Section 3 of 6

Product information and disease description

67 evidence topics · 37 sources

Product description

Phase of product development

FDA orphan designation and approval status

“Date Designated: 03/21/2023” (opens the source at this quote in a new tab)
“Orphan Designation: Treatment of primary central nervous system lymphoma” (opens the source at this quote in a new tab)
“FDA Orphan Approval Status: Not FDA Approved for Orphan Indication” (opens the source at this quote in a new tab)

New drug application and FDA action date

“accepted for filing” (opens the source at this quote in a new tab)
“under the accelerated approval pathway” (opens the source at this quote in a new tab)
“PDUFA Date of December 18, 2026” (opens the source at this quote in a new tab)

Regulatory submission: NDA submitted December 2025

“As for VELEXBRU, as President Takino mentioned earlier, we filed an application in the US last December, and the application was accepted in February of this year.” (opens the source at this quote in a new tab)

Launch: Anticipated in the fiscal year ending March 2027

“Next, I will discuss the full-year forecast for the fiscal year ending March 31, 2027.” (opens the source at this quote in a new tab)
“One of these, tirabrutinib, ONO-4059, is currently under review for approval by the US FDA. We are looking forward to this being our third global product as we prepare for its launch this fiscal year.” (opens the source at this quote in a new tab)

Approval dates outside the United States

“In Japan, tirabrutinib was approved in March 2020” (opens the source at this quote in a new tab)
“in South Korea in November 2021 and in Taiwan in February 2022.” (opens the source at this quote in a new tab)

Taiwan assessment report: recorded approval date

“2021/10/29” (opens the source at this quote in a new tab)

Product information

Generic, brand name and therapeutic class of product

Manufacturer: Deciphera Pharmaceuticals

“Developed in collaboration with Deciphera’s parent company, Ono Pharma.” (opens the source at this quote in a new tab)

“Deciphera Pharmaceuticals, a member of Ono Pharmaceutical Co., Ltd.” (opens the source at this quote in a new tab)
“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.” (opens the source at this quote in a new tab)
“Through its affiliate, Deciphera Pharmaceuticals, Ono is accelerating clinical development and commercial operations in the US and Europe to drive global business expansion and further its commitment to patient care.” (opens the source at this quote in a new tab)

“As of July 1, 2025, Key function of ONO PHARMA USA was integrated into Deciphera.” (opens the source at this quote in a new tab)

Research name

“Code name: ONO-4059” (opens the source at this quote in a new tab)

Dosage forms and strengths

Dosage form: Japan

“Velexbru Tablets 80 mg” (opens the source at this quote in a new tab)

Research-use chemical safety data sheet

“Trade name: ONO-4059” (opens the source at this quote in a new tab)
“CAS Number: 1351636-18-4” (opens the source at this quote in a new tab)
“This product is for research use - Not for human or veterinary diagnostic or therapeutic use.” (opens the source at this quote in a new tab)

Average sales price and wholesale acquisition cost

United States average sales price and wholesale acquisition cost

No evidence found.

Medical costs: Japan

“Medical costs were calculated based on Japanese receipt scores.” (opens the source at this quote in a new tab)
“tirabrutinib cost 0.91 million JPY per month.” (opens the source at this quote in a new tab)

American hospital formulary service (AHFS), or other drug classification

ATC classification

“L01EL06 Tirabrutinib” (opens the source at this quote in a new tab)
“L01EL Bruton's tyrosine kinase (BTK) inhibitors” (opens the source at this quote in a new tab)

Indication

Approved indication: Taiwan

“Relapsed or refractory B-cell primary central nervous system lymphoma in adult patients.” (opens the source at this quote in a new tab)

Pharmacology

Mechanism of action

Covalent BTK binding

“Upon administration, tirabrutinib covalently binds to BTK within B cells, thereby preventing B-cell receptor signaling and impeding B-cell development.” (opens the source at this quote in a new tab)

