FDA Grants Birelentinib Fast Track Designation for Patients With Relapsed or Refractory CLL/SLL

Birelentinib (DZD8586; Dizal), a first-in-class, non-covalent, LYN/BTK dual inhibitor, received fast track designation (FTD) from the FDA for the treatment of adult patients with relapsed or refractory (R/R) chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have received at least 2 prior lines of therapy, including a Bruton tyrosine kinase (BTK) inhibitor and a BCL-2 inhibitor. The decision is supported by a pooled analysis of 2 phase ½ studies, of which the results were presented at the 2025 European Hematology Association Annual Congress and featured at the 2025 American Society of Clinical Oncology Annual Meeting and the 18th International Conference on Malignant Lymphoma.

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CLL/SLL prognoses have greatly improved over the past few decades with the emergence of novel targeted therapies and immunotherapies. A cornerstone of treatment for these patients is BTK and BCL-2 inhibitors, but many patients progress or relapse on these therapies. This is due to BTK C481X mutations and BTK-independent activation of the BCR signaling pathway, for which no targeted therapy concurrently addresses at this time.¹

Birelentinib is a first-in-class LYN/BTK dual inhibitor that demonstrates favorable pharmacokinetic properties, central nervous system permeability, complete inhibition of BCR signaling, and encouraging anti-tumor efficacy. Most notably, the agent has full blood-brain barrier (BBB) penetration, representing a critical step forward in drug development, as many agents are not able to cross the BBB.¹

The drug, originally designed as a potential treatment for B-cell non-Hodgkin lymphoma (B-NHL), is also highly selective against TEC family kinases such as TEC, ITK, TXK, and BMX. By targeting BTK and LYN, birelentinib inhibits tumor growth through interruption of BTK-dependent and -independent BCR-signaling pathways.¹

Birelentinib has demonstrated favorable clinical benefit across multiple clinical trials. The FTD is based on pooled data from 2 studies: TAI-SHAN5 (NCT05824585) and TAI-SHAN8 (NCT06539182). TAI-SHAN5 is a phase 1, open-label, multicenter study evaluating the safety, tolerability, pharmacokinetics, and anti-tumor efficacy of DZD8586 in patients with B-NHL. TAI-SHAN8 is the phase 2 trial of TAI-SHAN5. The primary outcomes measured were objective response rate (ORR), duration of response, and incidences of adverse events (AEs).^2-4

Across the trials, a total of 40 patients with R/R CLL/SLL (median age 64.5 years; 62.5% male; 60% EBOG score of 1 or 2) were treated with birelentinib at doses ranging from 25 mg to 100 mg once daily. The most common prior therapies were BTK (76.7%) and BCL-2 inhibitors (43.3%), but patients also reported treatment with non-covalent BTK inhibitors (13.3%) and BTK degraders (13.3%). Thirty out of the 40 patients were evaluable for efficacy.⁴

According to the data, 15 out of 30 patients achieved a tumor response with an ORR of 50% across dose levels. The ORR was higher (64.3%) in patients who received the recommended phase 2 dose of 50 mg once daily. Patients with prior BTK treatment achieved superior ORR compared with those who were previously treated with BCL-2 inhibitors (52.2% vs 46.2%). For those treated with BTK degraders, 75% achieved a partial response.⁴

Birelentinib was well-tolerated with a favorable safety profile across the doses. The most common grade 3 or higher AEs were neutropenia (15%) and pneumonia (10%) in patients treated with the recommended phase 2 dose. No grade 4 or 5 AEs were reported.⁴

“DZD8586 showed encouraging anti-tumor activity with a well-tolerated and manageable safety profile in heavily pre-treated CLL/SLL patients, including patients with prior covalent BTKi, non-covalent BTKi, BTK degrader and Bcl-2 inhibitor treatment,” the authors wrote in their abstract. “[Pharmacokinetic and pharmacodynamic] results confirmed dose/exposure-dependent pathway inhibition by DZD8586.”⁴

The FDA’s decision marks a critical step forward in overcoming BTK and BCL-2 inhibitor resistance, offering patients with poorer responses to such therapies alternative options. Continued research is needed to drive birelentinib forward on the path to approval.

"The granting of fast track designation underscores the US FDA's recognition of birelentinib's potential to address an unmet medical need in patients with CLL/SLL," Xiaolin Zhang, MD, chief executive officer of Dizal, said in a press release. "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."¹

REFERENCES

1. The U.S. FDA granted fast track designation to dizal's birelentinib for relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. PR Newswire. August 6, 2025. Accessed August 7, 2025. https://www.prnewswire.com/news-releases/the-us-fda-granted-fast-track-designation-to-dizals-birelentinib-for-relapsedrefractory-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma-302523083.html

2. DZD8586 in patients with relapsed or refractory B-cell non-hodgkin lymphoma. Updated July 23, 2024. Accessed August 7, 2025. https://clinicaltrials.gov/study/NCT05824585#study-plan

3. DZD8586 in patients with relapsed or refractory CLL/​SLL (TAI-SHAN8). Updated August 20, 2024. Accessed August 7, 2025. https://clinicaltrials.gov/study/NCT06539182

4. Li J, Shou KS, Zhu H, et al. Phase 1/2 studies of DZD8586 in CLL/SLL patients after covalent or non-covalent BTK inhibitors and BTK degraders. 2025 ASCO Annual Meeting. May 30, 2025, to June 3, 2025. Chicago, IL. Abstract 7010.