Effects of the Btk-Inhibitors Remibrutinib (LOU064) and Rilzabrutinib (PRN1008) With Varying Btk Selectivity Over Tec on Platelet Aggregation and in vitro Bleeding Time

R.D. Duan, L. Goldmann, R. Brandl, M. Spannagl, C. Weber, W. Siess, P. von Hundelshausen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background: Bruton tyrosine kinase inhibitors (BTKi) are used in B-cell malignancies and in development against various autoimmune diseases. Since Btk is also involved in specific pathways of platelet activation, BTKi might be considered to target platelet GPVI/GPIb-mediated atherothrombosis and platelet Fc gamma RIIA-dependent immune disorders. However, BTKi treatment of patients with B-cell malignancies is frequently associated with mild bleeding events caused possibly by off-target inhibition of Tec. Here, we compared the platelet effects of two novel BTKi that exhibit a high (remibrutinib) or low (rilzabrutinib) selectivity for Btk over Tec.</p>Methods and Results: Remibrutinib and rilzabrutinib were pre-incubated with anticoagulated blood. Platelet aggregation and in vitro bleeding time (closure time) were studied by multiple electrode aggregometry (MEA) and platelet-function analyzer-200 (PFA-200), respectively. Both BTKi inhibited atherosclerotic plaque-stimulated GPVI-mediated platelet aggregation, remibrutinib being more potent (IC50 = 0.03 mu M) than rilzabrutinib (IC50 = 0.16 mu M). Concentrations of remibrutinib (0.1 mu M) and rilzabrutinib (0.5 mu M), >80% inhibitory for plaque-induced aggregation, also significantly suppressed (>90%) the Btk-dependent pathways of platelet aggregation upon GPVI, von Willebrand factor/GPIb and Fc gamma RIIA activation stimulated by low collagen concentrations, ristocetin and antibody cross-linking, respectively. Both BTKi did not inhibit aggregation stimulated by ADP, TRAP-6 or arachidonic acid. Remibrutinib (0.1 mu M) only slightly prolonged closure time and significantly less than rilzabrutinib (0.5 mu M).</p>Conclusion: Remibrutinib and rilzabrutinib inhibit Btk-dependent pathways of platelet aggregation upon GPVI, VWF/GPIb, and Fc gamma RIIA activation. Remibrutinib being more potent and showing a better profile of inhibition of Btk-dependent platelet activation vs. hemostatic impairment than rilzabrutinib may be considered for further development as an antiplatelet drug.</p>
Original languageEnglish
Article number749022
Number of pages12
JournalFrontiers in Cardiovascular Medicine
Volume8
DOIs
Publication statusPublished - 24 Sept 2021

Keywords

  • atherothrombosis
  • platelet-aggregation
  • bleeding
  • PFA
  • MEA
  • BRUTONS TYROSINE KINASE
  • X-LINKED AGAMMAGLOBULINEMIA
  • THROMBUS FORMATION
  • CLOSURE TIME
  • ACTIVATION
  • ASPIRIN
  • PFA-100(TM)
  • IBRUTINIB
  • ABSENCE
  • TRIAL

Cite this