Velexbru (tirabrutinib) / Ono Pharma, Gilead - LARVOL DELTA

A Case of IgM-Type Proliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposits Developing During the Course of Lymphoplasmacytic Lymphoma (KIDNEY WEEK 2025) - "We report a case of IgM-type PGNMID associated with lymphoplasmacytic lymphoma (LPL) which progressed and developed nephrotic syndrome despite sustained serologic remission with tirabrutinib, necessitating a repeat kidney biopsy. Case Description A 72-year-old male patient with a 14-year history of LPL underwent treatment with corticosteroids and rituximab, yet exhibited a suboptimal therapeutic response...IgM-type PGNMID is associated with a poor kidney prognosis, with a median kidney survival of 44 months, which is consistent with this case. Retrospectively, despite the achievement of serologic remission, the deterioration in kidney function may have warranted consideration of subsequent treatment strategies, such as the use of proteasome inhibitors or B-cell lymphoma-2 inhibitors."

Clinical • B Cell Lymphoma • Fibrosis • Glomerulonephritis • Immunology • Lupus Nephritis • Lymphoma • Lymphoplasmacytic Lymphoma • Monoclonal Gammopathy • Nephrology • Renal Disease • Waldenstrom Macroglobulinemia • BCL2

A retrospective study of the BTK-inhibitor tirabrutinib for the treatment of recurrent/refractory primary CNS lymphoma (EANO 2025) - "In real-world settings, tirabrutinib has shown to be an effective and well-tolerated treatment for recurrent or refractory PCNSL."

Retrospective data • CNS Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Central Nervous System Lymphoma

A Study to Investigate the Pharmacokinetics of Tirabrutinib in Participants With Mild, Moderate, and Severe Hepatic Impairment Compared to Healthy Participants (clinicaltrials.gov) - P1 | N=24 | Not yet recruiting | Sponsor: Ono Pharmaceutical Co. Ltd

New P1 trial • CNS Lymphoma • Hematological Malignancies • Hepatology • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Central Nervous System Lymphoma

Bruton tyrosine kinase inhibitor in non-IgM lymphoplasmacytic lymphoma: a case report and literature review. (PubMed, J Clin Exp Hematop) - "We report a case of IgG-type non-WM LPL successfully treated with a second-generation BTK inhibitor, tirabrutinib. The patient demonstrated a rapid decline in M-protein and improvement in anemia, with a durable partial response. This case adds to the limited literature supporting BTK inhibitor use in non-WM LPL and highlights the need for further studies to define optimal treatment strategies."

Journal • Review • Hematological Disorders • Hematological Malignancies • Lymphoma • Lymphoplasmacytic Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Waldenstrom Macroglobulinemia

Membranous nephropathy preceding Bing-Neel syndrome: successful treatment with tirabrutinib. (PubMed, J Nephrol) - "Despite initial partial remission with corticosteroids and cyclosporine, neurological symptoms emerged alongside nephrotic syndrome relapse two years after onset...After bendamustine-rituximab therapy showed partial effectiveness, tirabrutinib, a Bruton tyrosine kinase inhibitor, achieved complete remission of both renal and neurological manifestations with sustained response over three years. Immunofluorescence staining revealed increased nuclear factor (NF)-κB and STAT3 expression in infiltrating immune cells and elevated NF-κB in surrounding tubular epithelial cells, suggesting activation of these pathways downstream of the MYD88 mutation in kidney pathology. Our findings suggest a potential contribution of Bruton's tyrosine kinase signaling to both kidney and neurological pathology in Bing-Neel syndrome, with tirabrutinib achieving clinical improvement in both organ manifestations."

