cambritaxestat (IOA-289) / iOnctura - LARVOL DELTA

Patient tumor profiling supports the antitumor activity of the autotaxin inhibitor cambritaxestat (IOA-289) as monotherapy and in combination with standard of care in hepatocellular carcinoma and cholangiocarcinoma (ESMO-GI 2026) - "Cambritaxestat was tested as monotherapy or with SoC agents bevacizumab plus durvalumab, and compared with SoC alone. In CC models, combination therapy led to responses in 3/5 samples (60%) compared to 1/5 samples (20%) for SoC alone. Conclusions Across independent human liver tumor platforms, cambritaxestat showed antitumor activity as monotherapy in immune-infiltrated HCC and enhanced efficacy with SoC in HCC and CC, supporting further clinical evaluation of ATX inhibition in liver-associated cancers."

Clinical • Combination therapy • Monotherapy • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

Autotaxin inhibitors: an updated patent review (2021-present). (PubMed, Expert Opin Ther Pat) - "Currently, beyond the Phase II candidates PAT409 and HW021199, ATX inhibitors FTP-198 and HNC1058 have entered Phase I clinical trials for pulmonary fibrosis, while IOA-289 and HNC664 have advanced to clinical studies for solid tumors, underscoring the immense therapeutic potential of ATX. Although the identification of type V and VI ATX inhibitors has broadened the design landscape, most emerging entities since 2020 remain analogs of GLPG1690 and PAT409, presumably being attributed to the unavailable data of most clinical candidates, and despite the absence of approved drugs, the continued evolution of drug design strategies and application of novel technologies would further facilitate the discovery of ATX candidates, ultimately offering more therapeutic options for patients."

Journal • Review • Immunology • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor

Proteomic evidence of on-target activity of cambritaxestat (IOA-289) in patients with metastatic pancreatic ductal adenocarcinoma (ESMO-GI 2026) - "The ATX inhibitor cambritaxestat (IOA-289) was investigated in a phase I study in patients with mPDAC in combination with standard-of-care gemcitabine + nab-paclitaxel (SoC). Conclusions Proteomic evidence of cambritaxestat + SoC treatment reveals changes in key biomarkers of PDAC. These findings provide mechanistic support for ATX inhibition, identify candidate pharmacodynamic biomarkers, and inform dose selection, thus supporting further clinical development of cambritaxestat against tumors characterized by fibrosis."

Clinical • Metastases • Gastrointestinal Cancer • Oncology • Pancreatic Ductal Adenocarcinoma • ENPP2

IOA-289-102: A Study to Assess an ATX Inhibitor (IOA-289) in Patients With Metastatic Pancreatic Cancer (clinicaltrials.gov) - P1/2 | N=16 | Completed | Sponsor: iOnctura | Active, not recruiting ➔ Completed | N=24 ➔ 16 | Trial completion date: Mar 2026 ➔ Aug 2025 | Trial primary completion date: Dec 2025 ➔ Aug 2025

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CA 19-9

Spatial T1-Mapping of Cardiac Fibrosis Identifies Causal Protein Drivers through Deep Learning and Mendelian Randomization (AHA 2025) - "eQTL SMR identified LMF1 (p=8.3×10-5), JMJD6 (p=1.7×10-4), RIT1 (p=3.96×10-4). Targets with existing inhibitors include CTSS (VBY-036, RO5459072), PDE5A (sildenafil, tadalafil), and ENPP2 (ONO-8430506, PF-8380, IOA-289).Conclusions AI-derived spatial fibrosis phenotypes using VAE decomposition of T1 maps reveal hidden prognostic information and region-specific biological drivers invisible to conventional mean T1 analysis, identifying causal protein targets (FOLH1, ENPP2, CTSS, PDE5A) amenable to existing inhibitors for precision anti-fibrotic therapies."

Cardiovascular • Congestive Heart Failure • Coronary Artery Disease • Fibrosis • Heart Failure • Immunology • CTSS • DLG2 • ENPP2 • FABP4 • FOLH1 • LEP • PDE5A • RIT1 • TMPRSS6 • TNFRSF1A

Safety and clinical efficacy of cambritaxestat (IOA-289), a novel autotaxin inhibitor, plus gemcitabine and nab-paclitaxel (GnP) in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC) (ESMO 2025) - P1/2 | "Patients in the higher-dose cohorts had consistent CA19-9 reductions. The delayed but durable nature of observed responses supports a potential contribution of cambritaxestat's immunomodulatory and anti-fibrotic mechanisms to its therapeutic effect."

