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

Bexobrutideg (NX-5948), a novel Bruton's tyrosine kinase (BTK) degrader, shows high clinical activity and tolerable safety in patients with Waldenström macroglobulinemia: Updated results from an ongoing Phase 1a/b study (ASH 2025) - "Bexobrutideg was well tolerated in patients with WM, consistent with previous disclosuresin the overall study population. Bexobrutideg demonstrated a notably high level of clinical activity withsteady reduction in IgM levels and deepening responses over time in heavily pre-treated patients (all ofwhom had prior cBTKi exposure), and in patients whose tumors had MYD88 and CXCR4 mutations.Bexobrutideg Phase 1b dose expansion is underway."

Clinical • IO biomarker • P1 data • Chronic Lymphocytic Leukemia • CNS Disorders • Hematological Malignancies • Infectious Disease • Influenza • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Respiratory Diseases • Targeted Protein Degradation • Waldenstrom Macroglobulinemia • BTK • CRBN • CXCR4 • MYD88

Inhibition of platelet kinase signaling and scaffolding activities with small molecule proteolysis-targeting chimeras (PROTACs) (ASH 2025) - "Bleeding risks areparticularly notable for patients with B cell malignancies treated with TKIs such as ibrutinib, a Bruton'styrosine kinase (BTK) inhibitor...For example, Abl inhibitorasciminib does not affect platelet function and is not associated with bleeding, while other Abl inhibitorslike ponatinib abrogate platelet function and increase risk of thrombosis.Beyond off-target toxicities of TKIs, evolving therapeutic resistances to TKIs present challenges in theclinic, fueling the need for novel agents to modulate signaling systems in disease...We found that treatment of human platelets withBTK PROTACs (DD-03-171, NX-5948) for 2 hours led to loss of BTK protein and reduced phosphorylationof the BTK substrate PLCγ2 pY1217 following stimulation of platelets with the immunotyrosine activationmotif (ITAM) receptor glycoprotein GPVI...Control experiments show that PROTAC reagents alone didnot alter platelet function, as platelets treated with PROTACs for 10 min..."

Targeted Protein Degradation • Thrombosis • ABL1 • PLCG2

Diverse signaling and vulnerabilities accompany distinct BTK mutations associated with clinical resistance to COVALENT, non-COVALENT and protacs targeting BTK in MYD88 mutated lymphomas. (ASH 2025) - "Sensitivity to cBTK-i (zanubrutinib); ncBTK-i (pirtobrutinib); BTK PROTACs (BGB-16673, NX-2127, NX-5948); and a novel oral compound (DFCI-002-06)developed and characterized by us (Liu et al, Blood 2024; 144 Supp1: 834) that degrades HCK,LYN, and BTK were evaluated using CellTiter-Glo and apoptosis assays. Engineered TMD8 and BCWM.1 lines expressing various BTK mutations showedexpected resistance profiles: C481S conferred resistance to covalent BTKi, while all othermutations conferred resistance to pirtobrutinib. Our findings showed diverse signaling and vulnerabilities that accompany distinctBTK mutations associated with clinical resistance to covalent, non-covalent and PROTACstargeting BTK. We identified HCK and LYN dependent alternative pro-survival signaling in V416L,A428D, and L528W BTK mutant expressing cells which were deficient for BTK Y223 kinasesignaling. Importantly, we observed that the DFCI-002-06 which degrades HCK, LYN and BTKbroadly overcame..."

Clinical • B Cell Lymphoma • Chronic Lymphocytic Leukemia • CNS Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Primary Central Nervous System Lymphoma • Targeted Protein Degradation • Waldenstrom Macroglobulinemia • BTK • HCK • LYN • MYD88 • NFKBIA • PLCG2 • STAT3

Molecular and structural basis of pan-resistance to BTK targeting therapies via BTK A428D mutation (ASH 2025) - P1 | "BTK A428D was detected at baseline but not at progression in a second patient.To evaluate the impact of BTK A428D on drug response, we transduced BTK-dependent TMD8 cells withBTK WT, C481S, L528W, and A428D, and found that BTK A428D uniquely conferred resistance to all FDA-approved BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib, pirtobrutinib) as well as three BTKdegraders under clinical evaluation (zelebrudomide, bexobrutideg, BGB-16673). Combining the BTK degraders with venetoclax slowedthe emergence of the BTK A428D resistant population and, in the case of zelebrudomide, eradicated boththe wild-type and A428D clones.In summary, we identified and validated BTK A428D as a clinically relevant acquired pan-resistancemutation that confers resistance by blocking access to the ATP binding pocket. This mechanism differsfrom other kinase dead BTK mutations in which the kinase's enzymatic pocket remained accessible.Thesedata also provide rationale for combining..."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • CRBN • SF3B1 • TP53

Efficacy and mechanism of BTK degrader nx-5948 in secondary hemophagocytic lymphohistiocytosis (ASH 2025) - "Subsequently,the anti-inflammatory potency of the JAKinhibitor ruxolitinib, BTK inhibitors ibrutinib and zanubrutinib, as well as BTK degrader NX-5948 wascompared. The BTK degrader NX-5948 exerted potent therapeutic effects against HLH pathogenesis inboth in vitro and in vivo models. These findings indicate that BTK degraders represent a noveltherapeutic strategy for the clinical management of HLH."

