Interferon alfa

慢性乙型肝炎（CHB）迄今仍是全球最为严峻的公共卫生挑战之一。目前全球乙型肝炎病毒（HBV）感染者约2.54亿例，我国感染者规模达7900万例。CHB功能性治愈率较低，随着疾病进展可逐步引发肝硬化，甚至进展为肝细胞癌。相关研究数据表明，CHB所致肝癌病例占比高达56%。 不过，全球即将进行CHB功能性治愈的时代！ 官方披露，Bepirovirsen的两项全球多中心、随机、双盲、对照Ⅲ期临床试验（B-Well 1与B-Well 2）取得积极结果。该药物计划于2026年第一季度启动全球监管申报，申报范围覆盖包括中国在内的29个国家。 除Bepirovirsen外，中国多款CHB功能性治愈候选药物正处于临床研发后期阶段，本文将对其进行系统汇总。 图源：医会宝编辑部 乙肝功能性治愈定义：乙型肝炎表面抗原（HBsAg）持续阴性（治疗后≥24周）、伴或不伴乙型肝炎表面抗体（HBsAb）血清学转化，且在有限治疗疗程后乙型肝炎e抗原（HBeAg）与血清HBV DNA均不可检测、肝功能恢复正常，且肝脏病理学和组织学得到改善[1]。 Part.1 AHB-137 AHB-137与Bepirovirsen一样，也是一种非偶联的反义寡核苷酸（ASO）药物。 在两项Ⅱ（a+b）期临床研究中[2]，纳入了119例HBeAg阴性、稳定核苷（酸）类似物（NA）单药治疗、基线HBsAg>100-3000 IU/mL且HBV DNA<100 IU/mL的CHB参与者。 在Ⅱa期研究中，参与者每周接受AHB-137（300mg或225mg）治疗，持续24周； 在Ⅱb期研究中，参与者接受AHB-137 300mg治疗24周，或接受安慰剂治疗8周后，再接受AHB-137 300mg治疗16周。 AHB-137治疗结束后，参与者继续接受核苷单药治疗24周，之后进入24周的随访，期间根据NA停药标准决定维持或停用治疗（停药标准：HBsAg<0.05 IU/mL且HBV DNA<10 IU/mL）。 结果显示，在接受300mg AHB-137治疗24周（第48周）的参与者中，26.6%（17/64例） 在第48周实现了持续的完全应答。该应答率在不同基线HBsAg水平的亚组中具有可比性。在这些应答者中，82.4%（14/17例）的抗-HBs抗体滴度达到了≥10 IU/L。此外，29.7%（19/64例）的参与者达到了部分应答（即HBsAg≥0.05至<10 IU/mL且HBV DNA <10 IU/mL）。 A：根据2a期与2b期临床试验分组 B：根据基线HBsAg水平分组 实现HBsAg清除或降至＜10 IU/mL的患者占比（图源：文献2） 安全性方面，治疗期间出现的不良事件主要发生在AHB-137治疗期间。未报告与治疗相关的严重不良事件，也没有因不良事件导致治疗中止、提前停药或死亡的情况。 Part.2 GST-HG131 GST-HG131是全球首创的口服HBsAg抑制剂，它通过调节宿主PAPD5/7活性，抑制HBV mRNA的聚腺苷酸尾组装并使HBV mRNA去稳定化。临床前研究显示了强大的疗效和良好的安全性，在I期试验中也表现出良好的安全性、耐受性和药代动力学特征。 一项双盲、随机、安慰剂对照的II期研究显示[3]，针对正在接受NA单药治疗超过6个月、HBsAg水平介于100至1500 IU/mL之间，血清ALT水平低于正常值上限的1倍的CHB患者，接受12周的30 mg每日两次方案的患者（n=25)，76.5% 的受试者达到了HBsAg<100 IU/mL，安慰剂相比，在第85天时平均HBsAg降低了0.89 log₁₀ IU/mL（p<0.001），最大降幅达1.64 log₁₀ IU/mL。 在安全性方面，在所有队列中，治疗耐受性良好，未出现剂量相关毒性或新的安全信号。大多数不良事件为轻度或中度。在实验室检查、生命体征或心电图方面未观察到临床相关的异常。 Part.3 HT-101+HT-102  HT-101是一种靶向乙肝肝炎病毒（HBV）基因组S区的N-乙酰半乳糖胺（GalNAc）偶联小干扰核糖核酸（siRNA），在Ⅰ期研究中显示出对HBsAg的持久降低效果。 HT-102是一种针对HBsAg抗原环的人源单克隆抗体，在Ⅰ期研究中实现了血清HBsAg的快速下降。 在一项多中心、开放性、部分剂量递增的Ib/IIa期研究中显示[4]，针对 HBeAg阴性、正在接受稳定NA背景治疗且HBsAg水平在100-3000 IU/mL之间的CHB患者，所有接受HT-101+HT-102 联合治疗12周的参与者，64.3%（18/28例）患者实现了HBsAg消失，值得注意的是，高剂量组（HT-101 400 mg + HT-102 300 mg） 中有20%（2/10例）的参与者在治疗第4周就实现了HBsAg消失。 基线HBsAg<1000 IU/mL的参与者中，92.8%（13/14例）实现了HBsAg消失； 基线HBsAg≥1000 IU/mL的参与者中，有35.7%（5/14例）实现了HBsAg消失。 各治疗组随时间不同HBsAg水平的患者占比（图源：文献4） 另外，治疗耐受性良好，大多数治疗相关不良事件为1-2级（如注射部位反应）。未观察到药物相关的严重不良事件、≥3级事件、丙氨酸氨基转移酶（ALT）骤升或其他安全信号。 Part.4 BRII-179序贯Elebsiran+PEG-IFN-α-2a BRII-179是一种含Pre-S1/Pre-S2/S三种抗原的治疗性疫苗，Elebsiran是一种靶向HBV的小干扰RNA药物。 一项多中心、开放标签II期研究[5]，评估了BRII-179序贯Elebsiran联合聚乙二醇干扰素α-2a（PEG-IFN-α-2a）进行治疗的疗效和安全性。 研究纳入标准为：HBeAg阴性、HBV DNA<20 IU/mL（接受NA治疗中）、HBsAg>10 IU/mL且≤3000 IU/mL、抗-HBs <10 mIU/mL的非肝硬化CHB患者。 研究分为两个阶段： ①预激阶段：所有患者在第0、4、12周皮下注射BRII-179（50 μg），在第12周评估CHB患者对BRII-179的抗体应答。 ②联合治疗阶段：自第24周起，所有患者继续接受皮下注射Elebsiran（200 mg，每4周一次）联合PEG-IFN-α-2a（180 μg，每周一次）治疗，持续24周，直至第48周。 截至2023年7月，有45名患者完成治疗，并接受24周的随访（第72周），有12名（26.7%）实现了持续HBsAg清除（HBsAg<0.05 IU/mL）。 根据BRII-179应答状态进行分层分析显示： 在治疗第12周被归类为 BRII-179“应答者”（n=20）的患者中，有50%（10名）在第72周实现了持续HBsAg清除，并HBV DNA持续检测不到。 在治疗第12周被归类为 BRII-179“无应答者”（n=25）中，仅有8.0%（2名）实现了持续HBsAg清除，并HBV DNA持续检测不到。 *1例受试者在第24周时HBsAg水平低于0.05 IU/mL，但后续在第48周前出现反弹；另有2例受试者在第24-48周期间实现HBsAg清除 各治疗组随时间在不同HBsAg水平的患者占比（图源：文献5） 安全性方面，治疗耐受性良好，大多数不良事件与PEG-IFN-α-2a的已知副作用（如流感样症状、疲劳、中性粒细胞减少）一致，且严重程度为轻度至中度。未发现与BRII-179或Elebsiran相关的意外安全信号。 【最后一天】免费领取——《消化科医师处方手册》 1. 点击下方公众号名片，关注“医会宝消化肝病视界” 2. 进入公众号，后台回复“处方”参与领取！ END 参考文献： [1]何婧雯,柏涛,韩阳.慢性乙肝功能性治愈新型药物研发与治疗策略优化的研究进展[J/OL].