zelebrudomide (NX-2127) / Nurix Therap - LARVOL DELTA

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

SGR-1505, a potent and selective MALT1 inhibitor with preliminary efficacy in BTKi exposed Waldenström macroglobulinemia (WM) and "double-exposed" CLL/SLL (ASH 2025) - P1 | "In B-cell lymphoma lines with acquired BTKiresistance, SGR-1505 exhibited comparable IC50 values as compared to the parental cell lines, andcombining SGR-1505 with venetoclax or NX-2127 enhanced growth inhibition.As of 13 May 2025, a total of 49 patients had been treated in study SGR-1505-101, including 6 WMrelapsing or refractory to BTKi and 6 CLL/SLL who were double-exposed to prior BTKi and BCL2i.In the 6 WM subjects, median prior lines of therapy was 2 (range: 2-6) and all received prior BTKi as theirlast line of therapy and were refractory or relapsed due to development of BTK resistance mutations orbypass mechanisms...Preclinically, SGR-1505 demonstrated the ability to overcome BTKi resistance in multiple in vitro and invivo models. Clinically, SGR-1505 demonstrated encouraging anti-tumor activity in prior BTKi exposedWM, BTKi/BCL2i double-exposed CLL/SLL and other B-cell malignancies. MALT1 inhibition represents apromising novel therapeutic option with broad..."

Clinical • IO biomarker • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Lymphoplasmacytic Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Small Lymphocytic Lymphoma • Waldenstrom Macroglobulinemia • CARD11 • MALT1 • MYD88

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

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

A First-in-Human Phase 1 Trial of NX-2127, a First-in-Class Bruton's Tyrosine Kinase (BTK) Dual-Targeted Protein Degrader with Immunomodulatory Activity, in Patients with Relapsed/Refractory B Cell Malignancies (ASH 2023) - P1 | "This first-in-human study of NX-2127 is actively enrolling and dose-expansion cohorts in DLBCL and MCL have been initiated at the 300 mg daily dose. Findings include dose-dependent PK accompanied by degradation of BTK and Ikaros. Encouraging and persistent responses were observed in heavily pretreated patients with relapsed/refractory CLL and NHL with a manageable safety profile."

Clinical • First-in-human • Immunomodulating • IO biomarker • P1 data • Anemia • Atrial Fibrillation • B Cell Lymphoma • Cardiovascular • Chronic Lymphocytic Leukemia • CNS Disorders • Cognitive Disorders • Diffuse Large B Cell Lymphoma • Fatigue • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Hypertension • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • Waldenstrom Macroglobulinemia • BTK • CRBN • IKZF1

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

Zelebrudomide: (Yahoo Finance) - "Nurix is conducting a Phase 1a/1b clinical trial, including a Phase 1b expansion cohort focused on patients with diffuse large B-cell lymphoma and mantle cell lymphoma. Nurix is enrolling a dose escalation study within the current Phase 1a/1b trial using the chirally controlled drug product."

Trial status • Diffuse Large B Cell Lymphoma • Mantle Cell Lymphoma

Resistance Mutations in CLL: Genetic Mechanisms Shaping the Future of Targeted Therapy. (PubMed, Genes (Basel)) - "Venetoclax, a BCL2i, induces apoptosis in CLL cells through selective inhibition of the anti-apoptotic BCL2 protein, while BTKis, such as ibrutinib and its next-generation analogs, disrupt B-cell receptor signaling critical to CLL cell survival...This review outlines the molecular basis and clinical implications of these resistance mechanisms, as well as emerging therapeutic solutions, including non-covalent BTKis like pirtobrutinib and BTK-targeting PROTAC degraders such as BGB-16673 and NX-2127...Finally, we highlight the growing role of measurable residual disease (MRD) as a biomarker to guide treatment duration and evaluate therapeutic success. As resistance mechanisms continue to emerge, tailoring therapy based on underlying biology will be critical to sustaining disease control and enhancing outcomes in patients with CLL."

