STRUCTURE:
Remibrutinib (brand name Rhapsido™) has the empirical formula C2 7 H2 7 F2 N5 O3 with a molecular weight of approximately 507.54 g/mol. The molecule contains a pyrimidine ring system with amino and ethoxy substituents, connected to a fluorinated methylphenyl group and a cyclopropyl-fluorobenzamide moiety, featuring an acrylamide warhead for covalent BTK binding.
MECHANISM OF ACTION:
Chronic spontaneous urticaria (CSU) is a mast cell-mediated disorder characterized by recurrent wheals, pruritus, and/or angioedema lasting more than six weeks. Despite being the first-line treatment for CSU, second-generation H1-antihistamines provide inadequate disease control for the majority of patients. Data from the CURE registry demonstrate that only approximately 10% of CSU patients achieve complete response, the primary therapeutic goal, with any dose of second-generation H1-antihistamines. Bruton's tyrosine kinase (BTK) is an intracellular tyrosine kinase expressed in mast cells, basophils, B cells, macrophages, and thrombocytes that plays a central role in intracellular signaling through Fc epsilon receptor-1 (FcεR1), Fc gamma receptors (FcγR), and the B cell antigen receptor (BCR). Given its role in these pathways, BTK is central to CSU pathogenesis: IgG autoantibodies targeting FcεRI or IgE, as well as pathogenic IgE autoantibodies, activate mast cell surface receptors, triggering BTK-mediated signaling through PLCγ2, calcium mobilization, and protein kinase C activation, ultimately leading to degranulation. This degranulation releases histamine and other proinflammatory mediators responsible for the clinical manifestations of CSU. BTK exists in an autoinhibited conformation, in which intramolecular domain interactions hold the kinase in a closed, catalytically inactive state, and an active conformation, in which these contacts are released, the αC-helix rotates inward, and the activation loop is phosphorylated, enabling catalytic activity. Remibrutinib is an oral, highly selective covalent BTK inhibitor that binds to cysteine 481 in the inactive conformation of BTK, preventing its activation. This preference for the inactive conformation provides exceptional kinase selectivity compared to first-generation BTK inhibitors that target the active conformation and exhibit broader off-target effects limiting their use to oncology indications. By covalently binding to BTK, remibrutinib blocks mast cell and basophil degranulation mediated by FcεR1 and FcγR signaling, thereby preventing the release of histamine and other inflammatory mediators. Additionally, BTK inhibition suppresses autoantibody production by B cells, addressing another pathogenic mechanism in chronic spontaneous urticaria.
NAME:
Remibrutinib (also known as LOU064); brand name is Rhapsido.
DRUG CLASS:
Small-molecule, covalent, highly selective Bruton's tyrosine kinase (BTK) inhibitor, first BTK inhibitor approved for chronic spontaneous urticaria.
CLINICAL USE:
RHAPSIDO® is a kinase inhibitor indicated for the treatment of chronic spontaneous urticaria (CSU) in adult patients who remain symptomatic despite H1 antihistamine treatment.
DEVELOPED BY:
Novartis Pharmaceuticals
ADVERSE EFFECTS:
During clinical trials, serious adverse reactions occurred in 3.3% of patients receiving remibrutinib, with no serious adverse event occurring in more than one patient and none considered treatment-related by investigators. The most common adverse effects were nasopharyngitis (11%), bleeding (9%), headache (7%), nausea (3%), and abdominal pain (3%). Petechiae (4%) and contusion (2%) were the most reported bleeding reactions. However, no severe bleeding reactions occurred. Liver enzyme elevations (ALT/AST greater than 3 times ULN) occurred in approximately 1% of patients, with no cases of clinically significant hepatotoxicity.
TIMELINE:
18 August 2016, completed, Phase 1 trial, NCT03918980
June 2019, completed, Phase 2b trial, NCT03926611
August 2021, completed, Phase 3 trial, NCT05030311, REMIX-1
August 2021, completed, Phase 3 trial, NCT05032157, REMIX-2
30 September 2025, FDA approval for Rhapsido™ (remibrutinib), NDA: 218436
Acknowledgments
J.T. is supported by the NIGMS/NIH (R35GM151109), NCI/NIH (R01CA292653), the Florida Department of Health Bankhead Coley Cancer Research Program (24B15), and the Edward P. Evans Foundation. E.L. is supported by the NIGMS/NIH (T32GM145462).
Footnotes
Declarations of Interest
No interests are declared.
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