Journal • Glomerulonephritis • Hematological Disorders • Lymphoma • Lymphoplasmacytic Lymphoma • Nephrology • Renal Disease • Waldenstrom Macroglobulinemia • MYD88 • STAT3

Diagnosis and Management of Waldenstrom's Macroglobulinemia (ICML 2025) - P2 | "New or emerging options for patients progressing on c-BTKi include pirtobrutinib, BGB-16673, venetoclax, and sonrotoclax...CXCR4 antagonists such as plerixafor or ulocuplumab can sensitize CXCR4Mut-expressing WM cells to ibrutinib [22-24]...6 BTK Mutations BTKCys481 is the binding site for covalent BTK inhibitors (cBTK-i), including ibrutinib, zanubrutinib, acalabrutinib, orelabrutinib and tirabrutinib...For symptomatic treatment-naïve patients, chemoimmunotherapy with bendamustine and rituximab (Benda-R), dexamethasone, rituximab, and cyclophosphamide (DRC), as well as cBTK-i can be considered...Additional options in second or later relapse include re-use of chemotherapy if a response lasted for > 3 years, alternative chemoimmunotherapy, nucleoside analogs, or everolimus [38]...Zanubrutinib in combination with ixazomib and dexamethasone (ZID) is being investigated in a study in China (NCT04463953) and has shown high levels of response activity and good..."

IO biomarker • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Waldenstrom Macroglobulinemia • BCLAF1 • CXCL12 • FOXO3 • IL10 • IL6 • IRAK4 • MYD88 • PLCG2 • SYK • TNFAIP3 • TRAF3IP2

Effect of plasma exchange on tirabrutinib plasma concentration in a patient with lymphoplasmacytic lymphoma: A case report. (PubMed, Cancer Chemother Pharmacol) - "PE appeared to have minimal impact on the tirabrutinib plasma concentration, likely due to its large volume of distribution. Although further cases are needed, this case supports the feasibility of concomitant PE during tirabrutinib therapy without significant compromise of drug efficacy."

Journal • Hematological Disorders • Hematological Malignancies • Lymphoma • Lymphoplasmacytic Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Pain • Waldenstrom Macroglobulinemia

Structure-based design of tirabrutinib derivatives as inhibitors of bacterial tryptophanyl-tRNA synthetase. (PubMed, Bioorg Chem) - "Notably, WRS22 displayed no affinity to human cytoplasmic TrpRS (HcTrpRS) and its interaction with human BTK is likely to be disrupted, indicating high degree of target selectivity. Therefore, the structure-guided design successfully developed new tirabrutinib analogues as inhibitors of bacterial TrpRS, presenting a promising lead compound for the development of AARS-based antibacterial agents."

Journal

Comparison of Survival Outcomes Between Chimeric Antigen Receptor T-Cell Therapy Recipients With and Without Central Nervous System Involvement. (PubMed, Clin Lymphoma Myeloma Leuk) - "CNS involvement was significantly associated with poor prognosis, highlighting the need for further strategies, such as tirabrutinib, to improve outcomes in this population."

Journal • B Cell Lymphoma • CNS Lymphoma • Hematological Malignancies • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Central Nervous System Lymphoma • Secondary Central Nervous System Lymphoma

Study of Tirabrutinib vs Rituximab/Temozolomide for Relapsed/Refractory Primary Central Nervous System Lymphoma (PCNSL) (clinicaltrials.gov) - P3 | N=132 | Not yet recruiting | Sponsor: Ono Pharmaceutical Co. Ltd

New P3 trial • CNS Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Central Nervous System Lymphoma

An open-label randomized parallel-group phase I study of the oral Bruton tyrosine kinase inhibitor tirabrutinib in systemic sclerosis. (PubMed, Br J Dermatol) - "This study suggests that tirabrutinib is tolerable in patients with SSc and acts by suppressing B-cell activity."

Journal • P1 data • Immunology • Rheumatology • Scleroderma • Systemic Sclerosis • FAS

The Impact of Tirabrutinib Monotherapy for the Treatment of Bing-Neel Syndrome: A Multicenter Retrospective Study. (PubMed, Am J Hematol) - No abstract available

Journal • Monotherapy • Retrospective data • Hematological Disorders • Lymphoma • Lymphoplasmacytic Lymphoma • Waldenstrom Macroglobulinemia

Progression of IgM Monoclonal Gammopathy of Renal Significance (MGRS) to Symptomatic Waldenström Macroglobulinemia: A Case Report. (PubMed, Cancer Rep (Hoboken)) - "This case highlights the importance of early renal biopsy and prompt intervention in suspected IgM-MGRS."

