A single ascending dose study of single-stranded oligodeoxyribonucleotide RO7062931 in Chinese healthy volunteers

Abstract

RO7062931 is an N-acetylgalactosamine (GalNAc)-conjugated single-stranded oligodeoxyribonucleotide complementary to hepatitis B virus RNA. GalNAc conjugation targets the liver through the asialoglycoprotein receptor (ASGPR). This phase I single ascending dose (SAD) study evaluated the safety, tolerability, and pharmacokinetics of RO7062931 in Chinese healthy volunteers. There were four SAD cohorts (0.3, 1.0, 2.0, and 4.0 mg/kg), in each of which healthy volunteers were randomized to a single subcutaneous (s.c.) injection of RO7062931 or matching placebo in a 4:1 ratio. Placebo recipients were pooled as one treatment group for safety assessments. A total of 41 healthy Chinese men received one dose of RO7062931 (n = 33) or placebo (n = 8) and completed the study (85-day follow-up). Adverse events (AEs) were reported in 22 of 33 (66.6%) RO7062931 recipients (n = 80 treatment-related) and seven of eight (87.5%) placebo recipients (n = 1 treatment-related). Apart from two moderate-intensity AEs, all AEs were mild. The most frequently reported AEs were influenza, injection-related reactions, and headache. Dose-proportional increases in plasma RO7062931 exposure were observed between the 0.3 and 1.0 mg/kg doses, whereas a supra-dose-proportional increase occurred at doses greater than or equal to 2.0 mg/kg, along with a marked increase in urinary excretion. Single s.c. dose of RO7062931 up to 4.0 mg/kg were safe and well-tolerated in healthy Chinese volunteers. Pharmacokinetic data suggested that ASGPR saturation had commenced between doses of 2.0 and 4.0 mg/kg. Results were broadly consistent with observations in primarily White subjects in the global first-in-human study of RO7062931.

FIGURE 1

Mean RO7062931 plasma concentration‐time profile over (a) 24 h and (b) 168 h after single doses (0.3–4.0 mg/kg).

FIGURE 2

Mean plasma AUC_0–inf versus total dose. The orange line is a Loess regression line of the observed AUC in all healthy volunteers, and the red dashed line is a linear regression line of the observed AUC at the doses of 0.3, 1 and 2 mg/kg. AUC_0–inf, area under the plasma concentration‐time curve from zero to infinity.

FIGURE 3

Mean fraction of RO7062931 dose recovered unchanged in urine (Fe) at 24 h versus dose. There were three for the 1 mg/kg cohort due to missing urine samples at later time points.