Abstract Number: LB 02.1
Meeting: ISTH 2021 Congress
Background: Factor VIII (FVIII) circulates in a non-covalent complex with 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 ≤4-fold by competing for its clearance in healthy volunteers.
Aims: To test the hypotheses that BT200 mediated prolongation of FVIII half-live (i) increases post infusion trough levels in severe haemophilia A patients and (ii) increases circulating FVIII levels in mild/moderate haemophilia A patients.
Methods: In a phase 2 trial, 3mg of BT200 were administered subcutaneously on days 1, 4 and 7, followed by 4-9 mg every week until day 28. Factor VIII clotting activity and VWF-levels were measured. Data are presented as medians and range and analysed by Friedman ANOVA.
Results: Eighteen patients (eight with severe, two with moderate, eight with mild haemophilia A, age 42; 20-62y) received six doses of BT200 without any relevant adverse events. BT200 rapidly increased circulating VWF:Antigen from 97% (51-172%) to 294% (129-421%, p<0.001), whereas VWF:RCo remained stable at ~80% in all patients. Median FVIII activity increased from 24% to 53% in mild haemophilia A (p<0.001), from 3 to 7.5% in moderate haemophilia A, and trough levels increased during regular substitution/prophylaxis intervals from 0-1% to >15% in haemophilia A. The half-lives of 5 different FVIII products increased 2 to 7-fold from a median of 11 to 38 hours (p<0.01).
Conclusions: 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 haemophilia A. In addition, BT200 is the first drug that could allow regular prophylaxis in non-severe haemophilia A patients by increasing their endogenous FVIII levels.
To cite this abstract in AMA style:Ay C, Derhaschnig U, Jilma B, Schoergenhofer C, Kovacevic K, Quehenberger P, Jilma P, Gilbert JC, Zhu S, Kraemmer D, Iorio A, Pabinger I. 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 [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/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/. Accessed August 16, 2022.
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