Nurix Therapeutics' NX-5948, an orally bioavailable and brain-penetrant degrader of Bruton's tyrosine kinase (BTK), has demonstrated promising clinical activity in patients with relapsed or refractory Waldenstrom's macroglobulinemia (WM). The data, presented at the 12th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-12), highlight the potential of NX-5948 to address unmet needs in WM, particularly in patients who have failed prior BTK inhibitor therapies.
Clinical Efficacy in Heavily Pretreated Patients
The ongoing Phase 1a/1b clinical trial of NX-5948 included patients with a median age of 74 years and a median of three prior lines of therapy. Notably, all 13 patients had previously been treated with both BTK inhibitors and chemotherapy/chemo-immunotherapy, indicating a heavily pretreated and refractory patient population. Data from the October 10, 2024, cut-off showed that among nine response-evaluable patients, seven (77.8%) achieved an objective response, while the remaining two experienced stable disease.
"We are encouraged by the emerging positive data from NX-5948 in patients with Waldenstrom’s macroglobulinemia, which add to the previously disclosed robust clinical activity observed in patients with chronic lymphocytic leukemia," said Paula G. O’Connor, M.D., chief medical officer of Nurix.
Durable Responses and Brain Penetration
The responses to NX-5948 were not only robust but also durable. All seven responses were observed at the first assessment at 8 weeks, and five patients remained on treatment, with two continuing for over a year. Furthermore, the responses were independent of baseline mutations in MYD88 and CXCR4, common mutations in WM. Of particular interest is NX-5948's ability to penetrate the brain, potentially offering a distinct advantage in treating Bing-Neel syndrome, a rare form of WM with central nervous system involvement.
Safety and Tolerability
Based on the April 17, 2024 data cut (n=79), NX-5948 demonstrated a tolerable safety profile across doses ranging from 50 mg to 600 mg administered orally once daily. The safety profile for patients with WM was consistent with that of the overall study population.
Case Studies Highlight Clinical Benefit
Two illustrative case studies further underscored the clinical benefit of NX-5948. One patient with both MYD88 and CXCR4 mutations, who had undergone four prior lines of therapy including autologous bone marrow transplantation and ibrutinib, achieved a rapid response and remained on the study for over a year. Treatment with NX-5948 led to a deepening of response over time, as evidenced by a reduction in serum IgM levels, a key biomarker in WM. Another patient, who had progressed on zanubrutinib, also experienced a rapid response with decreasing IgM levels while on NX-5948 treatment.
Implications for WM Treatment
Waldenstrom's macroglobulinemia is a rare, slow-growing non-Hodgkin's lymphoma characterized by the overproduction of monoclonal IgM, leading to anemia, bleeding, and impaired immune function. While chemoimmunotherapy and BTK inhibitors are recommended first-line treatments, there are currently no approved therapies for patients who progress after BTK inhibitor therapy. The promising results from the NX-5948 trial suggest that it could fill this critical unmet need.
Nurix is advancing NX-5948 into the Phase 1b expansion cohort, which includes patients previously treated with BTK inhibitors and those with Bing-Neel syndrome. These data support the potential of NX-5948 as a novel therapeutic option for patients with relapsed/refractory WM, especially those with central nervous system involvement.
