lixumistat (IM156) / ImmunoMet - LARVOL DELTA

Shared mechanisms of resistance to zanubrutinib and ibrutinib via EGR1 and DNMT3A in mantle cell lymphoma (ASH 2025) - "While second-generation BTK inhibitors (e.g., zanubrutinib, acalabrutinib) offer improved selectivity and reduced toxicity compared to ibrutinib, resistance persists, and no standard of care has been established for relapsed/refractory MCL...Notably, IM156 , a clinical-grade OXPHOS inhibitor and metformin analog, synergized with zanubrutinib to induce cell death in primary MCL cells with ibrutinib resistance. These findings will be further validated using patient-derived xenograft (PDX) models. Together, our results highlight mitochondrial metabolism—via EGR1 and DNMT3A—as a key vulnerability in BTK inhibitor-resistant MCL and support combination strategies targeting OXPHOS to improve therapeutic outcomes."

Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • DNMT3A • EGR1 • PDP1

biomarker Driven Strategies for Targeted Elimination of Hypoxia Adapted Lymphoma Cells (ASH 2023) - "Sensitivity of HA cells to 2-deoxyglucose, an inhibitor of glycolysis was markedly increased (Figure 1)...Sensitivity of HA cells to a panel of the tested cytotoxic drugs (cytarabin, cisplatin, bortezomib) and targeted agents (venetoclax, S63545, A1155463, TRAIL, polatuzumab vedotin, IM-156, copanlisib) was either unchanged or increased (compared to sensitivity of the original cell lines cultured under normoxia)...In translation, P4HA1, BCL-XL, and structural proteins of the glycolytic pathway may represent novel drugable targets for more effective elimination of hypoxia-adapted lymphoma cells. Financial Support: Ministry of Health of the Czech Republic AZV NU23-03-00172, Grant Agency of the Czech Republic GA23-05377S, and National Institute for Cancer Research (EXCELES) LX22NPO5102."

Biomarker • B Cell Lymphoma • Burkitt Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2L1 • P4HA1

Enhanced Mitochondrial Activity in B cells from Females Is Required to Drive Increased T-bet Induction by TLR7 in Lupus (ACR Convergence 2025) - "These findings suggest that the development of T-bet⁺ B cells in female BXD2 mice is strongly dependent on increased mitochondrial OxPhos. Sex-biased differences in OxPhos may therefore act as an intrinsic factor, making it more likely for precursor B cells to reach the energy thresholds needed for differentiation into ABCs under TLR7 and type I IFN stimulation in females with lupus."

IO biomarker • Immunology • Inflammation • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • CD69 • IFNB1 • TLR7

A Phase 1b Study of Gemcitabine and Nab-paclitaxel in Combination With IM156 in Patients With Advanced Pancreatic Cancer. (clinicaltrials.gov) - P1 | N=19 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Recruiting ➔ Active, not recruiting

Enrollment closed • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

A phase Ib dose-escalation trial of gemcitabine and nab-paclitaxel in combination with lixumistat in patients with advanced pancreatic cancer (COMBAT-PC) (ESMO-GI 2025) - P1 | "Chemotherapy like FOLFIRINOX and Gemcitabine-Nab-Paclitaxel offers modest benefit... Lixumistat at 400 mg daily with Gem/NP is safe and shows promising efficacy in metastatic PDAC, supporting further study of this combination."

Clinical • Combination therapy • Metastases • P1 data • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Enhanced mitochondrial biogenesis in B cells from females is required to drive increased T-bet induction by TLR7 in lupus (IMMUNOLOGY 2025) - "Inhibition of the electron transport chain with IM-156 reduced T-bet and IRF7 induction in both sexes. Interestingly, complex I gene expression was higher in female versus male BXD2-Ifnar1−/− mice following TLR7 and IFNβ stimulation. These results suggest that female-biased mitochondrial biogenesis, albeit independent of IFN responses, supports the energy demands for TLR7 and IFNβ responses to promote T-bet+ B cell development, and potentially contributes to SLE pathogenesis in women.Keywords: Cells B Cells; Diseases Autoimmunity Systemic Lupus Erythematosus; Molecules Cytokines; Processes Cell Activation"

Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • CD69 • IFNAR1 • IFNB1 • IRF7 • NDUFB1 • TLR7

A Phase 1b Study of Gemcitabine and Nab-paclitaxel in Combination With IM156 in Patients With Advanced Pancreatic Cancer. (clinicaltrials.gov) - P1 | N=25 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Jan 2025 ➔ Feb 2027 | Trial primary completion date: Jan 2025 ➔ Feb 2027

Trial completion date • Trial primary completion date • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

A phase 1b dose escalation trial of gemcitabine and nab-paclitaxel in combination with lixumistat in patients with advanced pancreatic cancer. (ASCO-GI 2025) - P1 | "When combined with Gem and NP; a dose of 400 mg of Lixumistat QD was demonstrated to be safe, tolerable and identified as the RP2D. This trial is currently enrolling patients at the RP2D in the expansion cohort. Updated data on safety and efficacy will be presented at the meeting."

