AHR Antagonist Program

Ikena’s IK-175 is a Phase 1-stage oral AHR antagonist designed to modulate the tumor microenvironment.

AHR Antagonist Program

Ikena’s IK-175 is a Phase 1-stage oral AHR antagonist designed to modulate the tumor microenvironment.

IK-175

Aryl Hydrocarbon Receptor (AHR) is a ligand-dependent transcription factor that drives tumor progression through direct cancer cell and immunosuppressive effect in the tumor microenvironment.. AHR can be activated in tumor and immune cells by multiple ligands, including kynurenine. Activated AHR prevents immune recognition of a range of cancers by modulating both innate and adaptive immunity. This attribute makes AHR a compelling drug target, especially in patients who do not fully benefit from standard-of-care, including checkpoint inhibitors.

Ikena is advancing internally developed IK-175, an oral selective AHR antagonist. Although kynurenine is the best characterized endogenous ligand that activates AHR, other ligands induce AHR-mediated immunosuppression. Therefore, direct inhibition of AHR with antagonistic small molecules represents a distinct and broader approach from upstream targets within this pathway.

Passion, innovation and courage
Ikena is conducting a Phase 1 clinical trial to evaluate the safety of IK-175 as both a monotherapy and in combination with a PD-1 checkpoint inhibitor in solid tumors, including bladder cancer.

IK-175 is being evaluated as a single agent, and in combination with nivolumab, in cancers with activated AHR (NCT04200963) in an open-label Phase 1 trial. Ikena has employed a biomarker strategy to select lead cancer indications believed to have the highest likelihood of benefiting from IK-175. We have generated translational insights indicating that AHR is activated in a number of cancers including a subset of bladder cancers. We are deploying a multi-assay AHR activation biomarker strategy to enable prospective selection of patients.

We initiated monotherapy dose expansion in bladder cancer patients with tumors that exhibit activated AHR and we are enriching the clinical trial for these patients using our proprietary assays. We plan on assessing IK-175 in combination with nivolumab in patients with bladder cancer in the first half of 2021 in the Phase 1b portion of the clinical trial and expect to complete enrollment in both treatment arms in the second half of 2022. The primary endpoint of this trial is safety and tolerability. Our IK-175 program is partnered with BMS, which has the right to exclusively license the program through the completion of the Phase 1b portion of the clinical trial.For more information, please see the press release announcing the Ikena-Bristol Myers Squibb partnership.

Development Snapshot

AHR has potential applications in several high unmet need indications:

  • Potential for AHR antagonist single-agent activity in cancers with activated AHR
  • Thought to modulate the adaptive and innate immune systems
  • AHR is downregulated in autoimmune diseases

In pre-clinical studies, AHR antagonism:

  • Observed tumor cell intrinsic AHR dependence in certain cancers
  • Increases T-cell expansion as well as IL2 and IFN-γ
  • Reduces functional regulatory T-cells stimulated by kynurenine, and decreases suppressive cytokines and function of myeloid-derived suppressor cells

Our pipeline includes patient-directed targeted oncology and tumor microenvironment programs.