von Willebrand Factor-binding aptamer rondoraptivon pegol as treatment for severe and non-severe hemophilia A.

Factor VIII circulates in a non-covalent complex with von Willebrand Factor (VWF), the latter determining FVIII half-life. The VWF-binding aptamer rondoraptivon pegol (BT200) increases plasma levels of VWF/FVIII in healthy volunteers. This trial assessed its safety, pharmacokinetics and pharmacodynamics in hemophilia A. Nineteen adult hemophilia A (8 mild, 2 moderate and 9 severe) patients received subcutaneous injections of rondoraptivon pegol. After an initial fixed dose of 3 mg on days 0 and 4, patients received weekly doses of 2-9 mg until day 28. Severe hemophilia A patients underwent sparse sampling population pharmacokinetic individual profiling after the final dose of rondoraptivon pegol. Adverse events, pharmacokinetics and pharmacodynamics were assessed. FVIII activity and VWF-levels were measured. All patients (20-62 years, 4 women) tolerated rondoraptivon pegol well. The geometric mean half-life of rondoraptivon pegol was 5.4 days and rondoraptivon pegol significantly increased VWF levels. In severe hemophilia A, six doses of rondoraptivon pegol increased the half-lives of 5 different FVIII products from a median of 10.4h to 31.1h (range: 20.8-56.0). Median FVIII increased from 22% to 48% in mild hemophilia A and from 3% to 7.5% in moderate hemophilia A. Rondoraptivon pegol is a first-in-class pro-hemostatic molecule that extended ~3-fold the half-life of substituted FVIII and increased ~2-fold endogenous FVIII levels in hemophilia patients. (NCT04677803).