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 ImmunoMet Therapeutics, Inc.

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Literatures (Medical) associated with ImmunoMet Therapeutics, Inc.

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

AbstractPreclinical 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.

15 Jun 2022·Cancer Research

Abstract 4183: Differential modulation of tumor versus T cell oxidative phosphorylation potentiates anti-tumor immunity

Author: Cowen, Benjamin R. ; Morrow, Brittany ; Marszalek, Joseph R. ; Vellano, Christopher P. ; Welsh, Dean J. ; Bhanu, Krithikaa Rajkumar ; Curran, Michael A. ; Rice, Meghan ; Jayaprakash, Priyamvada ; Gay, Jason P.

AbstractWe sought to determine whether various inhibitors of Oxidative Phosphorylation (OxPhos) could restore tumor infiltrating T cell functionality and longevity while compromising metabolic fitness of tumor cells. Using a combination of in vitro metabolic profiling with the Seahorse XFe96 Analyzer and in vivo tumor immunotherapy in the immunocompetent TRAMP-C2 prostate adenocarcinoma model, we determined the differential impact of multiple OxPhos inhibitors on both tumor immune metabolic fitness and functional capacity. Impact on the tumor immune microenvironment of TRAMP-C2 tumors was assessed through high parameter flow cytometry on a BD X-30. While OxPhos inhibition compromised initial T cell activation, we found that two of the inhibitors increased the glucose uptake, proliferation, and activation status of effector T cells. In contrast, the same two inhibitors decreased the mitochondrial fitness, proliferation and OxPhos metabolic capacity of TRAMP-C2 tumor cells themselves. To determine whether this selective inhibition of tumor versus T cell metabolic function could improve immunotherapy responses in vivo, we implanted TRAMP-C2 tumors and treated them with these OxPhos inhibitors with or without concomitant immune checkpoint blockade (ICB). The combination of ICB and OxPhos inhibition achieved highly significant and durable rates of tumor control and regression suggesting that these approaches are potentially synergistic. Analysis of the tumor microenvironment has identified the cellular mechanisms underlying these therapeutic effects which may provide useful biomarkers as this novel combination is translated to the clinic.Citation Format: Krithikaa Rajkumar Bhanu, Priyamvada Jayaprakash, Meghan Rice, Brittany Morrow, Joseph R. Marszalek, Jason P. Gay, Christopher P. Vellano, Benjamin R. Cowen, Dean J. Welsh, Michael A. Curran. Differential modulation of tumor versus T cell oxidative phosphorylation potentiates anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4183.

01 Dec 2021·Journal of Pharmacology and Experimental TherapeuticsQ3 · MEDICINE

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

Q3 · MEDICINE

Article

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

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.

News (Medical) associated with ImmunoMet Therapeutics, Inc.

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

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