The VWF-A1 Domain Binding Aptamer BT200 Prolongs the Half-Lives of Different Factor VIII (FVIII) Products in Patients With Severe Hemophilia A and Increases FVIII Levels in Non-Severe Hemophilia A

Cihan Ay, M.D.
Medical University of Vienna
Vienna, Austria

On Wednesday, July 21, 2021, Cihan Ay, M.D., of the Medical University of Vienna in Vienna, Austria, presented findings from the late-breaking results of the PEGylated aptamer, BT200, in hemophilia A patients. Factor VIII protein (FVIII) as a coagulation replacement factor has for decades been used as the standard of care for management of patients with hemophilia A. It is effective for the treatment of bleeding events, as prophylaxis to prevent bleeding events and preserve joint function, and to support surgery in people with hemophilia A. FVIII circulates in a non-covalent complex with von Willebrand factor (VWF), which limits its terminal half-life. BT200 is a PEGylated aptamer targeting the A1 domain of VWF, shown to increase plasma levels of VWF/FVIII up to fourfold by competing for its clearance in healthy volunteers. BT200 is a PEGylated aptamer that binds to the A1 domain of human VWF. At low doses, it blocks the clearance of VWF from the circulation and causes an increase in concentrations of both VWF antigen and FVIII, but has negligible effect on the activity of either. At higher doses, BT200 blocks clearance of VWF and also inhibits its activity, but still does not inhibit FVIII activity. Therefore, low-dose BT200 could potentially be used to correct deficiency of VWF and/or FVIII in patients with hereditary bleeding disorders, such as von Willebrand disease or hemophilia A. Ay explained that BT200-mediated prolongation of FVIII half-life (i) increases postinfusion trough levels in severe hemophilia A patients and (ii) increases circulating FVIII levels in mild/moderate hemophilia A patients. Patients received 3 mg of BT200 subcutaneously on days 1, 4, and 7, followed by 4-9 mg once a week until day 28, along with measuring FVIII clotting activity and VWF levels.

Ay and colleagues remarked that 18 patients in total received six doses of BT200 without any relevant adverse events. BT200 rapidly increased circulating VWF antigen from 97% to 294%, whereas VWF:RCo remained stable at ~80% in all patients. Median FVIII activity increased from 24% to 53% in mild hemophilia A, from 3% to 7.5% in moderate hemophilia A, and trough levels increased during regular substitution/prophylaxis intervals from 0%-1% to >15% in hemophilia A. Population pharmacokinetics using WAPPS analysis indicated that the half-lives of five different FVIII products increased on average threefold from 12 to 34 hours in the one-stage clotting assay and to 36 hours in the chromogenic assay (range, 25-69 hours; P < .01).

This led Ay to conclude that BT200 is a first-in-class molecule with a novel mechanism of action representing a new therapeutic strategy to break the ceiling effect VWF imposes on FVIII half-life. This prolongs the half-life of both endogenous and substituted FVIII irrespective of the products used and should enable once weekly substitution in severe hemophilia A.

In addition, BT200 monotherapy is the first drug that could allow regular prophylaxis in non-severe hemophilia A patients by increasing their endogenous FVIII levels.