tegavivint (BC2059) / Iterion Therap, Apollomics - LARVOL DELTA

Phase 1/2 trial of the TBL1 inhibitor, tegavivint, in advanced hepatocellular carcinoma (aHCC) (AACR 2025) - P1/2 | "In these early cohorts, weekly tegavivint appears tolerable and demonstrates preliminary efficacy in aHCC."

Metastases • P1/2 data • Hepatocellular Cancer • Oncology • Solid Tumor • AFP • AXIN1

Targeting the DNA Damage Response through TBL1X in Mantle Cell Lymphoma. (PubMed, Blood Adv) - "Combining tegavivint with PARP-1/2 inhibitor talazoparib results in synergistic MCL cell death in vitro, and in vivo this combination significantly prolonging the survival of an MCL PDX. Together, our results define the role of TBL1X in maintaining genomic stability in MCL and establish targeting TBL1X as a novel therapeutic strategy for patients with this incurable disease."

Journal • B Cell Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CCND1 • RAD51

A clinical drug candidate that triggers non-apoptotic cancer cell death. (PubMed, Res Sq) - "TECR is canonically involved in the synthesis of very long chain fatty acids but appears to promote non-apoptotic cell death in response to CIL56 and tegavivint via the synthesis of the saturated long-chain fatty acid palmitate. These findings outline a lipid-dependent non-apoptotic cell death mechanism that can be induced by a drug candidate currently being tested in humans."

Journal • Oncology • Sarcoma • Solid Tumor

Tegavivint for the Treatment of Relapsed or Refractory Leukemia (clinicaltrials.gov) - P1 | N=9 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Dec 2024 ➔ Dec 2025 | Trial primary completion date: Dec 2024 ➔ Dec 2025

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Osimertinib and Tegavivint As First-Line Therapy for the Treatment of Metastatic EGFR-Mutant Non-small Cell Lung Cancer (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: Ohio State University Comprehensive Cancer Center | N=18 ➔ 24 | Trial completion date: Dec 2024 ➔ Jul 2029 | Trial primary completion date: Dec 2024 ➔ Jul 2025

Enrollment change • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • NOTCH3

TBL1 Inhibition Eradicates Drug Resistant Leukemia Initiating Cells in T-ALL (ASH 2024) - "This approach aims to sensitize T-ALL cells to standard chemotherapy agents (vincristine, dexamethasone, L-asparaginase, referred to as VDL) in both in vitro and in vivo settings, as part of the preclinical evaluation of tegavivint in T-ALL treatment. These findings support our hypothesis that inhibiting TBL1-β-catenin is a viable target in T-ALL. Further preclinical studies are ongoing to evaluate the potential of this approach for clinical use."

Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • ANXA5 • CD1a • CD7

Targeting the DNA Damage Response through TBL1X in Mantle Cell Lymphoma (ASH 2024) - "Moreover, proteasomal inhibitor MG132 restored RAD51 protein levels when combined with tegavivint suggesting that TBL1X is involved in controlling RAD51 protein stability rather than its transcription. We believe these findings support further exploration of targeting of TBL1X in MCL with tegavivint. To leverage this finding of TBL1X-mediated DDR regulation, we are currently exploring novel drug combinations targeting genomic instability to maximize the therapeutic potential of tegavivint in this disease."

IO biomarker • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • ANXA5 • CUL1 • MYC • PLK1 • RAD51

A Phase Ib Study of Osimertinib and Tegavivint as First-Line Therapy in Patients with Metastatic EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC) (IASLC-WCLC 2024) - P1 | "Once the dose escalation phase of this trial is complete, the dose expansion phase will include a total of 12 patients at the RP2D to further assess clinical outcomes, including response rate, progression free survival, duration of response, and overall survival. Correlative studies include PK analysis, the evaluation of pharmacodynamic markers of β-catenin pathway activity, assessment of the clearance of EGFR-mutant ctDNA, and CT tumor volumetric studies."