Clinical • Combination therapy • Metastases • P1 data • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

ImmunoMet Therapeutics Presents Updated Clinical Data from Phase 1b Study of Lixumistat in Pancreatic Cancer at ASCO-GI Meeting (Businesswire) - P1b | N=25 | NCT05497778 | "ImmunoMet Therapeutics...provided a data update from the ongoing single-arm Phase 1b trial of the Company’s Lixumistat in combination with gemcitabine and nab-paclitaxel as frontline therapy in patients with advanced pancreatic cancer (NCT05497778)....Of the fourteen patients that have been treated, 8 received Lixumistat at 400 mg QD and 6 at 800 mg QD dose....Among the 8 response-evaluable patients treated at the RP2D: 5 (62.5%) achieved an objective Partial Response (PR), 3 (37.5%) had Stable Disease (SD), and the Disease Control Rate was 100%. The estimated median Progression-free Survival (PFS) was 9.7 months (5.75-NA) and median Overall Survival (OS) was 18 months (8.5-NA)."

P1 data • Pancreatic Cancer

Mechanisms of Mitochondrial Complex-I sensitivity in GBM (SNO 2024) - P2 | "The mechanisms of action of metformin as an anti-neoplastic agent is still being investigated, but recent studies have unequivocally demonstrated that its therapeutic effects in tumor cell growth and signaling are dependent on inhibition of mitochondrial complex I. Based on the success of metformin in combination therapy in some cancers, new generation of mitochondrial complex I inhibitors (MCI-i) such as IM156, IACS-010759, are currently under investigation. We are performing joint pathway analysis by examining differentially expressed genes and stable isotope tracing studies to determine distinct metabolic signatures in the two subsets of GBM. We are also performing Classification And Regression Tree (CART) analysis on a cohort of sixty primary GBM lines and tissues to predict if PDHA expression provides a binary outcome for MCI-i sensitivity."

Diabetes • Glioblastoma • Metabolic Disorders • Type 2 Diabetes Mellitus • SLC22A1

Mitochondria Activity and CXCR4 Collaboratively Promote the Differentiation of CD11c+ B Cells Induced by TLR9 in Lupus. (PubMed, Immune Netw) - "The CXCR4 inhibitor AMD3100 and the mitochondrial complex I inhibitor IM156 significantly reduced the proportion of CD11c+ B cells and autoreactive plasmablasts. These results underscore the pivotal roles of mitochondria and CXCR4 in the production of autoreactive plasmablasts."

Journal • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • CXCR4 • ITGAX • TLR9

HL156A, an AMP-Activated Protein Kinase Activator, Inhibits Cyst Growth in Autosomal Dominant Polycystic Kidney Disease. (PubMed, Biomolecules) - "HL156A has potential as a drug that can restore kidney function in ADPKD patients by inhibiting cyst growth."

Journal • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • PKD1 • PRKD1 • TERT

Sex differences in B-cell mitochondrial complex I activity may contribute to increased toll-like receptor 7 signaling in females in lupus (IMMUNOLOGY 2024) - "Interestingly, in B cells from female BXD2 mice, inhibiting complex I with IM-156 in vitro leads to decreased differentiation into Tbet+CD11c+ IgD+ activated naive (aNAV) and Tbet+CD11c+ IgD− age-associated B cells (ABCs) in the presence of R848. Our results suggest that increased constitutive mitochondrial complex I activity may be an important property that promotes B-cell susceptibility to increased TLR7 response and development of Tbet+CD11c+ B cells in females."

Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • ITGAX • TLR7

IM156, a New AMPK Activator, Ameliorates Polymicrobial Sepsis by Regulating Inflammatory Responses (IMMUNOLOGY 2024) - "IM156, a biguanide with a higher potency of AMP-activated protein kinase (AMPK) activation than metformin, exhibits inhibitory activity against angiogenesis and cancer. In conclusion, these findings collectively indicate that IM156 can suppress the inflammatory response and provide protection against polymicrobial sepsis. These results suggest the potential of IM156 as a novel therapeutic agent for sepsis control."