Pharmacodynamics

Preclinical evidence

“In the TMD8 subcutaneous xenograft model, tirabrutinib showed a dose-dependent anti-tumor effect.” (opens the source at this quote in a new tab)
“Phosphoproteomic analysis revealed the downregulation of ERK and AKT pathways in TMD8.” (opens the source at this quote in a new tab)

Biochemical selectivity and off-target inhibition

“Tirabrutinib irreversibly and covalently binds to BTK Cys-481.” (opens the source at this quote in a new tab)

Pharmacokinetics

Pharmacokinetics: healthy subjects and rheumatoid arthritis

“A biphasic PK profile was shown with median half-life ranging from ~ 6.2 to ~ 7.3 hours.” (opens the source at this quote in a new tab)

Metabolism

“The primary metabolic enzyme of tirabrutinib was CYP3A4 (in vitro).” (opens the source at this quote in a new tab)

Contraindications/Warnings/Precautions/Adverse effects

Warnings and precautions

Safety precautions: Japan

“Oculomucocutaneous syndrome (Stevens-Johnson syndrome) or toxic epidermal necrolysis (TEN)” (opens the source at this quote in a new tab)
“Administration should be permanently discontinued.” (opens the source at this quote in a new tab)

Toxic epidermal necrolysis: DLBCL case report

“We present a case of a 74-year-old man with refractory DLBCL who developed TEN after 1 month of tirabrutinib treatment.” (opens the source at this quote in a new tab)

Skin-related adverse events across B-cell malignancies

“PCNSL and WM patients were most susceptible to skin-related AEs.” (opens the source at this quote in a new tab)

Special populations

Hepatic impairment: caution in the Japanese review

“careful use of tirabrutinib is essential for patients with hepatic impairment” (opens the source at this quote in a new tab)

Drug/Drug, drug/disease interactions

Effects of other drugs on Tirabrutinib

CYP3A4 and P-glycoprotein interactions

“Co-administration of the strong CYP3A4/P-gp inducer, rifampin, resulted in a significant decrease in tirabrutinib exposure (~70%).” (opens the source at this quote in a new tab)
“Co-administration of CYP3A4 inhibitors may increase tirabrutinib exposure.” (opens the source at this quote in a new tab)

Effects of Tirabrutinib on other drugs

In vitro CYP and transporter inhibition

“In vitro data indicate tirabrutinib has the potential to inhibit several CYPs and transporters.” (opens the source at this quote in a new tab)

In vitro anthracycline interactions

“Our in vitro data demonstrate that tirabrutinib influences daunorubicin pharmacodynamics by targeting both metabolic and transport pathways.” (opens the source at this quote in a new tab)

Dosing and administration

Dosage

Usual adult dosage: Japan

“The usual adult dosage is 480 mg of tirabrutinib administered orally once daily under fasting conditions.” (opens the source at this quote in a new tab)

Administration

Nasogastric administration and serum concentrations

“Tirabrutinib concentrations may increase with nasogastric administration using the simple suspension method.” (opens the source at this quote in a new tab)
“In patients unable to ingest tablets orally, careful clinical monitoring is warranted, and therapeutic drug monitoring may be considered in select cases.” (opens the source at this quote in a new tab)

Nasogastric administration in an elderly patient

“We report that tirabrutinib was administered via nasogastric tubes to treat an elderly patient with primary central nervous system lymphoma (PCNSL).” (opens the source at this quote in a new tab)

Access and distribution

Marketed access: Japan

“Tirabrutinib has been approved and is currently marketed in Japan for relapsed or refractory (R/R) PCNSL patients.” (opens the source at this quote in a new tab)

Co-prescribed/Concomitant therapies

Investigational chemotherapy combinations: PROSPECT Part B

“MTR: Methotrexate/ temozolomide/ rituximab” (opens the source at this quote in a new tab)
“R-MPV: Rituximab/ methotrexate/ procarbazine/ vincristine” (opens the source at this quote in a new tab)

Effect of Tirabrutinib on quality measures

No evidence found.