医药导报,1-26[2026-01-16]. [2]High Proportion of Participants Achieved Sustained Complete Response 24 Weeks After Discontinuation of AHB-137 Treatment in HBeAg-Negative Chronic Hepatitis B Patients Receiving Nucleos(t)ide Analog Therapy: Pooled Analysis of Two Phase 2 Studies Conducted in China. AASLD2025, Late-Breaking Abstract (5022). [3]Safety and Preliminary Efficacy of GST-HG131, A First-in-Class Oral HBsAg Inhibitor, in Patients with Chronic Hepatitis B: Phase 2 Clinical Trial Data. AASLD2025, Late-Breaking Abstract (5022). [4]Liang XE, et al. Combination therapy with HT-101 and HT-102 achieved rapid and progressive HBsAg loss in HBeAg-negative, nucleos(t)ide analogues-suppressed patients: 12-week interim results from an ongoing multicentre, open-label phase Ib/IIa study. AASLD2025, Late-Breaking Abstract (5013). [5]Chronic Hepatitis B Virus-Infected Participants Responding to Prior BRII-179 Treatment Achieve Higher Rates of Sustained Hepatitis B Surface Antigen Loss with Elebsiran Plus Pegylated Interferon Alfa: Follow-Up Data from the ENSURE Study. AASLD2025, Late-Breaking Abstract (5036). 声明：本文出自医会宝编辑部，旨在为医疗专业人士传递更多医学信息。本文并不能取代医生的专业诊疗意见，如有罹患，需前往专业医院检查诊断。 致：读者朋友 为了不让大家错过医会宝消化肝病视界 晚上17:30推送的医学知识和前沿资讯 下面教大家如何第一时间接收到我们的推文： 点击文章开头上方“医会宝消化肝病视界”→点击右上角“…” →点选“设为星标 ★ ” 加上星标 这样就不会找不到我们啦！

The collaborative clinical study will evaluate ADSTILADRIN ® (nadofaragene firadenovec-vncg) in combination with the investigational drug Ruvidar ® (TLD-1433) in patients with Bacillus Calmette-Guérin-unresponsive non-muscle invasive bladder cancer carcinoma in situ with or without papillary tumors (±Ta/T1) Combination therapy aims to offer a complementary approach that may provide additional treatment options for patients with NMIBC Collaboration reflects the shared commitment of Ferring and Theralase ® to advance additional treatment options for NMIBC patients PARSIPPANY, N.J.--(BUSINESS WIRE)--Ferring Pharmaceuticals and Theralase ® Technologies Inc. (TSXV:TLT) (OTCQB:TLTFF) are pleased to announce that they have entered into a collaborative clinical development agreement (“Agreement”) on January 9, 2026. The Agreement builds on Theralase ® ’s existing clinical program ( NCT03945162 ) with a new cohort investigating Theralase ® ’s investigational light-activated small molecule Ruvidar ® (TLD-1433) in combination with Ferring’s intravesical non-replicating gene therapy ADSTILADRIN ® (nadofaragene firadenovec-vncg) for adult patients diagnosed with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) carcinoma in situ (CIS) with or without papillary tumors (±Ta/T1). Under the terms of the Agreement, Theralase ® will remain the sponsor of the study, with both parties providing clinical overview of the new cohort through a joint development committee. The new cohort will be enrolled and treated in the United States and then subject to written agreement may expand into Canada or other countries. "The introduction of ADSTILADRIN, as the first intravesical gene therapy, has filled a critical unmet need for patients with BCG-unresponsive NMIBC who faced limited treatment options and needed an alternative to invasive bladder removal surgery,” said Ashish Kamat, MD, MBBS, Endowed Professor of Urologic Oncology (Surgery) and Cancer Research at University of Texas MD Anderson Cancer Center, Houston, Texas and President of the International Bladder Cancer Group. “As the BCG-unresponsive treatment paradigm continues to evolve, the combination of