Clinical • Metastases • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CA 19-9

iOnctura debuts cambritaxestat (IOA-289) clinical data in patients with pancreatic cancer at ESMO (PRNewswire) - "Sixteen patients received cambritaxestat orally, twice daily at doses of 100 mg (n=4), 200 mg (n=4), 400 mg (n=5) and 800 mg (n=3)....The results show no dose-limiting toxicities, and no treatment-emergent adverse events (TEAE) leading to drug discontinuation or dose modification. Pharmacodynamic analysis showed a dose dependent reduction in the ATX-dependent plasma lipid LPA C18:2 over 24 hours supporting cambritaxestat's on-target effects."

P1 data • Pancreatic Cancer

Response to "Comments on: 'Inhibition of autotaxin activity with IOA-289 decreases fibrosis in mouse E0771 breast tumors'". (PubMed, Int J Cancer) - No abstract available

Journal • Preclinical • Breast Cancer • Fibrosis • Immunology • Oncology • Solid Tumor

Comments on "Inhibition of autotaxin activity with IOA-289 decreases fibrosis in mouse E0771 breast tumors". (PubMed, Int J Cancer) - No abstract available

Journal • Preclinical • Breast Cancer • Fibrosis • Immunology • Oncology • Solid Tumor

Inhibition of autotaxin activity with IOA-289 decreases fibrosis in mouse E0771 breast tumors. (PubMed, Int J Cancer) - "ATX inhibitors are in clinical trials for treating idiopathic pulmonary fibrosis and pancreatic cancer. Our results support the development of ATX inhibitors as a strategy for improving the treatment of breast cancer and other diseases involving fibrosis."

Journal • Preclinical • Breast Cancer • Fibrosis • Hematological Malignancies • Idiopathic Pulmonary Fibrosis • Immunology • Leukemia • Oncology • Pancreatic Cancer • Pulmonary Disease • Respiratory Diseases • Solid Tumor • CD8 • COL1A1 • FN1 • LIF • NECTIN1 • TGFB1

A Study to Assess an ATX Inhibitor (IOA-289) in Patients with Metastatic Pancreatic Cancer (clinicaltrials.gov) - P1/2 | N=24 | Active, not recruiting | Sponsor: iOnctura | Recruiting ➔ Active, not recruiting | Trial completion date: Feb 2025 ➔ Mar 2026 | Trial primary completion date: Dec 2024 ➔ Dec 2025

Enrollment closed • Trial completion date • Trial primary completion date • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

A Study to Assess an ATX Inhibitor (IOA-289) in Healthy Volunteers (clinicaltrials.gov) - P1 | N=40 | Recruiting | Sponsor: iOnctura | Trial completion date: Dec 2024 ➔ Dec 2025 | Trial primary completion date: Dec 2024 ➔ Jun 2025

Trial completion date • Trial primary completion date

Pancreatic CAF-derived Autotaxin (ATX) drives autocrine CTGF expression to modulate pro-tumorigenic signaling. (PubMed, Mol Cancer Ther) - "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."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CAFs • CTGF • ENPP2

A Study to Assess an ATX Inhibitor (IOA-289) in Healthy Volunteers (clinicaltrials.gov) - P1 | N=40 | Recruiting | Sponsor: iOnctura | Completed ➔ Recruiting | Trial completion date: Dec 2021 ➔ Dec 2024 | Trial primary completion date: Sep 2021 ➔ Dec 2024

Enrollment open • Trial completion date • Trial primary completion date

Safety and clinical efficacy of IOA-289, a novel autotaxin inhibitor, plus gemcitabine and nab-paclitaxel (GnP) in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC). (ASCO 2024) - P1/2 | "IOA-289 is well tolerated at all dose levels in combination with standard GnP. Patients in the higher dose cohorts are experiencing robust CA19-9 reductions consistent with ORR. Occurrence of PRs occurred later than compared to historical controls and were durable, suggesting a differentiated mode of action."

