bexobrutideg (NX-5948) / Nurix Therap - LARVOL DELTA

NX-5948 is a CNS-penetrant catalytic Bruton's tyrosine kinase (BTK) degrader that breaks established design rules for CNS drugs (AACR 2025) - "In the clinic, NX-5948 is detectable in cerebrospinal fluid of patients with CNS-involved B-cell malignancies, with concentrations that exceed the minimum free plasma level that correlates with BTK degradation. NX-5948 has also demonstrated clinically meaningful responses in patients with primary CNS lymphoma or chronic lymphocytic leukemia with CNS involvement (Hansen, G., AACR San Diego, 2024; Linton, K., EHA Hybrid Congress, Madrid, Spain, 2024), supporting the therapeutic potential of NX-5948 in B-cell malignancies with CNS involvement."

Chronic Lymphocytic Leukemia • CNS Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Central Nervous System Lymphoma • BTK

An oral BTK degrader TGRX-3911 overcomes resistance conferred by kinase-proficient and kinase-impaired mutations (AACR 2025) - "TGRX-3911 potently inhibited proliferation of TMD8 parental cells and those harboring knock-in BTK mutations that are resistant to currently approved ibrutinib, zanubrutinib and/or pirtobrutinib, including C481S, T474I, L528W, V416L, A428D, T474I/C481S, T474I/L528W and C481S/L528W (IC50 from 0.4 to 9.9 nM). Remarkably, TGRX-3911 potently inhibited the A428D mutant which is still resistant to current BTK degraders, NX-5948, BGB-16673 and ABBV-101...By eliminating both the catalytic and scaffold functions of BTK, TGRX-3911 has the potential to overcome clinical resistance which can hardly be achieved by conventional BTKi. The potential clinical application of TGRX-3911 for patients with B-cell malignancies is worth exploring."

B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD86 • PLCG2

HP-002: A brain-penetrant PROTAC that demonstrated potent anti-proliferation activities on multiple BTK mutant (AACR 2025) - "In lymphoma cells e.g. REC-1 and TMD8, HP-002 demonstrated 2-digit pM IC50 with up to ~10-fold more potent than NX-5948 and BGB-16673. HP-002 is a potent and highly selective BTK degrader against BTK-WT and multiple BTK inhibitor-resistant mutations. Brain penetration was observed in the TMD8 xenograft tumor model with deeper BTK down-regulation on the HP-002 treatment and robust tumor growth inhibition. With no significant safety risk findings in the preliminary rat and NHP DRF studies, HP-002 is currently under IND-enabling development."

Late-breaking abstract • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Oncology • BTK • CRBN • GSPT1 • SALL4

Nurix Therapeutics Presents Positive Preclinical Data at the AACR 2025 Annual Meeting from Multiple Orally Available, Brain Penetrant Degraders Against Three High Value Oncology Targets (GlobeNewswire) - "In a poster titled: 'NX-5948 is a CNS-penetrant catalytic Bruton’s tyrosine kinase (BTK) degrader that breaks established design rules for CNS drugs,' data were presented that highlight the unique physico-chemical properties of NX-5948, now called bexobrutideg, that differentiate it from traditional brain penetrant drugs. Bexobrutideg exhibits CNS exposure in several preclinical models and, most importantly, is detectable in the cerebrospinal fluid of patients where it has demonstrated clinically meaningful responses in patients with primary CNS lymphoma or chronic lymphocytic leukemia with CNS involvement."

Preclinical • Chronic Lymphocytic Leukemia • CNS Lymphoma

Efficacy/Safety of the BTK Degrader NX-5948 in Chronic Lymphocytic Leukemia: An Ongoing Phase 1a/b Study (BSH 2025) - No abstract available

Clinical • P1 data • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

Upcoming Program Highlights: Bexobrutideg (NX-5948) (GlobeNewswire) - "In 2025, Nurix plans to commence a suite of clinical trials designed to support global registration of bexobrutideg for the treatment of patients with CLL. In addition, Nurix anticipates moving into autoimmune and inflammatory diseases and expects to open a new Phase 1b cohort for patients with CLL and associated autoimmune hemolytic anemia and is exploring the filing of a non-malignant hematology IND for autoimmune cytopenias in 2025. Future clinical updates in patients with both CLL and non-Hodgkin’s lymphoma are anticipated in 2025."

IND • New trial • Trial status • Autoimmune Hemolytic Anemia • Chronic Lymphocytic Leukemia • Non-Hodgkin’s Lymphoma

Nurix Therapeutics Announces Multiple Presentations at the American Association for Cancer Research (AACR) 2025 Annual Meeting (GlobeNewswire) - "Nurix Therapeutics...announced that company scientists will present preclinical data from its proprietary DEL-AI platform and several degrader programs in two oral presentations and two poster presentations at the American Association for Cancer Research (AACR) 2025 Annual Meeting..."

