The U.S. Food and Drug Administration has granted fast track designation to birelentinib (DZD8586), a novel dual kinase inhibitor developed by Dizal Pharmaceutical, for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.
Addressing Critical Resistance Mechanisms
Patients with CLL/SLL treated with BTK inhibitors or BCL-2 inhibitors often experience disease progression due to two major resistance mechanisms: BTK C481X mutations and BTK-independent activation of the BCR signaling pathway. Currently, no targeted therapy addresses both mechanisms simultaneously, creating an urgent clinical challenge in this patient population.
Birelentinib represents a first-in-class, non-covalent LYN/BTK dual inhibitor with complete blood-brain barrier penetration and high selectivity against other TEC family kinases (TEC, ITK, TXK and BMX). By targeting both BTK and LYN, the drug blocks both BTK-dependent and BTK-independent BCR signaling pathways, effectively inhibiting tumor growth in B-cell non-Hodgkin lymphomas.
Strong Clinical Efficacy Data
The fast track designation is supported by pooled analysis data from two phase I/II studies presented at the 2025 European Hematology Association Annual Congress and featured in oral presentations at both the 2025 American Society of Clinical Oncology Annual Meeting and the 18th International Conference on Malignant Lymphoma.
In heavily pretreated CLL/SLL patients previously exposed to covalent/non-covalent BTK inhibitors and BTK degraders, birelentinib demonstrated significant anti-tumor efficacy with an objective response rate of 84.2% and a favorable safety profile. Notably, tumor responses were observed irrespective of prior treatment history, including patients harboring classic BTK resistance mutations (C481X) as well as other BTK mutations such as kinase-dead mutations.
The durability of responses was particularly encouraging, with an estimated 9-month duration of response rate of 83.3%. Among patients treated with the recommended phase 3 dose of 50 mg once daily (n=19), the objective response rate reached 84.2%, while those receiving 75 mg once daily (n=15) achieved a 68.8% response rate. Across both dose levels, 94.1% of patients experienced tumor shrinkage.
Safety Profile and Development Timeline
At the 50-mg dose level, no instances of major cardiac adverse events such as atrial fibrillation or QT prolongation were reported. Additionally, no patients experienced drug-related bleeding, and no treatment-emergent adverse events related to treatment led to death.
"The granting of Fast Track Designation underscores the U.S. FDA's recognition of birelentinib's potential to address an unmet medical need in patients with CLL/SLL," said Dr. Xiaolin Zhang, CEO of Dizal. "We look forward to working closely with the FDA to accelerate the global clinical development of birelentinib and bring this treatment option to patients as quickly as possible."
Ongoing Clinical Development
The supporting data comes from an ongoing phase 2, open-label, multicenter study (NCT06539182) evaluating the efficacy, safety, tolerability, and pharmacokinetics of birelentinib monotherapy in patients with relapsed or refractory CLL or SLL. The study includes patients whose disease has progressed following prior therapy, is unresponsive to previous treatment, or has resulted in unacceptable toxicity from prior regimens.
Fast track designation is an FDA program designed to facilitate development and expedite review of drugs for serious conditions that address unmet medical needs. The designation enables frequent FDA interactions and may allow for rolling review, priority review, or accelerated approval if criteria are met.
