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

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

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

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

Mutation in Bruton Tyrosine Kinase (BTK) A428D confers resistance To BTK-degrader therapy in chronic lymphocytic leukemia (Nature) - "...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."

Clinical data • Chronic Lymphocytic Leukemia

Nurix Therapeutics Reports Second Quarter Fiscal 2024 Financial Results and Provides a Corporate Update (GlobeNewswire) - "Upcoming Program Highlights:...NX-2127:...Nurix plans to reinitiate enrollment with the new chirally controlled drug product in a standard dose escalation study within the current Phase 1a/1b trial in the second half of 2024....NX-1607:...In the second half of 2024, Nurix expects to present data from the Phase 1a dose-escalation portion of the trial of NX-1607 and to define dose(s) to enable Phase 1b cohort expansion."

Enrollment status • P1 data • Hematological Malignancies • Solid Tumor

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 Therapeutics Announces U.S. FDA Lifts Partial Clinical Hold on NX-2127 Phase 1 Trial (GlobeNewswire) - "Nurix Therapeutics, Inc...announced that the U.S. Food and Drug Administration (FDA) has lifted the partial clinical hold on the U.S. Phase 1a/1b study evaluating NX-2127 in adults with relapsed/refractory B-cell malignancies....Nurix plans to reinitiate enrollment with the new chirally controlled drug substance in a standard dose escalation study within the current Phase 1a/1b trial. Nurix plans to prioritize enrollment of patients with aggressive forms of non-Hodgkin’s lymphoma (NHL) including diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) where durable complete responses have previously been observed."

FDA event • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

New Compound Takes Aim at CLL (OncLive) - P1 | N=160 | NCT04830137 | Sponsor: Nurix Therapeutics, Inc. | "Researchers showed that NX-2127 efficiently destroyed its target in cells in a petri dish and in patient cells. The compound also destroyed BTK in cells resistant to approved BTK inhibitors. And it shrank tumors in 11 of 14 CLL patients, including tumors resistant to approved BTK drugs...One CLL patient had a particularly strong response to NX-2127. The elderly patient had been on pitoibrutinib for two years but developed resistance to it and other therapies...The researchers continued the study past the Sept. 2022 data cutoff for the Science publication and provided an update in December. The elderly patient was still responding to NX-2127. Overall, 41% of CLL patients responded to the new compound...NX-2127 could overcome resistance to all of these different types of mutations."

P1 data • Chronic Lymphocytic Leukemia

Nurix Therapeutics Reports Fourth Quarter and Fiscal Year 2023 Financial Results and Provides a Corporate Update (GlobeNewswire) - "NX-2127: Nurix is conducting a Phase 1a/b clinical trial of NX-2127, which includes three Phase 1b expansion cohorts in patients with DLBCL, MCL and CLL. Screening and enrollment of new study participants have been paused due to a partial clinical hold placed on the study by the FDA. Patients currently enrolled in the clinical study who are deriving clinical benefit may continue to receive treatment in accordance with the ongoing study protocol. In 2024, Nurix expects to resolve the partial clinical hold to enable the introduction of newly manufactured drug product into the ongoing Phase 1 clinical trial."

FDA event • Trial status • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

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

Discovery and Preclinical Pharmacology of NX-2127, an Orally Bioavailable Degrader of Bruton's Tyrosine Kinase with Immunomodulatory Activity for the Treatment of Patients with B Cell Malignancies. (PubMed, J Med Chem) - "NX-2127 is orally bioavailable, exhibits in vivo degradation across species, and demonstrates efficacy in preclinical oncology models. NX-2127 has advanced into first-in-human clinical trials and achieves deep and sustained degradation of BTK following daily oral dosing at 100 mg."

