Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura.

BACKGROUND: Acquired thrombotic thrombocytopenic purpura (TTP) is caused by aggregation of platelets on ultralarge von Willebrand factor multimers. This microvascular thrombosis causes multiorgan ischemia with potentially life-threatening complications. Daily plasma exchange and immunosuppressive therapies induce remission, but mortality and morbidity due to microthrombosis remain high. METHODS: Caplacizumab, an anti-von Willebrand factor humanized single-variable-domain immunoglobulin (Nanobody), inhibits the interaction between ultralarge von Willebrand factor multimers and platelets. In this phase 2, controlled study, we randomly assigned patients with acquired TTP to subcutaneous caplacizumab (10 mg daily) or placebo during plasma exchange and for 30 days afterward. The primary end point was the time to a response, defined as confirmed normalization of the platelet count. Major secondary end points included exacerbations and relapses. RESULTS: Seventy-five patients underwent randomization (36 were assigned to receive caplacizumab, and 39 to receive placebo). The time to a response was significantly reduced with caplacizumab as compared with placebo (39% reduction in median time, P=0.005). Three patients in the caplacizumab group had an exacerbation, as compared with 11 patients in the placebo group. Eight patients in the caplacizumab group had a relapse in the first month after stopping the study drug, of whom 7 had ADAMTS13 activity that remained below 10%, suggesting unresolved autoimmune activity. Bleeding-related adverse events, most of which were mild to moderate in severity, were more common with caplacizumab than with placebo (54% of patients vs. 38%). The frequencies of other adverse events were similar in the two groups. Two patients in the placebo group died, as compared with none in the caplacizumab group. CONCLUSIONS: Caplacizumab induced a faster resolution of the acute TTP episode than did placebo. The platelet-protective effect of caplacizumab was maintained during the treatment period. Caplacizumab was associated with an increased tendency toward bleeding, as compared with placebo. (Funded by Ablynx; ClinicalTrials.gov number, NCT01151423.).

von Willebrand factor inhibition improves endothelial function in patients with stable angina.

ALX-0081 is a novel nano-antibody inhibiting von Willebrand factor (vWF). We evaluated whether direct inhibition of vWF by ALX-0081 improves endothelial function. Stable patients (pts, n = 55) with single vessel disease undergoing percutaneous coronary intervention (PCI) were randomized to ALX-0081 (n = 38) or placebo (n = 17). vWF inhibition was assessed by vWF antigen level (vWF:Ag) and activity by ristocetin test (vWF:RiCo). Endothelial function was assessed before (BL), 6 h and 24 h after PCI by: (a) endothelial peripheral arterial tonometry (Endoscore); (b) endothelial microparticles (EMPs) by flow cytometry. vWF:Ag and vWF:RiCo decreased within 1 h from ALX-0081. In the placebo group, no significant Endoscore changes occurred from BL to 24 h. In ALX-0081 group, Endoscore increased from BL to 24 h (p = 0.014). A decrease in EMPs was observed after ALX-0081 (p < 0.01), while no changes occurred in placebo pts. An inhibition of vWF with ALX-0081 significantly improves peripheral endothelial function.