(MED-FR-08.3) Novel VWD treatment

Von Willebrand disease (VWD) is a heterogeneous group of disorders. However, for decades, patients were offered limited therapeutic options, essentially aiming to replenish circulating von Willebrand factor (VWF) and prevent fibrinolysis. Despite the effectiveness of these treatments, low quality of life in VWD patients was highlighted in numerous recent studies. In response, the scientific community has recognized that novel therapeutic alternatives are needed to better address the needs of the patients and decrease treatment burden. Importantly, rather than generalized approaches valid for all VWD patients, new options are designed to address specific needs shared by groups of patients with similar bleeding and pathogenic characteristics.
Improving the procoagulant potential was an attractive strategy for patients with VWD and a secondary factor VIII (FVIII) deficiency. If, for a long time, this approach was primarily limited by the short half-life of FVIII concentrates in such patients, the advent of non-factor therapies for people with hemophilia opened new horizons. A few clinical cases reported successful off-label use of emicizumab in VWD-type 3 patients with limited breakthrough bleeding, and an ongoing clinical trial aimed to assess efficacy in severe VWD patients. Studies are being conducted to understand if patients with various VWD subtypes could benefit from emicizumab, other FVIII-mimetics, and rebalancing agents, all of which generally have a relatively long half-life and are administered subcutaneously.
Rising endogenous VWF concentration was explored for patients with quantitative defects. A bispecific single-domain antibody named KB-V13A12, simultaneously binding to VWF and albumin, was developed in our laboratory. Pre-clinical testing in a humanized VWD-type 1 murine model (hVWD1 mice) proved that KB-V13A12 administered subcutaneously increased VWF antigen levels 2-fold. By interfering with VWF clearance, the inhibitory anti-VWF RNA aptamer rondoraptivon pegol increased VWF levels in healthy subjects, and VWF antigen & platelet counts in a few VWD-type 2B patients.
Platelet-inspired nanoparticles and siRNAs targeting VWF variants have been tested in vitro and in murine VWD models.
While pre-clinical research is expanding, some other considerations remain to be addressed. Clinical trials in VWD patients are complicated by the heterogeneity of patients’ symptoms, and assessment tools still fail to perceive some VWD-associated phenotypes.
After decades of stalling, times are finally encouraging for VWD treatment.