单剂量单克隆抗体 在 1 期试验中快速降低 HBsAg

StephenW

  

Single Dose of Monoclonal Antibody Quickly Cuts  HBsAg in Phase 1 Trial EASL International Liver Congress, June 23-26, 2021 Mark Mascolini Single low doses of the neutralizing vaccinal monoclonal antibody (mAb) VIR-3434 rapidly lowered hepatitis B surface antigen (HBsAg) levels in a phase 1 study of people with chronic HBV infection [1]. (HBsAg indicates current HBV infection.) Higher doses of VIR-3434 are being evaluated in this trial, and VIR-3434 will be studied in combination with the siRNA VIR-2218 [2]. Research suggests that VIR-3434, an engineered human mAb against HBsAg, may trim HBsAg concentrations by more than one mechanism: (1) inhibition of viral entry by neutralizing all 10 HBV genotypes, (2) cross-presentation to and stimulation of T cells (a vaccinal effect), and (3) clearance of HBsAg and delivery to dendritic cells. A separate part of this phase 1a study also presented at the EASL International Liver Congress found that healthy volunteers tolerated single doses of VIR-3434 up to 3000 mg and that pharmacokinetic properties support subcutaneous dosing [3]. The second part of this phase 1a trial enrolled people with chronic HBV who had suppression of HBsAg to below 3000 IU/mL. Researchers randomized 8 people in each of five dose cohorts in a 6:2 ratio to receive a single subcutaneous dose of VIR-3434 (6, 18, 75, <300, or <900 mg) or placebo. The presentation at EASL focused on HBsAg data up to 4 weeks after dosing in people receiving 6 or 18 mg of VIR-3434 or placebo. The study enrolled 18- to 65-year-olds with chronic HBV infection who had HBV DNA below 100 IU/mL. Everyone was negative for hepatitis B e antigen (HBeAg) and negative for hepatitis B surface antibody, had taken nucleos(t)ide therapy for at least 2 months, and had an HBsAg level below 3000 IU/mL. No one had significant fibrosis or cirrhosis, alanine or aspartate aminotransferase more than 2 times the upper limit of normal, active HIV, HCV, or hepatitis Delta virus infection, creatinine clearance below 75 mL/min, or a history of anaphylaxis. Compared with the 6-mg group, the 18-mg group was nonsignificantly younger (average 48.8 vs 56.5) and had a nonsignificantly higher initial average HBsAg level (837 vs 197 IU/mL). There were 8 men in the 6-mg group and 7 men and 1 woman in the 18-mg group. Proportions of Asians, Whites, and Blacks were 50%, 38%, and 12% in the 6-mg cohort and 50%, 12%, and 38% in the 18-mg cohort. Median body mass index stood at 25 kg/m2 in the 6-mg group and 26 kg/m2 in the 18-mg group. No one in either treatment arm had a serious adverse event or left the study. All adverse events were grade 1 or grade 2. The researchers observed no clinically significant lab abnormalities or changes in liver function tests and no injection-site reactions. No clinical or lab signs of immune complex disease developed in any participants in these two dose groups. Researchers remain blinded to VIR-3434 or placebo assignment, so virologic results did not indicate who was assigned to active treatment or a dummy injection. But results did separate the 6-mg/placebo group from the 18-mg/placebo group. Most participants in both dose groups had at least a 1 log10 IU/mL (10-fold) drop in HBsAg within the first 2 to 4 days after dosing. Maximum HBsAg declines usually came within 7 days of dosing. People in the 18 mg/placebo group had the biggest HBsAg drops-greater than 1.5-log10 IU/mL. Although the researchers stressed the preliminary nature of these findings, they suggested that the data "support the potential for VIR-3434 to have a meaningful role in the functional cure of chronic HBV infection." References 1. Agarwal K, Yuen MF, Wedemeyer H, et al. A phase 1 study evaluating the neutralizing, vaccinal monoclonal antibody VIR-3434 in participants with chronic hepatitis B virus infection: preliminary results. EASL International Liver Congress, June 23-26, 2021. Abstract OS-211. 2. Gane E, Lim YS, Cloutier D, et al. Safety and antiviral activity of VIR-2218, an X-targeting RNAi therapeutic, in participants with chronic hepatitis B infection: week 48 follow-up results. EASL International Liver  Congress, June 23-26, 2021. Abstract OS-44. 3. Gupta SV, Arizpe A, Fanget MC, et al. Preliminary pharmacokinetics and safety in healthy volunteers of VIR-3434, a monoclonal antibody for the treatment of chronic hepatitis B infection. EASL International Liver Congress, June 23-26, 2021. Abstract PO-43.

