Tirabrutinib PDUFA Dec 18: First Targeted Therapy for PCNSL

The FDA accepted for filing the NDA for tirabrutinib, a highly selective second-generation BTK inhibitor, for relapsed or refractory primary central nervous system lymphoma (R/R PCNSL). The PDUFA target action date is December 18, 2026, under the accelerated approval pathway. There is no US-listed ticker for this drug: Deciphera Pharmaceuticals was acquired by Japan’s ONO Pharmaceutical (TSE: 4528) in June 2024 and delisted. Investors seeking exposure would need to access the Tokyo Stock Exchange.

PCNSL is a rare and aggressive form of non-Hodgkin lymphoma confined to the brain, spinal cord, eye, or leptomeninges. Approximately 20 to 30 percent of newly diagnosed patients are refractory to initial treatment, and up to 60 percent eventually relapse. There are no FDA-approved therapies specifically indicated for R/R PCNSL. If approved, tirabrutinib would be the first targeted therapy for this disease in the United States.

What the Data Showed

The NDA is supported by the Phase 2 PROSPECT study, presented at the 2025 ASCO Annual Meeting. In 48 evaluable patients, tirabrutinib demonstrated an overall response rate (ORR) of 67% (95% CI, 52% to 80%) and a complete response (CR) rate of 44% (95% CI, 29% to 59%). The median duration of response was 9.3 months, and median progression-free survival was 6.0 months. The safety profile was described as manageable.

Tirabrutinib is a highly potent, selective, irreversible BTK inhibitor. Signaling through the B-cell receptor regulates cellular proliferation, activation, and survival of B-cells. By blocking BTK, tirabrutinib cuts off the signaling pathway that drives the malignant B-cells in PCNSL. The drug was discovered and developed by Ono Pharmaceutical, which already markets it in Japan under the brand name Velexbru.

The Context

The BTK inhibitor class is well established in blood cancers. Drugs like Pharmacyclics/Janssen’s Imbruvica (ibrutinib), AstraZeneca’s Calquence (acalabrutinib), and BeiGene’s Brukinsa (zanubrutinib) are approved in various B-cell malignancies including CLL, mantle cell lymphoma, and marginal zone lymphoma. None carry an indication for PCNSL. Tirabrutinib’s selectivity profile and CNS penetration are what differentiate it for this brain-confined disease.

The accelerated approval pathway the FDA chose signals receptivity to a surrogate endpoint approach for this ultra-rare indication. Accelerated approval allows the FDA to grant marketing authorization based on a surrogate endpoint, like response rate, that is reasonably likely to predict clinical benefit. The trade-off is a requirement for post-approval confirmatory trials.

ONO Pharmaceutical completed its acquisition of Deciphera in June 2024, and tirabrutinib’s approval would validate the acquisition strategy. Deciphera is best known for Qinlock (ripretinib), a gastrointestinal stromal tumor therapy, which ONO acquired as part of the deal. The tirabrutinib NDA represents ONO’s push to become a global specialty pharma company with a presence in the US oncology market.

What to Watch

The December 18 PDUFA is 146 days out. The drug is already approved in Japan, which provides real-world safety data that may de-risk the FDA review. The main risk is the single-arm Phase 2 design: no randomized controlled trial data exists for tirabrutinib in PCNSL. The FDA could require additional efficacy evidence or restrict the label. A second risk is that the 6.0-month median progression-free survival, while meaningful in this heavily pretreated population, is modest compared to the durability oncologists expect from BTK inhibitors in other indications. For background on how FDA review deadlines work, see our guide to PDUFA dates.

Source: ONO Pharmaceutical PROSPECT study results at ASCO 2025 | PROSPECT on ClinicalTrials.gov (NCT04947319)