iOnctura Develops Next-Generation PI3K-delta Inhibitors For Cancer
Emerging Company Profile: Switzerland’s iOnctura is working on PI3K-delta inhibitors and autotaxin inhibitors that have potential in solid tumors and cancer-associated fibrosis.
The European start-up iOnctura SA is developing candidate products with immuno-oncologic and direct anti-tumor properties, and has just dosed its first patient in a Phase I study with lead compound IOA-244, which is supported by funding from a €15m ($16.5m) series A round completed earlier this year.
Geneva, Switzerland-based iOnctura was spun out of Merck KGaA in June 2017 to work on compounds licensed from that company and Cancer Research UK with novel next-generation mechanisms of action and great potential in cancer and fibrosis, according to founder and CEO, Catherine Pickering.
Over the past two-to-three years, iOnctura’s strategy has been to "bring a basket of assets into the company, and to use our seed money to work closely with Cancer Research UK on all five molecules, and then to select the best two or three molecules to take forward," Pickering explained.
iOnctura’s CEO is well placed for that process, having led the global oncology and immuno-oncology licensing group at Merck KGaA, and having started her career in the industry in technology transfer at the UK’s Institute of Cancer Research.
“The concept of the company was created over a few months, and I talked it over with Merck KGaA’s corporate venture capital arm, Merck Ventures (now M Ventures) and the company’s management, and both were supportive,” Pickering said.
Merck Ventures provided the initial seed funding to iOnctura and Cancer Research Technology, the commercial arm of Cancer Research UK, has received an equity holding in exchange for iOnctura receiving an exclusive global option on three immuno-oncology assets. The company announced on 18 February that it exercised the global option on two projects from Cancer Research UK, an investigational new drug (IND) application-stage autotaxin inhibitor and a preclinical anti-CD73 antibody.
Merck’s corporate VC arm continued to support iOnctura in its series A round, completed in January, which was led by INKEF Capital and VI Partners, and joined by a new private equity investor, Schroder Adveq.
“We were very pleased with the series A, which validated the company’s approach, gave iOnctura visibility and indicated that our investors continue to be very supportive,” Pickering remarked. “It also allowed us to push the button on starting a clinical trial, which was something that as a company with a small team we’re very excited about.”
iOnctura is using the proceeds of the series A to move its lead molecule IOA-244, a highly selective PI3K-delta inhibitor, into a Phase I trial in solid tumors and a second compound, the autotaxin inhibitor IOA-289, through IND-enabling studies.
Phosphoinositide 3-kinase inhibitors are already available for the treatment of hematologic cancers, such as Gilead Sciences Inc.’s Zydelig (idelalisib), and Bayer AG’s Aliqopa (copanlisib), and others are in development, including TG Therapeutics Inc.’s umbralisib. (Also see “TG’s Follicular Lymphoma Data Suggest Umbralisib Could Succeed In PI3K Delta Class” – Scrip, 28 Oct, 2019.)
That said, the PI3K enzyme appears to be part of several cellular signaling pathways, and only relatively recently has the enzyme’s expression on regulatory T-cells attracted attention, Pickering explained.
“Our molecule has a suite of properties, including being exquisitely selective for delta. It is also a non-competitive ATP inhibitor on that enzyme (its potency shouldn’t be affected by increased levels of ATP seen in cancer and immune cells) and doesn’t appear to have any active metabolites,” Pickering noted.
Quite a few solid tumors have high expression of PI3K-delta and the pathway also appears to be active in regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs). IOA-244 is believed to have a dual mechanism of action, a direct effect on cancer cells and the reversal of Treg and MDSC-mediated local immunosuppression.
“In iOnctura’s clinical trial of IOA-244, we will select patients that not only have tumors with high expression of PI3K, but also those with an immunosuppressive tumor micro-environment – a high-Treg, high-MDSC environment,” Pickering said.
The Phase I study of IOA-244 in multiple solid tumor types is being led by Professor Jeff Evans of the University of Glasgow and Professor Michele Maio from the University Hospital of Siena, Italy. Results are expected in early 2021.
The company’s second molecule in development is a novel autotaxin (ATX) inhibitor, which is at the IND stage in patients with solid tumors and cancer-associated fibrosis.
Autotaxin is a secreted enzyme that converts lysophosphatidylcholine into the signaling molecule lysophosphatidic acid (LPA). Modulating autotaxin may reduce lung disease progression, including the progress of cancer metastases and idiopathic pulmonary fibrosis.
“We know that blocking the autotaxin-LPA axis is effective in organ-specific fibrosis, and we’re bringing that into oncology … We believe there’s an immune aspect of blocking autotaxin but equally there’s a direct anti-tumor effect as well.”
iOnctura believes its autotaxin inhibitor, IOA-289, is a potential first-in-class therapy for solid tumors which over-express autotaxin and are associated with cancer-associated fibrosis. IOA-289 has shown both anti-tumor and anti-fibrotic effect in preclinical models.
“We know that if you block autotaxin you will decrease the fibrosis around the tumor and there’s a link to metastasis,” Pickering noted. “So again, there’s a dual mechanism that we will be looking at in our clinical study.” The company is hoping to be heading towards its first clinical study of IOA-289 by the end of this year.
Other companies are evaluating autotaxin inhibitors, although usually for their anti-fibrotic effects. These include Belgian biotech Galapagos NV, whose compound GLPG1690 is in Phase III studies in idiopathic pulmonary fibrosis with partner Gilead Sciences. (Also see “$5bn Galapagos Deal Won’t Be Last For Gilead, Says O’Day” – Scrip, 15 Jul, 2019.)
And Boehringer Ingelheim International GmbH is collaborating with South Korea’s Bridge Biotherapeutics Inc. on the Phase I autotaxin inhibitor BBT-877 for idiopathic pulmonary fibrosis.
Pickering believes iOnctura, although small with less than a dozen employees, has in-house expertise to advance its candidates to the next value inflection point, probably Phase IIa.
Last year, it recruited Michael Lahn as chief medical officer, who was previously Incyte Corp.’s head of clinical development for Europe, and more recently has added to its clinical advisory board Hendrik-Tobias Arkenau of the Sarah Cannon Research Institute, UK, and Jordi Rodón Ahnert, clinical co-director of the MD Anderson Cancer Center.