Nurix Therapeutics presents data on NX-5948, NX-2127

Nurix Therapeutics announced the presentation of clinical and preclinical data from its targeted protein degradation programs, NX-5948 and NX-2127, which are being evaluated in ongoing Phase 1 clinical trials in patients with relapsed/refractory B cell malignancies. These data are being presented at the 17th International Conference on Malignant Lymphoma, ICML. Details of the ICML Presentations: A poster presentation titled “Proof of concept of NX-2127, a first-in-class Bruton’s Tyrosine Kinase dual-targeted protein degrader with immunomodulatory activity, in patients with DLBCL” disclosed updated safety and pharmacodynamic data from patients treated in the ongoing Phase 1 study of NX-2127. One patient, who entered the study with Stage IV DLBCL having received and failed four prior lines of systemic therapy, was treated at the 300mg once daily dose of NX-2127 and experienced a complete response at the first assessment, which was confirmed at week 16 and maintained through week 24. A second patient treated at the lower dose of 100mg of NX-2127, also with four prior lines of systemic therapy for DLBCL, experienced stable disease followed by progressive disease. A second poster presentation titled “Robust Bruton’s tyrosine kinase degradation with NX-5948, an oral BTK degrader, in a first-in-human phase 1a trial in patients with relapsed/refractory B cell malignancies” disclosed initial demographics and pharmacokinetic/pharmacodynamic data as of December 1, 2022, from the first seven patients enrolled in the ongoing Phase 1a trial in patients with relapsed or refractory B cell malignancies. The data suggest that NX-5948 exhibits dose-proportional pharmacokinetics, with rapid absorption and a half-life that supports daily dosing, as well as exposures that increase with dose. NX-5948 resulted in rapid, robust, and sustained BTK degradation in all patients dosed, regardless of their absolute BTK starting level or tumor type. A third poster presentation titled “BTK degradation as a novel therapeutic strategy in relapsed CNS lymphoma: Preclinical proof of concept studies in intracranial patient-derived model” describes preclinical results demonstrating the potential utility of NX-5948 in addressing the unmet need in patients with CNS lymphoma, which could include both primary and secondary CNS lymphoma. In this study the pharmacodynamic activity of NX-5948 was evaluated in an intracranial model of CNS lymphoma using patient-derived SC1 cells. Oral administration of NX-5948 in mice bearing established intracranial SC1 tumors yielded 98% degradation of BTK in SC1 lymphoma cells isolated six hours after NX-5948 dosing, as quantified by immunoblot analysis. Taken together, these preclinical results support the rationale for including patients with CNS lymphoma in the ongoing Phase 1 study of NX-5948. A fourth poster presentation titled “Drug-resistance mutations in BTK occur in distinct enzymatic classes and are overcome by BTK degradation.” The presentation highlights the discovery that Nurix’s BTK degraders are capable of overcoming treatment-emergent BTK inhibitor resistance mutations. In the presentation, five different clinically emergent BTK resistance mutations were analyzed and categorized as kinase proficient, kinase deficient, or kinase dead, each conferring a different spectrum of resistance to available therapies. NX-2127 was found to be broadly active against each of these mutations. These findings translated into clinically meaningful BTK degradation in the Phase 1 clinical trial and clinical activity independent of baseline BTK mutations.