Clinical • Metastases • P1 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

A phase 1/2 study of the TBL1 inhibitor, tegavivint (BC2059), in patients (pts) with advanced hepatocellular carcinoma (aHCC) with β-catenin activating mutations. (ASCO 2024) - P1, P1/2 | "If sufficient clinical benefit is observed, the combination of tegavivint plus pembrolizumab will be explored in the second part of the study in aHCC pts previously treated with a PD-1/PD-L1 inhibitor. The first patient began treatment in October of 2023 and the first dose escalation cohort was completed in January. Three institutions are open for enrollment; 5 other sites are pending site activation; all sites are in the United States and Canada."

Clinical • IO biomarker • Metastases • P1/2 data • Desmoid Tumors • Gastrointestinal Cancer • Hematological Malignancies • Hepatocellular Cancer • Hepatology • Lung Cancer • Lymphoma • Non Small Cell Lung Cancer • Oncology • Pediatrics • Sarcoma • Solid Tumor

Inhibition of TBL1 and β-catenin interaction sensitizes acute lymphoblastic leukemia to chemotherapy (AACR 2024) - "We hypothesize that interrupting the binding of TBL1 to β-catenin abrogates leukemia cell survival and test if tegavivint sensitizes these cells to chemotherapeutic agents such as VDL (Vincristine, Dexamethasone, L-asparaginase) as part of preclinical evaluation of tegavivint in T- and B-cell ALL. Four T-ALL cell lines one patient-derived T-ALL case, B-ALL cell lines and eight patient-derived B-ALL cases were used in vitro. Our preliminary data shows that T-ALL and B-ALL are sensitive to TBL1-β-catenin inhibition using tegavivint as a monotherapy. Tegavivint can also sensitize T-ALL and B-ALL to chemotherapy (VDL). As our data supports our hypothesis that TBL-1-β-catenin inhibition is a new target in ALL therapy, further studies are in progress to preclinically evaluate this approach for clinical care."

IO biomarker • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • ANXA5 • CTNNB1

In Vitro and In Vivo Models for the Development of Hair Growth Materials By Regulating the β-Catenin Signaling Pathways. (PubMed, J Med Food) - "We confirmed that 100 nM tegatrabetan (TG), a β-catenin inhibitor, decreased the proliferation of human hair follicle dermal papilla cells (HFDPCs) at 72 h...Moreover, TG inhibited the expression of cyclin D1, β-catenin, keratin 14, and Ki67. These results suggest that TG-induced inhibition of hair growth can be a promising model for developing new materials for enhancing β-catenin-mediated hair growth."

Journal • Preclinical • Alopecia • Immunology • CCND1 • KRT14

Cytosolic Cadherin 4 promotes angiogenesis and metastasis in papillary thyroid cancer by suppressing the ubiquitination/degradation of β-catenin. (PubMed, J Transl Med) - "CDH4 induces PTC angiogenesis and metastasis via the inhibition of β-TrCP1-dependent ubiquitination of β-Catenin."

Journal • Endocrine Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • CTNNB1

Iterion Therapeutics Announces First Patient Dosed in Phase 1b/2a Clinical Trial of Tegavivint in Patients with Advanced Hepatocellular Carcinoma Who Have Failed One or More Systemic Treatments (PRNewswire) - "Iterion Therapeutics...announced today it is actively enrolling a Phase 1b/2a clinical trial of its lead molecule, tegavivint, in patients with advanced hepatocellular carcinoma (HCC) that have failed at least one line of systemic therapy....The ongoing clinical trial will enroll approximately 35 patients in dose escalation and optimization cohorts of patients with unresectable locally advanced or metastatic HCC that have failed at least one line of systemic treatment."

