FDA Grants Fast Track Designation to Birelentinib for R/R CLL/SLL

The FDA has granted fast track designation to birelentinib (DZD8586), a first‑in‑class, noncovalent LYN/BTK dual inhibitor with full blood–brain barrier penetration, for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).1

The designation was supported by pooled data from a phase 2 study (NCT06539182)presented at the 2025 EHA Congress and the 2025 ASCO Annual Meeting evaluating birelentinib in heavily pretreated patients with CLL/SLL, including those previously exposed to covalent or noncovalent BTK inhibitors, BTK degraders, or BCL2 inhibitors.

Amongst this patient population, birelentinib produced an objective response rate (ORR) of 84.2%, with a favorable safety profile. Responses were observed irrespective of known BTK resistance mutations, including C481X and kinase‑dead variants. The estimated 9‑month duration of response (DOR) rate was 83.3%.

Patients treated with birelentinib at 50 mg once per day (n = 19) achieved an ORR of 84.2%.2 Those treated at a dose of 75 mg once per day (n = 15) had an ORR of 68.8%. Between these 2 dose levels, 94.1% of patients experienced tumor shrinkage.

These data supported the 50-mg dose as the recommended phase 3 dose. Regarding the safety of this dose level, no instances of major cardiac adverse effects (AEs), such as atrial fibrillation or QT prolongation, were reported. No patients experienced drug-related bleeding, and no treatment-emergent AEs related to treatment led to death.

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

Phase 2 CLL Trial Breakdown

This ongoing phase 2, open‑label, multicenter study is designed to evaluate the efficacy, safety, tolerability, and pharmacokinetics of birelentinib monotherapy in patients with relapsed or refractory CLL or SLL.3 Eligible patients must have disease that has progressed following prior therapy, is unresponsive to previous treatment, or has resulted in unacceptable toxicity from prior regimens. Patients were also required to have an ECOG performance status of 0 to 2, a confirmed diagnosis requiring treatment, and adequate bone marrow and organ function.

Key exclusions include central nervous system involvement, Richter transformation, recent stem cell or cell-based therapy, recent surgery or major injury, recent live vaccines, use of restricted medications, active infection, significant cardiac disease, thrombotic events within 6 months, uncontrolled gastrointestinal conditions, and other malignancies within 2 years, except for certain skin or in situ cancers.

The study’s primary objective is to assess the anti‑tumor activity of birelentinib as monotherapy. Secondary objectives include characterization of the safety profile, identification of treatment‑related adverse effects, and pharmacokinetic analysis to determine systemic exposure and drug metabolism.

Patients are assigned to 1 of 3 experimental treatment cohorts, receiving a daily oral dose of birelentinib at 25 mg, 50 mg, or 75 mg. Treatment continues until disease progression, unacceptable toxicity, or withdrawal of consent.

Efficacy will be assessed according to standard hematologic and radiologic criteria, and safety will be evaluated throughout the study. Pharmacokinetic sampling will be performed to measure birelentinib plasma concentrations and characterize drug disposition.

References

1. The U.S. FDA granted Fast Track designation to Dizal’s birelentinib for relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. News Release. Dizal Pharma. August 6, 2025. Accessed August 6, 2025. https://www.dizalpharma.com/news/detail?id=100&search=&currentPage=1
2. Li J, Zhou 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. Presented at: 2025 EHA Congress; June 12-15, 2025; Milan, Italy. Abstract PF570.
3. DZD8586 in patients with relapsed or refractory CLL/SLL (TAI-SHAN8). Clinicaltirals.gov. Updated August 20, 2024. Accessed August 6, 2025. https://clinicaltrials.gov/study/NCT06539182