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Jilma-Stohlawetz P.,Medical University of Vienna | Knobl P.,Medical University of Vienna | Gilbert J.C.,Archemix | Jilma B.,Medical University of Vienna
Thrombosis and Haemostasis | Year: 2012

Blockade of hyperactive von Willebrand factor (VWF) by ARC1779 blunted the platelet drop induced by desmopressin in patients with type 2B von Willebrand disease (VWD). Thus, we hypothesised that ARC1779 may increase VWF levels and correct thrombocytopenia. Three thrombocytopenic patients suffering from type 2B VWD received a loading dose of 0.23 mg/kg ARC1779 followed by 4 μg/kg/min intravenously for 72 hours in a prospective clinical trial. ARC1779 was well tolerated and safe. Plasma concentrations of ARC1779 increased to 76 μg/ml (59-130) leading to an immediate decrease of free VWF A1 domains. VWF/FVIII levels increased as early as 12 h after start of infusion, peaked near the end of infusion, and returned to baseline at follow-up.VWF ristocetin cofactor activity (VWF:RCo) showed a median 10-fold increase 8 hours after end of infusion, while the median VWF-antigen and FVIII increase was less (5-fold and 4-fold, respectively). Most importantly inhibition of hyperactive VWF rapidly increased platelet counts from 40x109/l (38-58 x109/l) to a maximum of 146 x109/l (107-248 x109/l). In conclusion, ARC1779 markedly increases VWF/FVIII levels and most importantly improves or even corrects thrombocytopenia in VWD type 2B patients. This underscores the in vivo potency of ARC1779. © Schattauer 2012. Source

Jilma-Stohlawetz P.,Medical University of Vienna | Gilbert J.C.,Archemix | Gorczyca M.E.,Medical University of Vienna | Knobl P.,Medical University of Vienna | Jilma B.,Medical University of Vienna
Thrombosis and Haemostasis | Year: 2011

Congenital thrombotic thrombocytopenic purpura (TTP) is a very rare but potentially life-threatening disorder. This phase I/II trial compared the pharmacokinetics and pharmacodynamics and safety of three different administration modes of the anti-von Willebrand factor (VWF) aptamer ARC1779. This was a prospective clinical trial with a partial cross-over design: three periods comprised subcutaneous injections of 50 mg of ARC1779 on seven subsequent days, a low-dose infusion of ARC1779 (0.002 mg/kg/min) for 24-72 hours and a high-dose infusion (0.004-0.006 mg/kg/min) up to 72 hours. ARC1779 concentrations were determined with high performance liquid chromatography, VWF inhibition was measured with enzyme immunoassay and platelet function was determined with the platelet function analyser (PFA-100) and impedance aggregometry. ARC1779 was well tolerated without any bleeding at concentrations spanning over three orders of magnitude. The daily s.c. injection yielded plasma levels (0.5 μg/ml) of the drug that were too low to sufficiently suppress VWF. The low-dose i.v. infusion increased platelet counts in one patient, whereas the high i.v. dose increased plasma concentrations up to 69 μg/ml, completely blocked free A1 domains, VWF-dependent platelet plug formation and enhanced platelet counts in 2/3 patients. In conclusion, infusion of ARC1779 dosedependently inhibits VWF-dependent platelet function and during infusion ARC1779 increases or stabilises platelet counts in congenital TTP. However, the tested doses, particularly the daily s.c. injections, did not correct all clinical or laboratory features of TTP. © Schattauer 2011. Source

Jilma-Stohlawetz P.,Medical University of Vienna | Gorczyca M.E.,Medical University of Vienna | Jilma B.,Medical University of Vienna | Siller-Matula J.,Medical University of Vienna | And 2 more authors.
Thrombosis and Haemostasis | Year: 2011

Thrombotic thrombocytopenic purpura (TTP) can cause severe organ damage due to enhanced platelet aggregation by ultra-large von Willebrand factor (VWF) multimers. Thus inhibition of VWF by the anti-VWF ARC1779 might potentially be beneficial for TTP patients. This prospective trial tested the safety, pharmacokinetics and pharmacodynamics of the anti-VWF aptamer ARC1779 added to plasma exchange therapy (PEX) in patients with acute TTP. Seven patients received bolus primed continuous i.v. infusions of ARC1779 (1-2 ìg/kg/min) in addition to PEX until remission of TTP was induced or for 14 days. Mean steady state ARC1779 plasma concentrations of 9.9 ìg/ml reduced VWF activity to 5% (mean baseline activity was 125% in TTP patients compared to a reference plasma). PEX reduced ARC1779 levels by 50%, but steady state concentrations were restored rapidly with a mini-bolus. After discontinuation of PEX, ARC1779 alone further increased platelet counts in one patient. Stopping ARC1779 was associated with an immediate drop of platelet counts in this patient. This suggests that ARC1779 can block the progression of TTP in patients with severe ADAMTS13 is deficiency. ARC1779 was generally well tolerated without any signs of bleeding. Pharmacokinetics and pharmacodynamics of ARC1779 were well predictable and in agreement with those observed in a previous trial with healthy volunteers. Based on its mechanism of action and the observed effect on platelet counts, ARC1779 used as an adjunctive to PEX may help accelerate recovery from organ dysfunction. © Schattauer 2011. Source

The invention provides nucleic acid therapeutics and methods for using these nucleic acid therapeutics in the treatment of complement-related disorders.

Materials and methods are provided for producing and using aptamers useful as oncology therapeutics capable of binding to PDGF, PDGF isoforms, PDGF receptor, VEGF, and VEGF receptor or any combination thereof with great affinity and specificity. The compositions of the present invention are particularly useful in solid tumor therapy and can be used one or in combination with known cytotoxic agents for the treatment of solid tumors. Also disclosed are aptarmers having one or more CpG motifs embedded therein or appended thereto.

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