Infectious Disease • Inflammation • Oncology • Septic Shock • IL10 • IL1B • IL6

Orphan Designation: Treatment of malignant glioma (FDA) - Date Designated: 12/27/2023

Orphan drug • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor

EGR1-mediated metabolic reprogramming to oxidative phosphorylation contributes to ibrutinib resistance in B cell lymphoma. (PubMed, Blood) - "Finally, we demonstrate that targeting OXPHOS with metformin or IM156, a newly developed OXPHOS inhibitor, inhibits the growth of ibrutinib-resistant lymphoma cells both in vitro and in a patient-derived xenograft mouse model. These findings suggest that targeting EGR1-mediated metabolic reprogramming to OXPHOS with metformin or IM156 provides a potential therapeutic strategy to overcome ibrutinib resistance in relapsed/refractory DLBCL or MCL."

Journal • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • EGR1 • PDP1 • TCF4

A Phase 1b Study of Gemcitabine and Nab-paclitaxel in Combination With IM156 in Patients With Advanced Pancreatic Cancer. (clinicaltrials.gov) - P1 | N=25 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Phase classification: P1b ➔ P1

Combination therapy • Metastases • Phase classification • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

Phase I study of an oxidative phosphorylation inhibitor IM156 in patients with advanced solid tumors (AACR 2019) - P1; "IM156 has been well tolerated with manageable AE profile. The dose escalation continues with a planned change from every other day administration to daily dosing."

Clinical • P1 data

Targeting EGR1-Medited Metabolic Reprogramming to Overcome Ibrutinib Resistance in Aggressive B Cell Lymphomas (ASH 2022) - "Finally, we demonstrate that targeting OXPHOS with IM156, a newly developed OXPHOS inhibitor, inhibits the growth of ibrutinib-resistant lymphoma cells both in vitro and in patient-derived xenograft mouse models. These findings suggest that targeting EGR1-medited metabolic reprogramming to OXPHOS with IM156 provides a potential therapeutic strategy to overcome ibrutinib resistance in relapsed/refractory DLBCL or MCL."

Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • EGR1 • PDP1

DNMT3A-Mediated Oxidative Phosphorylation and Ibrutinib Resistance in Mantle Cell Lymphoma (ASH 2022) - "Finally, we demonstrate that targeting DNMT3A by a low dose of decitabine, which induces the degradation of DNMT3A protein, synergizes with IM156, an inhibitor of mitochondrial complex I and currently in phase I clinical trial, in killing ibrutinib-resistant cell lines and primary MCL cells. Currently, we are testing this synergistic effect using patient-derived xenograft mouse models. Therefore, our study reveals a novel noncatalytic function of DNMT3A and suggests that DNMT3A is a potential biomarker and molecular target in treating MCL (Figure 1)."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BTK • DNMT3A

ImmunoMet Therapeutics Announces First Patient Dosed in a Phase 1b Trial of IM156 in Pancreatic Cancer (Businesswire) - "ImmunoMet Therapeutics...announces that the first patient has been dosed in the single-arm Phase 1b trial of IM156 in combination with gemcitabine and nab-paclitaxel as frontline therapy in patients with advanced pancreatic cancer....This clinical trial evaluates the potential of IM156 in combination with gemcitabine and nab-paclitaxel to address resistance and improve patient outcomes. The trial includes a dose escalation phase followed by an expansion phase, treating a total of approximately 25 patients with advanced pancreatic cancer.....ImmunoMet is also pleased to announce that it has received Orphan Drug Designation status for IM156 in patients with pancreatic cancer and closed a Series C-1 financing in October 2022."

Financing • Orphan drug • Trial status • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor

The oxidative phosphorylation inhibitor IM156 suppresses B-cell activation by regulating mitochondrial membrane potential and contributes to the mitigation of systemic lupus erythematosus. (PubMed, Kidney Int) - "Thus, our data indicated that IM156 suppressed the mitochondrial membrane potentials of activated B-cells in mice, contributing to the mitigation of lupus activity. Hence, IM156 may represent a therapeutic alternative for autoimmune disease mediated by B-cell hyperactivity."

Journal • Glomerulonephritis • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Systemic Lupus Erythematosus

A Phase 1b Study of Gemcitabine and Nab-paclitaxel in Combination With IM156 in Patients With Advanced Pancreatic Cancer. (clinicaltrials.gov) - P1b | N=25 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

A Phase 1b Study of Gemcitabine and Nab-paclitaxel in Combination With IM156 in Patients With Advanced Pancreatic Cancer. (clinicaltrials.gov) - P1b | N=25 | Not yet recruiting | Sponsor: M.D. Anderson Cancer Center | Initiation date: Feb 2023 ➔ Sep 2022

Combination therapy • Trial initiation date • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

A Phase 1b Study of Gemcitabine and Nab-paclitaxel in Combination With IM156 in Patients With Advanced Pancreatic Cancer. (clinicaltrials.gov) - P1b | N=25 | Not yet recruiting | Sponsor: M.D. Anderson Cancer Center

Combination therapy • New P1 trial • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor