Patients with immune thrombocytopenia display lowered platelet counts and impaired platelet production as a result of their immune system. Since this is an autoimmune condition, first-line therapies frequently consist of corticosteroids and IV immune globulin. The use of Bruton's tyrosine kinase (BTK) inhibitors has revolutionized the manner in which many B-cell hematologic malignancies are treated. In addition to these oncological indications, as a result of BTK's other activities, inhibitors of this enzyme are thought to have clinical relevance in inflammatory and autoimmune conditions.
The reversible BTK inhibitor rilzabrutinib (formerly known as PRN 1008) is being evaluated in a Phase I/II clinical trial (NCT03395210) among patients with previously treated immune thrombocytopenia. The team conducting this trial is being led by David J. Kuter, MD, DPhil, Director of Clinical Hematology at Massachusetts General Hospital and Professor of Medicine at Harvard Medical School.
"This Phase I/II clinical trial established a role for BTK inhibition in the treatment of immune thrombocytopenia," he noted. The findings from this study were recently published in the New England Journal of Medicine (2022; doi: 10.1056/NEJMoa2110297).
Immune Thrombocytopenia
Much is still not understood about the underlying mechanisms for immune thrombocytopenia. Currently, it is thought that platelets, which are coated with antibodies, are prematurely targeted for destruction, which occurs in the spleen and/or possible the liver via "interaction with Fc[gamma] receptors" on macrophages (N Engl J Med 2019; doi: 10.1056/NEJMcp1810479).
Immune thrombocytopenia arises in a patient when their immune system both targets platelets for destruction and hampers the ability of the bone marrow to produce additional platelets. "In many patients, there is no underlying disease with the primary disease being immune thrombocytopenia," Kuter stated. "This decrease in platelet levels, which can be persistent or intermittent, puts the patient at risk for increased bleeding and diminished quality of life."
Upon being diagnosed with immune thrombocytopenia, patients may be asymptomatic or display bleeding that can range from mild to life-threatening. Within 5 years of diagnosis, roughly 15 percent of people with immune thrombocytopenia will require hospitalization as a result of a bleeding incident. In addition to the risk for bleeding, patients with immune thrombocytopenia often report fatigue and are also at a higher risk for developing venous thromboembolism.
The management of venous thromboembolism, which is traditionally performed with anticoagulant therapy, is especially difficult. In the general population, immune thrombocytopenia occurs in somewhere between two and four people per 100,000, with two peaks in prevalence occurring between 20 and 30 years of age and greater than 60 years.
"For adults with immune thrombocytopenia, most current therapies attempt to address the bleeding issues by targeting the destruction of the platelets. This is often accomplished with treatments such as glucocorticoid or immunoglobulin therapies," Kuter explained.
Noting the challenges surrounding treating patients with this condition, he stated, "It can be difficult to predict the effectiveness of the therapies, and durable responses and long-term remissions are by no means a certainty." Although there are a number of therapies available, there is still a need for effective treatments that provide durable platelet level increases with enhanced safety and a reduced dependence on corticosteroids for disease management.
"Currently, there are no recommendations for the treatment of patients with immune thrombocytopenia who have had multiple relapses," Kuter observed. "Recent guidance from the American Society of Hematology recommends the use of rituximab, thrombopoietin agonists, or a splenectomy for the treatment of patients with immune thrombocytopenia lasting for 3 months or longer. Another difficulty when performing a trial for immune thrombocytopenia is that making comparisons are complicated by the use of different timepoints and platelet response endpoints."
Reversible BTK Inhibition
Initially, approved BTK inhibitors were irreversible inhibitors that formed a covalent bond to an active site cysteine (cysteine 481) (J Hematol Oncol 2021; doi: 10.1186/s13045-021-01049-7). A significant portion of the toxicities for these inhibitors resulted from the formation of bonds between the inhibitor and "off-target" cysteine residues.
When covalent BTK inhibitors are bound to cysteine 481, the pendant molecule occupies the ATP (the phosphate source for BTK) binding pocket in the active site. In an effort to maximize the "resident time" of BTK inhibitors-the time which the inhibitor is blocking BTK enzymatic activity-attempts were made to identify inhibitors of BTK, which could reversibly form a covalent bond to cysteine residues (Nat Chem Biol 2015; doi: 10.1038/nchembio.1817).
One possible advantage for reversible covalent inhibitors is that toxicities might be reduced because the bonds formed to off-target proteins would not be permanent. Additionally, by adjusting the structure of the inhibitor, one could potentially fine-tune the time that the inhibitor remains covalently bound to the target protein. This would allow for either prolonged or shortened resident time, depending upon what is best for the particular clinical indication.
BTK Inhibition & Immune Regulation
In animal models, the regulation of BTK has been shown to exert effects on autoimmunity (Expert Rev Clin Immunol 2016; doi: 10.1586/1744666X.2016.1152888). In one preclinical study with mice that overexpressed BTK, increased autoantibody production resulted in the development of a "systemic lupus erythematosus-like autoimmune pathology which affected several organs (Blood 2012; doi: 10.1182/blood-2011-12-397919)." The autoimmune condition was shown to be dependent upon BTK's kinase activity, as treatment with a BTK inhibitor normalized the B cells' activities. In addition, transgenic mice with a kinase-inactive mutant BTK lacked the aforementioned autoantibodies. In addition to autoantibody production, BTK is vital for Fc[gamma]-mediated phagocytosis and cytokine production by macrophages.
Patients were eligible for participation if they had immune thrombocytopenia with a platelet count of less than 30x103 per mm3 on two occasions (no less than 7 days between incidents within 15 days prior to entering the clinical study) and were 18-80 years of age. Additionally, participants were required to have had a clinical response to at least one prior therapy for their immune thrombocytopenia, but not to their last therapy before baseline.
As previously noted, this open-label Phase 1/II study followed a 3+3 dose-escalation schedule. Participants could receive the following as their initial dose: 200 mg once daily, 400 mg once daily, 300 mg twice daily, or 400 mg twice daily (this study's highest dosage). The participant's dosage could be increased every 28 days at the discretion of the investigator. Prior to dose escalation, effects of patient exposure to the drug were evaluated by a data and safety monitoring committee. The participants in this trial received a median of four different prior therapies for their immune thrombocytopenia, which they had for a median period of 6.3 years.
In this 24-week clinical study 100 percent (60) of the participants were evaluable for the primary efficacy endpoint, platelet response, which was defined as at least two consecutive platelet counts (separated by 5 days or more) of at least 50x103 per cubic millimeter and an increase from baseline of at least 20x103 per cubic millimeter without the use of rescue medication for immune thrombocytopenia in the 4 weeks before the latest elevated platelet count).
A total of 40 percent (24) of the participants met the primary study endpoint. The breakdown of response by dosage was as follows: 200 mg once daily-11 percent (1 of 9); 400 mg once daily-25 percent (2 of 8); 300 mg twice daily-33 percent (4 of 12); 400 mg twice daily-38 percent (20 of 52).
"It is important to note, that patients could have displayed a response at more than one dosage level," Kuter explained. "Of the 45 patients who initiated their participation in this trial at the highest dosage level (400 mg twice daily), 40 percent met the primary endpoint of platelet response. Of the patients who had a response in this study, 24 maintained a platelet level of 50,000 per cubic millimeter for a median 16 weeks, while 18 of the participants initiated at 400 mg twice daily maintained that platelet level for a median 14 weeks."
Discussion
"The use of rilzabrutinib in this trial was effective at reducing the immune system-mediated destruction of platelets in patients with immune thrombocytopenia," Kuter noted. "These results provided evidence for this novel therapy, which targeted the underlying mechanism that causes immune thrombocytopenia," he added.
Positive results were also noted with regards to the safety of rilzabrutinib. "Treatment with rilzabrutinib at all levels, even the highest included in this study, 400 mg twice daily, only showed mild, low-grade symptoms, which was in agreement with earlier studies of this BTK inhibitor," Kuter observed.
Regarding the safety of rilzabrutinib, he noted, "A prior clinical study conducted in healthy volunteers showed that there were no clinically significant adverse events. Moreover, altered platelet aggregation, which had been seen with other BTK inhibitors, was not observed in these healthy volunteers taking rilzabrutinib."
When asked about the next steps for evaluating rilzabrutinib in this clinical setting, Kuter replied, "Currently, there is the ongoing Phase III LUNA 3 trial (NCT04562766), which is comparing rilzabrutinib to placebo in patients with chronic or persistent immune thrombocytopenia. The goal of this trial is to assess the strength and durability of the clinical response to rilzabrutinib in these patients," Kuter concluded.
Richard Simoneaux is a contributing writer.