Product comparison

Meta-analysis of tirabrutinib monotherapy across B-cell malignancies

“seven clinical trials involving a total of 301 patients with CLL, PCNSL, MCL, and WM” (opens the source at this quote in a new tab)

Meta-analysis including tirabrutinib treatment regimens

“Only two studies including 188 patients evaluated tirabrutinib-based treatment regimens” (opens the source at this quote in a new tab)

Place of product in therapy

Disease description

Definition and etiology

Disease definition

“lymphoma limited to the cranial-spinal axis” (opens the source at this quote in a new tab)
“without systemic disease (stage IE)” (opens the source at this quote in a new tab)

Epidemiology

Incidence of Primary central nervous system lymphoma

United States epidemiology

“Incidence rate increased from 0.1/100,000 to 0.5/100,000 with an AAPC of 5.3% from 1975 to 2017.” (opens the source at this quote in a new tab)

Prevalence of Primary central nervous system lymphoma

No evidence found.

Natural history, survival, and mortality

Overall survival in published trials

“the median overall survival in published trials generally ranges from 2 to 5 years.” (opens the source at this quote in a new tab)

Survival in older adults: United States registry analysis

“The 5-year survival rate for elderly patients was about 30% in the 2010s.” (opens the source at this quote in a new tab)

Pathophysiology

B-cell histology

“more than 95% of PCNSL cases are diffuse large B cell lymphoma (DLBCL)” (opens the source at this quote in a new tab)

Immunosuppression and viral association

“Immunosuppression-related primary CNS lymphomas are almost always associated with the Epstein-Barr virus.” (opens the source at this quote in a new tab)

Diagnosis

Histopathological confirmation

“PCNSL diagnosis must be confirmed by histopathological examination of tumour biopsy” (opens the source at this quote in a new tab)

Clinical presentation - signs and symptoms

Neurological and gastrointestinal symptoms: headache, seizures, nausea, and vomiting

“Signs and symptoms of primary CNS lymphoma may include nausea and vomiting or seizures.” (opens the source at this quote in a new tab)
“Headaches.” (opens the source at this quote in a new tab)

Motor symptoms: limb weakness

“Arm or leg weakness.” (opens the source at this quote in a new tab)

Cognitive symptoms: confusion

“Confusion.” (opens the source at this quote in a new tab)

Visual and auditory symptoms

“Double vision.” (opens the source at this quote in a new tab)
“Hearing loss.” (opens the source at this quote in a new tab)

Long-term morbidity

High-dose brain radiation: possible cognitive and communication effects

“can affect thinking, learning, problem solving, reading, writing, speech, and memory.” (opens the source at this quote in a new tab)

Burden of Primary central nervous system lymphoma

Humanistic burden and health-related quality of life

Long-term survivors: neuroimaging and quality of life after whole-brain radiotherapy

“Total T2 abnormalities after WBRT were more than twice the mean of any non-WBRT group and were associated with poorer neuropsychological and QOL outcomes.” (opens the source at this quote in a new tab)

Economic burden and healthcare resource utilization

PCNSL economic burden: Taiwan

“mean direct healthcare costs exceeding 1 million TWD (35,000 USD) concentrated within the first year following diagnosis.” (opens the source at this quote in a new tab)

Economic impact of Primary central nervous system lymphoma on families

No evidence found.

Economic impact of diagnostic testing

Stereotactic brain biopsy: Japanese medical costs

“The cost of the stereotactic brain tumor biopsy surgery was 0.2 million JPY.” (opens the source at this quote in a new tab)

Approaches to treatment

Current treatment options and standard of care

Systemic chemotherapy

High-dose methotrexate: induction therapy

“high-dose methotrexate is the most frequently used standard induction therapy.” (opens the source at this quote in a new tab)

Non-myeloablative consolidation regimen

“cytarabine/etoposide” (opens the source at this quote in a new tab)

