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

Abstract 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.