Novel Therapies to Address Unmet Needs in ITP

Abstract

Primary immune thrombocytopenia (ITP) is an autoimmune disorder that causes low platelet counts and subsequent bleeding risk. Although current corticosteroid-based ITP therapies are able to improve platelet counts, up to 70% of subjects with an ITP diagnosis do not achieve a sustained clinical response in the absence of treatment, thus requiring a second-line therapy option as well as additional care to prevent bleeding. Less than 40% of patients treated with thrombopoietin analogs, 60% of those treated with splenectomy, and 20% or fewer of those treated with rituximab or fostamatinib reach sustained remission in the absence of treatment. Therefore, optimizing therapeutic options for ITP management is mandatory. The pathophysiology of ITP is complex and involves several mechanisms that are apparently unrelated. These include the clearance of autoantibody-coated platelets by splenic macrophages or by the complement system, hepatic desialylated platelet destruction, and the inhibition of platelet production from megakaryocytes. The number of pathways involved may challenge treatment, but, at the same time, offer the possibility of unveiling a variety of new targets as the knowledge of the involved mechanisms progresses. The aim of this work, after revising the limitations of the current treatments, is to perform a thorough review of the mechanisms of action, pharmacokinetics/pharmacodynamics, efficacy, safety, and development stage of the novel ITP therapies under investigation. Hopefully, several of the options included herein may allow us to personalize ITP management according to the needs of each patient in the near future.

Safety and Efficacy of Tyrosine Kinase Inhibitors in Immune Thrombocytopenic Purpura: A Systematic Review of Clinical Trials

“…A phase III trial NCT05029635 is in progress to further assess the safety and efficacy of HMPL-523 in patients with refractory ITP. It can be used as an alternative agent to fostamatinib for SYK inhibition [ 27 , 28 ]. The drug is not yet approved by FDA and is not available in the market for ITP.…”

Rilzabrutinib versus placebo in adults and adolescents with persistent or chronic immune thrombocytopenia: LUNA 3 phase III study

“…Elucidating the mechanisms underlying ITP and designing novel therapies to address the current care gap continue to be active areas of research that are reviewed in detail elsewhere. 12,15,56 A growing number of therapies with various mechanisms of action are being investigated in latephase clinical trials, with expected readouts within journals.sagepub.com/home/tah TherapeuTic advances in hematology the next 5 years. Among emerging therapeutic agents developed for ITP, the putative mechanisms of action of rilzabrutinib in ITP are thought to target both immune-mediated platelet destruction through blocking FcR-mediated platelet destruction and inhibition of platelet production, and by reducing the level of pathogenic antiplatelet antibodies due to suppression of autoreactive B cells.…”

“…However, splenectomy might be associated with short-term surgery-related complications and long-term increased risks of thrombosis and infection. 14,15 The disease burden is more significant in patients with severe and chronic thrombocytopenia requiring ongoing treatment and those who are unresponsive to current therapy, contributing to elevated mortality rates relative to the general population. 16,17 Adult patients with chronic thrombocytopenia have up to a 10% risk of bleeding or hemorrhage that increases with age, and intracranial hemorrhage has been reported in ~1-2% of patients.…”

“… 11 Other first-line therapies include intravenous immunoglobulins (IVIG) and anti-D. Second-line treatment options of rituximab and thrombopoietin receptor agonists (TPO-RA) have shown durable treatment response rates of 60–80%, whereas durable response rates with fostamatinib have reported 18% in a very heavily pretreated set of ITP patients. 13 – 15 Splenectomy as a second-line treatment choice has the benefit of high responses along with durable off-treatment remission rates of 60–70%. However, splenectomy might be associated with short-term surgery-related complications and long-term increased risks of thrombosis and infection.…”

Analysis of the Mechanism of T Lymphocytes Promoting Immune Platelet Transfusion Refractoriness by Gene Chip Technique

“…Studies have found that both Cluster of Differentiation 8 + (CD8 + ) T cells and Cluster of Differentiation 4 + (CD4 + ) T cells with antiplatelet reactivity are found in peripheral blood. CD8 + T cells can inhibit B lymphocytes from producing platelet antibodies, while the decrease in the number of CD4 + T cells can make auto reactive B lymphocytes proliferate accordingly, thereby producing some antibodies that promote platelet destruction [5][6][7] , indicating that T lymphocytes can regulate platelet antibody production. The immune response of T lymphocytes may be another mechanism that causes immune PTR, but there are few studies on the regulation mechanism of T lymphocytes on immune PTR.…”