IO biomarker • Journal • Review • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation

New Targets and Drugs on the Horizon in Chronic Lymphocytic Leukemia (SOHO 2025) - P1, P1/2 | "12 Treatment planning for patients with " double refractory " CLL — CLL that is resistant to a covalent BTKi and venetoclax — is a relatively novel but emerging scenario in the clinic...Noncovalent (Reversible) BTK Inhibitors In the BRUIN-321 phase 3 randomized trial of pirtobrutinib monotherapy versus the control arm of the investigator's choice between idealisib plus rituximab or bendamustine plus rituximab, pirtobrutinib had improved PFS (14 vs 8.7 months, Hazard ratio [HR] 0.54, P = 0.0002) and a superior time to next treatment or death compared to the control arm (24 vs 10.9 months, HR 0.37, P < 0.0001)...Nemtabrutinib is another noncovalent BTKi under clinical investigation, demonstrating an overall response rate (ORR) of 36.4% in CLL patients in the phase 1 study (n = 22 patients)...23,24 Thus far, data for three orally administered BTK degraders — NX-2127, NX-5948 and BGB-16673 23–25— have been presented, and there are ongoing clinical..."

IO biomarker • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Leukemia • Lymphoma • Oncology • CD20 • PRKCB • PRKCH • ROR1

Zelebrudomide (NX-2127) is a cereblon-modulating BTK degrader that reverses immune dysfunction and modifies both T-cell and CLL-cell transcriptional signatures in patients with CLL (IWCLL 2025) - P1 | "Lenalidomide and ibrutinib were used as controls. Zelebrudomide and bexobrutideg induce rapid BTK degradation in primary CLL cells. Through CRBN engagement, zelebrudomide induces anti-proliferative activity in primary CLL cells. Furthermore, zelebrudomide uniquely restores Th1 polarization, suppresses Tregs, and enhances cytotoxic immune function in vitro, while reducing tumor burden in vivo."

Clinical • IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • CCR7 • CD40LG • CD69 • CD8 • CRBN • CXCL10 • CXCL11 • DNAJB1 • GATA3 • GZMB • HSPD1 • HSPH1 • ICAM1 • IFNG • IKZF1 • IL15 • IL2 • IL21 • IL2RA • IL4 • LY9 • PD-1

A Phase 1 Trial of NX-2127, a First-in-Class BTK Dual-Targeted Protein Degrader, in Patients With Relapsed/Refractory B-cell Malignancies (SOHO 2025) - P1 | "Endpoints will be assessed using data from patients receiving new drug product NX-2127. Phase 1a is currently enrolling."

Clinical • P1 data • Chronic Lymphocytic Leukemia • CNS Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Marginal Zone Lymphoma • Oncology • Primary Central Nervous System Lymphoma • IKZF1

Nurix Therapeutics Reports Second Quarter 2025 Financial Results and Provides a Corporate Update (GlobeNewswire) - "Upcoming Program Highlights:...Zelebrudomide (NX-2127):...Nurix is conducting a Phase 1a/1b clinical trial, including a Phase 1b expansion cohort focused on patients with diffuse large B-cell lymphoma and mantle cell lymphoma. Nurix is enrolling a dose escalation study within the current Phase 1a/1b trial using its new chirally controlled drug product. Future clinical updates are anticipated in the second half of 2025."

P1 data • Trial status • Diffuse Large B Cell Lymphoma • Mantle Cell Lymphoma

A PHASE 1 TRIAL OF NX-2127, A FIRST-IN-CLASS BTK DUAL-TARGETED PROTEIN DEGRADER, IN PATIENTS WITH RELAPSED/REFRACTORY B-CELL MALIGNANCIES (ICML 2025) - P1 | "Phase 1a is currently enrolling. Keyword: ongoing trials"

Clinical • P1 data • Chronic Lymphocytic Leukemia • CNS Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Marginal Zone Lymphoma • Oncology • Primary Central Nervous System Lymphoma • IKZF1

BTK-A428D IS A CROSS-RESISTANT MUTATION TO BOTH BTK INHIBITORS AND DEGRADERS (EHA 2025) - "BTK-A428D is a mutation that exhibits cross-resistance to multiple BTK degraders (BGB-16673, NX-2127, NX-5948, Abbv Compound 1) and inhibitors (ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib) both in vitro and in vivo, as supported by evidence from multiple aspects. In the future, BTK-A428D mutated cancer cells may be treated by other targeted therapies."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • PLCG2

Upcoming Program Highlights: NX-2127 (GlobeNewswire) - "Following a decision in March 2024 in which the FDA lifted a manufacturing-related, partial clinical hold on the NX-2127 clinical trial, Nurix reinitiated enrollment in a dose escalation study within the current Phase 1a/1b trial using its new chirally controlled drug product. Future clinical updates are anticipated in 2025."

