To learn if adding a new medication, IM156, to treatment with gemcitabine and nab-paclitaxel is safe and tolerable. The ability of this combination to improve the success of this treatment for these patients will also be studied.

Start Date21 Oct 2022

Sponsor / Collaborator

The University of Texas MD Anderson Cancer Center

[+1]

NCT03272256 / CompletedPhase 1

A Multi Center, Open-label, Phase 1 Clinical Trial to Evaluate the Safety, Tolerability, and Preliminary Efficacy of IM156 in Patients With Advanced Solid Tumors and Lymphoma

The main purpose of first-in-human IM156 study is to evaluate the safety and tolerability, and to determine the maximum tolerated dose and recommended phase 2 dose of IM156.

Start Date09 Oct 2017

Sponsor / Collaborator

ImmunoMet Therapeutics, Inc.Startup

100 Clinical Results associated with Lixumistat

100 Translational Medicine associated with Lixumistat

100 Patents (Medical) associated with Lixumistat

Literatures (Medical) associated with Lixumistat

30 Nov 2023·Blood

EGR1-mediated metabolic reprogramming to oxidative phosphorylation contributes to ibrutinib resistance in B-cell lymphoma

Article

Author: Song, Longzhen ; Lu, Li ; Daenthanasanmak, Anusara ; Ngo, Vu N. ; Bebel, Samantha ; Rui, Lixin ; Chen, Ruoyu ; Capitini, Christian M. ; Chen, Madelyn ; Zhang, Xiyu ; Bates, Paul D. ; Gao, Xiaoyue ; Kimpara, Shuichi ; Li, Yangguang ; Hoang, Nguyet M. ; Selberg, Paul E. ; Liu, Yunxia ; Waldmann, Thomas A. ; Kenkre, Vaishalee P.

Abstract:

The use of Bruton tyrosine kinase inhibitors, such as ibrutinib, to block B-cell receptor signaling has achieved a remarkable clinical response in several B-cell malignancies, including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). Acquired drug resistance, however, is significant and affects the long-term survival of these patients. Here, we demonstrate that the transcription factor early growth response gene 1 (EGR1) is involved in ibrutinib resistance. We found that EGR1 expression is elevated in ibrutinib-resistant activated B-cell–like subtype DLBCL and MCL cells and can be further upregulated upon ibrutinib treatment. Genetic and pharmacological analyses revealed that overexpressed EGR1 mediates ibrutinib resistance. Mechanistically, TCF4 and EGR1 self-regulation induce EGR1 overexpression that mediates metabolic reprogramming to oxidative phosphorylation (OXPHOS) through the transcriptional activation of PDP1, a phosphatase that dephosphorylates and activates the E1 component of the large pyruvate dehydrogenase complex. Therefore, EGR1-mediated PDP1 activation increases intracellular adenosine triphosphate production, leading to sufficient energy to enhance the proliferation and survival of ibrutinib-resistant lymphoma cells. 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.

01 Feb 2023·Kidney international

The oxidative phosphorylation inhibitor IM156 suppresses B-cell activation by regulating mitochondrial membrane potential and contributes to the mitigation of systemic lupus erythematosus

Article

Author: Kim, Aekyong ; Kim, Beom Seok ; Kim, Jieun ; Song, Jason Jungsik ; Lim, Beom Jin ; Son, Jimin ; Shim, Joo Sung ; Kim, Joon Ye ; Cheong, Jae-Ho ; Kim, Hanna ; Ha, Sang-Jun ; Lee, Lucy Eunju ; Cho, Yuri ; Jang, Sung Hoon ; Kim, Eun Jee

Current treatment strategies for autoimmune diseases may not sufficiently control aberrant metabolism in B-cells. To address this concern, we investigated a biguanide derivative, IM156, as a potential regulator for B-cell metabolism in vitro and in vivo on overactive B-cells stimulated by the pro-inflammatory receptor TLR-9 agonist CpG oligodeoxynucleotide, a mimic of viral/bacterial DNA. Using RNA sequencing, we analyzed the B-cell transcriptome expression, identifying the major molecular pathways affected by IM156 in vivo. We also evaluated the anti-inflammatory effects of IM156 in lupus-prone NZB/W F1 mice. CD19⁺B-cells exhibited higher mitochondrial mass and mitochondrial membrane potential compared to T-cells and were more susceptible to IM156-mediated oxidative phosphorylation inhibition. In vivo, IM156 inhibited mitochondrial oxidative phosphorylation, cell cycle progression, plasmablast differentiation, and activation marker levels in CpG oligodeoxynucleotide-stimulated mouse spleen B-cells. Interestingly, IM156 treatment significantly increased overall survival, reduced glomerulonephritis and inhibited B-cell activation in the NZB/W F1 mice. 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.

01 Oct 2022·Investigational new drugs

First-in-human study of IM156, a novel potent biguanide oxidative phosphorylation (OXPHOS) inhibitor, in patients with advanced solid tumors

Article

Author: Janku, Filip ; Kim, Sun Young ; Geiger, Barb ; Beom, Seung-Hoon ; Kim, Hyo Song ; Moon, Yong Wha ; Rudoltz, Marc S ; Cheong, Jae-Ho ; Yim, Dong-Seok ; Welsch, Dean ; Shin, Young G ; Rha, Sun Young ; Kim, Tae Won ; Lee, Young Woo ; Yoo, Sanghee ; Thurston, Archie ; Kim, Gun Min

Abstract:

Preclinical models suggest anticancer activity of IM156, a novel biguanide mitochondrial protein complex 1 inhibitor of oxidative phosphorylation (OXPHOS). This first-in-human dose-escalation study enrolled patients with refractory advanced solid tumors to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Eligible patients received oral IM156 every other day (QOD) or daily (QD) and were assessed for safety, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary signals of efficacy. 22 patients with advanced cancers (gastric, n = 8; colorectal, n = 3; ovarian, n = 3; other, n = 8) received IM156 100 to 1,200 mg either QOD or QD. There were no DLTs. However, 1,200 mg QD was not well tolerated due to nausea; 800 mg QD was determined as the RP2D. The most frequent treatment-related AEs (TRAEs) were nausea (n = 15; 68%), diarrhea (n = 10; 46%), emesis (n = 9; 41%), fatigue (n = 4; 18%) and abdominal pain, constipation, and blood lactate increased (n = 2 each; 9%). Grade 3 nausea (n = 3; 14%) was the only grade ≥ 3 TRAE. Plasma exposures increased dose proportionally; mean Day 27 area under the curve (AUC0-24) values were higher following QD administration compared to the respective QOD regimen. Stable disease (SD), observed in 7 (32%) patients (confirmed in 2 [9%]), was the best response. To our knowledge, this is the first phase 1 study of an OXPHOS inhibitor that established a RP2D for further clinical development in cancer. Observed AEs of IM156 were manageable and SD was the best response.

News (Medical) associated with Lixumistat

18 Nov 2022

·www.businesswire.com

ImmunoMet Therapeutics Announces First Patient Dosed in a Phase 1b Trial of IM156 in Pancreatic Cancer

HOUSTON--(BUSINESS WIRE)--ImmunoMet Therapeutics, Inc., a clinical stage biotechnology company targeting metabolism to develop novel anti-cancer and anti-fibrotic therapies, today 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. The study is led by Shubham Pant, MD, Professor in Department of Gastrointestinal (GI) Medical Oncology and Associate Professor, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. 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. The primary endpoint is to evaluate the safety and tolerability of the combination. Exploratory efficacy endpoints include objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) using RECIST v1.1 criteria. “Pancreatic cancer continues to be defined by high unmet need, morbidity, and mortality. There is substantial evidence that differential cancer cell metabolism, and oxidative phosphorylation (OxPhos) in particular, plays a key role in the development of resistance to current therapies. We are hopeful that this potentially best-in-class OxPhos inhibitor can improve outcomes for these patients,” said Dean Welsch, CEO of ImmunoMet Therapeutics. Additional information about the trial, which is recruiting patients, can be found on clinicaltrials.gov using the identifier NCT05497778. 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. ImmunoMet continues to investigate additional indications where emerging data implicate OxPhos inhibition will demonstrate anti-tumor effects. About IM156 IM156 is a Protein Complex 1 (PC1) inhibitor that targets the oxidative phosphorylation (OXPHOS) pathway that is required to drive tumor growth and proliferation in some tumors. IM156, ImmunoMet’s lead drug candidate, is solely owned by ImmunoMet and is currently in development for the treatment of selected cancers. About ImmunoMet Therapeutics ImmunoMet is a clinical stage biotechnology company targeting metabolism for the treatment of selected cancers and fibrotic diseases. ImmunoMet’s lead molecule, IM156, is the first PC1 inhibitor to complete Phase 1 with good tolerability. In addition to IM156, ImmunoMet owns a large library of biguanides with the potential for development, internally or with partners, for multiple indications. The company was founded in 2015, is headquartered in JLABS @ TMC in Houston and has raised $34M to date. For more information about the company, please visit www.immunomet.com.

