病毒持续存在的根源位置进行干预，已获得FDA快速通道资格认定。2026年EASL大会披露的肝脏活检数据提供了患者体内cccDNA被消除或失活的早期证据，并观察到从cccDNA转录生成的pgRNA下降和HBsAg下降等抗病毒活性信号。虽然PBGENE-HBV仍处于早期临床阶段，但它让行业看到了治愈乙肝的另一种可能：从降低病毒抗原，到直接干预病毒储库，乙肝治疗的“治愈”概念正在被不断拓展。 从bepirovirsen的3期临床积极结果到AHB-137、HRS-5635等管线的快速推进，小核酸药物正在“照亮”乙肝功能性治愈之路。化学修饰与递送系统的持续突破有望进一步提升小核酸药物的靶向特异性、疗效及安全性，使siRNA和ASO药物在乙肝功能性治愈领域拥有更广阔的临床应用前景。尽管cccDNA的持久存在、宿主免疫耐受等根本性难题仍有待攻克，但随着联合免疫治疗、表观遗传编辑疗法、体内基因编辑疗法等新兴策略的探索，乙肝功能性治愈有望惠及更多患者。 How Close Are We to a Functional Cure for Hepatitis B? Oligonucleotide Therapeutics Are Beginning to Offer a Path Forward World Hepatitis Day 2026, observed on July 28, brought renewed attention to chronic hepatitis B virus (HBV) infection as a major global public health challenge. The World Health Organization (WHO) estimates that approximately 287 million people worldwide are living with chronic hepatitis B or C. To meet the WHO’s goal of eliminating viral hepatitis by 2030 and enable more patients to achieve a functional cure, researchers are actively pursuing new therapeutic approaches. Among these approaches, oligonucleotide therapeutics, particularly antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), have demonstrated novel mechanisms of action and generated encouraging early-stage results that may contribute to a functional cure for hepatitis B. As a global enabler of pharmaceutical innovation, WuXi AppTec leverages its integrated, end-to-end CRDMO platform to support partners worldwide in advancing innovative therapies for hepatitis B and other diseases, helping bring potential benefits to patients sooner. Image source: 123RF For people living with chronic hepatitis B, the loss of hepatitis B surface antigen (HBsAg) represents more than a laboratory result. It may indicate that the host immune system has regained control over the virus rather than continuing to rely solely on long-term antiviral suppression. Clinically, a functional cure is defined as sustained HBsAg loss and HBV DNA below the lower limit of quantification (LLOQ) 24 weeks after treatment cessation. International guidelines currently recommend nucleos(t)ide analogues (NAs) and/or pegylated interferon alfa (PEG-IFNα) as antiviral therapies for chronic hepatitis B. Treatment with NAs can achieve sustained suppression of HBV DNA, improve liver histology, and reduce the risk of end-stage liver disease. In selected patient subgroups, combining NAs with PEG-IFNα may also increase the likelihood of achieving a functional cure. However, sustained suppression of HBV DNA alone does not fully address patients’ treatment needs, as hepatocellular carcinoma (HCC) can still occur in patients receiving long-term NA therapy. Moreover, NAs often require prolonged administration, while reported HBsAg seroclearance rates among treatment-naïve patients remain low (approximately 0–9%) whether NAs are used alone or in combination with PEG-IFNα. Further improving HBsAg seroclearance rates and enabling more patients to achieve a functional cure therefore remain urgent global priorities. Image source: 123RF Oligonucleotide Therapeutics Represent a Promising Approach to a Functional Cure for HBV Infection Three major factors contribute to the persistence of HBV infection: covalently closed circular DNA (cccDNA), the integration and continued expression of HBV DNA, and impaired host immune responses. Achieving a functional cure will therefore likely require a dual strategy that both suppresses viral replication and restores effective host immune function. Therapeutic strategies for HBV can be broadly divided into two categories. The first directly targets the viral life cycle. Examples include sodium taurocholate cotransporting polypeptide (NTCP) inhibitors that block viral entry, nucleic acid polymers, and RNA interference–based oligonucleotide therapeutics that reduce viral RNA and antigen expression. The second category comprises immunomodulatory approaches designed to restore or enhance HBV-specific host immunity. Among these strategies, oligonucleotide therapeutics have produced notable reductions in HBsAg levels and increased HBsAg seroclearance rates during treatment. ASOs and siRNAs, in particular, are advancing rapidly and show promise as components of therapeutic regimens aimed at achieving a sustained functional cure. According to public sources, 23 ASO or siRNA candidates for hepatitis B were in active development as of June 2026. ▲Mechanisms of oligonucleotide therapies（Image source: reference [1]） ASOs are single-stranded oligonucleotides that bind to HBV messenger RNA (mRNA) or precursor mRNA (pre-mRNA) through complementary base pairing, thereby inhibiting viral protein production. By contrast, siRNAs are short, double-stranded RNAs that direct the degradation of HBV-derived mRNA, blocking