Novel therapeutics and future directions for refractory immune thrombocytopenia

Abstract

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder affecting approximately 1 in 20 000 people. While most patients with ITP are successfully managed with the current set of standard and approved therapeutics, patients who cannot be adequately managed with these therapies, considered to have refractory ITP, are not uncommon. Therefore, there remains an ongoing need for novel therapeutics and drug development in ITP. Several agents exploiting novel targets and mechanisms in ITP are presently under clinical development, with trials primarily recruiting heavily pretreated patients and those with otherwise refractory disease. Such agents include the neonatal Fc receptor antagonist efgartigimod, the Bruton tyrosine kinase inhibitor rilzabrutinib, the complement inhibitors sutimlimab and iptacopan and anti-CD38 monoclonal antibodies such as daratumumab and mezagitamab, among others. Each of these agents exploits therapeutic targets or other aspects of ITP pathophysiology currently not targeted by the existing approved agents (thrombopoietin receptor agonists and fostamatinib). This manuscript offers an in-depth review of the current available data for novel therapeutics in ITP presently undergoing phase 2 or 3 studies in patients with heavily pretreated or refractory ITP. It additionally highlights the future directions for drug development in refractory ITP, including discussion of innovative clinical trial designs, health-related quality of life as an indispensable clinical trial end-point and balancing potential toxicities of drugs with their potential benefits in a bleeding disorder in which few patients suffer life-threatening bleeding.

Keywords: daratumumab; efgartigimod; immune thrombocytopenia; iptacopan; mezagitamab; platelets; refractory; rilzabrutinib; rozanolixizumab; sutimlimab; umbrella trials.

Figure 1.. FcRn mode of action in protection of IgG from degradation and how FcRn inhibitors disrupt IgG recycling.

(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. (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 with permission from Patel and Bussel (56).

Figure 2.. Course of platelet counts, IgG levels, and bleeding scores over the course of a phase 2 study of efgartigimod to treat ITP.

Mean platelet count ±SEM (×109/L, circles), mean percentage change from baseline of total IgGs ±SEM (triangles), and percentage of patients with total WHO score >0 (squares) assessed per treatment group. (A) Placebo, (B) efgartigimod 5 mg/kg, and (C) efgartigimod 10 mg/kg. Patients receiving rescue medication were excluded from the analysis from the day of rescue (as indicated in the table below the figure). Arrows on the X-axis indicate time points of treatment administration. Reproduced with permission from Newland et al (18).

Figure 3.. Clinical efficacy of rozanolixizumab in a phase 2 trial in ITP.

(A) Mean platelet count over time after rozanolixizumab subcutaneous infusion (per protocol set). Arrows indicate time of rozanolixizumab subcutaneous infusion. *Baseline platelet counts were derived from central laboratory data. (B) Time to first clinically relevant response (platelet count ≥50 × 109/L) in the patients classified as responders (per protocol set). Reproduced with permission from Robak et al (22).

Figure 4.. Platelet aggregation and function in healthy volunteers and ITP patients treated with rilzabrutinib or ibrutinib.

Plasma from human healthy volunteers [HVs; n = 5 (A)] or ITP patients treated with rilzabrutinib 1 μM [n = 7 (B)] or with ibrutinib 1 μM in HVs [n = 5 (C)] were studied to evaluate their impact on platelet aggregation. Plotted is the percent of maximum platelet aggregation of compound-treated samples normalized to that of untreated samples for each of the indicated platelet agonists and compared using a two-tailed t-test versus DMSO control. Only the ibrutinib-treated 2.5 μg/ml collagen group (in C) was statistically significant at *p < 0.05. Reproduced with permission from Langrish et al (30). Copyright 2021. The American Association of Immunologists, Inc.

Figure 5.. Platelet counts over time in a phase 1/2 study of rilzabrutinib in ITP.

The median platelet counts from the initiation of treatment through the 24-week treatment period are shown for all 60 patients (Panel A) and for the 45 patients with a starting rilzabrutinib dose of 400 mg twice daily (Panel B). 𝙸 bars indicate the interquartile range. The first platelet count was obtained on day 8. Horizontal lines at platelet counts of 30 × 10⁹/L and 50 × 10⁹/L represent clinically significant thresholds for platelet response. The primary end point of platelet response was defined as at least two consecutive platelet counts, separated by at least 5 days, of at least 50 × 10⁹/L and an increase from baseline of at least 20 × 10⁹/L without the use of rescue medication in the 4 weeks before the latest elevated platelet count. Reproduced with permission from Kuter et al (32).

Figure 6.

Schematic representation of the mechanism(s) of action of anti-CD38 monoclonal antibodies on plasma cells. NK cell, natural killer cell; ADCC, antibody-dependent cell-medicated cytotoxicity; CDC, complement-mediated cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; cADPR, cyclic adenosine diphosphate ribose; NAD⁺, nicotinamide adenine dinucleotide. Adapted from Morandi et al (33)., originally published in Frontiers in Immunology (copyright owner Frontiers Media S.A.) as per the Creative Commons Attribution License (CC BY).

Figure 7.. Changes in CH50 versus platelet count over the course of the study in a phase 1 trial of sutimlimab in ITP.

CAE, complement activity enzyme; EOS, end of study; EOT, end of treatment; SEM, standard error of the mean. ^aFor patients enrolled in protocol version 3 or higher, washout period starts at Day 147 and ends at Day 196. The value at Part A baseline is the average of all platelet counts during the screening period, including Day 0 predose. The value at Part B baseline is the average of all platelet counts during the screening period in Part B. Reproduced with permission from Broome et al (46).