Nurix has launched the Phase 3 DAYBreak CLL-306 trial comparing the BTK degrader bexobrutideg with pirtobrutinib in patients with relapsed or refractory CLL/SLL after covalent BTK inhibitor therapy.
Written By: Umesh Hanumante,
MPharm (Reg. Affairs)
Reviewed By: Pharmacally Editorial Team
Nurix Therapeutics has initiated the global Phase 3 DAYBreak CLL-306 trial (NCT07516093) evaluating bexobrutideg (NX-5948) against pirtobrutinib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have progressed after treatment with a covalent Bruton’s tyrosine kinase (BTK) inhibitor. The pivotal study marks a major step in the clinical development of the investigational BTK degrader and could support future regulatory submissions if superiority is demonstrated.
Bexobrutideg Targets BTK Through Protein Degradation
Bexobrutideg is an investigational, orally available, brain-penetrant, highly selective small-molecule BTK degrader being co-developed by Nurix and Roche. Unlike conventional BTK inhibitors that block enzyme activity, the molecule promotes degradation of the BTK protein, a strategy intended to overcome resistance mechanisms associated with long-term BTK inhibition.
BTK remains a well-established therapeutic target in CLL, yet many patients eventually develop disease progression while receiving covalent BTK inhibitors. Effective treatment options after resistance or intolerance remain limited, creating a continued need for therapies with novel mechanisms of action.
Phase 3 Trial Compares Bexobrutideg with Pirtobrutinib
The randomized, open-label Phase 3 DAYBreak CLL-306 trial is expected to enroll approximately 620 patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) whose disease has progressed after treatment with a covalent BTK inhibitor. Participants will be randomized in a 1:1 ratio to receive either bexobrutideg 600 mg orally once daily or pirtobrutinib. The study has two dual primary endpoints, objective response rate (ORR) and progression-free survival (PFS), both of which will be assessed by an independent review committee. The trial is intended to determine whether bexobrutideg can provide superior clinical benefit over pirtobrutinib and generate evidence to support future global regulatory submissions.
Clinical Development Program Continues to Expand
Commenting on the program, Paula O’Connor, M.D., Chief Medical Officer of Nurix, said bexobrutideg has demonstrated robust clinical activity in relapsed or refractory CLL together with a favorable safety and tolerability profile. She noted that the initiation of DAYBreak CLL-306 reflects the company’s commitment to expanding treatment options for patients who continue to face significant unmet medical needs after BTK inhibitor therapy.
The Phase 3 study builds on encouraging clinical experience generated across Nurix’s broader development program for bexobrutideg.
Broad Clinical Program Supports Multiple Future Indications
Beyond DAYBreak CLL-306, bexobrutideg is being investigated in several ongoing studies across hematologic malignancies and additional therapeutic areas.
The DAYBreak CLL-201 pivotal single-arm Phase 2 study (NCT07221500) is evaluating the agent in relapsed or refractory CLL, while the ongoing NX-5948-301 Phase 1a/1b trial (NCT05131022) continues to assess safety and clinical activity in patients with relapsed or refractory B-cell malignancies.
Nurix also plans to evaluate combination treatment in the NX-5948-203 Phase 1/2 study (NCT07520006), which will investigate bexobrutideg with venetoclax, with or without an anti-CD20 antibody, in both relapsed/refractory and treatment-naïve CLL.
Outside oncology, a new tablet formulation is being studied in healthy volunteers through the Phase 1 first-in-human trial (NCT06717269). The formulation supports future development in immunology and neurology, reflecting the broader therapeutic potential of selective BTK degradation.
If DAYBreak CLL-306 confirms superiority over pirtobrutinib, bexobrutideg could emerge as a new treatment option for patients whose disease progresses after covalent BTK inhibitor therapy and strengthen its position within Nurix’s expanding global development strategy.