the production of HBsAg and hepatitis B e antigen (HBeAg) and suppressing the formation of new virions. Advances in Chemical Modification and Delivery Systems Are Increasing the Potential for a Functional Cure Although oligonucleotide therapeutics offer a promising approach to treating hepatitis B, translating these molecules from research concepts into practical medicines is far from straightforward. In the complex physiological environment of the human body, how can oligonucleotides be protected from rapid degradation by nucleases so that sufficient systemic exposure and duration of action can be maintained? How can they cross biological membrane barriers, reach the intended tissues, enter target cells, and be released into the appropriate intracellular compartments? Advances in chemical modification and delivery technologies have been central to addressing these challenges and moving oligonucleotide therapies for hepatitis B closer to clinical application. Chemical Modification Oligonucleotide therapeutics consist of three fundamental structural components: a phosphate backbone, ribose sugars, and nucleobases. Chemical modification of these components has become a central strategy for improving the stability, efficacy, and safety of oligonucleotide medicines. Modifications to the phosphate backbone and ribose ring serve as cornerstones for improving molecular stability. Among the most widely used approaches is phosphorothioate (PS) modification, in which a nonbridging oxygen atom in the phosphodiester backbone is replaced with sulfur. This modification reduces hydrophilicity, increases resistance to nuclease degradation, and promotes binding to plasma proteins, thereby improving pharmacokinetic properties. Common ribose modifications include 2′-O-methoxyethyl (2′-MOE), locked nucleic acid (LNA), and methylated LNA analogues. These modifications further improve binding affinity and nuclease resistance while enabling the fine-tuning of interactions between oligonucleotides and intracellular proteins. Among nucleobase modifications, 5-methylcytosine modification is commonly used to strengthen hybridization between an oligonucleotide and its target mRNA while potentially reducing immunogenicity-related adverse effects. In practice, oligonucleotide therapeutics typically incorporate strategic combinations of different chemical modifications. Bepirovirsen, for example, uses a gapmer architecture. The first and last five nucleotides of its sequence contain 2′-MOE modifications, while the central region incorporates PS backbone modifications. Together, these modifications enhance enzymatic stability, increase plasma protein binding, and reduce renal clearance. Delivery Systems Although chemical modifications can improve nuclease resistance and reduce immunogenicity, substantial physiological barriers remain. The high molecular weight, strong hydrophilicity, and substantial negative charge of oligonucleotides impede their passage across cell membranes. Unconjugated oligonucleotides also generally lack tissue specificity, increasing the risk of off-target distribution. Efficient delivery systems are therefore essential for improving cellular uptake and tissue targeting, reducing off-target exposure, and unlocking the full clinical potential of oligonucleotide therapeutics. N-acetylgalactosamine (GalNAc) is a well-established ligand for hepatocyte-targeted delivery. GalNAc binds with high affinity to the asialoglycoprotein receptor (ASGPR), which is highly expressed on the surface of hepatocytes. GalNAc-conjugated oligonucleotides are therefore taken up efficiently by the liver through receptor-mediated endocytosis. This approach combines relatively straightforward conjugation chemistry with a favorable safety profile. Lipid nanoparticles (LNPs) are another well-established delivery platform for nucleic acids. Typically about 100 nm in diameter, LNPs are self-assembled structures in which ionizable lipids encapsulate negatively charged nucleic acids through electrostatic interactions. Additional surface modifications can further optimize pharmacokinetics and tissue targeting, making LNPs an important platform for both hepatic and extrahepatic delivery. Against the backdrop of rapid advances in oligonucleotide drug discovery, integrated capabilities spanning sequence design through functional validation are critical for improving development efficiency and success rates. WuXi Biology has established an end-to-end oligonucleotide discovery platform covering design, screening, evaluation, and translational research, providing comprehensive oligonucleotide development support for global partners. Leveraging a proprietary in silico sequence design system, the platform enables