crenigacestat (LY3039478) / Eli Lilly, BMS - LARVOL DELTA

The Role of Trogocytosis in BCMA CAR T Cell Therapy with Gamma-Secretase Inhbition (IMS 2025) - P1 | "We investigated the effects of GSI on trogocytosis kinetics and its consequences in vitro, and in concert with clinical data from two Phase I trials of BCMA-targeted CAR T therapy. Human T cells transduced with BCMA-directed 4-1BB/CD3ζ CAR (EGFRt⁺), were expanded and sorted. MM cell lines (H929, MM.1R, MOLP8) and BCMA-mCherry⁺ K562 cells were co-cultured with CAR T cells (E:T 1:1) for 10 min–24h ± GSI [crenigacestat] (0.1 μM, 24h).BCMA density and trogocytosis were evaluated by flow cytometric (FC) analysis.Latrunculin A (1 μM) was used to inhibit trogocytosis.BCMA-acquiring CAR T cells (Trogo⁺) were sorted after 6h co-culture and re-plated with naí¯ve CAR T cells for 24h to assess fratricide.Patient samples from two Phase I trials—FCARH143 (NCT03338972) and FCARH143+GSI (NCT03502577) were analyzed for trogocytosis, CAR T persistence (qPCR) and clinical response. GSI significantly increased BCMA density, enhanced CAR T cell cytotoxicity, but also..."

CAR T-Cell Therapy • IO biomarker • Hematological Malignancies • Multiple Myeloma • CD4 • CD8 • HAVCR2 • LAG3 • PD-1

KarMMa-7: Safety and Efficacy of bb2121 (Ide-cel) Combinations in Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=21 | Terminated | Sponsor: Celgene | Completed ➔ Terminated; Business objectives have changed

Trial termination • Hematological Malignancies • Multiple Myeloma • Oncology

Impact of Gamma-Secretase Inhibition on Outcomes Following BCMA CAR-T Therapy in Multiple Myeloma: A Comparison of Two Phase 1 Trials. (PubMed, Transplant Cell Ther) - "Co-administration of a GSI with BCMA CAR-T therapy was associated with improved survival in BCMA-naïve RRMM patients, particularly those with low baseline tumor BCMA levels. These findings suggest GSI modulation of BCMA surface expression may enhance CAR-T efficacy in select patients and support further prospective investigation."

IO biomarker • Journal • P1 data • Hematological Malignancies • Multiple Myeloma • Oncology

A Study of LY3039478 in Participants With Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=94 | Terminated | Sponsor: Eli Lilly and Company | Phase classification: P1b ➔ P1 | Completed ➔ Terminated; The study was terminated due to business considerations

Phase classification • Trial termination • Biliary Cancer • Breast Cancer • Cholangiocarcinoma • Colon Cancer • Colorectal Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Triple Negative Breast Cancer

Notch pathway inhibition with crenigacestat (LY3039478) in a phase I first-in-human clinical trial for patients with relapsed or refractory non-Hodgkin lymphoma and B-cell chronic lymphocytic leukemia. (PubMed, Ther Adv Drug Saf) - P1 | "Crenigacestat demonstrated a modest clinical activity at the recommended dose in adult patients with relapsed or refractory NHL or CLL. NCT01695005."

Journal • P1 data • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Chronic Lymphocytic Leukemia • Fatigue • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma

KarMMa-7: Safety and Efficacy of bb2121 (Ide-cel) Combinations in Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=21 | Completed | Sponsor: Celgene | Active, not recruiting ➔ Completed | N=312 ➔ 21

Enrollment change • Trial completion • Hematological Malignancies • Multiple Myeloma • Oncology

Immunosuppressive JAG2+ tumor-associated neutrophils hamper PD-1 blockade response in ovarian cancer by mediating the differentiation of effector regulatory T cells. (PubMed, Cancer Commun (Lond)) - "The emergence of JAG2+ TANs is crucial for the differentiation of eTregs, which triggers immune evasion and resistance to anti-PD-1 therapy. Inhibiting Notch signaling with LY3039478 or JAG2 neutralization antibodies may overcome this anti-PD-1 resistance in HGSOC."

IO biomarker • Journal • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • CD14 • PD-L1

Structural basis of human γ-secretase inhibition by anticancer clinical compounds. (PubMed, Nat Struct Mol Biol) - "Here we report the cryo-electron microscopy structures of human γ-secretase bound individually to five clinically tested GSIs (RO4929097, crenigacestat, BMS906024, nirogacestat and MK-0752) at overall resolutions of 2.4-3.0 Å. The size and shape of the binding pocket are induced by the bound GSI. Analysis of these structural features suggest strategies for modification of the GSI with improved inhibition potency."