Trial status • Gastrointestinal Cancer • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor

Tegavivint for the Treatment of Relapsed or Refractory Leukemia (clinicaltrials.gov) - P1 | N=9 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Recruiting ➔ Active, not recruiting | N=54 ➔ 9 | Trial completion date: Dec 2023 ➔ Dec 2024 | Trial primary completion date: Dec 2023 ➔ Dec 2024

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Preclinical efficacy of targeting epigenetic mechanisms in AML with 3q26 lesions and EVI1 overexpression. (PubMed, Leukemia) - "Tegavivint (TV, BC-2059), known to disrupt the binding of nuclear β-catenin and TCF7L2/LEF1 with TBL1, also inhibited co-localization of EVI1 with TBL1 and dose-dependently induced apoptosis in AML cell lines and patient-derived (PD) AML cells with 3q26.2 lesions. TV treatment repressed EVI1, attenuated enhancer activity at ERG, TCF7L2, GATA2 and MECOM loci, abolished interactions between MYC enhancers, repressing AML stemness while upregulating mRNA gene-sets of interferon/inflammatory response, TGF-β signaling and apoptosis-regulation. Co-treatment with TV and BETi or venetoclax induced synergistic in vitro lethality and reduced AML burden, improving survival of NSG mice harboring xenografts of AML with 3q26.2 lesions."

Journal • Preclinical • Acute Myelogenous Leukemia • Inflammation • BRD4 • CDK4 • CTNNB1 • GATA2 • MCL1 • MECOM • MYC • TCF7L2 • TGFB1

Osimertinib and Tegavivint as First-Line Therapy for the Treatment of Metastatic EGFR-Mutant Non-small Cell Lung Cancer (clinicaltrials.gov) - P1 | N=18 | Recruiting | Sponsor: Ohio State University Comprehensive Cancer Center | Trial primary completion date: Dec 2023 ➔ Dec 2024

Metastases • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • NOTCH3

Actionable Findings from an Unbiased Drug Screen for Novel Single Agent and Combination Therapies Against AML with Mecom Re-Arrangement (ASH 2023) - "This was consistent with previous reports that BET inhibitors (e.g., OTX015, mivebresib or ABBV-075 and JQ1) are effective against 3q26.2-r AML cell lines, patient-derived (PD) AML cells and PDX models...In follow-up experiments, XIAP/cIAPs inhibitors birinapant (10-1000 nM) or SM-164 (30-1000 nM), chosen based on the MIPE screen outcomes, induced significantly more dose-dependent apoptosis in 3q26.2-r versus the other AML cell lines...Treatment with the dual mTOR/PIK3CA inhibitor NVP-BGT226 (1-30 nM) or navitoclax or Bcl-xL-specific BH3 mimetic A-1155463 also exerted lethality and synergistically induced apoptosis with mivebresib in AML cells with inv3/t(3; 3)...Co-treatment with birinapant and tegavivint also synergistically induced apoptosis in 3q26.2-r AML cells...Additionally, compared to each drug or vehicle control, co-treatment with birinapant and the BETi OTX015 (30 mg/kg/day, by oral gavage) was more effective in reducing AML burden in the xenograft model...."

Combination therapy • Acute Myelogenous Leukemia • Oncology • BCL2L1 • BRD4 • CASP3 • CDK4 • CTNNB1 • GATA2 • HEXIM1 • MCL1 • MECOM • MYC • PIK3CA • SF3B1 • XIAP

How can we target drug tolerant persistent cell populations in #EGFR NSCLC? Dr. Regan Memmott describes a trial exploring the beta catenin inhibitor tegavivint with osimertinib @EGFRSummit .

A Study of Tegavivint (BC2059) in Patients With Advanced Hepatocellular Carcinoma (clinicaltrials.gov) - P1/2 | N=108 | Recruiting | Sponsor: Iterion Therapeutics | Not yet recruiting ➔ Recruiting | Initiation date: May 2023 ➔ Sep 2023

Enrollment open • Metastases • Trial initiation date • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • AXIN1

Targeting Oncogenic Wnt/β-Catenin Signaling in Adrenocortical Carcinoma Disrupts ECM Expression and Impairs Tumor Growth. (PubMed, Cancers (Basel)) - "To investigate the preclinical potential of Wnt/β-catenin inhibition in the adrenal microenvironment, we developed a minimally invasive orthotopic xenograft model of ACC and demonstrated that treatment with the newly developed Wnt/β-catenin:TBL1 inhibitor Tegavivint significantly reduced tumor growth...Furthermore, this β-catenin-dependent oncogenic program can be therapeutically targeted with a newly developed Wnt/β-catenin inhibitor. These results show promise for the further clinical development of Wnt/β-catenin inhibitors in ACC and unveil a novel Wnt/β-catenin-regulated transcriptome."