Journal • Hematological Disorders • Hematological Malignancies • Lymphoma • Lymphoplasmacytic Lymphoma • Monoclonal Gammopathy • Oncology • Renal Disease • Waldenstrom Macroglobulinemia

Whole-Eye Radiation for the Local Control of Choroidal Lymphoma in Primary Central Nervous System Lymphoma: A 14-Year Case Study. (PubMed, Cureus) - "He underwent chemotherapy using rituximab combined with high-dose methotrexate and high-dose cytarabine in association with intrathecal methotrexate and cytarabine injections, leading to complete remission...The brain lesions showed a marked response to four weeks of oral tirabrutinib as a salvage therapy, but the lesions regrew, and the patient died seven months later. Throughout the treatment, he maintained a visual acuity of 0.7 (decimal scale) in both eyes. In conclusion, whole-eye radiation should be considered as a treatment option for the local control of active intraocular lymphoma, especially choroidal lesions, for patients with primary central nervous system lymphoma with no active brain lesions and without systemic treatment."

Journal • B Cell Lymphoma • Cataract • CNS Lymphoma • Diffuse Large B Cell Lymphoma • Eye Cancer • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Ophthalmology • Palliative care • Primary Central Nervous System Lymphoma • Primary Vitreoretinal Lymphoma

Multifocal Cutaneous Amyloidosis Mimicking Scleroderma Associated With Primary Cutaneous Marginal Zone Lymphoma. (PubMed, J Dermatol) - No abstract available

Journal • Amyloidosis • Dermatopathology • Hematological Malignancies • Immunology • Lymphoma • Marginal Zone Lymphoma • Oncology • Primary Cutaneous Marginal Zone Lymphoma • Scleroderma • Systemic Sclerosis

TIRABRUTINIB FOR THE TREATMENT OF RELAPSED OR REFRACTORY PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: EFFICACY AND SAFETY FROM THE PHASE II PROSPECT STUDY (ICML 2025) - P2 | "With an ORR of 66.7%, CR/CRu rate of 43.8%, median DOR of 9.3 mo, and a manageable safety profile, the PROSPECT trial supports tirabrutinib monotherapy as a potentially effective treatment option for patients with r/r PCNSL. Keyword: molecular targeted therapies"

Clinical • P2 data • CNS Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Central Nervous System Lymphoma

THE IMPACT OF TIRABRUTINIB, A SECOND-GENARATION BRUTON'S TYROSINE KINASE INHIBITOR, FOR BING-NEEL SYNDROME: A MULTICENTER RETROSPECTIVE STUDY (EHA 2025) - "The standard therapy remains to be elucidated; however, treatment with Bruton's tyrosine kinase inhibitor (BTKi), such as ibrutinib, has favorable efficacy and toxicity. The present study suggests that tirabrutinib is a promising treatment option for BNS, demonstrating sustained efficacy with manageable toxicity."

Retrospective data • Ataxia • CNS Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Lymphoplasmacytic Lymphoma • Movement Disorders • Non-Hodgkin’s Lymphoma • Oncology • Primary Central Nervous System Lymphoma • Waldenstrom Macroglobulinemia

TIRABRUTINIB FOR THE TREATMENT OF RELAPSED OR REFRACTORY PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: EFFICACY AND SAFETY FROM THE PHASE II PROSPECT STUDY (EHA 2025) - P2 | "With an ORR of 66.7%, CR/CRu rate of 43.8%, median DOR of 9.3 mo, and a manageable safety profile, the PROSPECT trial supports tirabrutinib monotherapy as a potentially effective treatment option for patients with r/r PCNSL"

Clinical • P2 data • Anemia • CNS Disorders • CNS Lymphoma • Dermatology • Epilepsy • Fatigue • Hematological Disorders • Hematological Malignancies • Infectious Disease • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Pneumonia • Primary Central Nervous System Lymphoma • Pruritus • Respiratory Diseases

Tirabrutinib for the treatment of relapsed or refractory primary central nervous system lymphoma: Efficacy and safety from the phase II PROSPECT study. (ASCO 2025) - P2 | "With an ORR of 66.7%, CR/CRu rate of 43.8%, median DOR of 9.3 mo, and a manageable safety profile, the PROSPECT trial supports tirabrutinib monotherapy as a potentially effective treatment option for patients with r/r PCNSL."