Journal • Oncology • NICD

Gamma Secretase Inhibition May Mitigate the Impact of Low BCMA Target Density in Relapsed/Refractory Multiple Myeloma: Results from a Comparative Analysis of Two Phase 1 Clinical Trials (ASH 2024) - "Pts on FH9952 received the γ-secretase inhibitor (GSI), crenigacestat, during a pre-CAR-T run-in (3 doses 48 h apart) followed by post-infusion dosing 3x weekly for up to 9 doses. Limitations of this study include a small sample size and retrospective analysis. A randomized prospective study is needed to confirm a survival benefit of incorporating a GSI into treatment with FCARH143, or other BCMA CAR-T products."

Clinical • P1 data • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology

KarMMa-7: Safety and Efficacy of bb2121 (Ide-cel) Combinations in Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=312 | Active, not recruiting | Sponsor: Celgene | Trial completion date: Dec 2026 ➔ Jan 2025

Trial completion date • Hematological Malignancies • Multiple Myeloma • Oncology

GINS1 Enhances Glycolysis, Proliferation and Metastasis in Lung Adenocarcinoma Cells by Activating the Notch/PI3K/AKT/mTORC1 Signaling Pathway (PubMed, Zhongguo Fei Ai Za Zhi) - "The expression of GINS1 enhances the expression of Notch1 and Notch3 receptors, and then phosphorylates and activates the downstream PI3K/AKT/mTORC1 signaling pathway to enhance the glycolysis, proliferation and metastasis of LUAD cells."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • GINS1 • NOTCH1 • NOTCH3

Targeting cancer-associated fibroblasts/tumor cells cross-talk inhibits intrahepatic cholangiocarcinoma progression via cell-cycle arrest. (PubMed, J Exp Clin Cancer Res) - "The hCAFs/iCCA cross-talk is a new target for reducing cancer progression with drugs such as Crenigacestat."

Journal • Tumor cell • Biliary Cancer • Cholangiocarcinoma • Fibrosis • Gastrointestinal Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • CAFs • CCNE2 • NOTCH1

Single-cell analysis of the multiple myeloma microenvironment after gamma-secretase inhibition and CAR T-cell therapy. (PubMed, Blood) - "Leveraging a phase I clinical trial of the gamma-secretase inhibitor (GSI), crenigacestat, with anti-BCMA CAR T-cells (FCARH143), we utilized single-nuclei RNA sequencing and Assay for Transposase-Accessible Chromatin (ATAC) sequencing to characterize the effects of GSI on the tumor microenvironment. Finally, we detected monoallelic deletion of the BCMA locus in some patients with prior exposure to anti-BCMA therapy, which significantly correlated with reduced progression-free survival (median PFS 57 days versus 861 days). GSIs are being explored in combination with the full spectrum of BCMA targeting agents, and our results reveal widespread effects of GSI on both tumor and immune cell populations, providing insight into mechanisms for enhancing BCMA-directed therapies."

CAR T-Cell Therapy • IO biomarker • Journal • Hematological Malignancies • Multiple Myeloma • Oncology

Ex vivo model of pathological calcification of human aortic valve. (PubMed, Front Cardiovasc Med) - "To validate the model, we tested a Notch inhibitor Crenigacestat (LY3039478), which has been previously shown to have an anti-calcifying effect on interstitial cell of the aortic valve. We demonstrate here an approach to testing calcification inhibitors using an ex vivo model of cultured human aortic valve tissue fragments. Thus, we propose that ex vivo models may warrant further investigation for their utility in studying aortic valve disease and performing pre-clinical assessment of drug efficacy."

Journal • Preclinical

A Study of CC-99712, a BCMA Antibody-Drug Conjugate, in Participants With Relapsed and Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=47 | Terminated | Sponsor: Celgene | N=160 ➔ 47 | Active, not recruiting ➔ Terminated; Slow accrual

Enrollment change • Trial termination • Hematological Malignancies • Multiple Myeloma • Oncology

Disrupting SIV Reservoir Seeding by Targeting Stemness Pathways in Rhesus Macaques (CROI 2024) - "This proof-of-concept study suggests that the combined pharmacological modulation of Wnt and Notch pathways during acute SIV infection of RMs impacts viral reservoir seeding by transiently reducing the relative contribution of the CM cells to the peripheral CD4+ T cell compartment and to the pool of the infected CD4+ T cells."

Human Immunodeficiency Virus • Infectious Disease • CD4

NOTCH Pathway Inhibition Increases Radiosensitivity in a Context-Dependent Manner (DKK 2024) - " Two rectal cancer cell lines with different modes of NOTCH activation were treated with LY3039478, a y-secretase-inhibitor, and with RIN1, which targets RBPJ, the key downstream transcription factor of the NOTCH pathway... We demonstrated that inhibitors of the NOTCH signaling pathway may play a role in sensitizing rectal cancer to irradiation therapy, and should be further evaluated. Indication of source: 1 Koerdel K, et al. NOTCH Activation via gp130/STAT3 Signaling Confers Resistance to Chemoradiotherapy."

