On July 28, 2020 Iterion Therapeutics, Inc., a venture-backed, clinical stage biotechnology company developing novel cancer therapeutics, reported that enrollment has commenced in its multicenter Phase 2a dose expansion clinical study of Tegavivint, a novel, potent and selective nuclear β-catenin inhibitor, in patients with desmoid tumors (Press release, Iterion Therapeutics, JUL 28, 2020, View Source [SID1234562476]). The Phase 2a trial builds on a recently completed open-label, non-randomized Phase 1 study that established safety and initial clinical efficacy of Tegavivint in patients with progressive desmoid tumors.
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Nuclear β-catenin is a highly-studied oncology target associated with numerous cancer types. Tegavivint is unique among nuclear β-catenin inhibitors in that it binds to TBL1 (Transducin βeta-like Protein One), a novel downstream target in the Wnt-signaling pathway. As such, Tegavivint enables silencing of Wnt-pathway gene expression without affecting other Wnt/β-catenin functions in the cell membrane, thus avoiding toxicity issues common to other drugs in this pathway.
Desmoid tumors are rare, non- metastasizing sarcomas that overexpress nuclear β-catenin. An estimated 1,500 patients in the US are newly diagnosed with desmoid tumors each year. Desmoids are most commonly diagnosed in young adults between 30-40 years of age and are associated with significant morbidities, including severe pain, disfigurement, internal bleeding and organ damage, range of motion loss and, in rare cases, death. Iterion has received Orphan Drug Designation for Tegavivint to treat desmoid tumors, a disease for which there are no FDA approved therapies.
"We are very pleased to advance the clinical development of Tegavivint in desmoid tumors as this disease target is greatly underserved and provides an optimal indication for demonstrating the drug’s safety and potential clinical utility in multiple cancer settings," said Rahul Aras, CEO of Iterion. "Desmoid tumors are driven primarily by nuclear β-catenin signaling, a historically ‘undruggable’ oncology target implicated in cell proliferation, differentiation and immune evasion. Efforts to develop inhibitors of β-catenin through drugging upstream targets in the Wnt-signaling pathway have been plagued by toxicity issues, greatly limiting their therapeutic use. Research suggests that these toxicity concerns can be negated by targeting TBL1, a novel downstream target necessary for β-catenin’s oncogenic activity. Our development plan for Tegavivint is to advance its development in desmoid tumors as a launching point for additional programs in acute myeloid leukemia, non-small cell lung cancer, and certain pediatric cancers for which nuclear β-catenin signaling has been identified as a potential therapeutic target."
The Phase 2a trial in desmoid tumors is expected to enroll up to 25 patients who will be treated with the recommended Phase 2 Dose (RP2D), which was established based on pharmacokinetic exposure levels and clinical responses in the recently completed Phase 1 study.
In addition to desmoid tumors, Iterion is preparing to initiate clinical programs to investigate Tegavivint in acute myeloid leukemia (AML), non-small cell lung cancer (NSCLC), and pediatric cancers, including sarcomas, lymphoma and other solid tumors. These cancers are often characterized by nuclear β-catenin overexpression, providing potential high-value target expansions for Tegavivint. The RP2D established in the desmoid tumor program is expected to be utilized in the planning and execution of the clinical trials in these additional indications, offering the potential to expedite the advancement of the individual clinical studies.