Nurix Therapeutics, Inc. announced the presentation of the first findings of clinical responses in the brain for NX-5948, an orally available, selective degrader of Bruton's tyrosine kinase (BTK). The presentation included case studies for two patients, one with CLL with CNS involvement and the other with PCNSL, each demonstrating clinically meaningful responses. The presentation also provided evidence of measurable drug levels in the CNS of multiple patients in the ongoing Phase 1 trial who had CNS tumor involvement.

These data were presented by Gwenn M. Hansen, Ph.D., chief scientific officer of Nurix, as part of the Major Symposium session Molecular Glues, PROTACs, and Next-Gen Degraders: Discovery and Early Preclinical Advances at the AACR 2024 Annual Meeting, which is being held from April 5-10, 2024, in San Diego, CA. Dr. Hansen's presentation included new data from the dose escalation stage of Nurix's Phase 1a/1b clinical trial evaluating daily oral dosing of BTK degrader NX-5948 in patients with relapsed or refractory B-cell malignancies. Data were presented demonstrating detection of NX-5948 in the cerebrospinal fluid (CSF) from all patients with available CSF samples.

Case studies were presented for two of these patients. In one case study, a CLL patient was enrolled with secondary CNS involvement whose disease progressed following three prior lines of treatment, including both a BCL2 inhibitor in combination with rituximab and a BTK inhibitor (acalabrutinib). This patient, who presented with malignant cells in the CSF at study entry and the high-risk cytogenetic marker Del17p, received NX-5948 at a once daily dose of 100 mg.

By week 8, the patient had significant lymph node reduction and spleen reduction consistent with stable disease. By week 16, the patient had experienced continued reduction in lymph nodes and spleen size and improvements in hematologic measures consistent with a partial response. By week 24, the partial response was confirmed and the patient no longer had measurable tumor cells in the CSF.

As of March 4th, the patient remains on treatment in cycle 10 of therapy (>36 weeks). In the other case study, a patient was enrolled with primary central nervous system lymphoma (PCNSL) with the high-risk cytogenic marker of MYC rearrangement and whose disease progressed after two prior lines of therapy, including high dose multi-drug chemotherapy with rituximab in the first-line setting, and ibrutinib in the second line, which yielded a best response of stable disease. The patient presented with three measurable lesions in the right temporal lobe and received NX-5948 at the 450 mg once daily dose.

By week 8, the patient experienced complete regression of all three lesions and demonstrated a complete response (CR). A subsequent 16 week scan revealed that this patient?s disease had progressed with the emergence of a new brain lesion. CNS involvement of B cell malignancies span various conditions including: Primary CNS lymphoma (PCNSL) comprising 4% of all primary CNS tumors and 4-6% of all extranodal lymphomas; secondary CNS lymphoma (SCNSL) which represents a risk of approximately 5% in patients with diffuse large B cell lymphoma (DLBLC); and CNS involvement in CLL which albeit rare, presents a poor prognosis in patients with clinically significant disease.

NX-5948 is an investigational, orally bioavailable, brain penetrant, small molecule degrader of BTK. NX-5948 is currently being evaluated in a Phase 1 clinical trial in patients with relapsed or refractory B cell malignancies. Nurix has previously reported that NX-5948 is highly potent against a range of tumor cell lines that are resistant to current BTK inhibitor therapies, an important consideration in heavily pretreated CLL/SLL patient populations.