Tirabrutinib is a targeted therapy designed to interfere with specific molecular pathways that support the growth and survival of certain cells. Unlike traditional chemotherapy, which broadly affects rapidly dividing cells, tirabrutinib precisely targets these molecules. This approach represents an advancement in treating diseases where overactive cellular signals drive abnormal cell proliferation.
Mechanism of Action
Tirabrutinib operates as a Bruton’s tyrosine kinase (BTK) inhibitor, an enzyme involved in the B-cell antigen receptor (BCR) signaling pathway. B-cells are a type of immune cell that produces antibodies. In certain diseases, the BCR pathway in B-cells can become overactive, leading to uncontrolled B-cell growth and survival.
BTK relays signals that instruct B-cells to activate, multiply, and survive. Tirabrutinib works by irreversibly binding to a specific cysteine residue (Cys481) in the active site of BTK. This binding disables BTK, preventing its phosphorylation and activation. By blocking BTK, tirabrutinib disrupts the entire downstream signaling cascade that B-cells rely on, ultimately hindering their abnormal proliferation and leading to their programmed cell death.
Medical Applications and Efficacy
Tirabrutinib has received regulatory approval in Japan for specific conditions, including relapsed or refractory primary central nervous system lymphoma (PCNSL) and pemphigus. PCNSL is a rare and aggressive form of non-Hodgkin lymphoma affecting the brain, spinal cord, or eyes, where treatment options are often limited for patients. In a Japanese phase 1/2 study (ONO-4059-02) for relapsed/refractory PCNSL, the overall response rate was 63.6%, with some patients achieving complete responses. A US-based Phase 2 study, PROSPECT, showed an overall response rate of 66.7% and a complete response rate of 43.8% in relapsed/refractory PCNSL patients. The median duration of response in this study was 9.3 months.
Beyond PCNSL, tirabrutinib is also approved in Japan for Waldenström’s macroglobulinemia and lymphoplasmacytic lymphoma. For pemphigus, an autoimmune blistering skin disease, a phase 2 study in Japan showed promising results. Patients with refractory pemphigus receiving tirabrutinib 80 mg once daily achieved a complete remission rate of 18.8% after 24 weeks, increasing to 50.0% by Week 52. The treatment also allowed for a reduction in corticosteroid dosage. Clinical development is underway for other conditions, including rheumatoid arthritis, chronic lymphocytic leukemia, and other B-cell lymphomas.
Administration and Dosage
Tirabrutinib is administered orally as a tablet. The usual adult dosage for conditions like primary central nervous system lymphoma is 480 mg, taken once daily. It is generally recommended to take the medication under fasting conditions to ensure proper absorption.
Taking the dose at the same time each day helps maintain consistent drug levels. The dosage may be adjusted by a healthcare provider based on the patient’s individual condition and how they tolerate the medication. Adhering to the prescribed schedule is important for the medication’s effectiveness.
Side Effects and Safety Profile
Like all medications, tirabrutinib can cause side effects. Common reactions reported by patients include fatigue, gastrointestinal disturbances such as nausea, vomiting, diarrhea, and abdominal pain. Skin reactions, including rashes and itching, are also noted, with some patients experiencing more severe forms.
More serious adverse events include hematologic effects such as neutropenia (low white blood cell count), lymphopenia (low lymphocyte count), leukopenia (overall low white blood cell count), and thrombocytopenia (low platelet count). Infections, including pneumonia, can occur due to the drug’s impact on the immune system. Liver dysfunction, indicated by elevated liver enzymes, and bleeding complications are other serious effects. Patients are advised to promptly report any new or worsening symptoms to their healthcare provider for appropriate management.
Regulatory Status and Clinical Trials
Tirabrutinib has received regulatory approval in several countries, predominantly in Asia. It was approved in Japan in March 2020 for relapsed or refractory primary central nervous system lymphoma (PCNSL) and launched under the brand name Velexbru. Subsequent approvals for this indication followed in South Korea in November 2021 and Taiwan in February 2022. Additionally, Velexbru received approval in Japan in August 2020 for the treatment of Waldenström’s macroglobulinemia and lymphoplasmacytic lymphoma.
In the United States, tirabrutinib has not yet received full approval for PCNSL. However, the U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation to tirabrutinib for the treatment of PCNSL in March 2023. This designation aims to support the development of drugs for rare diseases affecting fewer than 200,000 people in the U.S. An ongoing Phase 2 clinical trial, known as the PROSPECT study, is evaluating tirabrutinib’s safety and efficacy in U.S. patients with newly diagnosed or relapsed/refractory PCNSL. The study includes both monotherapy for relapsed/refractory cases and combination therapy with high-dose methotrexate-based regimens for newly diagnosed patients.