Clinical • Hematological Disorders • Hemophagocytic lymphohistiocytosis • Immunology • Nephrology • Rare Diseases • Renal Disease • Targeted Protein Degradation • ANXA5 • CRBN • IFNG • IL1B • IL2 • IL6 • NFKBIA • PLCG2 • TNFA

Bexobrutideg (NX-5948), a novel Bruton's tyrosine kinase (BTK) degrader, demonstrates rapid and durable clinical responses in Relapsed/Refractory chronic lymphocytic leukemia (CLL): New and updated findings from an ongoing Phase 1a/b trial (ASH 2025) - "In the largest Ph1a/b cohort of pts with relapsed/refractory CLL treated with bexobrutidegreported to date, bexobrutideg was well tolerated across dose levels and treatment durations.Bexobrutideg showed rapid and durable responses in a heavily pre-treated population of pts with CLL,including those with baseline BTK mutations and high-risk molecular features. Additional follow-up andpreliminary results from the 200 mg vs 600 mg randomized dose-expansion cohorts will be presented."

Clinical • IO biomarker • P1 data • Atrial Fibrillation • Cardiovascular • Chronic Lymphocytic Leukemia • Hematological Malignancies • Infectious Disease • Leukemia • Neutropenia • Pneumonia • Respiratory Diseases • Septic Shock • Targeted Protein Degradation • Thrombocytopenia • BTK • CRBN • PLCG2 • TP53

Advances in the Management of Relapsed/Refractory CLL and Richter Transformation (ICML 2025) - P=N/A, P2, P3 | "BRUIN CLL-321 is a phase 3, registrational study that evaluated pirtobrutinib compared to the investigator's choice of idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) [23]...Nemtabrutinib is now being evaluated in the registrational, phase 3 BELLWAVE-010 trial (NCT05947851) for patients with R/R CLL, comparing nemtabrutinib plus venetoclax to venetoclax plus rituximab...An ongoing, open-label, first-in-human phase 1/2 study is evaluating the BTK degrader BGB-16673 as monotherapy in patients with R/R CLL [27, 28]...NX-2127 is an investigational, first-in-class BTK degrader currently being evaluated in a phase 1 trial for patients with relapsed or refractory B-cell malignancies, CLL [29, 30]...NX-5948 is another investigational and more selective BTK degrader in an ongoing Phase 1a/1b clinical trial...This trial aims to establish lisaftoclax plus acalabrutinib as a potential alternative to venetoclax-based BTKi combination..."

IO biomarker • Acute Myelogenous Leukemia • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • Small Lymphocytic Lymphoma • BCL2L1 • TP53

Nurix Therapeutics Presents New Data from the Phase 1 Trial of Bexobrutideg (NX-5948) in Waldenström Macroglobulinemia at the 67th American Society of Hematology (ASH) Annual Meeting and Exposition (GlobeNewswire) - "As of the September 19, 2025 data cut, 28 patients were evaluable for response. Bexobrutideg demonstrated an objective response rate (ORR) of 75.0%, including very good partial responses (VGPR) in three patients (10.7%), partial responses (PR) in 14 patients (50.0%), and minor responses (MR) in four patients (14.3%). Six patients (21.4%) had a best response of stable disease (SD). In a subgroup analysis of patients with 2 or more disease assessments (n=23), ORR was 82.6% and disease control rate (DCR) was 100.0%."

P1 data • Waldenstrom Macroglobulinemia

Data presented at the 2025 ASH Annual Meeting include baseline demographics and safety findings for all patients with CLL/SLL in the ongoing Phase 1a/1b study (n=126) and safety findings for patients treated at the RP2D of 600 mg (n=70). (GlobeNewswire) - "Bexobrutideg was well tolerated across all dose levels evaluated...The updated Phase 1a dataset includes patients treated at starting dose levels ranging from 50 mg to 600 mg once daily with a median follow-up of 19.0 months (range = 13.5 – 32.3). Among the 47 efficacy evaluable patients, the objective response rate (ORR) was 83.0% including two patients (4.3%) with a complete response, an improvement from earlier disclosures due to additional follow-up and deepening of response. Overall, the disease control rate (DCR) was 95.7%. Importantly, the median progression-free survival was 22.1 months, and the median duration of response (DOR) was 20.1 months....In the randomized Phase 1b cohort, 42 patients were assigned to receive either 200 mg (n = 22) or 600 mg (n = 20) once daily. Among the 37 efficacy evaluable patients, preliminary data showed the 600 mg dose with an ORR of 83.3% compared to 73.7% for the 200 mg dose."

