The small interfering RNA imdusiran as single and multiple doses in healthy, randomised individuals and non-randomised individuals with chronic hepatitis B (AB-729-001): a phase 1a/b trial.

We aimed to investigate the safety, antiviral activity, and anti-HBV immune responses of the N-acetylgalactosamine-conjugated, small interfering RNA imdusiran, a therapeutic strategy designed to reduce viral antigens on the path to achieving immune control.

我们旨在调查N-乙酰半乳糖胺偶联的小干扰RNA药物imdusiran的安全性、抗病毒活性以及抗乙型肝炎病毒免疫反应，这是一种旨在减少病毒抗原以实现免疫控制的治疗策略。

Methods

AB-729-001 was a phase 1a/b trial conducted at 11 centres and hospitals: three in Australia, one in New Zealand, three in Thailand, one in Hong Kong, two in South Korea, and one in Moldova.

AB-729-001 是一项在 11 个中心和医院进行的 1a/b 期试验：澳大利亚三个，新西兰一个，泰国三个，香港一个，韩国两个，摩尔多瓦一个。

In part 1, which had a double-blinded, single ascending dose design consisting of four sequential dose groups, healthy individuals aged 18-45 years were randomly assigned (2:1), using fixed block randomisation (block number of two for 1:1 active:placebo sentinel dosing, followed by block number of four for 3:1 active:placebo for the next four participants), into three equal-sized cohorts and received subcutaneous imdusiran or placebo as a single dose of 60 mg, 180 mg, or 360 mg.

在第一部分，采用双盲、单次递增剂量设计，包括四个顺序剂量组，18-45 岁的健康个体被随机分配（2:1），使用固定块随机化（对于 1:1 活性：安慰剂哨兵剂量，使用两个的块数，随后对于接下来的四个参与者使用四个的块数进行 3:1 活性：安慰剂），分成三个等大小的队列，并接受了 60 mg、180 mg 或 360 mg 的单剂量皮下注射imdusiran 或安慰剂。

Participants and investigators were masked to treatment assignment until part 1 was complete.

在第一部分完成之前，参与者和研究人员对治疗分配情况保密。

Parts 2 and 3 were open-label and enrolled individuals aged 18-65 years with chronic hepatitis B, who were HBeAg-positive or HBeAg-negative and were taking or not taking nucleoside or nucleotide (nucleos[t]ide) analogue therapy (continued during the imdusiran treatment period), and who had HBsAg concentrations of at least 250 international units per mL, no clinically significant abnormalities on liver ultrasound, and an absence of cirrhosis.

第二部分和第三部分是开放标签的，招募了18-65岁的慢性乙型肝炎患者，这些患者可以是HBeAg阳性或HBeAg阴性，正在使用或未使用核苷或核苷类似物（核苷[酸]类似物）治疗（在imdusiran治疗期间继续），并且HBsAg浓度至少为250国际单位/毫升，肝超声检查无临床显著异常，且无肝硬化。

These participants received subcutaneous imdusiran as a single dose of 60 mg, 90 mg, or 180 mg (part 2) or as repeat doses of 60 mg or 90 mg every 4, 8, or 12 weeks for up to 48 weeks (part 3).

这些参与者接受了皮下注射imdusiran，作为单剂量的60 mg、90 mg或180 mg（第2部分）或作为重复剂量的60 mg或90 mg，每4、8或12周一次，持续长达48周（第3部分）。

The primary endpoint for all parts of the study was to evaluate the frequency and severity of treatment-emergent adverse events, discontinuations due to adverse events, and laboratory abnormalities following the administration of single doses to healthy participants (evaluated until day 29 after dosing) and of single and multiple doses of imdusiran to participants with chronic hepatitis B (evaluated until week 48 of follow-up and until month 36 of follow-up for participants who discontinued nucleos[t]ide analogue therapy after completing imdusiran treatment and meeting eligibility criteria).

该研究所有部分的主要终点是评估治疗后出现的不良事件的频率和严重程度、因不良事件导致的停药以及实验室异常，对健康参与者进行单剂量给药（在给药后第29天进行评估）和对慢性乙型肝炎患者进行单剂量和多剂量imdusiran给药（在随访48周内进行评估，对于在完成imdusiran治疗并满足入选标准后停用核苷类似物治疗的参与者，在随访36个月内进行评估）。

All individuals who received at least one dose of study drug comprised the safety population and were included in safety analyses.

所有至少接受了一剂研究药物的个体构成了安全性人群，并被纳入安全性分析。

This study was registered with the Australia New Zealand Clinical Trials Registry-ACTRN12619000954123 (part 1), ACTRN12619001197123 (part 2), and ACTRN12620000295943 (part 3)-and is complete.