Immunomodulating • Journal • Preclinical • Hematological Disorders • Hematological Malignancies • Oncology • Targeted Protein Degradation • BTK • CRBN • IKZF1 • IKZF3

Nurix Therapeutics Announces Publication in the Journal Science Identifying a New Class of BTK Mutations That Are Susceptible to NX-2127, a Novel BTK and IKZF1/3 Degrader (GlobeNewswire) - "Nurix Therapeutics...announced the publication of a manuscript in the journal Science...that elucidates a previously unappreciated oncogenic scaffold function of BTK responsible for clinical resistance to enzymatic inhibitors and shows that NX-2127...can overcome this resistance across a broad range of acquired mutations....A Drug Annotation manuscript published contemporaneously in The Journal of Medicinal Chemistry...reports data detailing the discovery and optimization of NX-2127, including characterization of NX-2127’s activity in preclinical tumor models, cross-species pharmacokinetics and in vitro safety which supported the advancement of this molecule into clinical testing."

Preclinical • Chronic Lymphocytic Leukemia

Dr Danilov on Addressing BTK Inhibitor Resistance in Relapsed/Refractory CLL and MCL (OncLive) - "Alexey Danilov, MD, PhD...discusses how further research, including the development of NX-2127, may address unmet needs related to disease progression in patients with chronic lymphocytic leukemia (CLL) or mantle cell lymphoma...NX-2127 comprises 3 components...One component acts as a hook that grabs the kinase, the second part serves as a harness, attaching to the E3 ligase, and the third part is a linker, he elucidates. The resulting agent binds to BTK, shuttling it to the proteasome for degradation through its interaction with the E3 ubiquitin ligase. NX-2127 also alters the function and substrate activity of the E3 ligase that regulates the activation of immune cells, much like lenalidomide...Accordingly, NX-2127 operates as a BTK degrader with additional immunomodulatory functions..."

Preclinical • Chronic Lymphocytic Leukemia • Mantle Cell Lymphoma

Nurix Therapeutics Outlines 2024 Strategic Priorities with Advancement of Targeted Protein Modulation Pipeline in Cancer and Autoimmune Diseases (BioSpace) - "The company plans to accelerate Phase 1 clinical trial enrollment to enable pivotal trials. In addition, Nurix expects to complete ongoing preclinical studies that can enable an investigational new drug (IND) application for NX-5948 in autoimmune indications. NX-2127: Nurix expects to resolve the partial clinical hold on the Phase 1 clinical trial to enable the introduction of newly manufactured drug product into the ongoing Phase 1 clinical trial. NX-1607: Nurix expects to present data from the Phase 1a stage of the monotherapy and paclitaxel combination cohorts in its clinical trial of NX-1607 in a range of oncology indications, and to define plans and dose(s) for Phase 1b cohort expansion."

Enrollment status • P1 data • Preclinical • Castration-Resistant Prostate Cancer • Chronic Lymphocytic Leukemia • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Gynecologic Cancers • Head and Neck Cancer • Hematological Malignancies • Leukemia • Lung Cancer • Lymphoma • Metastatic Castration-Resistant Prostate Cancer • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

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 • Immunomodulating • IO biomarker • P1 data • Anemia • Atrial Fibrillation • 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

Nurix Therapeutics Presents Positive Clinical Data from Its Novel Bruton’s Tyrosine Kinase (BTK) Degrader Programs, NX-5948 and NX-2127, at the 65th American Society of Hematology (ASH) Annual Meeting (GlobeNewswire) - P1 | N=160 | NCT04830137 | Sponsor: Nurix Therapeutics, Inc. | "The presentation included data from 54 patients with r/r B-cell malignancies treated once daily with NX-2127 at doses that ranged from 100 to 300 mg....Treatment with NX-2127 resulted in encouraging rapid and durable responses in this heavily pre-treated patient population with complete responses (CR) reported in two (MCL and DLBCL) of the 17 evaluable NHL patients. These responses were durable for over one year. Two PRs in other NHL patients (MZL and FL) were also reported. Among the 27 evaluable patients with CLL, 11 experienced a PR for an overall response rate (ORR) of 40.7%."

P1 data • Chronic Lymphocytic Leukemia • CNS Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Small Lymphocytic Lymphoma • Waldenstrom Macroglobulinemia