iOnctura: realising the potential of autotaxin therapy in cancer
There’s an increasing focus on using drugs to modify the tumour microenvironment, reducing immunosuppression and breaking down the barrier of fibrotic scar tissue that blocks many therapies. Optimum Strategic Communications’ Richard Staines talked to our client iOnctura, about the Company’s plans to use an autotaxin inhibitor to remove this obstacle.
Scientists are looking at a range of different drug classes that could tackle this fibrotic barrier such as lysyl oxidase (LOX) inhibitors and NADPH-oxidase inhibitors – but another obvious choice is a class of drugs known as autotaxin (ATX) inhibitors.
First discovered in the early nineties, ATX inhibitors work by preventing the action of the enzyme, which converts the precursor lysophosphatidylcholine (LPC) into a signalling molecule known as lysophosphatidic acid (LPA), which can induce various responses along multiple cellular signalling pathways.
Currently there are no approved ATX inhibitors but they are being actively trialled in fibrotic diseases, although in 2021 one of the leaders in the field, Gilead, suffered a setback when its ziritaxestat failed in the phase III ISABELA study in the lung scarring disease idiopathic pulmonary fibrosis (IPF).
But other companies continue to see the potential of this drug class in cancer and fibrotic diseases, although there is only one in the clinic for oncology, under development by iOnctura, a biotech based in Amsterdam and Geneva.
iOnctura points out that in addition to its anti-fibrotic mechanism, ATX also directly promotes cancer cell division and prevents the host making an immune response against the cancer. Thus, targeting this pathway may promote synergistic anti-cancer effects.
With supportive preclinical and early-stage study data recently published in a peer-reviewed journal, iOnctura is eyeing the next stage of development with its ATX inhibitor, IOA-289, initially in combination with standard-of-care chemotherapy in pancreatic cancer.
Giusy Di Conza, Head of Research at iOnctura said: “We chose pancreatic cancer because it is highly fibrotic. The fibrosis is immunosuppressive and impairs access to chemotherapies which makes this disease very difficult to treat.”
According to Di Conza the presence of ATX is a “stress signal” indicating hypoxic conditions surrounding the tumour and the presence of a feedback reaction, whereby cancer cell proliferation is boosted while immune responses from tumour targeting T-cells are suppressed.
Georgia Konstantidinou, Assistant Professor at the Institute of Pharmacology, University of Bern, Switzerland, said at a recent symposium discussing the ATX in cancer: “In my lab we study how lipid metabolism affects pancreatic cancer. The LPA is present at high levels in healthy patients, but even more in [pancreatic ductal adenocarcinoma] PDAC patients. We are using IOA-289 to bring down these LPAs and we are very excited about what we are seeing in our mouse models.”
But there are challenges to be overcome as the early generations of ATX inhibitors resulted in substantial toxicity.
This became most apparent with Galapagos and Gilead’s ziritaxestat, which was trialled in combination with pirfenidone and nintedanib in IPF.
Numerically higher mortality rates in the treatment arm, combined with a lack of efficacy meant that Gilead and Galapagos opted to end development of ziritaxestat.
It’s still not clear what caused the toxicity issues in the negative readout from the phase 3 ISABELA studies announced in 2021.
But Di Conza said that iOnctura’s data from IOA-289 is encouraging on the safety front, noting that another competitor in the ATX field, Blade Therapeutics, ran a study suggesting that interaction between the drugs in combination could have led to the toxicity seen in ISABELA. She noted: “We have done a healthy volunteer study and we have not seen any toxicity in these subjects.”
These findings give iOnctura confidence for the ongoing AION-02 study with standard chemotherapy in metastatic pancreatic cancer patients.
Experts and KOLs discussed IOA-289 at an iOnctura ATX Symposium, held in Naples, Italy, in May 2023.
Gianluigi Giannelli, Scientific Director of the National Institute of Gastroenterology “Saverio de Bellis”, Research Hospital, Bari, Italy, said that there is potential in stomach cancer based on preclinical data.
He told the symposium in Naples: “We are testing IOA-289 in several types of GI tract cancer. It is rare to see that a small molecule has both antiproliferative and antimigratory effect in all the cell lines tested.”
Hilary Sandig is Group Leader at Cancer Research Horizons, an innovation unit that is part of Cancer Research UK, where IOA-289 was first discovered.
Sandig said: “We have identified a tumorigenic crosstalk between [cancer associated fibroblasts] and pancreatic cancer cells and are continuing to collaborate with iOnctura to understand the biological effects of ATX inhibition by IOA-289.”
“It is very encouraging to see that inhibiting ATX can impair this crosstalk and lead to antitumoral effect. We look forward to seeing the clinical data.”
Following the findings in pancreatic cancer, preclinical research published in Springer Nature Group’s Journal of Experimental & Clinical Cancer Research showed IOA-289 is able to inhibit both growth and migration of gastrointestinal tract tumour cell lines, both in 2D crystal violet assay and 3D in vitro models.
Further lines of investigation could include metabolic dysfunction-associated steatohepatitis (MASH), the liver disease that shows rising global incidence and puts patients at high risk of developing liver cancer.
Ruchi Bansal, an Associate Professor and Group Leader of Translational Liver Research at the University of Twente, the Netherlands, said: “We aim to continue exploring the potential of IOA-289 in reducing the progression of hepatocellular carcinoma, one of the most commonly diagnosed cancers and the third leading cause of cancer-related deaths worldwide.”
Novel biomarkers
Alongside common tumour markers such as CA19-9, iOnctura will also be using novel biomarkers to gather further evidence during clinical development about whether the ATX inhibitor is working as expected.
The company aims to explore a panel of fibrotic proteins that may indicate whether the drug has resulted in alterations of the fibrotic scar tissue surrounding the tumour.
Immune responses will also be measured by testing levels of cytokines, the molecular signals that indicate immune activity.
The iOnctura team also plans to test whether IOA-289 could be used in combination with immunotherapy, a treatment approach that has had limited success in fibrotic cancers.
There is also potential for the drug to be used in other cancer indications such as breast cancer, following supportive preclinical data published earlier this year.
Combining the drug with immunotherapy is another logical step, given that scar tissue surrounding tumours has been blamed for several clinical trial failures in this branch of cancer research.
David Brindley, Professor at the Department of Biochemistry at the University of Alberta, Canada, agreed that combination therapies are one exciting therapeutic avenue to pursue given the drug’s mechanism of action. “Given the effect of IOA-289 to decrease fibrosis and increase access of other drugs to the cancer, one of the ways we should look at autotaxin inhibitors is as an adjunct to improving the effectiveness of multiple existing cancer therapies.
Brindley also pointed out there is potential across indications: “In addition to the clinical investigation of IOA-289 in pancreatic cancer, iOnctura and ourselves have recently published its potential in breast cancer too, further pressing its potential across indications.”
The theory is that the wall of cells surrounding the tumour hinders or inhibits the influx of T-cells following the action of checkpoint inhibitor drugs.
Di Conza said: “Because of the mechanism of action it makes a lot of sense to combine IOA-289 with immunotherapy. We are using a data-driven approach to determine our combination strategy.”
“We are taking a risk with pioneering the technology in oncology, but also a great opportunity for a high reward in those difficult to treat fibrotic cancers” Di Conza concluded.
