Embryo-Fetal Development and Maternal-Fetal Exposure of the Von Willebrand Factor Binding Aptamer Rondaptivon Pegol...

Rondaptivon pegol (BT200) is a PEGylated RNA aptamer that prolongs von Willebrand factor (VWF) and factor VIII half-lives in patients with hemophilia A and von Willebrand disease (VWD) type 2B. Embryo-fetal safety is particularly relevant given the disproportionate disease burden in women with VWD. Data on placental transfer and developmental safety of PEGylated aptamers remain limited. An embryo-fetal development study was conducted in pregnant rabbits. Animals received rondaptivon pegol subcutaneously (0, 1.5, 5, or 15 mg/kg/day) from gestational days (GDs) 7-19. Maternal toxicokinetic samples and pooled fetal plasma concentrations were collected during gestation to quantify transplacental exposure. Rondaptivon pegol was well tolerated, with no maternal toxicity, no effects on implantation, and no treatment-related fetal malformations. Dose-related reductions in mean fetal body weight (<11%) were considered adverse only at the highest dose level. Maternal systemic exposure was supratherapeutic, with mean C_max ranging from 133 to 807 µg/mL on GD19, far exceeding the human target concentration (∼1.2 µg/mL). Fetal plasma concentrations were <0.25% of maternal levels across all dose groups, confirming minimal placental transfer. The no-observed-adverse-effect level was 5 mg/kg/day. At maternal systemic exposures ranging from 110- to 670-fold above anticipated clinical levels, rondaptivon pegol did not adversely affect implantation, embryonic viability, or fetal development. These findings provide the first quantitative maternal-fetal pharmacokinetic and developmental safety data for a PEGylated aptamer, supporting further clinical evaluation of rondaptivon pegol in women of reproductive age.