Ono Pharmaceutical recently announced that its BTK inhibitor Velexbru (tirabrutinib hydrochloride, 80mg tablet) has been approved in Japan for the treatment of Fahrenheit macroglobulinemia (WM) and lymphocytic lymphoma (LPL). Velexbru is a highly selective oral Bruton tyrosine kinase (BTK) inhibitor developed in Japan for the treatment of B-cell tumors and autoimmune diseases.
With this approval, Velexbru is now the first BTK inhibitor approved in Japan for the treatment of previously untreated or relapsed WM patients and LPL patients. In November 2019, Japan’s Ministry of Health and Labor (MHLW) granted Velexbru the right to treat WM and LPL as orphan drugs.
In March this year, Velexbru won the world’s first batch in Japan for the treatment of recurrent or refractory primary central nervous system lymphoma (PCNSL). It is worth mentioning that Velexbru is the first BTK inhibitor approved for the treatment of recurrent or refractory PCNSL in the world. Previously, Velexbru was granted the qualification to treat PCNSL as an orphan drug. In terms of medication, Velexbru was taken on an empty stomach and 480mg was taken once a day.
The approval of WM and LPL indications is based on the results of a multicenter, open-label, single-arm II study (ONO4059-05). This study assessed the efficacy and safety of Velexbru in previously untreated or recurrent/refractory WM and LPL patients. In the study, patients were given Velexbru 480mg on an empty stomach and taken orally once a day until disease progression or unacceptable toxicity were observed. The primary endpoint of the study was the overall remission rate determined by the independent review committee (IRC). The secondary endpoints of (ORR), included progression-free survival (PFS) and overall survival (OS).
In the study, a total of 27 patients received Velexbru treatment, 18 patients were previously untreated and 9 patients were relapsed or refractory. The results showed that the ORR of the untreated group was 88.9%, and that of the relapse or refractory treatment group was 88.9%. In terms of secondary endpoints, the progression-free survival rate and overall survival rate at 6 months were both 100% in the untreated group and the relapse or refractory treatment group. In the study, the most common grade three adverse events observed were neutropenia and lymphocytopenia (11.1% each) and leukopenia (7.4%).
Both WM and LPL are malignant lymphomas and are classified as “inert lymphomas”, that is, lymphomas with relatively slow progression. It is estimated that there are about 240 new cases of LPL in Japan each year. WM and LPL usually grow and spread slowly in the clinical process, with a median survival time of more than 5 years, but these are refractory diseases that cannot be cured with existing treatments. In Japan, there is no standard treatment for untreated or recurrent / refractory WM and LPL patients, so there is an urgent need to provide a new treatment option for these patient groups.
The active drug ingredient of Velexbru is tirabrutinib, which was discovered and developed by Ono Pharmaceuticals, a highly selective, oral Bruton tyrosine kinase (BTK) inhibitor developed in Japan for the treatment of B-cell tumors and autoimmune diseases. B cell receptor (BCR) signal plays a central role in the survival, activation, proliferation, maturation and differentiation of B cell lymphocytes. BTK is an important regulator of BCR signaling pathway, and tirabrutinib plays a therapeutic role by inhibiting BTK. BTK is a kind of cytoplasmic protein. After BCR receptor activation, Lyn, Fyn and other kinases downstream of the receptor are activated, which further activates the downstream BTK kinase. After BTK activation, it regulates several downstream signals.
In December 2014, Gilead reached a licensing agreement with Ono Pharmaceuticals to obtain exclusive rights to develop and commercialize (ASEAN) in other countries except Japan, South Korea, China and ASEAN countries.
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2. Danilov, A. V., Herbaux, C., Walter, H. S., Hillmen, P., Rule, S. A., Kio, E. A., … & Humeniuk, R. (2020). Phase Ib Study of Tirabrutinib in Combination with Idelalisib or Entospletinib in Previously Treated Chronic Lymphocytic Leukemia. Clinical Cancer Research.