Preclinical • Oncology

A Food-Effect, Drug-Drug Interaction, and Pharmacokinetics Study of NX-5948 in Healthy Adult Subjects (clinicaltrials.gov) - P1 | N=32 | Completed | Sponsor: Nurix Therapeutics, Inc. | Active, not recruiting ➔ Completed

Trial completion

NX-5948-303: Absolute Bioavailability, Absorption, Metabolism, Excretion, and Mass Balance Study of [14C] NX-5948 (clinicaltrials.gov) - P1 | N=8 | Completed | Sponsor: Nurix Therapeutics, Inc. | Recruiting ➔ Completed

Trial completion

Nurix Announces U.S. FDA Orphan Drug Designation Granted to Bexobrutideg (NX-5948) for the Treatment of Waldenström Macroglobulinemia (GlobeNewswire) - "Nurix Therapeutics, Inc...announced that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation (ODD) to bexobrutideg (NX-5948) for the treatment of Waldenström macroglobulinemia (WM)....In collaboration with the national naming authority, United States Adopted Name (USAN) Council, Nurix’s lead BTK degrader, NX-5948, was assigned the nonproprietary name 'bexobrutideg'....Nurix continues to enroll patients with WM in an ongoing Phase 1b expansion cohort and anticipates sharing additional clinical data in 2025."

Commercial • Orphan drug • P1 data • Waldenstrom Macroglobulinemia

Breakthroughs in treatment for hematological malignancies: latest updates on molecular glue, PROTACs and RNA degraders from ASH 2024. (PubMed, J Hematol Oncol) - "Currently, the main categories developed based on degraders include molecular glue (such as Cemsidomide, NX-5948), PROTACs (such as BGB-16673, AC-676, KT-333 ), and RNA degraders (such as SKY-1214). This correspondence summarizes the preclinical and clinical updates on degrader therapies presented at the ASH 2024 annual meeting."

Journal • Review • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Targeted Protein Degradation

Bruton Tyrosine Kinase Degraders: Current Concepts. (PubMed, Am J Clin Oncol) - "While BTK inhibitors (BTKi), such as ibrutinib, have been effective, resistance-both intrinsic and acquired-poses a significant challenge, often associated with BTK mutations like C481S...Agents such as NRX-0492, BGB-16673, NX-5948, NX-2127, HZ-Q1060, ABBV-101, and AC676 have shown significant BTK degradation in preclinical and early clinical trials...These BTK degraders have demonstrated favorable safety profiles, with manageable adverse events, and offer a novel therapeutic avenue for patients with BTKi-resistant malignancies. As clinical trials progress, these degraders hold the potential to significantly enhance treatment outcomes, offering a new frontier in personalized cancer therapy."

Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Targeted Protein Degradation • BTK

BTK Is the Target That Keeps on Giving: A Review of BTK-Degrader Drug Development, Clinical Data, and Future Directions in CLL. (PubMed, Cancers (Basel)) - "We focus on four agents which are under investigation in B-cell malignancies in early clinical trials: BGB-16673, NX-2127, NX-5948, and AC676. Further trials investigating these agents in combination with other targeted CLL agents may help to further understand their applicability. An effective, tolerable oral class of drugs would be invaluable in the treatment of patients with multiply relapsed CLL/SLL."

Clinical data • Journal • Review • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • Targeted Protein Degradation • BCL2

A Validated Liquid Chromatography-Tandem Mass Spectrometry Assay for the Determination of NX-5948 in Beagle Dog Plasma: Application to a Pharmacokinetic Study. (PubMed, Biomed Chromatogr) - "NX-5948 was demonstrated to be stable under the present storage conditions. After validation, the method was successfully applied for the quantification of NX-5948 in beagle dog plasma after oral and intravenous administration of the NX-5948."

Journal • PK/PD data • Oncology • Targeted Protein Degradation • BTK

BTK Is the Target That Keeps on Giving: A Review of BTK-Degrader Drug Development, Clinical Data, and Future Directions in CLL (Multidisciplinary Digital Publishing Institute) - "Encouraging pre-clinical data show that this MOA allows BTK protein degraders to overcome common BTK mutations. We focus on four agents which are under investigation in B-cell malignancies in early clinical trials: BGB-16673, NX-2127, NX-5948, and AC676. Preliminary data suggest a comparable safety and toxicity profile between agents across this drug class with many patients on phase 1 trials deriving durable clinical benefit. Optimal sequencing of BTK degraders in the therapeutic landscape of CLL/SLL treatment is yet to be established."

