Page 13 - Haematologica Vol. 107 - September 2022

EDITORIAL C.V. Denis and P.J. Lenting
Figure 1. Mode of action of BT200. BT200 is a pegylated aptamer that binds with high affinity to the platelet-binding site within the von Willebrand factor (VWF) A1 domain. It was previously shown that BT200 interferes with VWF-dependent thrombus formation, which endows the molecule with efficient antithrombotic activity.13 In their study, Kovacevic and colleagues now demonstrate that BT200 also delays clearance of the VWF/factor VIII (FVIII) complex, resulting in transient increases in plasma levels of both proteins. This approach could thus be a strategy to increase endogenous VWF/FVIII levels in patients with mild/moderate forms of von Willebrand disease and hemophilia A.
type 2B.16 These results prompted the investigators to initiate a larger first-in-human prospective phase I study using the improved BT200 variant, the outcomes of which are reported in this issue of Haematologica.12 In a single-dose bioavailability study, participants received 0.18 to 36 mg BT200 subcutaneously. This resulted in a dose-dependent increase in BT200 plasma concentra- tions, with maximal levels being around 3 mg/mL after 168 h when the highest dose was given. Increasing doses were associated with a dose-dependent occupation of the VWF A1 domain, with 75%-90% of A1 domains being occupied at doses between 12 and 24 mg. Maximal oc- cupation was observed between 1 and 4 days after in- jection, after which free A1 domains gradually re-appeared and returned to normal levels 2 weeks after the injection. Interestingly, the administration of BT200 at these doses was associated with 3- to 4-fold in- creases in VWF antigen levels. However, VWF antigen levels peaked between 7 and 14 days after injection, somewhat later compared to maximal occupation of the A1 domains. Concurrent to the increase of VWF antigen, there was also a 2.5-fold increase in FVIII activity. Of note, FVIII levels could be further increased via the ad- ministration of desmopressin, indicating that the mech- anisms by which FVIII levels are increased by BT200 and
desmopressin are different. Indeed, BT200 appears to act by prolonging the half-life of VWF rather than modifying its synthesis or secretion. As such, its mode of action is fundamentally different from that of desmopressin or in- terleukin-11.
In view of this listing of impressive data, it seems con- ceivable that BT200 is an attractive candidate to amelior- ate endogenous levels of the FVWF/FVIII complex. Of course, these data are derived from an initial phase I study, and several issues would require additional inves- tigations. For instance, BT200 is designed to interfere with VWF activity, and data presented in the Online Supple- mentary Material show that doses inducing the highest in- crease in VWF/FVIII levels were also associated with prolonged closure times in the platelet function analyzer assay and provoked reduced platelet aggregation activity, at least during (part of) the first week.12 It is therefore going to be key to find the optimal dosing that allows in- creased FVIII and VWF levels, without compromising the patient’s hemostatic potential. It should be noted that in the case that the activity of BT200 needs to be neutral- ized, the authors have already developed an efficient re- versal agent, i.e., a complementary aptamer designated BT101, which specifically binds BT200 with high affinity.17 It is interesting to speculate further on the clinical ap-
Haematologica | 107 September 2022
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