本研究已在澳大利亚新西兰临床试验注册处注册，注册号为ACTRN12619000954123（第一部分）、ACTRN12619001197123（第二部分）和ACTRN12620000295943（第三部分），研究已经完成。

Results

Between July 16 and Aug 30, 2019, 18 individuals (18 [100%] male) were enrolled in part 1 and randomly assigned (12 [67%] to imdusiran and six [33%] to placebo).

2019年7月16日至8月30日期间，共有18名个体（18名[100%]为男性）参与了第一部分的研究，并被随机分配（12名[67%]接受imdusiran治疗，六名[33%]接受安慰剂）。

Between Sept 3, 2019, and June 11, 2020, of 43 individuals assessed for eligibility, 22 (51%) were enrolled in part 2, of whom 15 (68%) were male and seven (32%) were female. 78 individuals were assessed for eligibility in part 3 between April 30, 2020, and June 26, 2021, of whom 43 (55%) were enrolled (26 [60%] male and 17 [40%] female).

2019年9月3日至2020年6月11日期间，共有43名个体接受了资格评估，其中22名（51%）参与了第二部分的研究（其中15名[68%]为男性，七名[32%]为女性）。2020年4月30日至2021年6月26日期间，第三部分共有78名个体接受了资格评估，其中43名（55%）参与了研究（其中26名[60%]为男性，17名[40%]为女性）。

All 83 enrolled participants received at least one dose of imdusiran or placebo and were included in the safety analyses.

所有纳入的83名参与者至少接受了imdusiran或安慰剂的一次剂量，并被纳入安全性分析。

Across all parts, no participants discontinued imdusiran owing to an adverse eventand no dose-related trends in reported treatment-emergent adverse events were observed across groups.

在所有部分中，没有参与者因不良事件而停止使用imdusiran，且在报告的治疗后不良事件中未观察到剂量相关的趋势。

There were no deaths.

没有发生死亡事件。

The most commonly reported treatment-emergent adverse events occurring in two or more participants in part 1 were an increase in alanine aminotransferase concentration (n=2; both reported as treatment-related), dizziness (n=2), medical device site reaction (n=3), headache (n=2), and oropharyngeal pain (n=2).

在第一部分中，报告的最常见治疗相关不良事件发生在两个或更多参与者中，包括丙氨酸氨基转移酶浓度增加（n=2；两者均被报告为与治疗相关）、头晕（n=2）、医疗器械部位反应（n=3）、头痛（n=2）和口咽痛（n=2）。

The most commonly reported treatment-emergent adverse events in part 2 were transient injection-site pain (n=5; all reported as treatment-related), headache (n=4; two treatment-related), an increase in alanine aminotransferase (n=3; two treatment-related) and aspartate aminotransferase (n=2; one treatment-related) concentrations, and dizziness (n=2).

在第二部分中，最常报告的治疗后不良事件是短暂的注射部位疼痛（n=5；全部报告与治疗相关），头痛（n=4；两个与治疗相关），丙氨酸氨基转移酶（n=3；两个与治疗相关）和天冬氨酸氨基转移酶（n=2；一个与治疗相关）浓度增加，以及头晕（n=2）。

The most commonly reported treatment-emergent adverse events in part 3 were coronavirus infection (n=18), injection-site pain (n=8; all of which were reported to be treatment-related), injection-site erythema (n=4; all treatment-related), headache (n=4), upper respiratory tract infection (n=4), pyrexia (n=4), fatigue (n=3; one treatment-related), and injection-site bruising (n=3; all treatment-related).

在第三部分中，最常报告的治疗后不良事件是冠状病毒感染（n=18），注射部位疼痛（n=8；全部报告与治疗相关），注射部位红斑（n=4；全部与治疗相关），头痛（n=4），上呼吸道感染（n=4），发热（n=4），疲劳（n=3；一个与治疗相关），以及注射部位瘀伤（n=3；全部与治疗相关）。

All were reported as grade 1.

所有不良事件均被报告为1级。

No clinically relevant changes in clinical laboratory, vital signs, and electrocardiogram values over time were noted in any part of the study.

研究期间，临床实验室、生命体征和心电图值未见任何部分有临床相关的变化。

interpretation

Single and multiple doses of imdusiran were safe and well tolerated in healthy individuals and in individuals with chronic hepatitis B, supporting drug development of imdusiran as a future treatment targeting functional cure for chronic hepatitis B.

单剂和多剂的imdusiran在健康人群和慢性乙型肝炎患者中显示出良好的安全性和耐受性，这支持了imdusiran作为未来针对慢性乙型肝炎功能性治愈治疗的药物开发。

funding

Arbutus Biopharma.

Arbutus Biopharma公司。