StephenW

单剂量单克隆抗体
在 1 期试验中快速降低 HBsAg


  EASL 国际肝脏大会，2021 年 6 月 23-26 日

马克·马斯科利尼

在一项针对慢性 HBV 感染者的 1 期研究中，单次低剂量的中和疫苗单克隆抗体 (mAb) VIR-3434 迅速降低了乙型肝炎表面抗原 (HBsAg) 水平 [1]。 （HBsAg 表示当前的 HBV 感染。）本试验正在评估更高剂量的 VIR-3434，并将与 siRNA VIR-2218 联合研究 VIR-3434 [2]。

研究表明，VIR-3434 是一种针对 HBsAg 的工程化人类 mAb，可以通过多种机制降低 HBsAg 浓度：(1) 通过中和所有 10 种 HBV 基因型抑制病毒进入，(2) 交叉呈递和刺激 T 细胞（疫苗效应），和（3）清除 HBsAg 并递送至树突细胞。该 1a 期研究的另一部分也在 EASL 国际肝脏大会上发表，发现健康志愿者可以耐受高达 3000 mg 的单剂量 VIR-3434，并且药代动力学特性支持皮下给药 [3]。

该 1a 期试验的第二部分招募了 HBsAg 抑制至低于 3000 IU/mL 的慢性 HBV 患者。研究人员以 6:2 的比例将 5 个剂量组中的每组 8 人随机分组，分别接受单次皮下注射 VIR-3434（6、18、75、<300 或 <900 毫克）或安慰剂。在 EASL 上的演讲重点是在接受 6 或 18 毫克 VIR-3434 或安慰剂的人给药后长达 4 周的 HBsAg 数据。

该研究招募了 18 至 65 岁的慢性 HBV 感染者，他们的 HBV DNA 低于 100 IU/mL。所有人乙肝e抗原（HBeAg）阴性，乙肝表面抗体阴性，接受核苷（酸）类药物治疗至少2个月，HBsAg水平低于3000 IU/mL。没有人出现明显的纤维化或肝硬化、丙氨酸或天冬氨酸转氨酶超过正常、活动性 HIV、HCV 或丁型肝炎病毒感染上限的 2 倍，肌酐清除率低于 75 mL/min，或有过敏反应史。

与 6-mg 组相比，18-mg 组年轻（平均 48.8 对 56.5）且初始平均 HBsAg 水平无显着升高（837 对 197 IU/mL）。 6 毫克组中有 8 名男性，18 毫克组中有 7 名男性和 1 名女性。亚洲人、白人和黑人的比例在 6 毫克队列中分别为 50%、38% 和 12%，在 18 毫克队列中分别为 50%、12% 和 38%。中位体重指数在 6 毫克组为 25 公斤/平方米，在 18 毫克组为 26 公斤/平方米。

任一治疗组中都没有人发生严重不良事件或退出研究。所有不良事件均为 1 级或 2 级。研究人员没有观察到临床上显着的实验室异常或肝功能测试的变化，也没有注射部位反应。这两个剂量组的任何参与者均未出现免疫复合物疾病的临床或实验室迹象。

研究人员仍然对 VIR-3434 或安慰剂分配不知情，因此病毒学结果并未表明谁被分配到积极治疗或假注射。但结果确实将 6 毫克/安慰剂组与 18 毫克/安慰剂组分开。在给药后的前 2 至 4 天内，两个剂量组的大多数参与者的 HBsAg 至少下降了 1 log10 IU/mL（10 倍）。 HBsAg 最大下降通常在给药后 7 天内出现。 18 毫克/安慰剂组的人 HBsAg 下降幅度最大 - 大于 1.5-log10 IU/mL。

尽管研究人员强调了这些发现的初步性质，但他们认为这些数据“支持 VIR-3434 在慢性 HBV 感染的功能性治愈中发挥重要作用的潜力”。

参考
1. Agarwal K、Yuen MF、Wedemeyer H 等。一项评估慢性乙型肝炎病毒感染参与者中和疫苗单克隆抗体 VIR-3434 的 1 期研究：初步结果。 EASL 国际肝脏大会，2021 年 6 月 23-26 日。摘要 OS-211。
2. Gane E、Lim YS、Cloutier D 等。 VIR-2218（一种 X 靶向 RNAi 治疗剂）在慢性乙型肝炎感染参与者中的安全性和抗病毒活性：第 48 周随访结果。 EASL 国际肝脏大会，2021 年 6 月 23-26 日。摘要 OS-44。
3. Gupta SV、Arizpe A、Fanget MC 等。 VIR-3434（一种用于治疗慢性乙型肝炎感染的单克隆抗体）在健康志愿者中的初步药代动力学和安全性。 EASL 国际肝脏大会，2021 年 6 月 23-26 日。摘要 PO-43。