P1 data • Chronic Lymphocytic Leukemia • Small Lymphocytic Lymphoma

Relative Bioavailability of NX-5948 Tablets vs Capsules and the Effect of Covariates on the PK of NX-5948 Tablets (clinicaltrials.gov) - P1 | N=18 | Recruiting | Sponsor: Nurix Therapeutics, Inc. | Trial completion date: Mar 2025 ➔ Dec 2025 | Trial primary completion date: Feb 2025 ➔ Nov 2025

Trial completion date • Trial primary completion date

Nurix Therapeutics Announces Webcast to Review New and Updated Data from the Phase 1 Clinical Trial of BTK Degrader Bexobrutideg (NX-5948) To Be Presented at the 67th American Society of Hematology (ASH) Annual Meeting and Exposition (GlobeNewswire) - "The webcast will feature a presentation by guest speaker and clinical study investigator Alvaro Alencar...who will present clinical data from the ongoing Phase 1a/1b trial of bexobrutideg in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and Waldenström macroglobulinemia (WM)."

P1 data • Chronic Lymphocytic Leukemia • Waldenstrom Macroglobulinemia

Initial Findings from a First-in-Human Phase 1a/b Trial of NX-5948, a Selective Bruton's Tyrosine Kinase (BTK) Degrader, in Patients with Relapsed/Refractory B Cell Malignancies (ASH 2023) - "Current findings in this heavily pre-treated population of patients with CLL and NHL are encouraging and indicate that NX-5948 is safe and well tolerated and has clinical activity, supporting continuation of its development in CLL and NHL. NX-5948 also exhibits dose-proportional PK, resulting in rapid, robust and sustained BTK degradation. Additional data with higher dose levels and longer treatment duration will be presented at the meeting."

Clinical • First-in-human • IO biomarker • P1 data • Atrial Fibrillation • B Cell Lymphoma • Cardiovascular • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Hypertension • Leukemia • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Targeted Protein Degradation • Thrombocytopenia • BTK • CRBN

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 • Primary Central Nervous System Lymphoma • Secondary Central Nervous System Lymphoma • Targeted Protein Degradation • CD79B • CRBN • CXCL12 • ETV6 • MYD88 • TCF19

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 • Pulmonary Embolism • Respiratory Diseases • Targeted Protein Degradation • Thrombocytopenia • BCL2 • BTK • CRBN • PLCG2 • TP53

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

Bexobrutideg (NX-5948), a novel Bruton's tyrosine kinase (BTK) degrader, demonstrates rapid and durable clinical responses in relapsed/refractory (R/R) CLL: updated findings from an ongoing Phase (Ph) 1a study (DGHO 2025) - "Bexobrutideg was well tolerated in patients, including those with longer duration of treatment and higher doses. Rapid and durable responses were observed independent of prior treatment or high-risk features. Ph1b dose expansion (200 and 600 mg cohorts) is underway with plans to initiate pivotal trials in 2025."

Clinical • IO biomarker • Atrial Fibrillation • Cardiovascular • Chronic Lymphocytic Leukemia • Fatigue • Hematological Malignancies • Infectious Disease • Neutropenia • Targeted Protein Degradation • BCL2 • BTK • CRBN • PLCG2 • TP53

Nurix Therapeutics…announced that updated clinical data from the NX-5948-301 Phase 1a/1b clinical trial have been selected for presentation at the 67th American Society of Hematology (ASH) Annual Meeting… (GlobeNewswire) - "The data will be featured in two presentations: an oral presentation with new results in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and a poster presentation with updated results in patients with Waldenström macroglobulinemia."

P1 data • Chronic Lymphocytic Leukemia • Waldenstrom Macroglobulinemia

BEXOBRUTIDEG (NX-5948), A NOVEL BRUTON'S TYROSINE KINASE (BTK) DEGRADER, DEMONSTRATES RAPID AND DURABLE CLINICAL RESPONSES IN RELAPSED/REFRACTORY CLL: UPDATED FINDINGS FROM AN ONGOING PHASE 1A STUDY (SIE 2025) - "Table 1. Overall response assessment in patients with CLL (Phase 1a)."

