safimaltib (JNJ-6633) / J&J - LARVOL DELTA

First-in-class dual BTK-MALT1 fusion inhibitors for treating resistant Mantle Cell Lymphoma (ASH 2025) - "Lead compounds were identified through iterativechemical optimization and efficacy/toxicity assessments.ResultsThe initial lead compound, MZ0150-1, demonstrated potent anti-tumor activity across all tested models.Compared to reference agents—pirtobrutinib (BTKi) and safimaltib (MALT1i)—MZ0150-1 showedsignificantly enhanced cytotoxicity (IC50 = 1.6-2.4 µM in MCL cell lines, 3-4 fold lower than that ofpirtobrutinib-safimaltib combination), both as a monotherapy and relative to the BTKi-MALT1icombination. Notably, no apparent toxicity or adverse effects were observed in treated mice, as assessedby body weight monitoring and serum chemistry panels.ConclusionThis study introduces a promising therapeutic strategy for R/R MCL through dual targeting of BTK andMALT1 using single-molecule BTK-MALT1 fusion inhibitors. These first-in-class agents demonstratesuperior efficacy, overcome resistance mechanisms, and hold strong potential to improve clinicaloutcomes in aggressive..."

B Cell Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • MALT1

A Phase 1, Open-Label, Multicenter, Dose-Escalation Study of Sgr-1505 As Monotherapy in Subjects with Mature B-Cell Malignancies (ASH 2023) - P1 | "Furthermore, a MALT1 inhibitor (JNJ-67856633) showed efficacy in mature B cell malignancies from phase 1 studies (ref 1, 2)...SGR-1505 administered as a single agent and in combination with the approved Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, demonstrates tumorostatic and regressive antitumor activity in ABC-DLBCL cell line-derived and patient-derived xenograft models...Subjects with symptomatic or active CNS involvement, and other conditions or laboratory findings placing them at increased risk to the use of an investigational drug are excluded. SGR-1505 is initially dose-escalated using an accelerated titration design in cohorts of 1-6 subjects, and at higher dose levels using a conventional 3+3 design."

Clinical • Monotherapy • P1 data • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Extranodal Marginal Zone Lymphoma • Hematological Malignancies • Indolent Lymphoma • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Waldenstrom Macroglobulinemia • CARD11 • MALT1

Sgr-1505 Is a Potent MALT1 Protease Inhibitor with a Potential Best-in-Class Profile (ASH 2023) - P1 | "When administered as a single agent and in combination with the approved Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, SGR-1505 demonstrated tumorostatic and regressive antitumor activity in ABC-DLBCL cell line-derived xenograft and patient-derived xenograft models... SGR-1505, a MALT1 protease small molecule inhibitor, consistently demonstrated better potency in in vitro and ex vivo assays when compared to the clinical-stage JNJ-6633 compound and greater effects on NF-kB pathway gene expression in in vivo tumor samples based on RNA-seq analysis. Changes in biological pathways mediated by MALT1 were also observed at relevant doses in the ongoing SGR-1505 healthy volunteer study. Currently, a phase 1 clinical trial in patients with mature B cell neoplasms is also ongoing (NCT05544019)."

B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Extranodal Marginal Zone Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CARD11 • MALT1

A Highly Selective and Orally Bioavailable CK1α Molecular Glue Degrader Targets B-Cell Lymphoma Cells (ASH 2024) - "Lenalidomide's clinical efficacy in del(5q) myelodysplastic syndrome is linked to CK1α degradation, though it more potently degrades IKZF1/3...In an OCI-Ly3 xenograft model, INNO-220 exhibits dose-dependent and more robust tumor inhibition compared to JNJ-67856633, a MALT1 inhibitor currently in clinical trials for lymphoma...In summary, our findings underscore the potential of INNO-220, a selective CK1α degrader that targets both the NF-κB and p53 pathways, in offering new treatment strategy for lymphoma, including those resistant to BTK inhibitors. The results from this study not only position INNO-220 as a promising anti-cancer agent for B-cell lymphomas but also suggest a potential strategy for patient stratification, a crucial aspect of personalized medicine."