Clinical • P2 data • Anemia • CNS Disorders • CNS Lymphoma • Dermatology • Epilepsy • Fatigue • Hematological Disorders • Hematological Malignancies • Infectious Disease • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Pneumonia • Primary Central Nervous System Lymphoma • Pruritus • Respiratory Diseases

The mechanism of lineage-specific tRNA recognition by bacterial tryptophanyl-tRNA synthetase and its implications for inhibitor discovery. (PubMed, Nucleic Acids Res) - "Through compound screening, we identified tirabrutinib and its analogues as selective inhibitors of bacterial TrpRS. These compounds occupy the l-Trp and tRNATrp CCA end binding sites of bacterial TrpRS, both of which exhibit less conservation compared to the ATP binding site between bacterial and eukaryotic TrpRSs. These findings enhance our understanding of the lineage-specific recognition of tRNATrp by bacterial TrpRS and highlight the CCA end binding site as a promising target for the future development of selective bacterial TrpRS inhibitors as potential antimicrobials."

Journal

Phase I Study Evaluating Tolerability, Safety, Pharmacokinetics, and Efficacy of Combined ONO-4059 and R-MPV Therapy for PCNSL (clinicaltrials.gov) - P1 | N=20 | Active, not recruiting | Sponsor: Ono Pharmaceutical Co. Ltd | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Central Nervous System Lymphoma

ONO PHARMA Presents Positive Results from Pivotal Trial in U.S. Patients with Relapsed or Refractory PCNSL at 2025 ASCO Annual Meeting (Ono Pharmaceuticals Press Release) - P2 | N=112 | PROSPECT (NCT04947319) | Sponsor: Ono Pharmaceutical Co. Ltd. | "Ono Pharmaceutical...announced that the results from the open label Phase 2 PROSPECT Study of tirabrutinib is to be presented at the 2025 American Society for Clinical Oncology (ASCO) annual meeting. Patients in the U.S. with relapsed or refractory primary central nervous system lymphoma (R/R PCNSL) who received oral tirabrutinib as a monotherapy achieved an overall response rate (ORR) of 67%....After a median follow-up of 11.5 months, ORR was 67%, with a complete response rate of 44%. Median DOR was 9.3 months, and median TTR was 1.0 months. Exploratory endpoints included median overall survival, which was not reached, and median progression-free survival, which was 6.0 months."

Diagnostic • P2 data • CNS Lymphoma • Oncology

Assessment of Conditional Listing for Highly Uncertain and High-Priced Drugs in Taiwan (ISPOR 2025) - " A total of 12 drugs were considered for conditional listing between 2022 and 2024, which included Pemazyre, Tepmetko, Qarziba, Kymriah, Vitrakvi, Blincyto, Vydamax, Takhzyro, Polivy, Velexbru, Spevigo, and Koselugo. The conditional listing opens up new opportunities for high-priced drugs. However, the 2-year real-world evidence for Pemazyre remains insufficient for the government to make a final reimbursement decision. Consequently, the results of the HTA will pose challenges in the future in Taiwan."

Post-marketing surveillance of tirabrutinib in 189 patients with r/r primary central nervous system lymphoma. (PubMed, Future Oncol) - "This surveillance confirmed the tolerability and effectiveness of tirabrutinib in patients with r/r PCNSL in the real-world setting. Japan Registry of Clinical Trials: jRCT2011210002."

Journal • P4 data • CNS Lymphoma • Dermatology • Hematological Disorders • Hematological Malignancies • Hepatology • Immunology • Infectious Disease • Interstitial Lung Disease • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Central Nervous System Lymphoma • Pulmonary Disease • Respiratory Diseases

Tirabrutinib-associated toxic epidermal necrolysis: a case report and review of the literature. (PubMed, Skin Health Dis) - "Tirabrutinib's selective BTK inhibition may activate cytotoxic CD8+ T cells, contributing to Stevens-Johnson syndrome/TEN pathogenesis. Further studies are needed to clarify the mechanisms and develop better diagnostic approaches for BTK inhibitor-related drug eruptions."

Journal • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Steven-Johnson Syndrome • CD8