Hou Jinlin, Zhang Wenhong, Xie Qing, Hua Rui, Tang Hong, Morano Amado Luis Enrique, Yang Sheng-Shun, Peng Cheng-Yuan, Su Wei-Wen, Chuang Wan-Long, Kim Dong Joon, Avihingsanon Anchalee, Kao Jia-Horng, Leerapun Apinya, Yuen Man-Fung, Asselah Tarik, Liang Xieer, Bo Qingyan, Canducci Filippo, Catanese Maria Teresa, Chen Ethan, Cheng Cong, Chughlay Farouk, Das Sudip, Glavini Katerina, Guerreiro Nelson, Huang Yan, Kakrana Priyanka, Kazma Rémi, Patil Avinash, Pavlovic Vedran, Surujbally Bernadette, Triyatni Miriam, Upmanyu Ruchi, Wat Cynthia, Gane Edward
From the Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University (J.H., X.L.), and the State Key Laboratory of Organ Failure Research, Key Laboratory of Infectious Diseases Research in South China, Ministry of Education, Guangdong Institute of Hepatology, Nanfang Hospital (J.H.), Guangzhou, the Department of Infectious Diseases and Biosafety Emergency Response, Huashan Hospital, Fudan University (W.Z.), the Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine (Q.X.), Roche Holding (Q.B., E.C.), Roche Research and Development Center (C.C., Y.H.), and Takeda APAC Biopharmaceutical Research and Development (Q.B.), Shanghai, the Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, First Hospital of Jilin University, Changchun (R.H.), the Center of Infectious Diseases, Laboratory of Infectious and Liver Disease, Institute of Infectious Diseases, West China Hospital, Sichuan University, Chengdu (H.T.), and the Department of Medicine and State Key Laboratory of Liver Research, Queen Mary Hospital, University of Hong Kong, Hong Kong (M.-F.Y.) - all in China; the Division of Infectious Diseases, University Hospital Álvaro Cunqueiro, Galicia Sur Health Research Institute, Servizo Galego de Saúde-Universidade de Vigo, Vigo, Spain (L.E.M.A.); the Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital (S.-S.Y.), and the Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, China Medical University (C.-Y.P.), Taichung, the Department of Internal Medicine, Changhua Christian Hospital, Changhua (W.-W.S.), Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung (W.-L.C.), and National Taiwan University Hospital, Taipei (J.-H.K.) - all in Taiwan; the Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, South Korea (D.J.K.); the HIV Netherlands Australia Thailand Research Collaboration, Thai Red Cross AIDS Research Center and the Center of Excellence in Tuberculosis, Faculty of Medicine, Chulalongkorn University, Bangkok (A.A.), and the Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai (A.L.) - both in Thailand; Université de Paris-Cité, Department of Hepatology, Assistance Publique-Hôpitaux de Paris, Hôpital Beaujon, Centre de Recherche sur l'Inflammation, INSERM Unité Mixte de Recherche 1149, Paris (T.A.); F. Hoffmann-La Roche, Basel, Switzerland (F. Canducci, M.T.C., F. Chughlay, K.G., N.G., P.K., R.K., M.T.); Roche Products, Welwyn Garden City (S.D., V.P., B.S., R.U., C.W.), and ID Pharma Consultancy, Yelverton (C.W.) - both in the United Kingdom; Enthera Pharmaceuticals, Milan (F. Canducci); Parexel International, Hyderabad, India (A.P.); and the New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand (E.G.).
N Engl J Med. 2024 Dec 5;391(22):2098-2109. doi: 10.1056/NEJMoa2405485.
Xalnesiran, a small interfering RNA molecule that targets a conserved region of the hepatitis B virus (HBV) genome and silences multiple HBV transcripts, may have efficacy, with or without an immunomodulator, in patients with chronic HBV infection.