Trial status • Diffuse Large B Cell Lymphoma • Mantle Cell Lymphoma

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

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 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

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 Announces Presentations at the 66th American Society of Hematology (ASH) Annual Meeting (GlobeNewswire) - "Nurix Therapeutics...announced that data will be presented from its two Bruton’s tyrosine kinase (BTK) degrader programs, NX-5948 and NX-2127, in two oral presentations and one poster at the 66th American Society of Hematology Annual Meeting and Exposition being held December 7-10, 2024, in San Diego, CA."

P1 data • Preclinical • Chronic Lymphocytic Leukemia • CNS Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Oncology

Nurix Therapeutics Reports Third Quarter Fiscal 2024 Financial Results and Provides a Corporate Update (GlobeNewswire) - "NX-5948 is an investigational, orally bioavailable degrader of BTK that is currently being evaluated in the Phase 1b portion of a Phase 1a/b clinical trial in adults with relapsed or refractory B-cell malignancies. By year-end 2024, Nurix plans to present additional clinical data from this study for patients with CLL...Nurix recently introduced a new chirally controlled drug product, which is being evaluated in a dose escalation within this Phase 1a/b trial. Future clinical updates are anticipated in 2025...Nurix is evaluating NX-1607 in an ongoing Phase 1 trial in monotherapy and in a combination cohort utilizing paclitaxel in adults in a range of oncology indications...Nurix anticipates providing a program update by year-end 2024."

P1 data • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Lymphoma • Mantle Cell Lymphoma • Oncology • Solid Tumor

Current Management of Waldenstrom Macroglobulinemia (SOHO 2024) - "Chemoimmunotherapy (cyclophosphamide, bendamustine + rituximab) and covalent Bruton tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib, zanubrutinib) are frequently used in the frontline setting.8-12 In the relapsed setting, chemoimmunotherapy and covalent BTK inhibitors are good options, if not previously used. Other treatments include proteasome inhibitors (bortezomib, carfilzomib, ixazomib) and BCL2 antagonists (venetoclax).13-16 Non-covalent BTK inhibitors (pirtobrutinib) have also been shown to be safe and effective in patients whose disease progresses on covalent BTK inhibitors.17 There is a paucity of prospective clinical trials comparing the efficacy of these regimens in WM...The combination of BTK inhibitors and chemoimmunotherapy (acalabrutinib, bendamustine, and rituximab; BRAWM) and a comparison between ibrutinib + rituximab versus venetoclax + rituximab are being explored in the frontline setting...In late relapses, the novel BCL2 antagonist..."

IO biomarker • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Lymphoplasmacytic Lymphoma • Marginal Zone Lymphoma • Multiple Myeloma • Oncology • Waldenstrom Macroglobulinemia • BCL2 • CXCR4 • MYD88

Mutation in Bruton Tyrosine Kinase (BTK) A428D confers resistance To BTK-degrader therapy in chronic lymphocytic leukemia. (PubMed, Leukemia) - "However, contrary to the presumption that protein degraders may be impervious to mutations in BTK, we now present clinical evidence that a mutation in the kinase domain of BTK, namely A428D, can confer disease resistance to a BTK degrader currently in clinical trials, that is BGB-16673. Modeling of a BTK A428D mutation places a negatively charged aspartic acid in place of the hydrophobic side chain of alanine within the binding pocket of another BTK-degrader in clinical development, namely NX-2127, suggesting that CLL cells with BTK A428D also may be resistant to NX-2127, as they already are known to be with either non-covalent or covalent inhibitors of BTK. Consequently, the two BTK degraders furthest advanced in clinical trials potentially may select for CLL cells with BTK A428D that are resistant to all approved BTKi's."

Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

NX-2127-001: A Study of NX-2127 in Adults With Relapsed/Refractory B-cell Malignancies (clinicaltrials.gov) - P1 | N=266 | Recruiting | Sponsor: Nurix Therapeutics, Inc. | Active, not recruiting ➔ Recruiting | N=160 ➔ 266 | Trial completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Dec 2024 ➔ Dec 2025

Enrollment change • Enrollment open • Trial completion date • Trial primary completion date • Chronic Lymphocytic Leukemia • CNS Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • Waldenstrom Macroglobulinemia • CD4 • TP53