Page 131 - Haematologica Vol. 107 - September 2022

ARTICLE - Effects of BT200 on VWF/FVIII in humans
K.D. Kovacevic et al.
The increased procoagulant properties are suboptimal for further development of BT200 for the secondary preven- tion of arterial diseases, because they would mandate simultaneous anticoagulation to prevent venous throm- bosis in an elderly population. The only exception may be rare patients with low FVIII levels, who require secondary prevention of arterial thrombosis with a potent antipla- telet drug, which clearly represents a therapeutic di- lemma.32
This requires strategic rethinking and pivoting BT200 as a pro-hemostatic agent. From a safety perspective, BT200 caused only a minor mucocutaneous bleeding pattern, with epistaxis seen at high doses (≥24 mg). This is con- sistent with the clinical phenotype of deficiency in VWD and consistent with the exaggerated pharmacology of other VWF inhibitors.15 If needed, a rapidly acting, specific, reversal agent has been developed,33 and will allow im- mediate restoration of VWF-dependent hemostasis, for example in the case of trauma or emergency surgery.
The dose- and concentration-response relationship be- tween BT200 and the inhibition of VWF-mediated platelet function, and the increase of FVIII, can, however, be par- tially separated. The FVIII elevating effect begins at a lower dose (~6 mg) while the VWF inhibiting effect does not yet occur (≥12 mg). In addition, the plasma levels of free A1- domains of VWF appear to stabilize mostly around 40% of normal values under repeated maintenance doses of 12 mg due to an increase in circulating VWF mass. It can be anticipated that repeated doses of ≥6 mg can be used to elevate VWF/FVIII, without inhibiting primary hemostasis by a relevant degree, and heavier patients or those with high baseline VWF levels may even benefit from higher doses.
Which groups of patients might potentially benefit from BT200? From the estimated 2-to 3-fold increase in FVIII half-life, one would expect a similar increase in half-life of exogenous FVIII in patients with severe hemophilia or type 3 VWD practising prophylactic replacement therapy. Such a half-life prolongation could be seen with regular FVIII products and even extended half-life products, which would be welcome because of the ceiling effect of VWF on the FVIII half-life. This property can be used to prolong the dosing interval, thus permitting treatment once a week rather than every second day. Additionally, dosages could also be individually tailored to obtain higher trough FVIII levels.
Apart from patients with severe hemophilia, BT200 could for the first time provide an opportunity for patients with moderate or mild hemophilia or female carriers with low FVIII levels and associated severe menstrual bleeding to practise prophylaxis. It has previously been shown that even a modest pharmacologically induced increase in plasma VWF levels can favorably affect the pharmacoki- netics of FVIII concentrates used in people with severe
hemophilia.34 Although desmopressin is effective in a ma- jority of such patients, its antidiuretic effects, adverse events, short duration of action and tachyphylaxis make it unsuitable for long-term prophylaxis.34,35 However, our data show that combined use of desmopressin with BT200 has an additive effect on VWF and FVIII levels, and to- gether with previous data on ARC1779, it appears that the effect of desmopressin could be prolonged by BT200.18 This could also allow lower doses or intranasal desmo- pressin to be used at intervals, which would minimize antidiuretic effects. However, based on the estimated 2.8- fold prolongation in half-life, we would expect that a 2- to 3-fold increase in endogenous FVIII levels can be achieved by BT200 alone. Finally, certain patients with other subtypes of VWD including, but not necessarily li- mited to, high clearance variants of type 1C VWD, or type 2B VWD may benefit from the use of BT200. In type 2B VWD, there are gain-of-function mutations often in the A1 domain, which increase the affinity of VWF for GpIb lead- ing to spontaneous VWF attachment to platelets. This often results in a loss of large multimers,36 and low VWF plasma levels due to high clearance, as indicated by the increased VWFpp:VWF ratios in type 2B patients.37 Simi- larly, murine variants carrying type 2B mutations result in a shortened VWF half-life, as well as increased clearance of platelets coated with such mutants.38 We previously provided proof of the concept that blocking the A1-domain of VWF by infusion of ARC1779 was able to increase VWF/FVIII levels, to normalize multimer patterns and to improve the associated thrombocytopenia in patients suf- fering from type 2B VWD.18,19 As BT200 increases VWF/FVIII levels by decreasing the clearance of these proteins in healthy individuals, it could potentially increase their levels in all VWD patients, but particularly in those with high clearance variants (VWD type 1C). For example, pa- tients with type Vicenza VWD may have a VWF half-life 10- fold shorter than normal, as well as FVIII deficiency.39 It is conceivable that BT200 may be beneficial as it counter- acts the increased clearance.
This study does have some limitations. We were only able to include women of non-childbearing potential due to a demand from the regulatory agency. Therefore, only 11 women participated in the trial. Similarly, ethnic diversity was limited. However, as BT200 is a large molecule, which predominantly distributes to the intravascular compart- ment without being metabolized, no relevant differences are expected between sexes or people of different ethnic- ity. As the bleeding burden in females with hemophilia A has long been neglected, which has only recently resulted in a new nomenclature,40 future trials will have to include a larger proportion of women.
In summary, BT200 is a first-in-class molecule with a novel mechanism of action representing a new therapeutic strategy to break the ceiling effect that VWF imposes on
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