We conducted a phase 2, multicenter, randomized, controlled, adaptive, open-label platform trial that included the evaluation of 48 weeks of treatment with xalnesiran at a dose of 100 mg (group 1), xalnesiran at a dose of 200 mg (group 2), xalnesiran at a dose of 200 mg plus 150 mg of ruzotolimod (group 3), xalnesiran at a dose of 200 mg plus 180 μg of pegylated interferon alfa-2a (group 4), or a nucleoside or nucleotide analogue (NA) alone (group 5) in participants with chronic HBV infection who had virologic suppression with NA therapy. The primary efficacy end point was hepatitis B surface antigen (HBsAg) loss (HBsAg level, <0.05 IU per milliliter) at 24 weeks after the end of treatment. Safety was also assessed.
Among 159 participants (30, 30, 34, 30, and 35 in groups 1 through 5, respectively), the primary end-point event occurred in 7% (95% confidence interval [CI], 1 to 22) of those in group 1, in 3% (95% CI, 0 to 17) of those in group 2, in 12% (95% CI, 3 to 28) of those in group 3, in 23% (95% CI, 10 to 42) of those in group 4, and in none (95% CI, 0 to 10) of those in group 5. In groups 1 through 5, respectively, HBsAg seroconversion occurred in 3%, none, 3%, 20%, and none of the participants at 24 weeks after the end of treatment. HBsAg loss with or without seroconversion occurred only in participants with a screening HBsAg level below 1000 IU per milliliter. In groups 1 through 5, respectively, grade 3 or 4 adverse events occurred in 17%, 10%, 18%, 50%, and 6% of the participants, with the most frequent event being an elevated alanine aminotransferase level.
Among participants with chronic HBV infection who had virologic suppression with NA therapy, treatment with xalnesiran plus an immunomodulator resulted in HBsAg loss at 24 weeks after the end of treatment in a substantial percentage of participants. Grade 3 or 4 adverse events were not uncommon. (Funded by F. Hoffmann-La Roche; Piranga ClinicalTrials.gov number, NCT04225715.).
Xalnesiran是一种靶向乙型肝炎病毒（HBV）基因组保守区域并使多种HBV转录本沉默的小分子干扰RNA分子，在慢性HBV感染患者中，无论是否联合免疫调节剂，它可能都具有疗效。
我们进行了一项2期、多中心、随机、对照、适应性、开放标签的平台试验，其中包括评估48周的Xalnesiran治疗，剂量分别为100mg（第1组）、200mg（第2组）、200mg加150mg鲁佐利莫德（第3组）、200mg加180μg聚乙二醇化干扰素α-2a（第4组），或单独使用核苷或核苷酸类似物（NA）（第5组），受试对象为接受NA治疗后病毒学得到抑制的慢性HBV感染患者。主要疗效终点是治疗结束后24周时乙肝表面抗原（HBsAg）消失（HBsAg水平<0.05IU/ml）。同时也评估了安全性。
159名参与者（第1至5组分别为30、30、34、30和35名）中，主要终点事件发生在第1组的7%（95%置信区间[CI]，1%至22%）、第2组的3%（95%CI，0%至17%）、第3组的12%（95%CI，3%至28%）、第4组的23%（95%CI，10%至42%）以及第5组的0%（95%CI，0%至10%）。在第1至5组中，治疗结束后24周时分别有3%、0%、3%、20%和0%的参与者发生HBsAg血清学转换。无论有无血清学转换，HBsAg消失仅发生在筛查时HBsAg水平低于1000IU/ml的参与者中。在第1至5组中，分别有17%、10%、18%、50%和6%的参与者发生3级或4级不良事件，最常见的事件是丙氨酸氨基转移酶水平升高。
在接受NA治疗后病毒学得到抑制的慢性HBV感染参与者中，Xalnesiran联合免疫调节剂治疗使相当比例的参与者在治疗结束后24周时出现HBsAg消失。3级或4级不良事件并不少见。（由F. Hoffmann-La Roche资助；Piranga ClinicalTrials.gov编号，NCT04225715。）