Anti-CD20 monoclonal antibodies

Rituximab-containing chemotherapy regimens

“MTR: Methotrexate/ temozolomide/ rituximab” (opens the source at this quote in a new tab)
“R-MPV: Rituximab/ methotrexate/ procarbazine/ vincristine” (opens the source at this quote in a new tab)

High-dose chemotherapy with autologous stem cell transplantation

Thiotepa-based consolidation

“consolidative HDC/ASCT, preferably conditioned by a thiotepa-based regimen” (opens the source at this quote in a new tab)

Radiotherapy

Whole-brain radiotherapy: salvage treatment

“Salvage WBRT may be proposed in radiotherapy-naïve patients” (opens the source at this quote in a new tab)

Bruton tyrosine kinase inhibitors

Relapsed or refractory PCNSL: EHA-ESMO guideline

“Tirabrutinib, a highly selective BTK inhibitor, is a valid option in this setting.” (opens the source at this quote in a new tab)

European Association of Neuro-Oncology guideline update

“signs of clinical activity of tirabrutinib, a second-generation BTK inhibitor, have also been found.” (opens the source at this quote in a new tab)

Immunomodulatory agents

Agents evaluated for relapsed or refractory disease

“lenalidomide and pomalidomide” (opens the source at this quote in a new tab)

Intrathecal and intravitreal chemotherapy

Local treatment for intraocular disease

“Intravitreal MTX injections” (opens the source at this quote in a new tab)

Combined intravenous and intrathecal treatment: cognitive-outcome literature

“intravenous and intrathecal chemotherapy.” (opens the source at this quote in a new tab)

Immune checkpoint inhibitors

Checkpoint inhibitor listed among active drugs for induction or relapsing disease

“Nivolumab.” (opens the source at this quote in a new tab)

CAR t-cell therapy

Investigational salvage treatment: guideline evidence

“CART have shown clinical activity” (opens the source at this quote in a new tab)

Corticosteroids and supportive care

Glucocorticoid antitumor activity

“Glucocorticoids are steroid drugs that have an anticancer effect in lymphomas.” (opens the source at this quote in a new tab)

Limitations of current therapies

Summary

The Chinese expert consensus reports no preferred standard regimen for relapsed or refractory PCNSL. Long-term survivor evidence links whole-brain radiotherapy with greater T2 abnormalities and poorer neuropsychological and quality-of-life outcomes. Thus, treatment selection must account for both disease control and treatment-related neurological burden; the cited survivorship findings do not establish the comparative safety of tirabrutinib.

Unmet treatment needs

“There is no standard regimen particularly preferred for relapsed/refractory (R/R) PCNSL.” (opens the source at this quote in a new tab)

Place in treatment, anticipated use, and care setting

Summary

Tirabrutinib's established marketed use in the cited Japanese sources is relapsed or refractory PCNSL. The usual adult Japanese dosage is 480 mg orally once daily under fasting conditions. The EHA-ESMO guideline identifies tirabrutinib as an option in relapsed or refractory disease and recommends specialist multidisciplinary care. PROSPECT Part B investigates its addition to MTR or R-MPV in newly diagnosed PCNSL; that investigational use should not be treated as an approved first-line indication.

Heterogeneity of treatment effect

Exploratory response subgroup: refractory after the last treatment

“Those who were refractory after the last treatment (ORR, 33.3%)” (opens the source at this quote in a new tab)

Care management intervention strategies

Specialist multidisciplinary care

“specialist centres by an experienced multidisciplinary team” (opens the source at this quote in a new tab)

Ongoing post-approval monitoring

Japanese approval condition: risk management

“The applicant is required to develop and appropriately implement a risk management plan.” (opens the source at this quote in a new tab)

Expected outcomes of therapy

Relapsed or refractory PCNSL: PROSPECT response and response duration

“With an ORR of 66.7%, CR/CRu rate of 43.8%, median DOR of 9.3 mo” (opens the source at this quote in a new tab)
“median PFS was 6.0 mo” (opens the source at this quote in a new tab)