Review • Chronic Lymphocytic Leukemia • Small Lymphocytic Lymphoma

Nurix Therapeutics Reports Fourth Quarter and Fiscal Year 2024 Financial Results and Provides a Corporate Update (GlobeNewswire) - "Upcoming Program Highlights: NX-5948:...Nurix...expects to open a new Phase 1b cohort for patients with CLL and associated autoimmune hemolytic anemia...in 2025. Future clinical updates in patients with both CLL and non-Hodgkin’s lymphoma are anticipated in 2025."

Clinical protocol • P1 data • Chronic Lymphocytic Leukemia • Non-Hodgkin’s Lymphoma

Nurix Therapeutics Reports Fourth Quarter and Fiscal Year 2024 Financial Results and Provides a Corporate Update (GlobeNewswire) - "Upcoming Program Highlights: NX-5948:...Nurix anticipates moving into autoimmune and inflammatory diseases...and is exploring the filing of a non-malignant hematology IND for autoimmune cytopenias in 2025."

IND • Hematological Disorders • Immunology • Inflammation

Nurix Therapeutics Outlines 2025 Goals and Objectives for Advancement of Its Robust Pipeline in Cancer and Autoimmune Diseases (GlobeNewswire) - "Initiate a suite of clinical trials in 2025 intended to support global registration of NX-5948 for the treatment of chronic lymphocytic leukemia....Drive NX-2127 to proof-of-concept data: Nurix is focusing development on aggressive lymphomas where the combination of BTK degradation and IKZF1/3 degradation have the potential for synergy and significant therapeutic benefit. The company plans to complete dose escalation with new chirally controlled drug product and select recommended Phase 1b dose for selected indications and expects to share additional clinical data after selection of a Phase 1b expansion dose(s) and indication(s). Drive NX-1607 to proof-of-concept data: Nurix is testing both once daily (QD) and twice daily (BID) dosing of NX-1607. With additional patients in the BID dosing arms, Nurix plans to establish a Phase 1b monotherapy dose and expects to share additional clinical data after selection of a Phase 1b expansion dose(s) and indication(s)."

New trial • P1 data • Breast Cancer • Cervical Cancer • Chronic Lymphocytic Leukemia • Colorectal Cancer • Diffuse Large B Cell Lymphoma • Melanoma • Non Small Cell Lung Cancer • Prostate Cancer • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer

BTK Degradation As a Novel Therapeutic Strategy in Relapsed CNS Lymphoma: Proof of Concept Studies in Intracranial Patient-Derived, Rodent Models (ASH 2024) - P1 | "Here we evaluated the pharmacodynamic properties of NX-5948 in an intracranial model of PCNSL using PC2 cells derived from a patient with highly refractory MYD88-, CD79B-mutant large B-cell PCNSL that had been treated withhigh-dose methotrexate/rituximab...By contrast, in vitro chemotaxis studies using OCI-LY10 cells, a cell line model of MYD88-mutant DLBCL, demonstrated that NX-5948 reproducibly antagonized SDF-1 mediated chemotaxis with greater potency compared to ibrutinib. This suggests that the enhanced efficacy of NX-5948 may be due, in part, to anattenuation of tumor invasion in a CNS lymphoma microenvironment. Taken together these preclinical results support the rationale for a phase I study of NX-5948 in relapsed primary and secondary CNS lymphoma (NCT05131022)."

Preclinical • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • CNS Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Secondary Central Nervous System Lymphoma • Targeted Protein Degradation • CD79B • CRBN • CXCL12 • ETV6 • MYD88 • TCF19

Nx-2127 and Nx-5948, Two Clinical Stage Cereblon-Recruiting BTK Degraders, Facilitate T Cell Functionality in Chronic Lymphocytic Leukemia (ASH 2024) - P1 | "Here, we begin to address these questions by comparing NX-2127 and NX-5948 to ibrutinib, a BTK inhibitor, and lenalidomide, a CRBN immunomodulatory compound. RNA sequencing highlighted distinct gene expression in NX-2127-treated patients. Overall, our findings provide a strong rationale for continued investigation of BTK degraders in CLL and lymphoid malignancies."

