Ono Pharmaceutical has filed in Japan to expand VELEXBRU® (tirabrutinib) for relapsed or refractory secondary CNS lymphoma, supported by Phase 2 CRYSTAL trial data. The application carries orphan drug designation and priority review, addressing a major unmet need in aggressive B‑cell malignancies.
Written By: Nikita Jha, BPharm
Reviewed By: Pharmacally Editorial Team
Ono Pharmaceutical has submitted a supplemental application in Japan to expand the approved use of VELEXBRU® (tirabrutinib hydrochloride) for patients with relapsed or refractory secondary central nervous system lymphoma (SCNSL).
The filing seeks a partial change to the drug’s manufacturing and marketing approval and has been granted orphan drug designation and priority review by Japan’s Ministry of Health, Labour and Welfare (MHLW). This marks a significant regulatory step for a patient population with few effective treatment options.
Addressing a Critical Unmet Need
SCNSL occurs when systemic malignant lymphoma spreads to the brain, spinal cord, meninges, or other CNS structures and differs from primary CNS lymphoma, which originates within the CNS. Patients often experience severe neurological complications such as cranial nerve palsy, limb weakness, visual disturbances, cognitive impairment, and psychiatric symptoms. Outcomes remain poor, particularly after relapse or progression.
High-dose methotrexate-based regimens are commonly used in Japan, but no established standard of care exists for patients who relapse or cannot tolerate intensive therapy, underscoring the need for new treatment options in this difficult-to-treat setting.
VELEXBRU’s Mechanism and Differentiation
VELEXBRU is a highly selective oral Bruton’s tyrosine kinase (BTK) inhibitor discovered by Ono. By blocking BTK signaling, the therapy disrupts B-cell receptor pathways that drive malignant B-cell survival and proliferation.
Tirabrutinib has shown clinical activity in central nervous system lymphoma settings, making BTK inhibition an attractive therapeutic approach for diseases involving CNS infiltration by malignant B cells.
CRYSTAL Trial Provides Supporting Evidence
The application is supported by the multicenter, open-label Phase 2 NCCH2201/MK013 study (CRYSTAL trial, jRCT2031220529) led by Japan’s National Cancer Center Hospital. VELEXBRU monotherapy was evaluated in patients with relapsed or refractory SCNSL.
The primary endpoint was centrally reviewed objective response rate, with secondary endpoints including progression-free survival, overall survival, duration of response, and safety. While detailed efficacy data remain undisclosed, Ono confirmed that trial results supported the submission. Full findings will be presented at the European Hematology Association (EHA) 2026 Congress in Stockholm from June 11–14.
The trial was conducted as part of the MASTER KEY Project, an industry-academia collaboration that supports clinical development programs for rare cancers in Japan.
Expanding Global Development Path
VELEXBRU already holds approvals in Japan, South Korea, and Taiwan for relapsed or refractory primary CNS lymphoma, and in Japan for Waldenström macroglobulinemia and lymphoplasmacytic lymphoma.
Earlier this year, the U.S. Food and Drug Administration accepted a New Drug Application for tirabrutinib in relapsed or refractory primary CNS lymphoma.
A positive review outcome in Japan could expand treatment options for patients with relapsed or refractory SCNSL, a disease area where effective therapies remain limited.
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About the Writer
Nikita Jha, BPharm (LinkedIn) a pharmacy graduate specializing in medical writing, with a strong ability to interpret complex medical and regulatory information and translate it into clear, accurate, and evidence-based healthcare content. Known for her attention to detail and precision, she focuses on delivering high-quality scientific communication that supports drug safety and informed decision-making.