Nurix Therapeutics Reports Positive Results for BTK Degrader NX-5948 in Relapsed/Refractory Waldenstrom’s Macroglobulinemia Trial

Nurix Therapeutics, Inc., a clinical-stage biopharmaceutical company, announced new findings from its Phase 1a/1b clinical trial of NX-5948. This drug is an orally bioavailable, brain-penetrant degrader of Bruton’s tyrosine kinase (BTK), aimed at treating patients with relapsed/refractory Waldenstrom’s macroglobulinemia (WM). These results were presented at the 12th International Workshop on Waldenstrom’s Macroglobulinemia (IWWM-12) in Prague, Czech Republic.

NX-5948 has shown significant clinical activity, with 77.8% of evaluable Waldenstrom’s patients experiencing objective responses. The responses were not only durable but also improved over time, with two patients remaining on treatment for over a year.

Paula G. O’Connor, M.D., the chief medical officer of Nurix, expressed optimism regarding these positive results. She highlighted that the data support the decision to advance NX-5948 into the Phase 1b expansion cohort. This cohort includes patients who have received prior treatments, including BTK inhibitors, and those with Bing-Neel syndrome, a rare form of WM involving the central nervous system. NX-5948’s ability to penetrate the brain offers a potential advantage for these patients.

The safety profile of NX-5948 was consistent across the study. Data from the April 17, 2024 cutoff showed that the drug was well-tolerated across doses ranging from 50 mg to 600 mg daily. The October 10, 2024 data update provided further insights into the baseline characteristics of the first 13 WM patients enrolled. These patients had a median age of 74 years and had undergone a median of three prior lines of therapy. All had previously been treated with both BTK inhibitors and chemotherapy. Some had also received non-covalent BTK inhibitors and BCL2 inhibitors. Mutations in MYD88 and CXCR4 were present in 61.5% and 15.4% of patients, respectively.

Among the nine patients evaluable for response, seven (77.8%) had an objective response, while the remaining two experienced stable disease. The responses were seen at the first assessment after eight weeks of treatment, and five patients remained on treatment, some for over a year. Responses were observed regardless of the presence of baseline mutations in MYD88 and CXCR4.

Two case studies illustrated the potential of NX-5948. The first case involved a patient with MYD88 and CXCR4 mutations who had undergone four prior lines of therapy, including autologous bone marrow transplantation and ibrutinib. This patient showed a rapid response at the first assessment and continued treatment beyond one year, with deepening responses over time. The second case involved a patient with a MYD88 mutation who had received three prior lines of therapy and showed a rapid response initially, with decreasing IgM levels, a key biomarker for WM.

Nurix Therapeutics focuses on developing innovative small molecules and antibody therapies aimed at modulating cellular protein levels for treating cancer and inflammatory diseases. Their proprietary DELigase platform leverages expertise in E3 ligases to identify and advance novel drug candidates. NX-5948 is part of Nurix's clinical-stage pipeline, which includes targeted BTK protein degraders and inhibitors of Casitas B-lineage lymphoma proto-oncogene B (CBL-B).

Waldenstrom’s macroglobulinemia is a rare type of non-Hodgkin’s lymphoma characterized by the replacement of normal bone marrow cells with malignant lymphocytes producing monoclonal IgM. This condition leads to anemia, bleeding, impaired immune function, and neurological symptoms due to elevated IgM levels. In the United States, the annual incidence is approximately three per million, with about 1,000 to 1,500 new cases diagnosed each year. Current first-line treatments include chemoimmunotherapy and BTK inhibitors, but there are no approved therapies for patients after BTK inhibitors, highlighting the need for additional therapeutic options.