IPN60090 / UT MD Anderson Cancer Center, Ipsen - LARVOL DELTA

Deciphering the landscape of allosteric glutaminase 1 inhibitors as anticancer agents. (PubMed, Bioorg Chem) - "We also summarize the most important biological studies conducted on CB-839 and IPN60090 and their significance for further assessment. The insights garnered from this paper are expected to guide future drug design endeavours toward the identification of novel therapeutics targeting GLS1 to complement and potentially enhance the arsenal of anticancer medications."

Journal • Review • Oncology

Glutaminase 1 plays critical roles in myelodysplastic syndrome and acute myeloid leukemia cells. (PubMed, Cancer Biomark) - "The efficacy of GLS inhibitors (CB839 or IPN60090) and BCL2 inhibitor venetoclax was also examined. Cells transfected with GLS1 short hairpin RNA showed suppressed proliferation under hypoxic conditions and increased sensitivity to venetoclax. Targeting glutaminolysis and BCL2 inhibition enhances the therapeutic efficacy and has been proposed as a novel strategy for treating high-risk MDS and AML."

IO biomarker • Journal • Acute Myelogenous Leukemia • Aplastic Anemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Myelodysplastic Syndrome • Oncology • GLS1 • GLS2

Co-targeting asparagine and glutamine metabolism is a viable treatment strategy for PI3K/PTEN mutated cervical cancer (AACR 2024) - "Treatment with glutamine antagonists (DON, JHU-083) and GLS inhibitors (CB-839 and IACS-6274), resulted in reduced cell viability and clonogenic survival in tumor cells with PI3K/PTEN mutation compared to wild-type. Orthogonal evaluations using glutamine agonists, GLS inhibitors, and mass spectrometric point to a significant role played by PI3K/PTEN mutations in altering cervix tumor cell metabolism towards a more glutamine dependent phenotype. This study suggests a potential strategy for improving the treatment of PI3K-AKT-altered cervical tumors by targeting glutamine and asparagine metabolism in combination with standard therapies. These treatment strategies are currently being evaluated in vivo using a patient derived xenograft model with PIK3CA E545K mutation as well as an immunocompetent cervical tumor model in mice with PTEN deletion."

Cervical Cancer • Oncology • Solid Tumor • PI3K • PIK3CA • PTEN

ZSWIM4 inhibition improves chemosensitivity in epithelial ovarian cancer cells by suppressing intracellular glycine biosynthesis. (PubMed, J Transl Med) - "ZSWIM4 inhibition enhanced EOC cell chemosensitivity by ameliorating intracellular glycine metabolism reprogramming, thus providing a new potential therapeutic strategy for EOC."

Journal • Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor

DIFFERENT ROLE OF GLUTAMINOLYSIS IN LUNG AND LIVER FIBROSIS (AASLD 2023) - "GLS1i reduced fibrosis markers in an acute liver fibrosis model (single injection of CCl4)4 and a bleomycin model (BleoM) of idiopathic pulmonary fibrosis (IPF)5...GLS1i IPN-60090 was tested at 100, 30, 10, and 3 mg/kg BID in a rat choline deficient high fat diet (CDHFD) model (6 wks diet plus 6 wks dosing) and mouse BleoM (dosing day 7-21)... In liver and lung fibrosis GLS1 expression is elevated, however, GLS1+ cell types and GLS2 expression differ in these organs. GLS1i resulted in opposite outcomes in liver vs lung fibrosis models. This could be due to differences in (1) mode of action in different cell types (2) adaptation mechanisms or (3) off-target effects of GLS1i."

Fibrosis • Hepatology • Idiopathic Pulmonary Fibrosis • Immunology • Liver Cirrhosis • Non-alcoholic Steatohepatitis • Pulmonary Disease • Respiratory Diseases • GLS1 • GLS2 • PDGFRA • TGFB1

IACS-6274 With or Without Bevacizumab and Paclitaxel for the Treatment of Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=54 | Recruiting | Sponsor: M.D. Anderson Cancer Center | N=84 ➔ 54

Enrollment change • Metastases • Monotherapy • Cutaneous Melanoma • Endometrial Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Refractory Ovarian Cancer • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Uterine Cancer • ARID1A • KEAP1 • NF1 • NFE2L2 • PD-1 • PD-L1 • PIK3CA • PTEN • STK11

A Novel Glutaminase 1 Inhibitor (IACS-6274) Radiosensitizes Mutant KEAP1 Lung Cancer Models to Photons and Protons (ASTRO 2023) - No abstract available

Preclinical • Lung Cancer • Oncology • Solid Tumor • KEAP1

Aspirin and the metabolic hallmark of cancer: novel therapeutic opportunities for colorectal cancer. (PubMed, Explor Target Antitumor Ther) - "Importantly, as aspirin treatment exposes metabolic vulnerabilities in tumour cells, there is an opportunity for the use of aspirin in combination with specific metabolic inhibitors in particular, glutaminase (GLS) inhibitors currently in clinical trials such as telaglenastat (CB-839) and IACS-6274 for the treatment of colorectal and potentially other cancers. The increasing evidence that aspirin impacts metabolism in cancer cells suggests that aspirin could provide a simple, relatively safe, and cost-effective way to target this important hallmark of cancer. Excitingly, this review highlights a potential new role for aspirin in improving the efficacy of a new generation of metabolic inhibitors currently undergoing clinical investigation."

