On the horizon: upcoming new agents for the management of ITP

Abstract

Treatment of immune thrombocytopenia (ITP) has evolved over the last 20 years in response to our increased understanding of the pathophysiology of this complex immune disorder. New treatments in development have taken advantage of our evolving understanding of the biology of this disease to target new mechanisms and expand the available ways in which to approach patients with this disorder. This review focuses on novel therapeutics in the ITP pipeline and discusses the pathophysiology of ITP that has led to their development.

Graphical abstract

Figure 1.

Pathophysiology of ITP and key therapeutic targets. AMR, Ashwell-Morell receptor; BAFF, B-cell activating factor; BCR, B-cell receptor; BLyS, B lymphocyte stimulator; BTK, Bruton's tyrosine kinase; FCR, Fc receptor; FcRn, neonatal Fc receptor; IgG, immunoglobulin; mTOR, mammalian target of rapamycin; Tc, cytotoxic T cell; Th, helper T cell. Drugs in light orange boxes are FDA approved for ITP and not discussed in this article but are shown for completeness; they include fostamatinib and TPO-RAs, thrombopoietin receptor agonists. Rituximab is shown and has sufficient literature to support its use, although it does not have FDA or other regulatory indication for use in ITP.

Figure 2.

Structure of rilzabrutinib and proposed function in ITP. Mechanism of action of rilzabrutinib in ITP. Reproduced from Kuter et al. Rilzabrutinib versus placebo in adults and adolescents with persistent or chronic immune thrombocytopenia: LUNA 3 phase III study. Ther Adv Hematol. 2023;14. doi:10.1177/20406207231205431.

Figure 3.

Mechanism of action of neonatal Fc receptors in maintaining IgG levels. (A) Protection of IgG from degradation, and (B) how FcRn inhibitors disrupt IgG recycling. In (A), IgG is ingested by pinocytosis. Pinocytotic vesicles fuse with acidic endosomes in which FcRn can bind IgG. Excess unbound IgG and other proteins enter the lysosome and are degraded. IgG bound to FcRn is retained and released by exocytosis. In (B), FcRn inhibitors bind to FcRn in both neutral and acidic environments. In the presence of FcRn inhibitors, ingested IgG is unable to bind to FcRn; the unbound IgG enters the lysosome and is degraded. For illustrative purposes, albumin binding is not shown. Reproduced from Patel and Bussel with permission under CC license.

Figure 4.

The complement cascade and the locations where inhibitors being studied in ITP act. The places where C3b is generated are noted. C3b is a potent opsonin increasing phagocytosis of platelets. Deposition of complement on platelets and megakaryocytes leads to the formation of the terminal complement complex (membrane attack complex) and cell death.