cambritaxestat (IOA-289)

P1, N=40, Recruiting, iOnctura | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Jun 2025

Using the clinical-stage ATX inhibitor, IOA-289, we identified connective tissue growth factor (CTGF) as a downstream mediator of ATX signaling in the PDAC CAF-derived cell line, 0082T...Despite the loss of ATX function, extracellular levels of LPA were paradoxically increased, indicating a role for ATX beyond its enzymatic activity and suggesting a role for its LPA chaperone function in the LPA/LPAR signaling in CAFs. As CAFs are the main source for CTGF in the PDAC TME, these findings suggest a role for ATX in promoting pro-tumorigenic microenvironment via modulation of CAF secretion, not only via its LPA-producing activity but also via its LPA chaperone function, providing a potential mechanism for the anti-tumor effects of ATX inhibition.

P1, N=40, Recruiting, iOnctura | Completed --> Recruiting | Trial completion date: Dec 2021 --> Dec 2024 | Trial primary completion date: Sep 2021 --> Dec 2024

P1/2, N=24, Recruiting, iOnctura | Phase classification: P1b --> P1/2 | Trial completion date: Apr 2024 --> Feb 2025 | Trial primary completion date: Oct 2023 --> Dec 2024

The autotaxin inhibitor IOA-289 suppressed NF-κB activation in PDAC cells and overcame resistance to galunisertib and gemcitabine. Most importantly, treatment with galunisertib significantly increased plasma levels of autotaxin in patients enrolled in the H9H-MC-JBAJ study, and median progression free survival was significantly longer in patients without an increase of autotaxin upon treatment with galunisertib compared to those with increased autotaxin. These results establish that autotaxin secretion by CAFs is increased by TGFβ inhibition and that circulating autotaxin levels predict response to the combination treatment approach of gemcitabine plus galunisertib.

These results indicate that IOA-289 may be an effective drug for the treatment of tumors of the gastrointestinal tract, particularly those characterized by a high degree of fibrosis.

This confirms the relevance of results from autotaxin inhibition in the mouse model. We propose that inhibiting autotaxin activity that is derived from cells presenting breast tumors such as fibroblasts, leukocytes, or endothelial cells changes the tumor micro-environment in such a way as to inhibit tumor growth.

Our data show that IOA-289 is a novel ATX inhibitor with a unique chemical structure, excellent potency and an attractive safety profile. Our data support the further development of IOA-289 as a novel therapeutic approach for the treatment of cancer, particularly those with a high fibrotic and immunologically cold phenotype.

P1b, N=24, Recruiting, iOnctura

The predicted biologically effective dose of IOA-289 has been calculated using PK/PD modelling combining data from preclinical studies and from the phase Ia healthy volunteer study. IOA-289 is scheduled to enter a phase Ib clinical trial in pancreatic cancer.