Phase 1Orphan DrugImmunotherapy

17 Nov 2022

·pipelinereview.com

ImmunoMet Therapeutics Announces First Patient Dosed in a Phase 1b Trial of IM156 in Pancreatic Cancer

HOUSTON, TX, USA I November 17, 2022 I ImmunoMet Therapeutics, Inc., a clinical stage biotechnology company targeting metabolism to develop novel anti-cancer and anti-fibrotic therapies, today 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. The study is led by Shubham Pant, MD, Professor in Department of Gastrointestinal (GI) Medical Oncology and Associate Professor, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. 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. The primary endpoint is to evaluate the safety and tolerability of the combination. Exploratory efficacy endpoints include objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) using RECIST v1.1 criteria. “Pancreatic cancer continues to be defined by high unmet need, morbidity, and mortality. There is substantial evidence that differential cancer cell metabolism, and oxidative phosphorylation (OxPhos) in particular, plays a key role in the development of resistance to current therapies. We are hopeful that this potentially best-in-class OxPhos inhibitor can improve outcomes for these patients,” said Dean Welsch, CEO of ImmunoMet Therapeutics. Additional information about the trial, which is recruiting patients, can be found on clinicaltrials.gov using the identifier NCT05497778. 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. ImmunoMet continues to investigate additional indications where emerging data implicate OxPhos inhibition will demonstrate anti-tumor effects. About IM156 IM156 is a Protein Complex 1 (PC1) inhibitor that targets the oxidative phosphorylation (OXPHOS) pathway that is required to drive tumor growth and proliferation in some tumors. IM156, ImmunoMet’s lead drug candidate, is solely owned by ImmunoMet and is currently in development for the treatment of selected cancers. About ImmunoMet Therapeutics ImmunoMet is a clinical stage biotechnology company targeting metabolism for the treatment of selected cancers and fibrotic diseases. ImmunoMet’s lead molecule, IM156, is the first PC1 inhibitor to complete Phase 1 with good tolerability. In addition to IM156, ImmunoMet owns a large library of biguanides with the potential for development, internally or with partners, for multiple indications. The company was founded in 2015, is headquartered in JLABS @ TMC in Houston and has raised $34M to date. For more information about the company, please visit www.immunomet.com . SOURCE: ImmunoMet Therapeutics

Phase 1Orphan DrugImmunotherapy

100 Deals associated with Lixumistat

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Indication	Highest Phase	Country/Location	Organization	Date
Melanoma	Phase 2	-	ImmunoMet Therapeutics, Inc.Startup	31 May 2023
Advanced Pancreatic Adenocarcinoma	Phase 1	US	National Cancer Institute	21 Oct 2022
Pancreatic Cancer	Phase 1	US	ImmunoMet Therapeutics, Inc.Startup	21 Oct 2022
Advanced Malignant Solid Neoplasm	Phase 1	KR	ImmunoMet Therapeutics, Inc.Startup	09 Oct 2017
Lymphoma	Phase 1	KR	ImmunoMet Therapeutics, Inc.Startup	09 Oct 2017
Castration-Resistant Prostatic Cancer	Preclinical	US	ImmunoMet Therapeutics, Inc.Startup	31 May 2023
Gastrointestinal Stromal Tumors	Preclinical	US	ImmunoMet Therapeutics, Inc.Startup	31 May 2023
Glioblastoma Multiforme	Preclinical	US	ImmunoMet Therapeutics, Inc.Startup	31 May 2023

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03272256 (ASCO2020) Manual	Phase 1	HR-positive/HER2-low Solid Tumors	22	Lixumistat	tbaikbcafw(dxsyftidjo) = bmquyqvfxw fgncybkzgs (rgbdyhiwzk ) View more	Positive	29 May 2020

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