Eltrombopag tablet approved for treatment of ITP

Drug is first oral thrombopoietin receptor agonist approved for adult patients with ITP.

The FDA has approved eltrombopag tablets for the treatment idiopathic thrombocytopenic purpura in patients who have had insufficient response to corticosteroids, immunoglobulins or splenectomy.

The approval came after the evaluation of positive results from two double blind, placebo-controlled trials and one extension study.

The placebo-controlled trials enrolled 231 patients and were designed to evaluate safety and efficacy. All patients had undergone splenectomy or been treated with corticosteroids or immunoglobulins, and had baseline platelet counts <30,000/mcL. In the first study, participants were randomly assigned to placebo or eltrombopag (Promacta, GlaxoSmithKline) in 30 mg, 50 mg or 75 mg doses. In the second study, patients were assigned to either placebo or a 50 mg dose of eltrombopag. The six-week trials were followed by six weeks of observation after treatment was discontinued.

The primary endpoint of response rate was defined as an increase from baseline platelet count to a platelet count >50,000/mcL. The 50-mg dose resulted in a response rate of 70% in the first study and 59% in the second study compared with placebo response rates of 11% in the first study and 16% in the second study (P<.01 for both). Response rates for eltrombopag were similar regardless of splenectomy status.

An additional open-label extension study included 109 patients. In this trial, eltrombopag was administered to 74 patients for at least three months, 53 patients for at least six months and three patients for at least one year. The median platelet count for these patients was 18,000/mcL at baseline. Platelet counts increased to 74,000/mcL at three months, 67,000/mcL at six months and 95,000/mcL at nine months.

The clinical studies identified risks for hepatotoxicity, worsened thrombocytopenia compared to baseline and hemorrhage following eltrombopag discontinuation and a risk for cataracts. Potential risks for TPO receptor agonists include bone marrow reticulin formation and marrow fibrosis during long-term therapy and a risk for thromboses due to excessive platelet increases. – by Rob Volansky

Over half a century ago, William J. Harrington first showed that a factor in plasma from patients with ITP could induce thrombocytopenia in healthy patients. Since then, the primary focus of the treatment of ITP patients has been targeted at decreasing or interfering with the mechanisms leading to the accelerated immune destruction of platelets. This has encompassed corticosteroids, intravenous gamma globulins, splenectomy and immunosuppressive agents. A key subsequent observation has been that ITP patients have not only enhanced platelet destruction but also impaired platelet production, the latter providing a strong scientific rationale for evaluating the role of agents that stimulate megakaryocytes in this disorder. The approval by the FDA of two thrombopoiesis stimulating agents - oral eltrombopag most recently and subcutaneously administered romiplastim a few months ago, provides major and welcome additions to the therapeutic armamentarium in patients with chronic ITP who have insufficient response to corticosteroids, immunoglobulins or splenectomy. Both agents are effective for increasing platelet counts. The safety concerns with these agents have included increased bone marrow reticulin formation and fibrosis, increased thrombotic events with markedly elevated platelet counts, and worsening of platelet counts relative to baseline on drug discontinuation.
Eltrombopag, the first oral agent to be approved in this category, comes with a boxed warning regarding potential hepatotoxicity. Given the disease chronicity, extended administration of these agents is expected, at least in some ITP patients, and this calls for careful long-term trials to delineate the risk-benefit balance. Irrespective of this, these thrombopoietin-receptor activating agents induce a remarkable paradigm shift both in our thinking of the pathogenetic mechanisms in chronic ITP and in the potential therapeutic approaches to manage these patients. Further trials that define their place in the current algorithms for treating chronic ITP and other thrombocytopenias are keenly awaited.

– A. Koneti Rao, MD

HemOnc Today Editorial Board member