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.

开始日期2017-10-09

申办/合作机构

ImmunoMet Therapeutics, Inc.初创企业

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项与 ImmunoMet Therapeutics, Inc. 相关的文献（医药）

2022-10-01·Investigational new drugs

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

Article

作者: Janku, Filip ; Kim, Sun Young ; Geiger, Barb ; Kim, Hyo Song ; Beom, Seung-Hoon ; Moon, Yong Wha ; Rudoltz, Marc S ; Cheong, Jae-Ho ; Welsch, Dean ; Yim, Dong-Seok ; 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.

2021-12-01·The Journal of pharmacology and experimental therapeutics3区 · 医学

Modulation of Oxidative Phosphorylation with IM156 Attenuates Mitochondrial Metabolic Reprogramming and Inhibits Pulmonary Fibrosis

3区 · 医学

Article

作者: Welsch, Dean J ; Willette, Robert N ; Cowen, Benjamin R ; Yoo, Sanghee ; Lee, Christopher Young Woo ; Rudoltz, Marc S ; Pondell, Stephen M ; Mangrolia, Parth

Metabolic reprogramming of the myofibroblast plays a fundamental role in the pathogenesis of fibrosing interstitial lung diseases. Here, we characterized the in vitro and in vivo metabolic and antifibrotic effects of IM156, an oxidative phosphorylation (OXPHOS) modulator that acts by inhibiting protein complex 1. In vitro, IM156 inhibited transforming growth factor β (TGFβ)-dependent increases in mitochondrial oxygen consumption rate and expression of myofibroblast markers in human pulmonary fibroblasts without altering cell viability or adding to TGFβ-induced increases in the extracellular acidification rate. IM156 significantly increased cellular AMP-activated protein kinase (AMPK) phosphorylation and was 60-fold more potent than metformin. In vivo, chronic oral administration of IM156 was highly distributed to major peripheral organs (i.e., lung, liver, kidney, heart) and had significant dose-related effects on the plasma metabolome consistent with OXPHOS modulation and AMPK activation. IM156 increased glycolysis, lipolysis, β-oxidation, and amino acids and decreased free fatty acids, tricarboxylic acid cycle activity, and protein synthesis. In the murine bleomycin model of pulmonary fibrosis, daily oral administration of IM156, administered 7 days after lung injury, attenuated body/lung weight changes and reduced lung fibrosis and inflammatory cell infiltration. The plasma exposures of IM156 were comparable to well tolerated doses in human studies. In conclusion, the metabolic and antifibrotic effects of IM156 suggest that OXPHOS modulation can attenuate myofibroblast metabolic reprogramming and support testing IM156 as a therapy for idiopathic pulmonary fibrosis and other fibrotic diseases. SIGNIFICANCE STATEMENT: Fibrosing interstitial lung diseases have a poor prognosis, and current antifibrotic treatments have significant limitations. This study demonstrates that attenuation of fibrogenic metabolic remodeling, by modulation of oxidative phosphorylation with IM156, prevents myofibroblast phenotype/collagen deposition and is a potentially effective and translational antifibrotic strategy.

2018-12-01·Experimental & molecular medicine

A novel and safe small molecule enhances hair follicle regeneration by facilitating metabolic reprogramming

Article

作者: Ryu, Jae-Sung ; Chung, Kyung-Sook ; Kook, Jiae ; Lee, Hongbum ; Kim, Hye Jin ; Kim, Janghwan ; Kwon, Youjeong ; Kim, Sung-Wuk ; Jeong, Jae Kap ; Yoo, Sanghee ; Son, Myung Jin ; Mun, Seon Ju

Targeting hair follicle regeneration has been investigated for the treatment of hair loss, and fundamental studies investigating stem cells and their niche have been described. However, knowledge of stem cell metabolism and the specific regulation of bioenergetics during the hair regeneration process is currently insufficient. Here, we report the hair regrowth-promoting effect of a newly synthesized novel small molecule, IM176OUT05 (IM), which activates stem cell metabolism. IM facilitated stemness induction and maintenance during an induced pluripotent stem cell generation process. IM treatment mildly inhibited mitochondrial oxidative phosphorylation and concurrently increased glycolysis, which accelerated stemness induction during the early phase of reprogramming. More importantly, the topical application of IM accelerated hair follicle regeneration by stimulating the progression of the hair follicle cycle to the anagen phase and increased the hair follicle number in mice. Furthermore, the stem cell population with a glycolytic metabotype appeared slightly earlier in the IM-treated mice. Stem cell and niche signaling involved in the hair regeneration process was also activated by the IM treatment during the early phase of hair follicle regeneration. Overall, these results show that the novel small molecule IM promotes tissue regeneration, specifically in hair regrowth, by restructuring the metabolic configuration of stem cells.

项与 ImmunoMet Therapeutics, Inc. 相关的新闻（医药）

2022-11-18

·Business Wire

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.

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2022-11-17

·PipelineReview

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

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