Chang Yi-Chung, Chen Yi-Fen, Yang Chi-Fan, Ho Hui-Ju, Yang Jen Fu, Chou Yuan-Lin, Lin Ching-Wen, Yang Pan-Chyr
Oneness Biotech Company Limited, Taipei, Taiwan.
Microbio (Shanghai) Biotech Company, Shanghai, China.
Clin Transl Sci. 2025 Mar;18(3):e70202. doi: 10.1111/cts.70202.
Severe acute respiratory syndrome caused by the coronavirus (SARS-CoV-2) in the COVID-19 pandemic has highlighted the need for effective treatments, as rapid viral mutations complicate therapeutic development. SNS812, a fully modified inhaled siRNA that targets the conserved RNA-dependent RNA polymerase (RdRP) gene of SARS-CoV-2, has been shown to possess its suppression ability against wide-spectrum SARS-COV-2 variants preclinically. To evaluate the safety and tolerability of inhaled SNS812 in healthy participants, a randomized, double-blind, placebo-controlled phase 1 trial was conducted. To justify the first-in-human inhalation study, this research was divided into two parts: single ascending doses (0.3, 0.6, and 1.2 mg/kg) and multiple doses (0.6 and 1.2 mg/kg) of daily inhalation for seven consecutive days to assess the safety, tolerability, immunogenicity, and pharmacokinetics of SNS812. Of the 44 participants, 3 in the 0.3 mg/kg single-dose group, 2 in the 1.2 mg/kg multiple ascending doses group, and 1 in the placebo group reported treatment-emergent adverse events (TEAEs). No serious adverse events (SAEs), treatment-related adverse events (TRAEs), or TEAEs caused discontinuation or deaths were observed. PK showed rapid absorption of SNS812, with peak concentrations (median T) reached at 1.5-2 h, and an elimination half-life (t ) between 4.96 and 7.08 h. No antidrug antibodies (ADAs) were detected in either group. The results demonstrated that the first-in-human, fully modified with wide-spectrum anti-SARS-COV2 siRNA by inhalation following a single dose and multiple doses was safe and well tolerated in healthy participants. Trial Registration: NCT05677893.
2019年冠状病毒病（COVID-19）大流行期间，由冠状病毒（SARS-CoV-2）引起的严重急性呼吸综合征凸显了有效治疗方法的必要性，因为病毒的快速变异使治疗开发变得复杂。SNS812是一种经过完全修饰的吸入式小干扰RNA（siRNA），靶向SARS-CoV-2保守的RNA依赖性RNA聚合酶（RdRP）基因，临床前研究表明它对广谱SARS-CoV-2变体具有抑制能力。为了评估吸入式SNS812在健康受试者中的安全性和耐受性，开展了一项随机、双盲、安慰剂对照的1期试验。为了证明首次人体吸入研究的合理性，本研究分为两部分：单次递增剂量（0.3、0.6和1.2mg/kg）和连续7天每日吸入多次剂量（0.6和1.2mg/kg），以评估SNS812的安全性、耐受性、免疫原性和药代动力学。在44名受试者中，0.3mg/kg单剂量组有3人、1.2mg/kg多次递增剂量组有2人、安慰剂组有1人报告了治疗期间出现的不良事件（TEAE）。未观察到严重不良事件（SAE）、与治疗相关的不良事件（TRAE）或导致停药或死亡的TEAE。药代动力学显示SNS812吸收迅速，在1.5-2小时达到峰值浓度（中位T），消除半衰期（t）在4.96至7.08小时之间。两组均未检测到抗药抗体（ADA）。结果表明，首次人体吸入经完全修饰的广谱抗SARS-CoV-2 siRNA单剂量和多次剂量后，在健康受试者中是安全且耐受性良好的。试验注册号：NCT05677893。
