PB0352 - Effects of the von Willebrand Factor binding Aptamer Rondaptivon Pegol (BT200) on Embryo-Fetal Development in Rabbits

Background: Rondaptivon pegol (BT200) is a von Willebrand factor binding aptamer (50kDa including PEG) that reduces the clearance and thereby increases the half-life of VWF/FVIII several-fold. Clinical trials showed its potential utility for the treatment of haemophilia A (doi: 10.1182/blood.2022016571) and type 2B Von Willebrand Disease (VWD; 10.1182/bloodadvances.2022007805), while application in a broader range of VWD types can be envisioned.

Aims: As VWD disproportionally affects women of childbearing potential, it was important to document the preclinical safety of BT200 in a reproductive toxicology study.

Methods: A standard reproductive toxicology study was conducted in rabbits. Animals received 1.5, 5 or 15 mg/kg of BT200 subcutaneously once daily from gestational days 7-19. Maternal blood samples were collected on days 7 and 19 and fetal blood samples on day 19.

Results: BT200 was well-tolerated at dose levels ≤15 mg/kg/day with regard to both maternal and embryo-fetal developmental toxicity. No BT200-related effects were observed on maternal clinical observations, gestation body weights, body weight gains, food consumption, or macroscopic observations in pregnant rabbits receiving ≤15 mg/kg/day. Fetal body weights were on average 8-11% lower in animals exposed to BT200 (at 100-1000-fold the human dose) compared with concurrent controls. The number of live fetuses was not adversely affected in any dose group.
Following daily subcutaneous injections of BT200 mean Cmax reached 133 and 807 mcg/mL in the low and high dose groups of maternal rabbits at day 19, exceeding human target concentrations roughly 70-700-fold, respectively. Fetal plasma levels of BT200 only reached ~0.2% of the maternal plasma concentrations.

Conclusion(s): This is the first report of the reproductive safety of a pegylated aptamer: diaplacental transfer of BT200 is very limited, and BT200 proved safe in maternal and fetal rabbits, paving the way for clinical trials in women of child bearing potential suffering from VWD.