Background and Objective

VIR-2218 is an investigational N-acetylgalactosamine–conjugated RNA interference therapeutic in development for chronic hepatitis B virus (HBV) infection. VIR-2218 was designed to silence HBV transcripts across all genotypes and uses Enhanced Stabilization Chemistry Plus (ESC+) technology.

This study was designed to evaluate the single-dose pharmacokinetics of VIR-2218 in preclinical species and healthy volunteers.

Methods

Preclinically, a single subcutaneous dose of VIR-2218 (10 mg/kg) was administered to rats and nonhuman primates (NHPs), and the pharmacokinetics were assessed in plasma, urine, and liver using standard noncompartmental analysis (NCA) methods. Clinically, healthy volunteers were randomized (6:2 active:placebo) to receive a single subcutaneous dose of VIR-2218 (50–900 mg) or placebo. Pharmacokinetics were similarly assessed within human plasma and urine using NCA methods.

Results

In rats and NHPs, VIR-2218 was stable in plasma and was converted to AS(N-1)3’VIR-2218, the most prominent circulating metabolite, at < 10% plasma exposure compared with parent. VIR-2218 rapidly distributed to the liver, reaching peak liver concentrations within 7 and 24 h in rats and NHPs, respectively. In humans, VIR-2218 was rapidly absorbed, with a median time to peak plasma concentration (t_max) of 4–7 h, and had a short median plasma half-life of 2–5 h. Plasma exposures for area under the plasma concentration–time curve up to 12 h (AUC_0–12) and mean maximum concentrations (C_max) increased in a slightly greater-than-dose-proportional manner across the dose range studied. Interindividual pharmacokinetic variability was low to moderate, with a percent coefficient of variation of < 32% for AUC and < 43% for C_max. A portion of VIR-2218 was converted to an active metabolite, AS(N-1)3’VIR-2218, with a median t_max of 6–10 h, both of which declined below the lower limit of quantification in plasma within 48 h. The pharmacokinetic profile of AS(N-1)3’VIR-2218 was similar to that of VIR-2218, with plasma AUC_0–12 and C_max values ≤ 12% of VIR-2218. VIR-2218 and AS(N-1)3’VIR-2218 were detectable in urine through the last measured time point, with approximately 17–48% of the administered dose recovered in urine as unchanged VIR-2218 over 0–24 h postdose. Based on pharmacokinetics in preclinical species, VIR-2218 localizes to the liver and likely exhibits prolonged hepatic exposure. Overall, no severe or serious adverse events or discontinuations due to adverse events were observed within the dose range evaluated for VIR-2218 in healthy volunteers (Vir Biotechnology, Inc., unpublished data).

Conclusions

VIR-2218 showed favorable pharmacokinetics in healthy volunteers supportive of subcutaneous dosing and continued development in patients with chronic HBV infection.

Clinical Trial Registration No

NCT03672188, September 14, 2018.

中文翻译：

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VIR-2218的临床和临床前单剂量药代动力学，一种靶向HBV感染的RNAi治疗剂

背景与目的

VIR-2218 是一种用于治疗慢性乙型肝炎病毒 (HBV) 感染的研究性N-乙酰半乳糖胺偶联 RNA 干扰疗法。VIR-2218 旨在沉默所有基因型的 HBV 转录物，并使用增强稳定化学加 (ESC+) 技术。

本研究旨在评估 VIR-2218 在临床前物种和健康志愿者中的单剂量药代动力学。

方法

临床前，对大鼠和非人灵长类动物 (NHP) 给予单次皮下剂量的 VIR-2218 (10 mg/kg)，并使用标准非房室分析 (NCA) 方法在血浆、尿液和肝脏中评估药代动力学。在临床上，健康志愿者被随机分配（6:2 活性：安慰剂）接受单次皮下剂量的 VIR-2218（50-900 mg）或安慰剂。使用 NCA 方法在人血浆和尿液中类似地评估药代动力学。

结果

在大鼠和 NHPs 中，VIR-2218 在血浆中是稳定的，与母体相比，血浆暴露量 < 10% 时转化为最突出的循环代谢物 AS(N-1)3'VIR-2218。VIR-2218 迅速分布到肝脏，分别在大鼠和 NHPs 中的 7 和 24 小时内达到肝脏峰值浓度。在人体中，VIR-2218 被迅速吸收，达到血浆浓度峰值的中位时间 ( t _max ) 为 4-7 小时，中位血浆半衰期较短，为 2-5 小时。血浆浓度 - 时间曲线下面积的血浆暴露长达 12 小时 (AUC _0-12 ) 和平均最大浓度 ( C _max) 在所研究的剂量范围内以略大于剂量比例的方式增加。个体间药代动力学变异性为低至中度，AUC 的变异系数 < 32% 和C _max的变异系数 < 43% 。一部分 VIR-2218 转化为活性代谢物 AS(N-1)3'VIR-2218，中位t _max为 6-10 h，两者均在 48 小时内降至血浆定量下限以下H。AS(N-1)3'VIR-2218 的药代动力学特征与 VIR-2218 相似，血浆 AUC _0-12和C _max值 ≤ VIR-2218 的 12%。在最后一个测量时间点，尿液中可检测到 VIR-2218 和 AS(N-1)3'VIR-2218，在给药后 0-24 小时内，约 17-48% 的给药剂量在尿液中恢复为未变化的 VIR-2218 . 根据临床前物种的药代动力学，VIR-2218 定位于肝脏并可能表现出长时间的肝脏暴露。总体而言，在健康志愿者的 VIR-2218 评估剂量范围内，未观察到严重或严重的不良事件或因不良事件导致的停药（Vir Biotechnology, Inc.，未发表的数据）。

结论

VIR-2218 在健康志愿者中显示出良好的药代动力学，支持皮下给药和慢性 HBV 感染患者的持续发展。

临床试验注册号

NCT03672188，2018 年 9 月 14 日。