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

From prediction to performance: In silico-supported formulation of amorphous solid dispersions for PROTAC NX-2127. (PubMed, Int J Pharm ) - "Overall, this study demonstrates that while in silico prediction represents a valuable tool for supporting early formulation development, experimental in vitro screening remains indispensable for reliable polymer selection. The combination of both approaches enabled the rational design of ASD formulations and led to substantial gains in dissolution performance of poorly soluble PROTACs."

Journal • Targeted Protein Degradation

Discovery of BTK degraders for the treatment of B-cell malignancies (ACS-Fall 2026) - "Covalent BTK inhibitors (e.g., ibrutinib, acalabrutinib) have demonstrated efficacy across diseases including CLL, MCL, MZL, and WM, but long-term benefit is frequently limited by resistance mutations, most commonly at BTKC481, that abrogate covalent binding and drive progression, and additional mutations may also reduce the activity of emerging noncovalent inhibitors, such as pirtobrutinib. Together, these data support BTK degraders as a promising modality to overcome BTK inhibitor resistance and broaden therapeutic impact, including in CNS disease. This presentation will describe the discovery of NX-2127 and NX-5948, pre-clinical characterization and translation to clinical effects in lymphoma and leukemia patients."

Chronic Lymphocytic Leukemia • CNS Disorders • Hematological Malignancies • Leukemia • Lymphoma • Marginal Zone Lymphoma • Oncology • Targeted Protein Degradation • CRBN • IKZF1 • IKZF3

A first-in-human phase 1 trial of NX-2127, a first-in-class oral BTK degrader with IMiD-like activity, in patients with relapsed and refractory B-cell malignancies. (ASCO 2022) - P1 | "Immunomodulatory drugs (IMiDs, e.g., lenalidomide) are approved as monotherapy for follicular lymphoma (FL), MZL, and MCL, in combination with other therapies for diffuse large B-cell lymphoma (DLBCL) and have shown synergy with BTK-targeted therapy...NX-2127 was shown to degrade both wild-type (WT) and C481-mutated (ibrutinib-resistant) BTK protein in vitro...The primary objectives are to evaluate safety and tolerability and to determine the maximum tolerated dose (Phase 1a), and to evaluate the early clinical activity of NX-2127 in expansion cohorts (Phase 1b). The Phase 1a part of this study is currently enrolling in the United States."

Clinical • P1 data • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Immune Modulation • Inflammation • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma • Targeted Protein Degradation • Waldenstrom Macroglobulinemia • CRBN • IKZF1 • IKZF3

NX-2127-001, a First-in-Human Trial of NX-2127, a Bruton's Tyrosine Kinase-Targeted Protein Degrader, in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia and B-Cell Malignancies (ASH 2022) - P1 | "All have previously received a BTKi and 76.5% had also received venetoclax. Double- and emerging triple-refractory CLL (patients who progressed on cBTKi, ncBTKi, and a BCL2 inhibitor) represents a major unmet medical need with no approved therapeutic options and poor survival. These patients may thus benefit from the interruption of BTK kinase-independent scaffolding signaling. In this first-in-human, first-in-class study of a BTK degrader, clinical responses and benefit were observed in heavily pretreated (median 6 prior therapies) patients with CLL who have poor prognostic factors, including those with BTK mutations resistant to cBTKi and ncBTKi, BCL2 mutations and those who were previously treated with both BTKi and BCL2 inhibitors."

Clinical • IO biomarker • P1 data • Alzheimer's Disease • Chronic Lymphocytic Leukemia • Cognitive Disorders • Hematological Malignancies • Immune Modulation • Inflammation • Leukemia • Oncology • Targeted Protein Degradation • BTK • IGH • IKZF1 • IKZF3 • TP53

Molecular and Structural Basis of Pan-Resistance to BTK Degraders and Inhibitors. (PubMed, Cancer Discov) - "Here we sequenced serial CLL samples from patients enrolled in the phase I trials of zelebrudomide and bexobrutideg and observed recurrent expansion of preexisting BTK A428D mutations at relapse. Combining BTK degraders with venetoclax mitigated the expansion of BTK A428D. These results provide the molecular basis for clinical resistance to BTK degraders and will inform the development of next-generation BTK degrader therapies."

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

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

Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127. (PubMed, Science) - "Treatment of chronic lymphocytic leukemia with NX-2127 achieves >80% degradation of BTK in patients and demonstrates proof-of-concept therapeutic benefit. These data reveal an oncogenic scaffold function of mutant BTK that confers resistance across clinically approved BTK inhibitors but is overcome by BTK degradation in patients."

Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BTK • IKZF1

Selective Degradation of Bruton's Tyrosine Kinase in Human Platelets Reveals a Signalling-Centric Strategy for Anti-thrombotic Therapy (ISTH 2026) - "Methods Human platelets were treated with two cereblon-recruiting BTK degraders NX-2127 and NX-5948 and BTK/TEC levels were assessed by immunoblotting. These findings establish protein degradation as a mechanistically precise strategy for platelet modulation and support BTK-directed PROTACs as a rational platform for next-generation anti-thrombotic therapy. Table or Figure Upload (1) Page 2 Table or Figure Upload (2) DOI*10.1016/j.rpth.2026.103597"

B Cell Lymphoma • Cardiovascular • Hematological Disorders • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Targeted Protein Degradation • Thrombosis • BTK • CRBN • PLCG2 • PLEK • SYK

Broader Pipeline Highlights (Nurix Press Release) - "Nurix has completed enrollment of current Phase 1a dose escalation cohorts of NX-1607, an investigational oral CBL-B inhibitor, across multiple solid tumor oncology indications and is reviewing the data to determine next steps....Zelebrudomide is an orally bioavailable degrader of BTK and the cereblon neosubstrates IKZF1 (Ikaros) and IKZF3 (Aiolos) designed for the treatment of relapsed or refractory B-cell malignancies. Nurix has completed enrollment in the current dose escalation cohorts of the Phase 1 trial (NCT04830137) and is reviewing the data to determine next steps."

Enrollment closed • Platinum resistant • Trial status • Castration-Resistant Prostate Cancer • Cervical Cancer • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Epithelial Ovarian Cancer • Follicular Lymphoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Malignant Pleural Mesothelioma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Melanoma • Non Small Cell Lung Cancer • Primary Central Nervous System Lymphoma • Richter's Syndrome • Small Lymphocytic Lymphoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • Urothelial Cancer • Waldenstrom Macroglobulinemia

Selective degradation of platelet BTK by PROTAC NX-5948 provides antithrombotic benefits without affecting haemostasis. (PubMed, Blood Adv) - "We here assessed the ability of the BTK degraders NX-2127 and NX-5948, currently in clinical trials for B cell pathologies, to target platelet BTK for degradation. In vivo, arterial thrombosis was markedly reduced, without an increase in bleeding time. Together, these results highlight NX-5948 as a potent, selective BTK degrader with antithrombotic potential and minimal haemostatic impact."

Journal • Cardiovascular • Hematological Disorders • Targeted Protein Degradation • Thrombosis

PROTEOLYSIS-TARGETING CHIMERA (PROTAC) TARGETING BRUTON TYROSINE KINASE (BTK) DEGRADATION IN MANTLE CELL LYMPHOMA (EHA 2026) - "Notably, compared with BGB-16673 and NX-2127, C23 not only efficiently degraded BTK but also induced the degradation of IKZF1 and IKZF3. Summary/Conclusion The C23 BTK-PROTAC inhibits MCL cells with BTK variants resistant to BTK-inhibitors in vitro and in vivo models. BTK-PROTAC C23 is a potential therapy of BTK-inhibitor resistant MCL."

Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Targeted Protein Degradation • BTK • IKZF1 • IKZF3

EPriL: A platform for the rapid identification of degraders of inhibitor-resistant kinases (AACR 2024) - "These include BTKC481S, which abrogates binding of covalent drugs, and BTKT474I, BTKL528W and BTKV416L which preclude binding of non-covalent inhibitors like pirtobrutinib...BTK degraders such as NX-5948 and NX-2127 are currently in clinical Phase 1.To show the applicability of the EPriL platform for the discovery of novel BTK degraders, we screened a library of more than 100 EPriL HKDs for biochemical binding to BTK, and tested their propensity to induce degradation of HiBiT-tagged BTKWT, BTKC481S and BTKT474I in HEK293 cell lines...In these lines, endogenous BTK was mutated by CRISPR to BTKC481S, BTKT474I, BTKL528W or BTKV416L. Several BTK degraders had potent (< 20 nM IC50) antiproliferative activity on most TMD8 lines, including difficult-to-target variants such as BTKV416L and BTKL528W.The unique binding mode of the EPriL scaffold thus translates to broad activity on resistance variants, while its selectivity ensures minimal degradation of off-target tyrosine..."

Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Oncology • Waldenstrom Macroglobulinemia

Nurix is conducting a Phase 1a/1b clinical trial (NCT04830137), including a Phase 1b expansion cohort focused on patients with diffuse large B-cell lymphoma and mantle cell lymphoma. (Nurix Press Release) - "Nurix is enrolling in the dose escalation cohort of the Phase 1a/1b trial using the chirally controlled drug product."

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

NX-2127-001: A Study of NX-2127 in Adults With Relapsed/Refractory B-cell Malignancies (clinicaltrials.gov) - P1 | N=248 | Recruiting | Sponsor: Nurix Therapeutics, Inc. | Trial completion date: Dec 2026 ➔ May 2027 | Trial primary completion date: Dec 2025 ➔ May 2026

First-in-human • Trial completion date • Trial primary completion date • B Cell Lymphoma • Chronic Lymphocytic Leukemia • CNS Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Central Nervous System Lymphoma • Small Lymphocytic Lymphoma • Waldenstrom Macroglobulinemia • CD4

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

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

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

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