Journal • Review • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • mTOR

Glutaminase inhibitors block metabolic switch in prostate cancer and prevents anti-androgen treatment resistance (AACR 2023) - "GLS inhibitors CB-839 and IACS-6274 are being clinically developed for treatment of various human malignancies. We have shown that growth of prostate cancer patient derived xenografts (PDX) is markedly inhibited by a combination treatment of a clinically used ASI enzalutamide (ENZA) followed by a GLS inhibitor. We followed the growth of one HSPC and two CRPC PDX tumors in mice and collected tumor tissues and circulating human tumor cells (CTC) from mouse blood samples at sacrifice. GLS inhibitors added to ASI could be effective against CRPC and mCRPC developing resistance to ASI treatment."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

IACS-6274 With or Without Bevacizumab and Paclitaxel for the Treatment of Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=84 | Recruiting | Sponsor: M.D. Anderson Cancer Center | N=36 ➔ 84

Enrollment change • Metastases • Monotherapy • Cutaneous Melanoma • Endometrial Cancer • Head and Neck Cancer • Melanoma • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Refractory Ovarian Cancer • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Uterine Cancer • ARID1A • KEAP1 • NF1 • NFE2L2 • PD-1 • PD-L1 • STK11

Dysregulation and epigenetic reprogramming of NRF2 signaling axis promote acquisition of cisplatin resistance and metastasis in head and neck squamous cell carcinoma (AACR 2023) - "Acquisition of cisplatin resistance and distant metastasis is associated with dysregulated and epigenetically reprogrammed KEAP1/NRF2 signaling pathway. A strategy targeting KEAP1/NRF2 pathway or glutamine metabolism deserves further clinical investigation in patients with cisplatin resistant head and neck tumors."

Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • GLS1

[VIRTUAL] Integrated approach towards defining mechanism based combinations to guide clinical development of glutaminase inhibitors (AACR 2021) - P1 | "IPN60090, dosed in combination with inhibitors of these pathways yields regressions and off-treatment, durable responses in preclinical models of KEAP1-mutant NSCLC. Based on these data, combination strategies are being developed for Phase 1b expansion cohorts."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KEAP1 • NFE2L2

[VIRTUAL] Asparagine synthetase (ASNS) expression predicts response to the GLS1 inhibitor IPN60090 in ovarian cancer through selective modulation of redox homeostasis (AACR 2021) - P1 | "Upon validation and CLIA certification, this assay was deployed across archival patient biopsies collected in the Department of Investigational Cancer Therapeutics at MD Anderson Cancer Center, and identified patients who showed no ASNS staining (ASNSnull) in their tumors, suggesting that they may benefit from treatment with IPN60090. Taken together, through a comprehensive translational effort we have identified ASNS as a predictive biomarker of response to GLS1 inhibitor-based therapeutic regimens."

Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • ASNS

[VIRTUAL] The GLS1 inhibitor IPN60090 enhances antitumor immune response through metabolic reprogramming of T cells and impacts on the tumor microenvironment (AACR 2021) - P1 | "The observed synergy is due in part to IPN60090-dependent depletion of regulatory T-cells (Treg) and a concurrent increase in the CD8+ T-cell to Treg ratio in the tumor microenvironment. These data suggest that IPN60090 may show clinical benefit by enhancing immune response in the context of checkpoint blockade and have served as the justification for phase 1b trials in combination with Pembrolizumab which will enroll in 2021."

Biomarker • IO biomarker • Tumor microenvironment • Oncology • CD4 • CD8

An updated patent review of glutaminase inhibitors (2019-2022). (PubMed, Expert Opin Ther Pat) - "Most recent patents and literature focus on GLS1 inhibitors IPN60090 and DRP104, which have entered clinical trials. While other patent disclosures during this period have not generated any drug candidates, the clinical update will inform the potential of these inhibitors as promising therapeutic agents either as single or as combination interventions."