B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Targeted Protein Degradation • CARD11 • CRBN • GSPT1 • IKZF1 • IKZF3 • LY9 • MALT1 • NFKBIA

Case study: Novel CARD11 gain-of-function mutation in patient with T-LGL leukemia and autoimmunity (DGHO 2025) - "Analysis of the patient's primary T cells revealed upregulated cytokine and inflammatory pathways, with a shift toward an effector memory phenotype confirmed via surface marker staining.Next, we evaluated the impact of immunosuppressive drugs targeting NFκB and cytokine signaling, including dimethylfumarate (NFκB inhibitor), safimaltib (MALT1 inhibitor), and ruxolitinib (JAK inhibitor)...Functional assays using an NFκB reporter cell line and primary T cells confirmed its role in T cell activation. We also demonstrate that targeted MALT1 inhibition effectively reduces NFκB signaling in this context, supporting its potential for therapeutic intervention."

Case study • Clinical • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Immunology • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Rheumatology • T Cell Non-Hodgkin Lymphoma • T-Cell Large Granular Lymphocyte Leukemia • CARD11 • MALT1

A Study of JNJ-67856633 in Participants With Non-Hodgkin's Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL) (clinicaltrials.gov) - P1 | N=226 | Completed | Sponsor: Janssen Research & Development, LLC | Active, not recruiting ➔ Completed

Trial completion • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A Study of the MALT1 Inhibitor JNJ-67856633 and Ibrutinib in Combination in B-cell NHL and CLL (clinicaltrials.gov) - P1 | N=45 | Completed | Sponsor: Janssen Research & Development, LLC | Active, not recruiting ➔ Completed

Trial completion • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A Study of JNJ-64264681 and JNJ-67856633 in Participants With Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia (clinicaltrials.gov) - P1 | N=75 | Completed | Sponsor: Janssen Research & Development, LLC | Active, not recruiting ➔ Completed | Trial completion date: Apr 2025 ➔ Jan 2025 | Trial primary completion date: Apr 2025 ➔ Jan 2025

Trial completion • Trial completion date • Trial primary completion date • B Cell Non-Hodgkin Lymphoma • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A Study of JNJ-67856633 in Participants With Non-Hodgkin's Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL) (clinicaltrials.gov) - P1 | N=226 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Jan 2026 ➔ Apr 2025

Trial completion date • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A Rollover Study for Continued Study Treatment and Ongoing Safety Monitoring (clinicaltrials.gov) - P1 | N=80 | Enrolling by invitation | Sponsor: Janssen Research & Development, LLC

New P1 trial • Acute Myelogenous Leukemia • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Castration-Resistant Prostate Cancer • Chronic Lymphocytic Leukemia • Genito-urinary Cancer • Hematological Malignancies • Leukemia • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Prostate Cancer • Solid Tumor

A Study of the MALT1 Inhibitor JNJ-67856633 and Ibrutinib in Combination in B-cell NHL and CLL (clinicaltrials.gov) - P1 | N=45 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Dec 2026 ➔ Apr 2025 | Trial primary completion date: Nov 2024 ➔ Apr 2025

Trial completion date • Trial primary completion date • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A Study of JNJ-67856633 in Participants With Non-Hodgkin's Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL) (clinicaltrials.gov) - P1 | N=226 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Trial primary completion date: Dec 2024 ➔ Apr 2025

Trial primary completion date • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A Study of JNJ-64264681 and JNJ-67856633 in Participants With Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia (clinicaltrials.gov) - P1 | N=75 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Dec 2026 ➔ Jul 2025

Combination therapy • Trial completion date • B Cell Non-Hodgkin Lymphoma • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A Study of the MALT1 Inhibitor JNJ-67856633 and Ibrutinib in Combination in B-cell NHL and CLL (clinicaltrials.gov) - P1 | N=45 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Nov 2024 ➔ Dec 2026

Trial completion date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A Study of JNJ-64264681 and JNJ-67856633 in Participants With Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia (clinicaltrials.gov) - P1 | N=75 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Jul 2025 ➔ Dec 2026