complementary therapies may offer additional treatment options to definitive therapy. This new study offers an opportunity to explore the possibility of enhancing efficacy and durability of response with a combination of a promising, investigational, light-activated small molecule with the leading gene therapy in NMIBC.” The collaboration between Ferring and Theralase ® underscores their shared commitment to advancing innovative therapies for patients with BCG-unresponsive bladder cancer. The new cohort of patients will explore the potential benefit of combining two innovative and complementary mechanisms of action. ADSTILADRIN is the first and only intravesical gene therapy approved by the U.S. Food and Drug Administration (FDA) for high-risk BCG-unresponsive NMIBC CIS with or without papillary tumors (±Ta/T1) that delivers the human interferon alpha-2b gene directly to bladder cells, prompting local secretion of interferon that exerts multiple anticancer and immunomodulatory effects. Ruvidar ® is an investigational small molecule that penetrates cancer cell walls and, upon light activation, delivers targeted cytotoxic effects to destroy cancer cells, while inducing immunogenic cell death, stimulating both innate and adaptive immune responses. “Underscoring our ambition to establish ADSTILADRIN as the backbone therapy in NMIBC, this collaborative clinical study with Theralase ® aims to explore whether combination approaches can further enhance patient outcomes, building on the strong foundation ADSTILADRIN has established in treating this challenging disease,” said Daniel Shoskes, M.D., MSc, FRCS (C), Vice President and Global Medical Director for Uro-Oncology, Ferring Pharmaceuticals. Roger DuMoulin-White, BSc, P.Eng, Pro.Dir, President, Chief Executive Officer and Chairman of the Board of Theralase ® , added, "We are honored to collaborate with Ferring, a worldwide leader in uro-oncology with deep expertise in bladder cancer treatment. As we approach completion of our clinical study and regulatory submissions for Ruvidar ® , this partnership provides the perfect opportunity to investigate whether we can deliver even greater benefits to patients through innovative combinational approaches." Study Details In Study II NCT03945162 , Theralase ® is clinically investigating light-activated Ruvidar ® in the treatment of patients diagnosed with BCG-Unresponsive NMIBC CIS (Study II). Theralase ® has enrolled and successfully treated 88 out of a planned 90 patients in Study II and plans to complete enrollment and treatment of the remaining 2 patients by 1Q2026 with follow-up completed by 2Q2027. In the Collaborative Clinical Study , Theralase ® will apply to the FDA to add a new cohort to Study II. This cohort will be treated with Theralase ® 's lead small molecule, light-activated Ruvidar ® , followed by treatment with Ferring's FDA-approved ADSTILADRIN. About NMIBC NMIBC is a form of bladder cancer that is found in the inner layer cells of the bladder and does not invade into or beyond the muscle wall. 1 In the United States, bladder cancer is the sixth most common cancer, 2 fourth among men, 3 and it is estimated that there will be approximately 84,870 new cases of bladder cancer in the U.S. in 2025. 3 Historically, 75% of bladder cancer presents as NMIBC. 