FDA Fast Track Designation Granted for Novel BTK/LYN Dual Inhibitor in CLL/SLL

The US FDA has granted fast track designation to birelentinib (DZD8586), an investigational, first-in-class, noncovalent dual inhibitor of LYN and BTK.¹ The designation is for the treatment of adult patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.

The FDA's fast track designation is a process designed to expedite the development and review of drugs for serious conditions that address an unmet medical need. This designation facilitates more frequent interaction with the FDA and may enable options such as rolling review and accelerated approval, potentially accelerating the drug's path to market.²

The FDA’s decision is supported by a pooled analysis of 2 phase 1/2 studies, the results of which were recently presented at major oncology and hematology conferences, including the 2025 European Hematology Association (EHA) Annual Congress and the American Society of Clinical Oncology (ASCO) Annual Meeting.¹ This pooled analysis demonstrated a compelling objective response rate of 84.2% in a cohort of heavily pretreated patients with CLL/SLL. Importantly, tumor responses were observed regardless of prior treatment with covalent or noncovalent BTK inhibitors, BTK degraders, or BCL-2 inhibitors.

"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," said Xiaolin Zhang, MD, CEO of Dizal, 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."

The need for new therapeutic options in this patient population is critical due to the high rate of relapse and the emergence of resistance mechanisms to current standard-of-care treatments. While BTK inhibitors have revolutionized the treatment of CLL/SLL, resistance often develops through two primary mechanisms: the BTK C481X mutation and BTK-independent activation of the B-cell receptor (BCR) signaling pathway.

The BTK C481X mutation is a common cause of resistance to covalent BTK inhibitors, as it prevents the irreversible binding of the drug to its target. Noncovalent BTK inhibitors, such as pirtobrutinib (Jaypirca), were designed to overcome this specific mutation. However, as noted by Dizal, resistance has also been reported with these agents, and some patients develop alternative mutations that interfere with drug effectiveness. Additionally, some CLL cells can bypass BTK entirely by activating the BCR signaling pathway through other kinases, such as LYN, leading to BTK-independent resistance. This presents a significant challenge as no currently approved targeted therapy effectively addresses both resistance mechanisms simultaneously.

Birelentinib's novel mechanism of action as a LYN/BTK dual inhibitor is designed to overcome these challenges. By noncovalently inhibiting both BTK and LYN, birelentinib aims to block both the BTK-dependent and BTK-independent signaling pathways, thus inhibiting tumor growth more comprehensively. This dual-targeting strategy is particularly promising in patients who have exhausted traditional BTK and BCL-2 inhibitor therapies and whose disease has developed resistance.

The data presented from the pooled analysis showed that the antitumor efficacy of birelentinib was observed even in patients with the classic C481X BTK resistance mutation and other BTK mutations. Furthermore, the responses were durable, with an estimated 9-month duration of response rate of 83.3%. The drug also demonstrated a favorable safety profile.

Notably, birelentinib is a small molecule with full blood-brain barrier penetration, a characteristic that may be beneficial for patients who develop central nervous system involvement of their disease, although the press release did not specifically address this patient group in the context of this designation.

As the clinical landscape for relapsed/refractory CLL/SLL continues to evolve, birelentinib's unique mechanism of action and encouraging early-phase data position it as a potential new therapeutic option. Ongoing clinical development will be crucial to further define its role and confirm its long-term efficacy and safety in this difficult-to-treat patient population.

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. August 6, 2025. Accessed August 7, 2025. https://tinyurl.com/53xncv89

2. Fast Track. US FDA. Updated August 13, 2024. Accessed August 7, 2025. https://tinyurl.com/y748ywj9