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NT219

Overview and Mechanism of Action

NT219 is a first-in-class, novel small molecule, covalently binds to Insulin Receptor Substrate, IRS1/2, and leads to degradation and blocks STAT3. these are two important oncogenic drivers and major drug resistance pathways in many hard-to-treat cancers. In preclinical studies, NT219 demonstrated strong efficacy in preventing acquired resistance and reversing tumor resistance when administered as a monotherapy and in combination with various existing oncology therapies. A Phase 1 dose escalation study was concluded as a monotherapy and in combination with cetuximab, in which NT219 demonstrated anti-tumor activity in combination with cetuximab in second-line patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).

IRS1/2

  • Scaffold proteins, mediating mitogenic, metastatic, angiogenic and anti-apoptotic signals from IGF1R, IR, IL4R and other oncogenes, overexpressed in multiple tumors
  • Regulates major survival pathways such as the PI3K/AKT, MEK/ERK and WNT/β-catenin
  • Activated as a feedback response to anti-cancer therapies
  • IRS plays an important role in promoting a tumor-protective microenvironment, by mediating upregulation of TAMs and CAFs

STAT3

  • Well-established transcription factor associated with the tumorigenic phenotype
  • STAT3 is broadly hyperactivated in many cancers, promoting proliferation, survival, angiogenesis and metastasis
  • STAT3 pathway is required for TGFβ-induced EMT and cancer cell migration and invasion
  • STAT3 is a critical player in tumor immune evasion, suppressing immune stimulators and enhancing immunosuppressive factors

Clinical Studies

A Phase 1 dose escalation study was concluded as a monotherapy and in combination with cetuximab, in which NT219 demonstrated anti-tumor activity in combination with cetuximab in second-line patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). We completed a Phase 1/2 investigator-initiated study in collaboration with the University of Colorado, to treat R/M SCCHN patients in combination with cetuximab or pembrolizumab. Further clinical development is paused while we seek a strategic partner or investment to advance the program.

 

NT219 - References (Download)
ClinicalTrials.gov NCT04474470 - A Study to Evaluate NT219 Alone and in Combination With ERBITUX® (Cetuximab) in Adults With Advanced Solid Tumors and Head and Neck Cancer
ClinicalTrials.gov NCT06919666 - NT219 Combined With Standard of Care Biologic Therapy in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma
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