Combination therapy • Trial completion date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A Study of JNJ-64264681 and JNJ-67856633 in Participants With Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia (clinicaltrials.gov) - P1 | N=75 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Trial primary completion date: Jul 2024 ➔ Jul 2025

Combination therapy • Trial primary completion date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A Study of JNJ-67856633 in Participants With Non-Hodgkin's Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL) (clinicaltrials.gov) - P1 | N=226 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Trial primary completion date: Oct 2023 ➔ Dec 2024

Trial primary completion date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A Study of the MALT1 Inhibitor JNJ-67856633 and Ibrutinib in Combination in B-cell NHL and CLL (clinicaltrials.gov) - P1 | N=45 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Phase classification: P1b ➔ P1 | Trial primary completion date: Nov 2023 ➔ Nov 2024

Phase classification • Trial primary completion date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A Study of JNJ-64264681 and JNJ-67856633 in Participants With Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia (clinicaltrials.gov) - P1 | N=75 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Phase classification: P1b ➔ P1

Combination therapy • Phase classification • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A Study of JNJ-64264681 and JNJ-67856633 in Participants With Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia (clinicaltrials.gov) - P1b | N=75 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Apr 2026 ➔ Jul 2025

Combination therapy • Trial completion date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A Study of JNJ-64264681 and JNJ-67856633 in Participants With Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia (clinicaltrials.gov) - P1b | N=75 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Dec 2024 ➔ Apr 2026

Combination therapy • Trial completion date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

PHASE 1 STUDY OF JNJ-67856633, A FIRST-IN-HUMAN HIGHLY SELECTIVE MALT1 INHIBITOR, IN RELAPSED/REFRACTORY (R/R) B-CELL NON-HODGKIN LYMPHOMA (B-NHL) AND CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) (EHA 2023) - P1 | "Preliminary data from this first-in-human MALT1 inhibitor (JNJ-67856633) phase 1 dose escalation study indicates that it has a manageable hematological and non-hematological safety profile. JNJ-67856633 hasdemonstrated clinical activity in indolent and aggressive lymphomas. LD may be associated with a higher ORR and is further explored in expansion cohorts."

P1 data • Acute Kidney Injury • Cardiovascular • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Febrile Neutropenia • Heart Failure • Hematological Malignancies • Hepatology • Lymphoma • Marginal Zone Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Renal Disease • CARD11 • MALT1 • NF-κβ

PHASE 1 STUDY OF JNJ-67856633, A FIRST-IN-HUMAN MALT1 INHIBITOR, IN RELAPSED/REFRACTORY (R/R) B-CELL NON-HODGKIN LYMPHOMA (B-NHL) AND CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) (ICML 2023) - "Preliminary data from this phase 1 dose escalation study of JNJ-6633 indicates it has a manageable hematological and non-hematological safety profile. JNJ-6633 demonstrated clinical activity in indolent and aggressive lymphomas. LD may be associated with higher ORR and is further explored in expansion cohorts."

P1 data • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CARD11 • MALT1 • NF-κβ

A Study of the MALT1 Inhibitor JNJ-67856633 and Ibrutinib in Combination in B-cell NHL and CLL (clinicaltrials.gov) - P1b | N=45 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Nov 2023 ➔ Nov 2024

Trial completion date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

BTK and MALT1 are critical for cell adhesion and dissemination in mantle cell lymphoma (AACR 2023) - "This is evident by multiple FDA approvals of covalent BTK inhibitors (BTKi, e.g. ibrutinib, acalabrutinib and zanubrutinib) and recent exciting clinical data on non-covalent BTKi pirtobrutinib. Furthermore, co-targeting MALT1 with safimaltib and BTK with pirtobrutinib induced potent anti-MCL activity in BTKi-resistant MCL cell lines and patient-derived xenografts. Therefore, we conclude that (1) BTK and MALT1 are key molecules that control MCL cell growth and dissemination, (2) MALT1 overexpression drives resistance to BTKi in MCL, (3) targeting MALT1 is a promising therapeutic strategy to overcome BTKi resistance, and (4) co-targeting of BTK and MALT1 improves efficacy and durability beyond single agents."

Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • CARD11 • MALT1