Clinical • IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • CD4 • CD69 • CD8 • CRBN • CTLA4 • GATA3 • GZMB • ICAM1 • IFNG • IKZF1 • IL17A • IL2 • IL2RA • IL4 • LY9 • PD-1

NX-5948-301: A Study of NX-5948 in Adults With Relapsed/Refractory B-cell Malignancies (clinicaltrials.gov) - P1 | N=492 | Recruiting | Sponsor: Nurix Therapeutics, Inc. | N=292 ➔ 492 | Trial completion date: Jan 2027 ➔ Jan 2028 | Trial primary completion date: Dec 2025 ➔ Jan 2027

Enrollment change • Trial completion date • Trial primary completion date • B Cell Lymphoma • Chronic Lymphocytic Leukemia • CNS Lymphoma • Diffuse Large B Cell Lymphoma • Extranodal Marginal Zone Lymphoma • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Central Nervous System Lymphoma • Secondary Central Nervous System Lymphoma • Small Lymphocytic Lymphoma • Splenic Marginal Zone Lymphoma • Waldenstrom Macroglobulinemia • BCL2 • BCL6

Efficacy and Safety of the Bruton's Tyrosine Kinase (BTK) Degrader NX-5948 in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL): Updated Results from an Ongoing Phase 1a/b Study (ASH 2024) - "Prior therapies : BTKi (97.1%), pirtobrutinib (23.5%), BCL2i (91.2%), BTKi + BCL2i (88.2%), chemo/chemoimmunotherapy (79.4%), PI3Ki (32.4%), CAR-T (5.9%). Responses observed in pts with PLCG2 mutations support a mechanism whereby NX-5948 disrupts the BTK signaling complex, potentiating broader targeting of oncogenic pathways downstream of BTK. The Phase 1b dose-expansion portion of the study is underway; data from additional pts are expected for the presentation."

Clinical • IO biomarker • P1 data • Atrial Fibrillation • Cardiovascular • Chronic Lymphocytic Leukemia • Fatigue • Hematological Disorders • Hematological Malignancies • Hypertension • Leukemia • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Pain • Pulmonary Embolism • Respiratory Diseases • Targeted Protein Degradation • Thrombocytopenia • BCL2 • BTK • CRBN • PLCG2 • TP53

Additional preclinical data presentations (GlobeNewswire) - "Preclinical data were presented demonstrating the positive effects of brain-penetrant NX-5948 treatment on survival in a patient-derived xenograft model of primary central nervous system lymphoma (PCNSL)....The data demonstrate that daily oral administration of NX-5948 drives potent degradation of BTK, inhibition of extracellular signal-regulated kinase (ERK) and prolonged survival in the setting of CNS lymphoma. In addition, transcriptional changes associated with enhanced tumor antigen presentation and reduced tumor progression were observed in NX-5948 treated animals....In addition, preclinical results were presented demonstrating that although both NX-2127 and NX-5948 effectively degrade BTK in primary CLL cells while preserving T-cell activation and survival in vitro, NX-2127 demonstrates unique immunomodulatory activity."

Preclinical • Chronic Lymphocytic Leukemia • CNS Lymphoma

Nurix Therapeutics Receives U.S. FDA Fast Track Designation for NX-5948 for the Treatment of Relapsed or Refractory Waldenstrom’s Macroglobulinemia (GlobeNewswire) - "Nurix Therapeutics, Inc...today announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for NX-5948, a highly selective degrader of Bruton’s tyrosine kinase (BTK), for the treatment of adult patients with relapsed or refractory Waldenstrom’s macroglobulinemia (WM) after at least two lines of therapy, including a BTK inhibitor...'This designation follows encouraging safety and efficacy data from our ongoing Phase 1 clinical trial, demonstrating early promise of clinical benefit with potential for durable outcomes. We continue to enroll Waldenstrom’s macroglobulinemia patients in the ongoing Phase 1b expansion cohort and anticipate sharing additional clinical data in 2025.'"

Fast track • P1 data • Waldenstrom Macroglobulinemia

Nurix Therapeutics Presents New Positive Data from Phase 1a/1b Clinical Trial of NX-5948 in Chronic Lymphocytic Leukemia at the 66th American Society of Hematology Annual Meeting (GlobeNewswire) - P1a/1b | N=292 | NCT05131022 | Sponsor: Nurix Therapeutics, Inc. | "The data presented at the ASH Annual Meeting include safety findings for all patients in the NX-5948 Phase 1a/1b dose escalation and expansion cohorts (n=125), including those with CLL/SLL and those with non-Hodgin’s lymphoma (NHL).....Among the efficacy evaluable patients with CLL/SLL (n=49), NX-5948 treatment resulted in a robust objective response rate (ORR) of 75.5% across all doses tested, with the majority of responses occurring at the first assessment (Week 8). With longer time on treatment, the ORR increased to 84.2% based on an exploratory efficacy analysis of patients who had at least two response assessments (Week 16)."

P1 data • Chronic Lymphocytic Leukemia • Non-Hodgkin’s Lymphoma • Small Lymphocytic Lymphoma