iOnctura's first-in-class autotaxin inhibitor cambritaxestat (IOA-289) has demonstrated encouraging safety and anti-tumor activity in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC), marking a significant milestone as the first autotaxin inhibitor to be investigated in cancer patients. The Phase Ib dose escalation study AION-02 met its primary endpoint, showing the oral therapy can be safely combined with standard-of-care chemotherapy while producing measurable clinical responses.
Study Design and Patient Population
The AION-02 study (NCT05586516) evaluated cambritaxestat in combination with gemcitabine and nab-paclitaxel (GnP) in 16 patients with previously untreated mPDAC. Patients received cambritaxestat orally twice daily at escalating doses of 100 mg (n=4), 200 mg (n=4), 400 mg (n=5), and 800 mg (n=3). The standard chemotherapy regimen was administered by IV infusion weekly for three weeks of each four-week cycle.
Safety Profile and Tolerability
The study demonstrated a favorable safety profile across all dose levels. Notably, no dose-limiting toxicities were observed, and no treatment-emergent adverse events led to drug discontinuation or dose modification. This safety profile is particularly significant given the aggressive nature of metastatic pancreatic cancer and the challenges associated with treating this patient population.
"Clinical activity alongside a manageable safety profile is particularly meaningful in a disease as aggressive and fibrotic as metastatic pancreatic cancer," said lead investigator Davide Melisi, M.D., Ph.D., Associate Professor of Medical Oncology and Director of the Digestive Molecular and Clinical Oncology Research Unit at the University of Verona.
Pharmacodynamic Evidence and Clinical Activity
Pharmacodynamic analysis provided compelling evidence of cambritaxestat's on-target effects. The study showed a dose-dependent reduction in the ATX-dependent plasma lipid LPA C18:2 over 24 hours, confirming the drug's mechanism of action. Patients in higher-dose cohorts experienced consistent and durable reductions in the tumor marker CA19-9, changes that correlated with radiographic responses and survival outcomes.
Novel Mechanism of Action
Cambritaxestat represents a novel therapeutic approach through its three-pronged mechanism targeting the autotaxin pathway. The drug directly inhibits tumor growth while simultaneously stimulating immune effector cells and reducing fibrosis to enhance drug and immune cell access to tumors. This multi-faceted approach addresses the complex biology of pancreatic cancer, particularly the characteristic fibrotic tumor microenvironment that has historically limited treatment effectiveness.
"These data reinforce the therapeutic promise of targeting the autotaxin pathway to address the complex biology of pancreatic cancer, and potentially other tumors with high expression of autotaxin and its associated signaling," said Dr. Michael Lahn, Chief Medical Officer at iOnctura.
Regulatory Recognition and Development Strategy
The U.S. Food and Drug Administration granted cambritaxestat Orphan Drug Designation in March 2024, recognizing its potential to address unmet medical needs in rare diseases. The drug is being developed as a first-in-class therapy across multiple cancer indications, with particular focus on highly fibrotic cancers including metastatic pancreatic cancer.
International Collaboration
The study was co-funded by the European Union and recruited patients across Italy and the United Kingdom, demonstrating international commitment to advancing treatment options for pancreatic cancer patients. The findings were presented at the European Society for Medical Oncology (ESMO) Congress in Berlin, Germany, highlighting the global significance of this research.
Dr. Melisi emphasized that "these findings warrant continued scientific exploration in autotaxin inhibition," suggesting the potential for expanded clinical development programs. As iOnctura advances cambritaxestat through clinical development, the company remains focused on unlocking its potential to improve outcomes for patients facing some of the most challenging and hard-to-treat cancers.