efficient design and prioritization of oligonucleotide candidates by integrating multiple parameters, including off-target risk, cross-species activity, and sequence characteristics. Combined with more than 1,500 cell resources and diverse cellular models, WuXi Biology supports high-throughput in vitro screening and functional evaluation to rapidly identify candidates with high knockdown efficiency and strong specificity. For safety and mechanism studies, the platform integrates RNA transcriptomic analysis, immunogenicity assessment, and cytotoxicity evaluation to enable systematic characterization of off-target effects and safety risks. For delivery, in addition to liver-targeting GalNAc, the platform also supports the discovery of extrahepatic delivery tools, including antibodies and peptides. We optimize conjugation sites and DAR to enhance delivery efficiency and provide comprehensive in vitro and in vivo evaluations for antibody-conjugated, peptide-conjugated, and lipid-conjugated oligonucleotides. In addition, in vivo PK/PD studies across multiple dosing routes, together with safety assessments, support the evaluation of efficacy and early toxicity signals in disease models. Overall, through cross-disciplinary integration and standardized workflows, WuXi Biology closely links ASO design and optimization, delivery, safety assessments and pharmacological evaluation, reducing early-stage development risk and accelerating the advancement of innovative oligonucleotide therapeutics toward clinical development. Emerging Therapies Offer New Possibilities for Achieving a Functional Cure for Hepatitis B Although finite-course treatment with oligonucleotide therapeutics can lower HBsAg levels, it remains unclear whether these therapies alone can restore durable host immune responses against HBV and HBV-infected cells or induce sustained HBsAg seroclearance after treatment ends. A direct-acting antiviral strategy alone is therefore unlikely to achieve a functional cure in every patient. As a result, combination immunotherapies, epigenetic silencing or editing approaches, and in vivo gene-editing strategies are being explored as part of a new treatment paradigm for chronic HBV infection. Therapeutic Vaccines Combined with Antiviral or Immunomodulatory Therapies The investigational HBV immunotherapy BRII-179 is being jointly developed by Brii Biosciences and VBI Vaccines. An exploratory analysis of the Phase 2 ENSURE trial, published in Nature Medicine, evaluated patients with chronic hepatitis B who had previously received combination therapy with the siRNA agent elebsiran and BRII-179, a potential first-in-class therapeutic vaccine targeting the Pre-S1, Pre-S2, and S antigens. Among patients who subsequently received elebsiran plus PEG-IFNα, those classified as anti-HBs responders achieved higher rates of HBsAg clearance. Anti-HBs responders were defined as participants whose peak anti-HBs titers reached at least 10 IU/L one month after the final dose of BRII-179, at week 44. HBsAg clearance was observed in 57.9% (11 of 19) anti-HBs responders, compared with 16.7% (2 of 12) nonresponders. These findings suggest that identifying or inducing an HBV-specific immune response before initiating combination therapy may represent a promising future treatment strategy. Image source: 123RF Epigenetic Silencing Therapy TUNE-401 is a potential first-in-class epigenetic silencing therapy developed using Tune Therapeutics’ multifunctional, modular TEMPO platform. The therapy is designed to epigenetically silence both integrated HBV DNA and cccDNA in host cells without cleaving DNA or altering its underlying sequence. At EASL 2026, Tune Therapeutics reported Phase 1b/2a data showing that TUNE-401 produced durable, dose-dependent suppression of multiple HBV biomarkers, including HBsAg and pregenomic RNA (pgRNA). In certain dose cohorts, suppression of HBV biomarkers was observed in 100% of treated patients, suggesting direct silencing of cccDNA. Suppression following a single dose was sustained for up to 17 months. In Vivo Gene-Editing Therapy Precision BioSciences’ PBGENE-HBV represents a gene-editing strategy for the treatment of hepatitis B. Designed to target and modify both cccDNA and integrated HBV DNA, PBGENE-HBV aims to intervene directly at the level of the viral reservoir. The therapy has received Fast Track designation from the U.S. Food and Drug Administration. Liver biopsy findings presented at EASL 2026 provided early evidence of cccDNA clearance or inactivation in some patients. These findings were accompanied by the loss of pgRNA transcribed from cccDNA and a decline in HBsAg, representing signals consistent with antiviral activity. Although PBGENE-HBV remains in early-stage