Clinical • IO biomarker • P1 data • Atrial Fibrillation • Cardiovascular • Chronic Lymphocytic Leukemia • Fatigue • Hematological Malignancies • Infectious Disease • Neutropenia • Targeted Protein Degradation • BCL2 • BTK • CRBN • PLCG2 • TP53

BEXOBRUTIDEG (NX-5948), A NOVEL BRUTON'S TYROSINE KINASE (BTK) DEGRADER, SHOWS HIGH CLINICAL ACTIVITY AND TOLERABLE SAFETY IN AN ONGOING PHASE 1A/ B STUDY IN PATIENTS WITH WALDENSTRÖM MACROGLOBULINEMIA (WM) (SIE 2025) - "Figure 1. Steady decrease in IgM levels in patients treated with bexobrutideg"

Clinical • IO biomarker • Atrial Fibrillation • Cardiovascular • Hematological Malignancies • Lymphoma • Lymphoplasmacytic Lymphoma • Targeted Protein Degradation • Thrombocytopenia • Waldenstrom Macroglobulinemia • BTK • CRBN • CXCR4 • MYD88

Exploring the Mechanism of Action and Related Biomarkers of BTK Inhibitor/Degrader in Systemic Lupus Erythematosus (ACR Convergence 2025) - "Normal, vehicle, Ibrutinib (BTK inhibitor), and NX-5948 (BTK degrader) were administered daily, and the mice were sacrificed around week 2. This study conducted a detailed comparative analysis at the cellular and protein levels among normal mice, SLE model mice, and those treated with a BTK inhibitor or degrader. Our study compared clinical data with disease model data to determine their correlation and used this model to explore the mechanisms of action of BTK inhibitors and degraders. We hope that this research approach can be applied to the study of more diseases."

Biomarker • Atopic Dermatitis • Dermatitis • Dermatology • Hematological Malignancies • Immunology • Inflammatory Arthritis • Lupus • Rheumatoid Arthritis • Rheumatology • Systemic Lupus Erythematosus • CD4 • CD69 • CD86 • CSF1 • IFNG • IL2RA • IL4 • IL6

Nurix Therapeutics, Inc…announced the initiation of the DAYBreak clinical trial, a pivotal single-arm Phase 2 study of bexobrutideg (NX-5948) in patients with relapsed or refractory chronic lymphocytic leukemia. (GlobeNewswire) - "The DAYBreak study will enroll patients with r/r CLL who have experienced disease progression following treatment with a covalent BTK inhibitor (cBTKi), a BCL-2 inhibitor (BCL-2i), and a non-covalent BTK inhibitor (ncBTKi)."

Trial status • Chronic Lymphocytic Leukemia

Nurix plans to initiate a randomized confirmatory Phase 3 trial in the first half of 2026 in r/r CLL patients whose disease has previously progressed while receiving a cBTKi (GlobeNewswire) - "This global Phase 3 confirmatory trial in patients treated in the second line or later setting will compare bexobrutideg monotherapy to an investigator’s choice of pirtobrutinib monotherapy (a ncBTKi), bendamustine + rituximab, or idelalisib + rituximab."

New P3 trial • Chronic Lymphocytic Leukemia

BTK-EndoMut Platform: Engineered Resistance Models Accelerating BTK-Targeted Drug Discovery (AACR-NCI-EORTC 2025) - "Mutant TMD8 lines display broad IC50 shifts: A428D and L528W confer >100-fold resistance to both ibrutinib and pirtobrutinib, C481S remains nanomolar to pirtobrutinib, whereas T474I/V416L stay responsive to zanubrutinib; all variants expect A428D retain low-nanomolar BGB-16673 and NX-5948 susceptibility. In vivo, C481F tumors show modest ibrutinib delay, whereas L528W xenografts resist ibrutinib yet regress under daily NX-5948 without overt weight loss. Proliferation assays mirror these drug-response patterns across the panel.Impact: Kyinno's BTK-mutant lines accelerate high-throughput screening of small-molecule inhibitors and targeted degraders, delineate resistance circuitry via isogenic comparisons, and improve translational relevance by faithfully modeling patient-derived escape variants."

Oncology • BTK

A Study of NX-5948 in Adults With CLL/SLL Previously Treated With a Bruton's Tyrosine Kinase Inhibitor and a B-cell Lymphoma-2 Inhibitor (DAYBreak CLL-201) (clinicaltrials.gov) - P2 | N=100 | Recruiting | Sponsor: Nurix Therapeutics, Inc.

New P2 trial • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • BCL2

Nurix is enrolling a Phase 1b cohort for patients with CLL and autoimmune hemolytic anemia and is conducting the necessary Phase 1 healthy volunteer studies to support a potential autoimmune IND in 2026. (Yahoo Finance)

Enrollment status • New trial • Autoimmune Hemolytic Anemia • Chronic Lymphocytic Leukemia