4 In patients with high-risk NMIBC, intravesical BCG remains the first-line standard-of-care; however, approximately one third of patients with NMIBC will not respond to BCG therapy and 50% of those with an initial response will experience recurrence or progression of their disease. 5 Current treatment options for BCG-unresponsive patients are very limited and National Comprehensive Cancer Network (NCCN) guidelines recommend cystectomy (partial or complete removal of the bladder). 6 About Ruvidar ® Ruvidar ® (TLD-1433) is a small molecule, able to be activated by light, radiation, sound and/or other drugs, intended for the safe and effective destruction of various cancers, bacteria and viruses. About ADSTILADRIN ADSTILADRIN ® (nadofaragene firadenovec-vncg) is the first and only FDA-approved intravesical non-replicating gene-therapy for the treatment of adult patients with high-risk BCG-unresponsive NMIBC CIS with or without papillary tumors (±Ta/T1). It is a non-replicating adenovirus vector-based therapy containing the gene interferon alfa-2b, administered locally as a monotherapy by catheter directly into the bladder once every three months. The vector enters the cells of the bladder wall, releasing the active gene and causing the bladder’s cell walls to secrete high and transient local expression of interferon alfa-2b protein, a naturally occurring protein the body uses to fight cancer. This approach essentially turns the bladder wall cells into interferon microfactories, enhancing the body’s own natural defenses against the cancer. ADSTILADRIN has been studied in a clinical trial program that includes 157 patients with high-risk, BCG-unresponsive NMIBC, who had been treated with adequate BCG previously and did not see benefit from additional BCG treatment (full inclusion criteria published on clinicaltrials.gov: NCT02773849 and final five-year follow-up analysis published in The Journal of Urology ). 7-8 INDICATION ADSTILADRIN is a non-replicating adenoviral vector-based gene therapy indicated for the treatment of adult patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) carcinoma in situ (CIS) with or without papillary tumors (±Ta/T1). IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS: ADSTILADRIN is contraindicated in patients with prior hypersensitivity reactions to interferon alfa or to any component of the product. WARNINGS AND PRECAUTIONS: Risk with delayed cystectomy: Delaying cystectomy in patients with BCG-unresponsive CIS could lead to development of muscle invasive or metastatic bladder cancer, which can be lethal. If patients with CIS do not have a complete response to treatment after 3 months or if CIS recurs, consider cystectomy. Risk of disseminated adenovirus infection: Persons who are immunocompromised or immunodeficient may be at risk for disseminated infection from ADSTILADRIN due to low levels of replication-competent adenovirus. Avoid ADSTILADRIN exposure to immunocompromised or immunodeficient individuals. DOSAGE AND ADMINISTRATION: Administer ADSTILADRIN by intravesical instillation only. ADSTILADRIN is not for intravenous use, topical use or oral administration. USE IN SPECIFIC POPULATIONS: Advise females of reproductive potential to use effective contraception during ADSTILADRIN treatment and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during ADSTILADRIN treatment and for 3 months after the last dose. ADVERSE REACTIONS: The most common (>10%) adverse