Clinical • Metastases • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CA 19-9

Orphan Designation: Treatment of pancreatic cancer (FDA) - Date Designated: 02/28/2024

Orphan drug

A Study to Assess an ATX Inhibitor (IOA-289) in Patients With Metastatic Pancreatic Cancer (clinicaltrials.gov) - P1/2 | N=24 | Recruiting | Sponsor: iOnctura | Phase classification: P1b ➔ P1/2 | Trial completion date: Apr 2024 ➔ Feb 2025 | Trial primary completion date: Oct 2023 ➔ Dec 2024

Combination therapy • Metastases • Phase classification • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

US FDA grants Orphan Drug Designation for iOnctura's first-in-class autotaxin cancer therapy (PRNewswire) - "iOnctura...announces that the US Food and Drug Administration (FDA) has granted Orphan Drug Designation (ODD) to its autotaxin inhibitor cambritaxestat for the treatment of pancreatic cancer....Following a separate submission process the World Health Organization has proposed the International Nonproprietary Name (INN) of cambritaxestat."

Commercial • Orphan drug • Pancreatic Cancer

New research highlights potential of iOnctura strategy combining autotaxin and TGF-β inhibitors in cancer (PRNewswire) - "iOnctura...announces publication of new research data in the peer-reviewed journal Cancer Research....The published research showed that blocking the TGF–β pathway in vivo or in in vitro co-culture models increased the number of autotaxin-producing inflammatory cancer associated fibroblasts (iCAFs)....Adding the autotaxin inhibitor IOA-289 to TGF-β pathway inhibitor galunisertib and standard of care in PDAC-bearing mice, suppressed NF-κB signaling, reduced MDSC and increased CD8 T-cell infiltration, resulting in prolonged overall survival and curing 40% of the mice."

Preclinical • Pancreatic Ductal Adenocarcinoma

Autotaxin secretion is a stromal mechanism of adaptive resistance to TGFβ inhibition in pancreatic ductal adenocarcinoma. (PubMed, Cancer Res) - "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."

Journal • Stroma • Ewing Sarcoma • Fibrosis • Gastrointestinal Cancer • Immunology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CAFs • TGFB1

Autotaxin inhibitor IOA-289 reduces gastrointestinal cancer progression in preclinical models. (PubMed, J Exp Clin Cancer Res) - "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."

Journal • Preclinical • Fibrosis • Gastrointestinal Cancer • Gastrointestinal Disorder • Immunology • Oncology • Solid Tumor • ANXA5

A novel orally available type IV autotaxin inhibitor, IOA-289, ameliorates steatosis and fibrosis in a preclinical model of non-alcoholic steatohepatitis (EASL-ILC 2023) - "In the last six weeks, IOA-289 (30 mg/kg) or PF-8380 (a type-I ATX inhibitor, 30mg/kg) was orally administered twice daily. Our results demonstrate that inhibition of the LPA-ATX pathway, particularly using a type IV inhibitor, represents a potential therapeutic target in NASH, by attenuating steatosis and fibrosis, with possible clinical implications."

Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Non-alcoholic Steatohepatitis • ACACA • ACTA2 • FASN • PDGFRB • TGFB1

Autotaxin Inhibition with IOA-289 Decreases Breast Tumor Growth in Mice Whereas Knockout of Autotaxin in Adipocytes Does Not. (PubMed, Cancers (Basel)) - "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."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • CCL2 • CXCL10 • CXCL9 • IL6 • TGFB1 • TGFB2

Characterization and translational development of IOA-289, a novel autotaxin inhibitor for the treatment of solid tumors. (PubMed, Immunooncol Technol) - "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."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Oncology • Respiratory Diseases • Solid Tumor

Peer-reviewed translational research paves the way for first-in-class autotaxin inhibitor IOA-289 in cancer (PRNewswire) - P1 | N=40 | NCT05027568 | Sponsor: iOnctura | "In this translational research, IOA-289 demonstrates positive effects in highly fibrotic cancer models, preventing metastasis and tumor outgrowth. In iOnctura´s Phase Ib clinical study, IOA-289 is being combined with standard of care nab-paclitaxel and gemcitabine. While assessing the safety of an ATX inhibitor in cancer patients for the first time, a broad biomarker program will investigate the translation of the non-clinical observations to clinical application. As demonstrated in healthy volunteers in this research, single ascending doses of IOA-289 were safe, tolerable and blood exposure showed a reduction of the pharmacologic marker circulating LPA. Disclosure of results of the ongoing Phase 1b study will be released at a future medical meeting."

P1 data • Preclinical • Oncology • Solid Tumor