从新药研究进展看乙型肝炎未来治疗趋势

摘要/Abstract

摘要： 乙型肝炎病毒(HBV)感染目前仍呈世界性流行,HBV感染治疗措施包括干扰素和核苷类似物,但均只能抑制HBV复制,不能完全根除HBV感染,因此研发能够根治乙型肝炎的药物就显得极为重要。近年来在研的治疗乙型肝炎新药种类繁多,国内外各大药商的药品研发管线加快更新迭代,本文依据美国乙型肝炎基金会(HBF)最新公布的“drug watch”及各大药企官网更新的产品管线信息进行汇总,对靶向病毒并干扰HBV复制过程的直接作用抗病毒药物中的小干扰RNA(siRNA)药物、反义RNA及基因编辑等作用机制的在研新药进行总结。

冷雪君, 颜学兵. 从新药研究进展看乙型肝炎未来治疗趋势[J]. 肝脏, 2025, 30(4): 563-567.

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参考文献

[1] World Health Organization.Global progress report on HIV,viral hepatitis and sexually transmitted infections,2021.Accountability for the global health sector strategies 2016-2021: actions for impact [EB/OL]. [2025-02-27]. https://iris.who.int/bitstream/handle/10665/342808/9789240030985-eng.pdf.
[2] 蔡南, 胡鹏. 慢性乙型肝炎抗病毒治疗新药研究进展 [J] . 中华肝脏病杂志, 2024, 32(4) : 295-299.
[3] 李德瑶, 陆丹娟, 曲晨箫, 等. 乙型肝炎病毒RNA的转录后调控机制及抗病毒策略 [J] . 中华肝脏病杂志, 2024, 32(5) : 474-480.
[4] Gane E J, Agarwal K, Bai W, et al. Vir-2218 and vir-3434 with or without pegylated interferon alfa-2a for the treatment of chronic HBV infection: end of treatment (eot) results after 24 weeks of therapy (march study part b). AASLD 2023. Abrasts 5013-C.
[5] Gane E, Lim Y S, Kim J B, et al. Evaluation of RNAi therapeutics VIR-2218 and ALN-HBV for chronic hepatitis B: results from randomized clinical trials[J]. J Hepatol, 2023,79(4):924-932.
[6] Yuen M F, Asselah T, Jacobson I M, et al. 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[J]. Lancet Gastroenterol Hepatol, 2023,8(9):790-802.
[7] Asselah T, Fung S K, Akhan S, et al. A phase 2 open-label study to evaluate safety, tolerability, efficacy, and pharmacodynamics of JNJ-73763989, nucleos(t)ide analogs, and a low-dose PD-1 inhibitor in patients with chronic hepatitis B-Interim results of the OCTOPUS-1 study[J].J Hepatol, 2024, 80(Sup1): S27-S28.
[8] Mak L Y L, Wooddell C, Lenz O, et al. Long-term hepatitis B surface antigen response after finite treatment with siRNAs ARC-520 or JNJ-3989[J].J Hepatol, 2024, 80(Sup1): S27.
[9] Agarwal K, Buti M, van Bömmel F, et al. JNJ-73763989 and bersacapavir treatment in nucleos(t)ide analogue-suppressed patients with chronic hepatitis B: REEF-2 [J]. J Hepatol, 2024, 81(3):404-414.
[10] Yuen M F, Heo J, Nahass R G, et al. Imdusiran (AB-729) administered every 8 weeks in combination with 24 weeks of pegylated interferon alfa-2a in virally suppressed, HBeAg-negative subjects with chronic HBV infection leads to HBsAg loss in some subjects at end of IFN treatment[J]. J Hepatol, 2024, 80(Sup1):S809-S810.
[11] Agarwal K, Yuen M F, Roberts S, et al. Imdusiran (AB-729) administered every 8 weeks for 24 weeks followed by the immunotherapeutic VTP-300 maintains lower HBV surface antigen levels in NA-suppressed CHB subjects than 24 weeks of imdusiran alone[J]. J Hepatol, 2024, 80(Sup1):S26-S27.
[12] Jucov A, Gane E, Fitzgerald M, et al. Safety, pharmacokinetics, and antiviral activity of single ascending doses of ALG-125755, a GalNAc-conjugated small interfering RNA, in subjects with chronic hepatitis B [EB/OL]. (2023-06-21)[2025-2-27]. https://aligos.wpenginepowered.com/wp-content/uploads/2023/07/EASL-ALG-125755-SAT-188.pdf.
[13] Hong J, Rajwanshi V K, Montero S M, et al. Second generation HBV siRNAs with novel chemistries demonstrate improved profiles compared with ALG-125755 and other clinical stage siRNAs[EB/OL]. (2024-06-5)[2025-02-27]. https://aligos.com/wp-content/uploads/2024/06/EASL-Abstract-TOP-357-Second-Gen-HBV-siRNA-Final.pptx58.pdf.
[14] Hong J, Cai D, Montero S M, et al. A potent human PD-L1 siRNA leads to significant reduction of AAV-HBV infected hepatocytes via immune activation in human PD-1/PD-L1 double knock in mice[EB/OL]. (2023-06-21)[2025-02-27]. https://aligos.wpenginepowered.com/wp-content/uploads/2023/07/EASL-PD-L1-siRNA-FRI-239.pdf.
[15] Yuen M F, Lim S G, Plesniak R, et al. Efficacy and safety of bepirovirsen in chronic hepatitis B infection [J]. N Engl J Med, 2022,387(21):1957-1968.
[16] GSK receives US FDA Fast Track designation for bepirovirsen in chronic hepatitis B[EB/OL]. (2024-02-12)[2025-02-27]. https://www.gsk.com/media/10959/gsk-receives-us-fda-fast-track-designation-for-bepirovirsen-press-release.pdf.
[17] Harrison E B, Dulmage K, Evans K, et al. Preclinical safety data for PBGENE-HBV gene editing program supports advancementto clinical trials as a potentially curative treatment for chronic hepatitis B[EB/OL]. (2024-06-05)[2025-02-27]. https://precisionbiosciences.com/wp-content/uploads/2024/06/PBGENEHBV-EASL-2024-poster_final.pdf.
[18] Neugebauer M E, Hsu A, Arbab M, et al. Evolution of an adenine base editor into a small, efficient cytosine base editor with low off-target activity[J]. Nat Biotechnol, 2023, 41(5):673-685.
[19] Smekalova E M, Martinez M G, Combe E, et al. Cytosine base editing inhibits hepatitis B virus replication and reduces HBsAg expression in vitro and in vivo[J]. Mol Ther Nucleic Acids, 2023, 35(1):102112.
[20] Hui R W, Mak L Y, Seto W K, et al. RNA interference as a novel treatment strategy for chronic hepatitis B infection[J]. Clin Mol Hepatol, 2022, 28(3):408-424.