A Double-Blind, Placebo-Controlled, Single-Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of HT-101, an RNAi Therapeutic Targeting HBV Infection

• Published in: Clinical pharmacology in drug development
• Main Authors: Zhang, Jianxiong, Li, Jiangshuo, Wu, Le, Song, Yuqin, Li, Xiao, Gao, Qiannan, Wu, Jingxuan, Wang, Dong, Zhang, Zhipeng, Zhang, Shanzhong, Ding, Lijuan, Ma, Yanqin, Ma, Hong, Jia, Jidong, Dong, Ruihua
• Format: Journal Article
• Language: English
• Published: United States 03.07.2025
• Subjects: pharmacokinetics; clinical trials; small interfering RNA; hepatitis B virus; safety
• ISSN: 2160-7648
• DOI: 10.1002/cpdd.1569

HT-101, a liver-targeted N-acetylgalactosamine-conjugated ribonucleic acid interference therapeutic, exhibits promising potential for the treatment of chronic hepatitis B virus infection. This randomized, double-blind, placebo-controlled, and single-ascending-dose Phase Ia study included 50 healthy volunteers. Regarding methods, 2 subjects received a single subcutaneous dose of HT-101 at 25 mg, while 48 volunteers were randomized (6:2 active:placebo) in the remaining 6 cohorts to receive a single subcutaneous dose of HT-101 (50-800 mg) or placebo. Afterward, serial blood samples were obtained for pharmacokinetic determination across a 48-hour postdose period. Safety assessments included clinical laboratory measures, vital signs, and 12-lead electrocardiogram before and after dosing. As a result, plasma pharmacokinetics characterized by functional antisense strand revealed a median time to peak plasma concentration of 2.5-6.0 hours, and a short median plasma half-life of 2.50-6.14 hours. It is underlined that peak and total plasma exposure to HT-101 increased in a slightly greater-than-dose-proportional manner following 25-800 mg administered subcutaneously. Moreover, a single dose of HT-101 at 25-800 mg was safe and well tolerated in healthy Chinese volunteers. These data can support further clinical development of HT-101 for hepatitis B virus infection treatment.