reactions; including, laboratory abnormalities (>15%), were increased glucose, instillation site discharge, increased triglycerides, fatigue, bladder spasm, micturition (urination urgency), increased creatinine, hematuria (blood in urine), decreased phosphate, chills, pyrexia (fever) and dysuria (painful urination). You are encouraged to report negative side effects of prescription drugs to FDA. Visit or call 1-800-332-1088. You may also contact Ferring Pharmaceuticals at 1-888-FERRING. Please click to see the full Prescribing Information . About Theralase ® Technologies Inc. Theralase ® is a clinical stage pharmaceutical company dedicated to the research and development of light, radiation, sound and drug-activated small molecule compounds and their associated formulations with a primary objective of efficacy and a secondary objective of safety in the destruction of various cancers, bacteria and viruses, with minimal impact on surrounding healthy tissue. Additional information is available at and . About Ferring Pharmaceuticals Ferring Pharmaceuticals is a privately-owned, specialty, biopharmaceutical group committed to building families and helping people live better lives. In the United States, Ferring is a leader in reproductive medicine and in areas of gastroenterology and orthopaedics. We are at the forefront of innovation in microbiome-based therapeutics and uro-oncology intravesical gene therapy. Our company was founded in 1950 and is headquartered in Saint-Prex, Switzerland. Ferring employs more than 7,000 people worldwide and markets its medicines in over 100 countries. Ferring USA is based in Parsippany, New Jersey, and employs more than 900 employees. For more information, please visit , call 1-888-FERRING (1-888-337-7464), or connect with us on LinkedIn , and X . References: Urology Care Foundation. Non-muscle Invasive Bladder Cancer. . Accessed November 2025. National Cancer Institute. Cancer Statistics. . Accessed November 2025. American Cancer Society. Cancer Facts & Figures 2025. . Accessed November 2025. Babjuk M, Burger M, Capoun O, et al. European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer. Eur Urol. 2022 Jan;81(1):75-94. . Accessed November 2025. Lidagoster S, et al. BCG and Alternative Therapies to BCG Therapy for Non-Muscle-Invasive Bladder Cancer. Curr Oncol. 2024 Feb 16;31(2):1063-1078. . Accessed November 2025. National Comprehensive Cancer Network. Bladder Cancer (Version 2.2025). . Accessed November 2025. ADSTILADRIN in Patients With High-Grade, Bacillus Calmette-Guerin (BCG) Unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC). Gov Identifier: NCT02773849. . Accessed November 2025. Narayan VM, Boorjian SA, Alemozaffar M, et al. Efficacy of intravesical nadofaragene firadenovec for patients with Bacillus Calmette-Guérin-unresponsive nonmuscle-invasive bladder cancer: 5-year follow-up from a phase 3 trial. J Urol. 2024;212(1):1-12. . Accessed November 2025. Additional information: Healthcare Providers: If you are interested in ordering ADSTILADRIN, please sign up for information and updates at . Patients and Consumers: For more information about ADSTILADRIN, please visit , or call 1-888-FERRING (888-337-7464), and select option number one. Contacts Media: Members of the press can contact Carol Ready , Director, Brand Communications, by phone at (973) 765-7307, or email at carol.ready@ferring.com .