Journal • Review • CNS Disorders • Oncology • Psychiatry • GLS1

IACS-6274 With or Without Pembrolizumab for the Treatment of Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=36 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Initiation date: Feb 2022 ➔ Sep 2021

Monotherapy • Trial initiation date • Cutaneous Melanoma • Endometrial Cancer • Head and Neck Cancer • Melanoma • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Refractory Ovarian Cancer • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Uterine Cancer • ARID1A • KEAP1 • NF1 • NFE2L2 • PD-1 • PD-L1 • STK11

THE PIVOTAL ROLE OF GLUTAMINOLYSIS IN MYELODYSPLASTIC SYNDROME (MDS): A NOVEL STRATEGY FOR THE TARGETED THERAPY OF MDS (EHA 2022) - "We also investigated the efficacy of GLS inhibitor (CB-839 or IPN-60090) and BCL2 inhibitor, venetoclax by using MDS and AML cell line, SKM-1, MDS-L, MOLM-14, THP-1, MV4;11 and osteoblastic cell line, MC3T3-E1. Conclusion Targeting of glutaminolysis and BCL2 inhibition combine to enhance therapeutic efficacy and has been proposed as a novel strategy high-risk MDS and AML. We also provide the promising clinical relevance as a candidate drug for treatment of MDS and AML patients."

IO biomarker • Acute Myelogenous Leukemia • Anemia • Aplastic Anemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • CASP3 • CASP7 • GLS1 • GLS2

[VIRTUAL] First-in-human biomarker-driven phase I trial of the potent and selective glutaminase-1 (GLS1) inhibitor IACS-6274 (IPN60090) in patients (pts) with molecularly selected advanced solid tumors. (ASCO 2021) - P1 | "IACS-6274 was well tolerated at biologically active doses with good human PK, significant PD target modulation and preliminary antitumor activity observed . The clinical trial assessment of rational combinations to maximize benefit in molecularly-selected pts is initiating."

Biomarker • Clinical • IO biomarker • P1 data • Acute Kidney Injury • Fatigue • Head and Neck Cancer • Leiomyosarcoma • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Renal Disease • Sarcoma • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • ASNS • KEAP1 • NF1 • NFE2L2 • PD-1 • STK11

IACS-6274 With or Without Pembrolizumab for the Treatment of Advanced Solid Tumors (clinicaltrials.gov) - P1; N=36; Recruiting; Sponsor: M.D. Anderson Cancer Center

Clinical • Monotherapy • New P1 trial • Cutaneous Melanoma • Endometrial Cancer • Head and Neck Cancer • Melanoma • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Refractory Ovarian Cancer • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Uterine Cancer • ARID1A • KEAP1 • NF1 • NFE2L2 • PD-1 • PD-L1 • STK11

Selective glutaminase-1 inhibitor shows antitumor activity across cancer types (Healio) - "'This was a phase 1 clinical trial that included a heavily pretreated patient population with a diverse range of very advanced cancers that were refractory to available existing therapies known to provide clinical benefit for their condition,' Yap told Healio. 'Most of our patients had progressed on multiple lines of prior therapies, including chemotherapy, immunotherapy and/or targeted agents. Therefore, to see a disease control rate at 12 weeks of 60% in this heavily pretreated and resistant population of [patients with advanced cancer] is certainly notable.'"

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Metabolic inhibitor IACS-6274 shows early antitumor effects in underserved patients (Eurekalert) - "'Within Therapeutics Discovery, we have focused our efforts to develop new therapies that meet the needs of our patients,' said principal investigator Timothy A. Yap...'Our comprehensive efforts to understand and advance IACS-6274 identified select groups of underserved patients as those most likely to benefit from treatment, and we are encouraged by the early results thus far in the study.'"

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Dose Escalation and Dose Expansion Study of IPN60090 in Patients With Advanced Solid Tumours (clinicaltrials.gov) - P1; N=22; Terminated; Sponsor: Ipsen; N=236 ➔ 22; Trial completion date: Oct 2021 ➔ Dec 2020; Recruiting ➔ Terminated; Trial primary completion date: Oct 2021 ➔ Dec 2020; Following an internal portfolio review, Ipsen has made the decision to terminate study D-US-60090-001. Ipsen would like to highlight that early termination was not due to any safety or tolerability issues with IPN60090

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Oncology • Solid Tumor

Discovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties. (PubMed, J Med Chem) - "We initiated a GLS-1 inhibitor discovery program focused on optimizing physicochemical and pharmacokinetic properties, and have developed a new selective inhibitor, compound 27 (IPN60090), which is currently in phase 1 clinical trials. Compound 27 attains high oral exposures in preclinical species, with strong in vivo target engagement, and should robustly inhibit glutaminase in humans."

Clinical • Journal • PK/PD data • Oncology

[VIRTUAL] IPN60090: A potent and selective inhibitor of glutaminase being developed for KEAP1/NFE2L2 mutant NSCLC and ASNS-low HGSOC patients (AACR-I 2020) - "IPN60090: A potent and selective inhibitor of glutaminase being developed for KEAP1/NFE2L2 mutant NSCLC and ASNS-low HGSOC patients"

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • KEAP1 • NFE2L2

Advance in new therapy with potential benefit for underserved patients with lung, ovarian cancers - "Identifying these putative predective biomarkers of response is critical for our ongoing clinical efforts to ensure that we're able to offer patients the most relavant therapies," said Timothy A.Yep."

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