香港大学Man-Fung Yuen等研究人员完成反义寡核苷酸bepirovirsen在慢性乙型肝炎患者中的2期临床试验。2021年10月12日，《自然—医学》杂志在线发表了这项成果。

研究人员表示，乙型肝炎病毒（HBV）的慢性感染会导致肝硬化和肝细胞癌的死亡风险增加。目前的治疗方案（核苷酸类似物（NA）和聚乙二醇干扰素）的功能治愈率很低。bepirovirsen是一种针对所有HBV信使RNA的反义寡核苷酸；在细胞培养和动物模型中，bepirovirsen会导致HBV衍生的RNA、HBV DNA和病毒蛋白的减少。

这项2期双盲、随机、安慰剂对照试验是首次评估针对HBV RNA的反义寡核苷酸在治疗无效和病毒抑制的慢性HBV感染者中的安全性和活性。主要目标是评估慢性乙型肝炎（CHB）患者使用贝碧欧维森的安全性和耐受性（NCT02981602）。次要目标是评估抗病毒活性，包括从基线到第29天的血清乙肝表面抗原（HBsAg）浓度变化。感染CHB≥6个月且血清HBsAg≥50 IU ml^-1的参与者来自中国香港和韩国的7个中心，并随机（每个剂量组内3:1）在第1和2周（第1、4、8和11天）通过皮下注射接受bepirovirsen或安慰剂，在第3和4周（第15和22天）每周一次。然后对参与者进行了26周的随访。24名参与者是治疗无效的，7名参与者正在接受稳定的NA治疗。

治疗中出现的不良事件大多为轻度/中度（最常见的是注射部位反应）。11名(61.1%)和3名(50.0%)治疗无效的参与者在bepirovirsen组和安慰剂组分别出现了一个或多个治疗突发的不良事件。在接受NA治疗的参与者中，相应的数字为3人（60.0%）和1人（50.0%）。在bepirovirsen治疗组中，有8名治疗无效的参与者和3名接受稳定NA治疗的参与者观察到短暂的、可自行缓解的丙氨酸氨基转移酶爆发（≥2倍的正常上限）。观察到HBsAg的降低，并且与安慰剂相比，接受bepirovirsen 300毫克的治疗无效的参与者有明显的降低（P=0.001），但bepirovirsen 150毫克组（P=0.245）或接受稳定NA治疗的参与者（P=0.762）没有降低。在300毫克剂量组中，每组有两名参与者在第29天（n=3）或第36天（n=1）时达到HBsAg水平低于定量下限。bepirovirsen具有良好的安全性。这些初步观察表明，需要在更大的CHB患者群体中进一步调查bepirovirsen的安全性和活性。

附：英文原文

Title: Safety, tolerability and antiviral activity of the antisense oligonucleotide bepirovirsen in patients with chronic hepatitis B: a phase 2 randomized controlled trial

Author: Yuen, Man-Fung, Heo, Jeong, Jang, Jeong-Won, Yoon, Jung-Hwan, Kweon, Young-Oh, Park, Sung-Jae, Tami, Yvonne, You, Shihyun, Yates, Phillip, Tao, Yu, Cremer, Jennifer, Campbell, Fiona, Elston, Robert, Theodore, Dickens, Paff, Melanie, Bennett, C. Frank, Kwoh, T. Jesse

Issue&Volume: 2021-10-12

Abstract: Chronic infection with hepatitis B virus (HBV) leads to an increased risk of death from cirrhosis and hepatocellular carcinoma. Functional cure rates are low with current treatment options (nucleos(t)ide analogs (NAs) and pegylated interferons). Bepirovirsen is an antisense oligonucleotide targeting all HBV messenger RNAs; in cell culture and animal models, bepirovirsen leads to reductions in HBV-derived RNAs, HBV DNA and viral proteins. This phase 2 double-blinded, randomized, placebo-controlled trial is the first evaluation of the safety and activity of an antisense oligonucleotide targeting HBV RNA in both treatment-nave and virally suppressed individuals with chronic HBV infection. The primary objective was to assess the safety and tolerability of bepirovirsen in individuals with chronic hepatitis B (CHB) (NCT02981602). The secondary objective was to assess antiviral activity, including the change from baseline to day 29 in serum hepatitis B surface antigen (HBsAg) concentration. Participants with CHB infection ≥6 months and serum HBsAg ≥50 IUml1 were enrolled from seven centers across Hong Kong and the Republic of Korea and randomized (3:1 within each dose cohort) to receive bepirovirsen or placebo via subcutaneous injection twice weekly during weeks 1 and 2 (days 1, 4, 8 and 11) and once weekly during weeks 3 and 4 (days 15 and 22). Participants were then followed for 26 weeks. Twenty-four participants were treatment-nave and seven were receiving stable NA therapy. Treatment-emergent adverse events were mostly mild/moderate (most commonly injection site reactions). Eleven (61.1%) and three (50.0%) treatment-nave participants experienced one or more treatment-emergent adverse event in the bepirovirsen and placebo groups, respectively. In participants receiving NA therapy, the corresponding numbers were three (60.0%) and one (50.0%). Transient, self-resolving alanine aminotransferase flares (≥2× upper limit of normal) were observed in eight treatment-nave participants and three participants on stable NA regimens in the bepirovirsen treatment arms. HBsAg reductions were observed and were significant versus placebo for treatment-nave participants receiving bepirovirsen 300mg (P=0.001), but not for the bepirovirsen 150mg group (P=0.245) or participants receiving stable NA therapy (P=0.762). Two participants in each of the 300 mg dose groups achieved HBsAg levels below the lower limit of quantitation by day 29 (n=3) or day 36 (n=1). Bepirovirsen had a favorable safety profile. These preliminary observations warrant further investigation of the safety and activity of bepirovirsen in a larger CHB patient population.

DOI: 10.1038/s41591-021-01513-4

Source: https://www.nature.com/articles/s41591-021-01513-4