Journal • Adrenal Cortex Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • COL11A1 • COL1A1

Iterion Therapeutics Announces the Initiation of a Phase 1 Clinical Trial for Tegavivint in Patients with c-Myc-overexpressing Relapsed or Refractory Large B-Cell Lymphomas (PRNewswire) - "Iterion Therapeutics...announced today its collaboration in a Phase 1 clinical trial for tegavivint in patients with relapsed or refractory c-Myc-overexpressing large B-cell lymphomas. The first patient has been enrolled to this National Cancer Institute-funded study, which is being conducted at The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute in Columbus, Ohio....The Phase 1 dose-escalation study will enroll up to 20 patients with relapsed or refractory c-Myc-overexpressing DLBCL, who have failed at least two lines of prior treatment."

Trial status • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Targeting TBL1 with tegavivint promotes anti-tumor and immunomodulatory responses in preclinical models of hepatocellular carcinoma (AACR 2023) - "Tegavivint monotherapy demonstrated antitumor activity in a range of HCC preclinical models. In vitro studies show correlation between tegavivint potency and beta-catenin mutation. In a syngeneic HCC mouse model with elevated beta-catenin, tegavivint reduces tumor growth and induces an activated T-cell subpopulation."

Immunomodulating • IO biomarker • Preclinical • Gastrointestinal Cancer • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • CD4 • PD-1

Preclinical efficacy of targeting epigenetic mechanisms in AML with 3q26 lesions and EVI1 overexpression (AACR 2023) - "We recently reported that tegavivint (TV) (BC-2059), a disruptor of the nuclear TBL1/R1-β-catenin-TCF7L2 complex represses c-Myc, cyclin D1 and Survivin and inhibits growth and survival of AML LSCs. Notably, in the flank-implanted PDX of AML191 or tail-vein infused PDX of AML242 models in NSG mice, treatment with OTX015 and TV, compared to vehicle control or each drug alone, significantly reduced AML growth and improved survival, without any host toxicity. These findings highlight the promising pre-clinical efficacy of novel BETi-based combinations against AML models harboring 3q26 lesions and EVI1 overexpression."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • BCL2L1 • BIRC5 • BRD4 • CCND1 • CD123 • CD99 • CDK4 • CDKN1A • CEBPA • CTNNB1 • GATA2 • HEXIM1 • ITGAM • KIT • MCL1 • MECOM • MYC • RUNX1 • TCF7L2

Serum protein changes in patients with desmoid tumors responsive to the TBL1 inhibitor, tegavivint (AACR 2023) - P1 | "A panel of beta-catenin regulated proteins and transcripts were identified as candidate pharmacodynamic biomarkers in patients whose desmoid tumor responded to tegavivint. Alterations in these serum proteins continued throughout the dosing interval and, for several proteins, a potential dose response correlation was observed. Further characterization of the relationship between tegavivint plasma levels, serum biomarkers, transcriptional changes and clinical responses in additional patients and time points will be presented."

Clinical • Desmoid Tumors • Oncology • Sarcoma • DKK1 • FGF2 • MMP1

Design, synthesis, and biological evaluation of transducin β-like protein 1 (TBL1) degraders (AACR 2023) - "Only one compound, BC-2059 (tegavivint, Iterion Therapeutics), has been reported to promote apoptosis by disrupting the TBL1/β-catenin interactions and show promising therapeutic effects in Wnt-driven cancers, such as colorectal cancer, breast cancer, and leukemia...The protein-protein interactions of the generated ternary complexes were analyzed by Rosetta and the interactions between the linkers and the protein were calculated by Autodock 4. The results suggested that short linkers (8-14 heavy atoms) are more suitable for N-linked series degraders in terms of PROTAC-induced ternary complex formation, while long linkers (>18 heavy atoms) are preferable for O-linked series."

Breast Cancer • Colorectal Cancer • Diffuse Large B Cell Lymphoma • Gastrointestinal Cancer • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor