On February 20, 2024 Iterion Therapeutics, an oncology-focused biopharmaceutical company developing small molecule inhibitors of Transducin beta-like protein 1 (TBL1), a downstream target in the Wnt/beta-catenin signaling pathway, reported that 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 (Press release, Iterion Therapeutics, FEB 20, 2024, View Source [SID1234640280]).
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Activation of the Wnt/beta-catenin pathway is a hallmark of several forms of cancer, including HCC, in which approximately half of patients have tumors with Wnt-activating mutations. Unfortunately, key members of this pathway (including beta-catenin) have either been resistant to conventional drug development or plagued with off-target toxicities. Extensive pre-clinical study results across multiple tumor types suggest that TBL1 is a downstream target that is necessary for Wnt/beta-catenin-activated oncogenesis. TBL1 binds nuclear beta-catenin thus stabilizing the transcription complex necessary to turn on cancer-causing genes. Tegavivint’s direct binding to TBL1 displaces beta-catenin and disrupts this complex, allowing the degradation of free nuclear beta-catenin and preventing downstream oncogenic gene transcription.
"By targeting TBL1, tegavivint promotes potent inhibition of nuclear beta-catenin oncogenic activity without inducing toxicities observed for other drugs that are upstream in the Wnt-pathway" stated Rahul Aras, Ph.D., President & CEO for Iterion Therapeutics. "HCC is a devastating cancer with a high prevalence of Wnt-activated tumors, and we are committed to developing tegavivint for this patient population that otherwise has very few therapeutic options".
HCC is the sixth most commonly diagnosed cancer and the third leading cause of cancer death globally. In 2023, the National Cancer Institute (NCI) estimated 41,210 new HCC cases diagnosed in the US, with 29,380 deaths. The overall prognosis is poor, with a 5-year survival rate of 21.6%. Wnt-activation plays multiple roles in the pathogenesis of HCC by initiating tumorigenesis, promoting metastasis, and enhancing an immunosuppressive tumor microenvironment. Patients with elevated nuclear beta-catenin and TBL1 demonstrate particularly poor outcomes. Despite this, there are no FDA-approved therapies targeting this pathway.
"There is a desperate need for novel targeted therapies to address the large unmet clinical need in HCC" expressed Casey Cunningham, M.D., Chief Medical Officer for Iterion Therapeutics. "Tegavivint has demonstrated excellent tolerability and has the potential to address a large portion of this population by directly inhibiting beta-catenin’s oncogenic activity".
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. The study will evaluate safety and clinical efficacy in addition to pharmacokinetic and pharmacodynamic markers to determine a Recommended Phase 2 Dose (RP2D) in HCC. Tegavivint has demonstrated safety, clinical and pharmacodynamic activity in a Phase 1 clinical study of patients with desmoid tumors.
For more information about this Phase 1b/2a clinical trial of tegavivint in patients with advanced HCC, please visit www.ClinicalTrials.gov using the identifier NCT05797805.