Colorectal Cancer • Gastrointestinal Cancer • Oncology • Rectal Cancer • Solid Tumor

A Study of CC-99712, a BCMA Antibody-Drug Conjugate, in Participants With Relapsed and Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=160 | Active, not recruiting | Sponsor: Celgene | Trial completion date: May 2025 ➔ Aug 2024 | Trial primary completion date: May 2025 ➔ Aug 2024

Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

A Study of CC-99712, a BCMA Antibody-Drug Conjugate, in Participants With Relapsed and Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=160 | Active, not recruiting | Sponsor: Celgene | Trial completion date: Apr 2024 ➔ May 2025 | Trial primary completion date: Apr 2024 ➔ May 2025

Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

A Study of LY3039478 in Japanese Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=11 | Completed | Sponsor: Eli Lilly and Company | Active, not recruiting ➔ Completed | Trial completion date: Oct 2023 ➔ May 2023

Metastases • Trial completion • Trial completion date • Oncology • Solid Tumor

NCI-2018-00514: BCMA-Specific CAR T-Cells Combined With a Gamma Secretase Inhibitor (JSMD194) to Treat Relapsed or Persistent Multiple Myeloma (clinicaltrials.gov) - P1 | N=19 | Terminated | Sponsor: Fred Hutchinson Cancer Center | Active, not recruiting ➔ Terminated; Closed per SRC Low Accrual Policy

CAR T-Cell Therapy • Combination therapy • IO biomarker • Trial termination • Hematological Malignancies • Multiple Myeloma • Oncology • SDC1

NCI-2018-00514: BCMA-Specific CAR T-Cells Combined With a Gamma Secretase Inhibitor (JSMD194) to Treat Relapsed or Persistent Multiple Myeloma (clinicaltrials.gov) - P1 | N=19 | Active, not recruiting | Sponsor: Fred Hutchinson Cancer Center | Suspended ➔ Active, not recruiting

CAR T-Cell Therapy • Combination therapy • Enrollment closed • IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • SDC1

Impact of Gamma-Secretase Inhibition on the Multiple Myeloma Immune Microenvironment (ASH 2023) - "In a phase I, first-in-human clinical trial (n=18; relapsed/refractory MM) combining the GSI, crenigacestat, with anti-BCMA CAR T-cell therapy (FCARH143), we recently demonstrated that plasma cell BCMA antibody-binding capacity increased a median of 12-fold among 17/18 (94%) of participants after they received a 5-day GSI "run-in" (25 mg orally administered QOD for 3 doses) [Cowan AJ, et al...Accessibility of CD38, the target of daratumumab, was significantly increased in B cells, and SLAMF7, the target of elotuzumab, was significantly increased in plasma cells... BCMA cleavage from myeloma cells' surface is a putative resistance mechanism to BCMA-targeting immunotherapy. This study assessed the single-cell transcriptome and chromatin accessibility in the bone marrow environment of 16 patients given GSI monotherapy to ultimately enhance the efficacy of subsequent anti-BCMA CAR T-cell therapy. We found that prior BCMA-targeted therapy resulted in reduced..."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • ERBB4 • HES1 • Neurl1 • NOTCH1 • NOTCH2 • SLAMF7 • TNFRSF17

Trogocytosis May Attenuate the Efficacy of Anti-BCMA CAR T Cells Administered in Combination with γ-Secretase Inhibitor (ASH 2023) - "Cells were incubated with GSI, LY3039478-crenigacestat (Eli Lilly) 0.1 μM for 24h and mean fluorescence intensity (MFI) of BCMA was defined as previously described (Pont, Blood 2019)... GSI increases BCMA surface density on MM cells and promotes CAR T cell trogocytosis which results in fratricide that appears proportional to tumor cell BCMA density. Trogocytosis and the ensuing fratricide following anti-BCMA CAR T cell therapy may contribute to reduced persistence of CAR T cells and relapse. This data may facilitate the optimal timing and frequency of GSI administration after BCMA CAR T-cell administration in future clinical trials."

CAR T-Cell Therapy • Clinical • Combination therapy • IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology

Optimization of a Three-Dimensional Culturing Method for Assessing the Impact of Cisplatin on Notch Signaling in Head and Neck Squamous Cell Carcinoma (HNSCC). (PubMed, Cancers (Basel)) - "Combining cisplatin with a γ-secretase inhibitor (crenigacestat) increased sensitivity and induced cell death in the less sensitive cell line, while cisplatin alone was more effective in the moderately sensitive line and sensitivity decreased with the Notch inhibitor. Additionally, the Notch ligand JAG2 had additional, protective effects reducing cell death from cisplatin exposure. In summary, we observed an inverse relationship between NOTCH1 and NOTCH3 levels and cisplatin responsiveness, overall protective effects by CAFs, and a potential link between JAG2 expression with tumor cell survival."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CAFs • NOTCH1 • NOTCH3