development, it illustrates an alternative path toward an HBV cure. Rather than focusing solely on reducing viral antigen levels, this approach directly targets the persistent viral reservoir and broadens the therapeutic concept of what a hepatitis B cure could entail. From the positive clinical readouts reported for bepirovirsen to the rapid advancement of candidates such as AHB-137 and HRS-5635, oligonucleotide therapeutics are illuminating new paths toward a functional cure for hepatitis B. Continued progress in chemical modification and delivery technologies is expected to further improve the targeting specificity, efficacy, and safety of oligonucleotide therapeutics, expanding the potential role of siRNA and ASO therapies in the functional cure landscape. Fundamental barriers including persistent cccDNA and host immune tolerance still need to be overcome. Nevertheless, emerging approaches such as combination immunotherapies, epigenetic silencing and editing therapies, and in vivo gene-editing technologies may help extend the possibility of a functional cure to more patients. Key Takeaways: WuXi Biology has established an end-to-end oligonucleotide discovery platform spanning design, screening, evaluation, and translational research, providing comprehensive oligonucleotide development support to partners worldwide. Achieving a functional cure will likely require both suppression of viral replication and restoration of effective host immunity. ASOs and siRNAs have produced encouraging reductions in HBsAg and may become important components of future combination regimens. Although oligonucleotide therapeutics offer a promising approach to hepatitis B treatment, translating these molecules from research into practical medicines remains challenging. Advances in chemical modification and delivery systems have been central to overcoming key development barriers and moving oligonucleotide therapies closer to clinical application. Emerging strategies, including combination immunotherapies, epigenetic silencing and editing therapies, and in vivo gene-editing technologies, may provide additional paths toward making a functional cure achievable for more patients. 参考资料： [1] Zhang L, Cao Y, Zhuang S, et al. Small nucleic acid drugs-the dawn of functional cure of chronic hepatitis B. Front Pharmacol, 2025 Sep 26;16:1633001. doi: 10.3389/fphar.2025.1633001. [2] Shechter O, Sausen DG, Dahari H, et al. Functional Cure for Hepatitis B Virus: Challenges and Achievements. Int J Mol Sci, 2025 Apr 11;26(8):3633. doi: 10.3390/ijms26083633. [3] Wang S, Weissman D, Dong Y. RNA chemistry and therapeutics. Nat Rev Drug Discov. 2025 Jul 14. doi: 10.1038/s41573-025-01237-x. Epub ahead of print. PMID: 40659813. [4]Lok ASF. Toward a Functional Cure for Hepatitis B. Gut Liver, 2024 Jul 15;18(4):593-601. doi: 10.5009/gnl240023. [5] Huang ZA, Yang Y, Yang S, et al. An RNA interference therapeutic potentially achieves functional cure of chronic hepatitis B virus infection. Nat Commun, 2025 Dec 1;17(1):179.  [6] Hui RW, Mak LY, Fung J, et al. Prospect of emerging treatments for hepatitis B virus functional cure. Clin Mol Hepatol, 2025 Feb;31(Suppl):S165-181. doi: 10.3350/cmh.2024.0855.  [7] Wang WX, Guo YM, Fei ZX, et al. Clinical research advances for small-molecule nucleic acid drugs in the treatment of chronic hepatitis B. Zhonghua Gan Zang Bing Za Zhi, 2025 Dec 20;33(12):1199-1206. Chinese. doi: 10.3760/cma.j.cn501113-20250114-00026. [8] WHO. Hepatitis B. Retrieved June 10, 2026. from https://www.who.int/news-room/fact-sheets/detail/hepatitis-b [9]余滢滢,李静,王文鑫，等. 慢性乙型肝炎病毒感染治疗新药物的研究进展. 中华肝脏病杂志，2025，33（5）：493-499.DOI:10.3760/cma.j.cn501113-20240521-00258. [10] 梁携儿，刘智泓，侯金林. 乙型肝炎功能性治愈新药： 聚焦反义寡核苷酸和小干扰RNA. 临床肝胆病杂志，2025，41（1）：7-14. [11] World hepatitis sday. Retrieved July 02, 2026. from https://www.worldhepatitisday.org/ [12] Wong, G.LH., Yuen, MF., Lin, B. et al. Elebsiran and PEG-IFNα for chronic hepatitis B infection: a partially randomized, open-label, phase 2 trial. Nat Med 32, 151–159 (2026). https://doi.org/10.1038/s41591-025-04049-z [13] Tune Therapeutics. Tune Therapeutics Presents Positive Phase 1b/2a Proof of Concept Data on TUNE-401: a First-in-Class Epigenetic Silencer for Patients with Hepatitis B at EASL 2026. Retrieved May 30, 2026. From https://tunetx.com/tune-therapeutics-presents-positive-phase-1b-2a-proof-of-concept-data-on-tune-401-a-first-in-class-epigenetic-silencer-for-patients-with-hepatitis-b-at-easl-2026/ [14] Precision BioSciences. Precision BioSciences Receives U.S. FDA Fast Track Designation for PBGENE-HBV, a First-In-Class Gene Editing Therapy Designed to Eliminate the Root Cause of Chronic Hepatitis B. Retrieved April 15, 2026. 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