Initial Report of Part B Phase 1/2 Efficacy and Safety Results for Bruton Tyrosine Kinase Inhibitor Rilzabrutinib in Patients with Relapsed Immune Thrombocytopenia
Authors: Cooper Nichola , Jansen A.J. Gerard , Bird Robert , Mayer Jiří , Sholzberg Michelle , Tarantino Michael D. , Garg Mamta , Ypma Paula F , McDonald Vickie , Percy Charles , Košťál Milan , Goncalves Isaac , Bogdanov Lachezar H. , Gernsheimer Terry B , Diab Remco , Yao Mengjie , Daak Ahmed , Kuter David J 
Published: December 2023

Introduction: Rilzabrutinib is a potent oral, reversible Bruton tyrosine kinase inhibitor that can treat hematological autoimmune diseases through multiple putative mechanisms of action: (1) inhibition of B-cell activation, (2) interruption of antibody-coated cell phagocytosis by FcϒR in spleen and liver, and (3) induce sustained anti-inflammatory effects (Langrish J Immunol 2021). Preliminary evidence showed that rilzabrutinib treatment resulted in rapid and durable platelet responses with a favorable safety profile in previously treated patients with immune thrombocytopenia (ITP) as studied in part A of a phase 1/2 clinical study (LUNA 2; Kuter N Engl J Med 2022). This abstract summarizes the results of part B that focused on the durability of response with rilzabrutinib in relapsed ITP patients.
Methods: Part B of the multicenter, open-label, phase 1/2 study evaluated the efficacy and safety of rilzabrutinib 400 mg bid in patients with relapsed ITP (NCT03395210). Adult patients aged 18-80 y were eligible with ≥2 baseline platelet counts &lt;30x10 9/L no less than 7 days apart in the 15 days before the first dose. Eligible patients were required to have a past response (achievement of platelet count ≥50x10 9/L) to intravenous immunoglobulin (IVIg)/anti-D or corticosteroid (CS) that was not sustained and failed ≥1 other ITP therapy (that was not IVIg or CS). Stable doses of concomitant CS/thrombopoietin receptor agonists (TPO-RA) were allowed with rilzabrutinib. The primary endpoints for part B were safety and durable platelet response defined as platelet counts ≥50x10 9/L on ≥8 of the last 12 weeks of rilzabrutinib without rescue medication. Patients completing 24 weeks of rilzabrutinib with platelet counts ≥50x10 9/L or ≥30x10 9/L and doubling from baseline in ≥4 of the last 8 weeks of treatment without rescue medication could continue rilzabrutinib in the long-term extension (LTE) period.
Results: At baseline, 26 enrolled patients had a median age of 57 y (range, 20-75), 62% were female, and median baseline platelet count was 13x10 9/L (range, 2-24x10 9/L). Patients had a median duration of ITP of 10.3 y (range, 0.7-48.2) and had received a median of 6 prior unique ITP therapies (range, 3-19; 46% splenectomy). Seventeen patients (65%) received concomitant non-rescue CS and/or TPO-RA. Nine patients (35%; 95% CI, 17%-56%) achieved the primary endpoint of durable platelet response. Approximately 25% of patients achieved platelet counts ≥50x10 9/L by day 15 of rilzabrutinib treatment (Figure 1A). In 16 patients who achieved platelet counts ≥50x10 9/L, median time to first platelet count ≥50x10 9/L was 15 days (range, 7-134). Median platelet counts for all patients (responders and non-responders) increased over time, exceeding the platelet count thresholds of 30x10 9/L at day 57 and 50x10 9/L at day 120 (Figure 1B). The mean number of weeks with platelet counts ≥50x10 9/L and/or ≥30x10 9/L and doubling from baseline was both 9.3 weeks (SD, 10.1). Three patients (12%) received rescue medication in the main treatment period. Fifteen patients (58%) completed 24 weeks of rilzabrutinib and 11 (42%) entered the LTE.
Over the main treatment period, the median duration of treatment was 167 days (range, 7-169). Sixteen patients (62%) had ≥1 related treatment-emergent adverse event (AE), including 35% diarrhea, 23% headache, and 15% nausea. Most AEs were grade 1 or 2; there was 1 treatment-related AE of grade 3 blood creatinine phosphokinase increase. There was no treatment-related grade ≥2 bleeding/thrombotic events or infections, serious AEs, or deaths.
Conclusion: Part B study results were consistent with part A. Rilzabrutinib demonstrated rapid, stable, and durable platelet responses in patients with relapsed ITP, with a favorable safety profile in part B.