Bexobrutideg Earns EMA Orphan Drug Designation for Waldenström Macroglobulinemia

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The European Medicines Agency (EMA) has granted orphan drug designation to the orally bioavailable, brain-penetrant BTK degrader bexobrutideg (NX-5948) for the treatment of patients with Waldenström macroglobulinemia.1

The agent is currently being investigated in a phase 1 trial (NCT05131022) in patients with relapsed/refractory B-cell malignancies. Previously reported data from the study demonstrated that in evaluable patients with Waldenström macroglobulinemia (n = 9), bexobrutideg generated an objective response rate of 77.8%, with all responses being partial or marginal.2 Stable disease was reported in 22.2% of patients.

“The EMA’s orphan drug designation for bexobrutideg represents an important milestone in our regulatory strategy and underscores the significant unmet medical need for improved treatments for Waldenström macroglobulinemia,” Arthur T. Sands, MD, PhD, president and chief executive officer of Nurix Therapeutics, stated in a news release.1 “Granting of the designation highlights bexobrutideg’s potential to provide patients with Waldenström macroglobulinemia a promising new therapeutic option.”

In March 2025, the agent also received orphan drug designation from the FDA for Waldenström macroglobulinemia.2

Phase 1 Trial Overview

During the dose-escalation portion of the first-in-human study, investigators are enrolling patients at least 18 years of age with histologically confirmed relapsed/refractory chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), select diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Waldenström macroglobulinemia, or primary central nervous system lymphoma (PCNSL).3 At least 2 prior lines of therapy and the absence of standard therapies is required for all patients, except those with PCSNL, in whom 1 prior line of therapy is required.

Dose expansion includes specified cohorts for patients with CLL/SLL, DLBCL, MCL, follicular lymphoma, MZL, Waldenström macroglobulinemia, or PCNSL/secondary CNSL. In this portion, measurable disease per response criteria specific to the malignancy; an ECOG performance status of 0 or 1; and adequate organ and bone marrow function are required. Notably, patients with PCNSL and secondary CNS involvement may have an ECOG performance status of 0 to 2.

Patients with known or suspected active prolymphocytic leukemia or Richter's transformation to Hodgkin's lymphoma are being excluded from the study.

In the dose-expansion portion of the study, 1 cohort included patients with second-line Waldenström macroglobulinemia, and another features patients with Waldenström macroglobulinemia being treated in the third line or later. Patients in all arms are receiving bexobrutideg.

The study’s primary end points are the incidence of dose-limiting toxicities; determining the maximum tolerated dose and/or recommended phase 2 dose; and safety. Pharmacokinetics and pharmacodynamics, complete response rate, progression-free survival, and time to next therapy are secondary end points.

Previously, the FDA also granted fast track designation to bexobrutideg for patients with Waldenström macroglobulinemia in December 2024 and for those with relapsed/refractory CLL/SLL after at least two lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor, in January 2024.1 The EMA awarded PRIME designation to bexobrutideg for the treatment of adult patients with relapsed/refractory CLL/SLL after treatment with at least a BTK inhibitor and a BCL-2 inhibitor in November 2024.

References

1. European Medicines Agency grants bexobrutideg (NX-5948) orphan drug designation for the treatment of lymphoplasmacytic lymphoma, also known as Waldenström macroglobulinemia. News release. Nurix Therapeutics. July 7, 2024. Accessed July 8, 2025. https://ir.nurixtx.com/news-releases/news-release-details/european-medicines-agency-grants-bexobrutideg-nx-5948-orphan
2. NX-5948: BTK degrader with activity in lymphoid malignancies. Nurix Therapeutics. October 19, 2024. Accessed July 8, 2025. https://www.nurixtx.com/wp-content/uploads/2025/01/2024-10-19-IWWM-Presentation.pdf
3. A study of NX-5948 in adults with relapsed/​refractory B-cell malignancies. ClinicalTrials.gov. Updated June 15, 2025. Accessed July 8, 2025. https://www.clinicaltrials.gov/study/NCT05131022