The U.S. Food and Drug Administration (FDA) has accepted for filing the New Drug Application (NDA)* under the accelerated approval pathway for tirabrutinib (ONO-4059), a highly selective, irreversible, second-generation Bruton tyrosine kinase (BTK-) inhibitor, for the treatment of relapsed or refractory primary central nervous system lymphoma (R/R PCNSL). Signaling through the B-cell receptor (BCR) regulates cellular proliferation and activation and promotes survival, differentiation, and clonal expansion of B cells. The BCR signaling pathway plays an important role in a number of B-cell malignancies.
The investigational drug is being developed by Deciphera Pharmaceuticals, a member of the Ono Pharmaceutical group of companies.
Orphan Drug Designation
The NDA application was based on the positive results from the Phase 2 PROSPECT Study (NCT04947319).
The FDA has set an action date of December 18, 2026, under the Prescription Drug User Fee Act (PDUFA). Earlier, in March 2023, tirabrutinib was granted orphan drug designation by the FDA.
Unmet medical need
PCNSL is a rare and aggressive extra-nodal non-Hodgkin lymphoma (NHL) that is confined to the brain parenchyma, spinal cord, eye, or leptomeninges without systemic involvement. The annual incidence rate of PCNSL is approximately five cases per 1,000,000 people in the U.S. The rate can further increase among immunocompromised people aged 65 years and older.[1][2]
The signs and symptoms presented in patients with PCNSL vary depending on the neuroanatomical site of the lesion, and include cranial neuropathy, neuropsychiatric symptoms, symptoms associated with increased intracranial pressure, seizures, ocular symptoms, headache, dysmotility, cranial neuropathy, and radiculopathy.
There is a high unmet medical need for a treatment with a favorable safety profile, and data guiding therapeutic approaches are very limited. Despite recent progress resulting in the improvement of clinical outcomes in newly diagnosed patients with PCNSL after an induction treatment, approximately 20% to 30% of patients are refractory to the initial treatment, and up to 60% of patients will eventually relapse.
“R/R PCNSL is a rare and aggressive form of non-Hodgkin lymphoma with particularly poor clinical outcomes. Patients often experience difficulty and delay in diagnosis, and once they are diagnosed, there is a high unmet need for a treatment with a favorable safety profile,” said Matthew L. Sherman, M.D., Chief Medical Officer of Deciphera.
“The FDA’s acceptance of tirabrutinib’s NDA for filing is an exciting milestone as it brings us one step closer to our goal of providing patients with R/R PCNSL an important new treatment option,” Sherman added.
“We are very pleased that the NDA for tirabrutinib has been accepted for filing,” said Toichi Takino, President and COO of Ono Pharmaceutical Co., Ltd.
“This is an important milestone on the way to expanding our commercial pipeline and achieving our goal of becoming a global specialty pharma. Tirabrutinib’s potential to address unmet patient needs embodies our corporate philosophy and we will continue to focus on developing and delivering innovative medicines to benefit patients worldwide,” Takino further noted.
The NDA is supported by the positive results from the Phase 2 PROSPECT study, presented at the 2025 American Society for Clinical Oncology (ASCO) Annual Meeting, in which tirabrutinib demonstrated an overall response rate of 67%, a complete response rate of 44%, and a manageable safety profile.[3]
Study outcomes
The PROSPECT trial results demonstrated a generally favorable safety profile. At data cutoff, 13 patients (27%) remained on tirabrutinib treatment. The main reasons for discontinuation were disease progression (54.2%) and death (8.3%); one patient discontinued due to an adverse event (AE). Incidence of grade ≥3 treatment-emergent adverse events (TEAEs) was 56.3%. Any-grade treatment-related TEAEs were experienced by 75.0%, and most frequently included anemia (18.8%), rash maculo-papular (16.7%), fatigue (14.6%), neutrophil count decreased (14.6%), lymphocyte count decreased (14.6%), pruritus (14.6%), and rash (14.6%). Two patients died of TEAEs, which were considered unrelated to study treatment.
Impact of regulatory decision
If approved, tirabrutinib will be the first BTK inhibitor therapy commercially available in the U.S. for the treatment of patients with R/R PCNSL, and the third commercial therapy for Ono group available in the U.S.
The study is currently recruiting patients with R/R PCNSL in a global Phase 3 randomized trial, which will serve as a confirmatory study for this indication (ClinicalTrials.gov NCT07104032.)
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Note: * In Japan, tirabrutinib was approved in March 2020 for the treatment of R/R PCNSL and launched under the tradename of Velexbru® in May 2020. It was subsequently approved in August 2020 for the treatment of Waldenstrom macroglobulinemia and lymphoplasmacytic lymphoma. Tirabrutinib was approved for the treatment of R/R PCNSL in South Korea in November 2021 and in Taiwan in February 2022.
Clinical trials
Study of Tirabrutinib (ONO-4059) in Patients With Primary Central Nervous System Lymphoma (PROSPECT Study) – ClinicalTrials.gov ID NCT04947319
Study of Tirabrutinib vs Rituximab/Temozolomide for Relapsed/Refractory Primary Central Nervous System Lymphoma (PCNSL) – ClinicalTrials.gov ID NCT07104032
Reference
[1] Ostrom QT, Price M, Neff C, Cioffi G, Waite KA, Kruchko C, Barnholtz-Sloan JS. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2015-2019. Neuro Oncol. 2022 Oct 5;24(Suppl 5):v1-v95. doi: 10.1093/neuonc/noac202. PMID: 36196752; PMCID: PMC9533228.
[2] Schaff LR, Grommes C. Primary central nervous system lymphoma. Blood. 2022;140(9):971-979. doi:10.1182/blood.2020008377.
[3] Nayak L, Grommes C, Kallam A, et al. Tirabrutinib for the treatment of relapsed or refractory primary central nervous system lymphoma: efficacy and safety from the phase II PROSPECT study. Presented at: 2025 American Society for Clinical Oncology (ASCO) meeting; May 30-June 3, 2025; Chicago, IL.
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DOI
 has accepted for filing the New Drug Application (NDA)* under the accelerated approval pathway for tirabrutinib (ONO-4059), a highly selective, irreversible, second-generation Bruton tyrosine kinase (BTK-) inhibitor, for the treatment of relapsed or refractory primary central nervous system lymphoma (R/R PCNSL).){kind=link}