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Preclinical assessment of a new recombinant ADAMTS ‐13 drug product ( BAX 930) for the treatment of thrombotic thrombocytopenic purpura
Author(s) -
Kopić A.,
Benamara K.,
Piskernik C.,
Plaimauer B.,
Horling F.,
Höbarth G.,
Ruthsatz T.,
Dietrich B.,
Muchitsch E.M.,
Scheiflinger F.,
Turecek M.,
Höllriegl W.
Publication year - 2016
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.13341
Subject(s) - medicine , pharmacokinetics , thrombotic thrombocytopenic purpura , dosing , safety pharmacology , pharmacology , platelet , fresh frozen plasma , drug , immunology
Essentials ADAMTS‐13‐deficiency is a cause of thrombotic thrombocytopenic purpura (TTP). Preclinical safety of recombinant human ADAMTS‐13 (BAX930) was shown in animal models. Preclinical efficacy of BAX930 was shown in a mouse model of TTP. BAX930 showed advantageous efficacy over fresh frozen plasma, the current standard of care.Click to hear Dr Cataland and Prof. Lämmle present a seminar on Thrombotic Thrombocytopenic Purpura (TTP): new Insights in Pathogenesis and Treatment Modalities . Summary Background Thrombotic thrombocytopenic purpura ( TTP ) is a rare blood disorder characterized by microthrombosis in small blood vessels of the body, resulting in a low platelet count. Baxalta has developed a new recombinant ADAMTS ‐13 (r ADAMTS ‐13) product ( BAX 930) for on‐demand and prophylactic treatment of patients with hereditary TTP (h TTP ). Objectives To evaluate the pharmacokinetics, efficacy and safety of BAX 930 in different species, by use of an extensive preclinical program. Methods The prophylactic and therapeutic efficacies of BAX 930 were tested in a previously established TTP mouse model. Pharmacokinetics were evaluated after single intravenous bolus injection in mice and rats, and after repeated dosing in cynomolgus monkeys. Toxicity was assessed in rats and monkeys, safety pharmacology in monkeys, and local tolerance in rabbits. Results BAX 930 was shown to be efficacious, as demonstrated by a stabilized platelet count in ADAMTS ‐13 knockout mice that were thrombocytopenic when treated. Prophylactic efficacy was dose‐dependent and comparable with that achieved by treatment with fresh frozen plasma, the mainstay of h TTP treatment. Therapeutic efficacy was treatment interval‐dependent. Safety pharmacology evaluation did not show any deleterious effects of BAX 930 on cardiovascular and respiratory functions in monkeys. The compound's pharmacokinetics were similar and dose‐proportional in mice, rats, and monkeys. BAX 930 was well tolerated in rats, monkeys, and rabbits, even at the highest doses tested. Conclusions These results demonstrate that BAX 930 has a favorable preclinical profile, and support the clinical development of r ADAMTS ‐13 for the treatment of h TTP .

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