Egaptivon pegol

Refrigeration-induced binding of VWF (von Willebrand factor) to platelets contributes to the rapid clearance of refrigerated platelets. In this study, we investigate whether inhibiting VWF binding by a DNA-based aptamer ameliorates the clearance of refrigerated platelets without significantly impeding hemostatic functions.

Platelets were refrigerated with or without aptamer ARC1779 for 48 hours. VWF binding, the effective lifetime of ARC1779, platelet post-transfusion recovery and survival, and the hemostatic function were measured. ARC1779 treatment during refrigeration inhibited the platelet-VWF interaction. ARC1779-treated refrigerated murine platelets exhibited increased post-transfusion recovery and survival than untreated ones (recovery of ARC1779-treated platelets: 76.7±5.5%; untreated: 63.7±0.8%; P <0.01. Half-life: 31.4±2.36 hours versus 28.1±0.86 hours; P <0.05). A similar increase was observed for refrigerated human platelets (recovery: 49.4±4.4% versus 36.8±2.1%, P <0.01; half-life: 9.2±1.5 hours versus 8.7±0.9 hours, ns). The effective lifetime of ARC1779 in mice was 2 hours. Additionally, ARC1779 improved the long-term (2 hours after transfusion) hemostatic function of refrigerated platelets (tail bleeding time of mice transfused with ARC1779-treated refrigerated platelets: 160±65 seconds; untreated: 373±96 seconds; P <0.01). The addition of an ARC1779 antidote before transfusion improved the immediate (15 minutes after transfusion) hemostatic function (bleeding time of treated platelets: 149±21 seconds; untreated: 320±36 seconds; P <0.01).

ARC1779 improves the post-transfusion recovery of refrigerated platelets and preserves the long-term hemostatic function of refrigerated platelets. These results suggest that a short-acting inhibitor of the platelet-VWF interaction may be a potential therapeutic option to improve refrigeration of platelets for transfusion treatment.

A novel approach to the treatment of thrombotic thrombocytopenic purpura (TTP) using ARC1779 to target the A1-domain of von Willebrand factor (VWF) to prevent the formation of microthombi has been developed.ARC1779 is a nucleic acid macromol., or aptamer, that inhibits the prothrombotic function of VWF by binding to the A1-domain of VWF, blocking its interaction with the platelet GPIb receptor.It has been hypothesized that ARC1779 prevents the formation of new microthrombi in patients with acute TTP, and may result in shorter courses of plasma exchange (PEX) and fewer end organ complications via the more rapid inhibition of microthrombotic disease.ARC1779-006 was a randomized, double-blinded, placebo controlled multicenter, international study in patients with TMA with a planned randomization ratio of ARC1779 to placebo of 3:1.The objectives of the study were to evaluate: (1) the safety and tolerability of ARC1779, (2) the concentration-response of ARC1779 in terms of efficacy and safety related effects, and (3) the ability of ARC1779 to prevent or minimize short-term neurol., cardiac, and renal injury from an acute episode of TTP.Prior to the premature closure of the study, nine patients were treated with either ARC1779 of placebo as an adjunct to PEX.Although limited, these data support the safety of this targeted approach to the treatment of TTP, providing the basis for continued study of this unique approach to therapy.