Lusutrombopag is an orally bioavailable thrombopoietin receptor (TPOR) agonist developed by Shionogi & Company (Osaka, Japan). TPOR is a regulatory target site for endogenous thrombopoietin, which acts as a primary cytokine to promote megakaryocyte proliferation and differentiation, and affect other hematopoietic lineages as well, including erythroid, granulocytic and lymphoid lineages. Thrombocytopenia, which indicates abnormally low levels of platelets, is a common complication related to chronic liver disease. This hematological abnormality, especially in cases of severe thrombocytopenia (platelet count <50,000/μL), creates challenges to patients requiring invasive medical procedures where there is a significant risk for spontaneous bleeding. Lusutrombopag binds to the transmembrane domain of TPOR expressed on megakaryocytes, and causes the proliferation and differentiation of megakaryocytic progenitor cells from hematopoietic stem cells. In September 2015, lusutrombopag received its first global approval in Japan to reduce the need for platelet transfusion in adults with chronic liver disease and thrombocytopenia who are schedule to undergo an invasive medical procedure. Lusutrombopag was approved by the FDA on July 31st, 2018 for the same therapeutic indication under the market name Mulpleta. In two randomized, double-blind, placebo-controlled trials, patients with chronic liver disease and severe thrombocytopenia who were undergoing an invasive procedure with a platelet count less than 50 x 10^9/L were administered lusutrombopag orally. Higher percentages (65-78%) of the patients receiving lusutrombopag required no platelet transfusion prior to the primary invasive procedure compared to those receiving placebo. Lusutrombopag is currently in phase III development in various European countries including Austria, Belgium, Germany, and the UK.

The thrombopoietin receptor agonists mimic the action of thrombopoietin on its receptor and stimulate the activation, proliferation and maturation of megakaryocytes, resulting in an increase in circulating platelet counts. Thrombopoietin itself acts in this manner, but when recombinant thrombopoietins were used clinically, they were found to cause rebound thrombocytopenia, probably due to induction of anti-thrombopoietin antibodies. For this reason, direct administration of thrombopoietin was abandoned as an approach to treating thrombocytopenia and other approaches to activating the thrombopoietin receptor were sought.

Several thrombopoietin receptor agonists were subsequently developed and are now in clinical use for chronic idiopathic thrombocytopenic purpura (ITP) and for raising platelet counts in persons with thrombocytopenia undergoing surgical procedures or other thrombocytopenic conditions. Eltrombopag, lusutrombopag and avatrombopag are peptide-like, small molecular weight agonists of the thrombopoietin receptor. These agents are given by mouth and result in significant increases in platelet counts in normal persons as well as patients with thrombocytopenia due to hematologic and liver diseases. Romiplostim, in contrast, is a recombinant polypeptide that binds to and activates the thrombopoietin receptor despite having no amino acid homology to native thrombopoietin. It also increases platelet counts in normal subjects as well as patients with chronic ITP but has not been associated with induction of anti-thrombopoietin antibodies.

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