IOmet Readies ID01 And TDO Immuno-Oncology Pipeline For 2016 Trials

As IDO inhibitors enter center stage in immune-oncology, the small Scottish start-up IOmet Pharma is busily preparing its cutting edge assets for preclinical studies, which the biotech believes will prove to be best-in-class and perhaps attract eager suitors.

IOmet Pharma, a privately held biotech based in Edinburgh, Scotland focused on IDO/TDO inhibitors in cancer immunotherapy, is drawing interest to its early preclinical pipeline amid parallels between its checkpoint programs and those of Flexus Biosciences Inc., which Bristol-Myers Squibb Co. bought earlier this year for $1.2 billion.

Combination therapies are generating big interest, especially immunotherapies, which may complement each other through multiple pathways of T-cell activation. An increasing body of evidence suggests such combinations will be necessary to achieve maximum clinical benefit for patients. That logic underpins the late January acquisition of Flexus, through which BMS gained early-stage immune checkpoint programs including F001287, a preclinical IDO1 inhibitor for which Flexus plans to file an IND later this year, and IDO/TDO candidates at the discovery phase [See Deal].

Enzymes IDO (indoleamine-2,3-dioxygenase) and TDO (tryptophan-2,3-dioxygenase) break down the essential amino acid tryptophan, and have emerged as key targets in the cancer immunotherapy field.

Overexpression of IDO and TDO is found in a variety of cancers, including melanoma, lung, glioma, ovarian and colorectal cancers, and is associated with poor prognosis and survival. IDO and TDO overexpression leads to tryptophan depletion and high tumor levels of the breakdown product kynurenine that hinders the body’s immune response to cancer, aiding tumor progression and metastasis. That’s because a high kynurenine concentration blocks the activation and proliferation of T cells, preventing the immune system from recognizing and killing damaged or mutated cells, such as tumor cells.

“IDO1 and TDO are the key enzymes that control production of kynurenine. If you can block IDO and TDO turning tryptophan into kyn, then the body’s immune system will function more efficiently and be better placed to fight off tumor growth wherever it finds it, and that’s why people are so excited about IDO1 and TDO,” said Peter Trill, co-founder and CFO of Iomet Pharma.

IOmet says in vivo tests of its IOmet IDO1-selective inhibitor conducted in mice completely blocked IDO1-driven kynurenine production in mouse lung.

Other IDO inhibitors in development include Incyte Corp.’s INCB24360, currently in Phase II, and NewLink Genetics Corp.’s NLG-919, which is in Phase I in collaboration with Roche unit Genentech Inc.[See Deal].

In terms of kynurenine control, IOmet says its IDO1 inhibitors when trialed in mice show it to have “superior in vivo potency and efficacy compared with the Incyte compound’s partial inhibition.” The Scottish company foresees its next generation IDO1 inhibitors as allowing once-daily oral dosing in humans. As they are also brain penetrant, they offer the ability to target primary gliomas and brain metastases.

By this time next year, “IOmet will be the only company with clinical assets covering all three flavors of inhibitor of kynurenine production: IDO1-selective inhibitors, IDO1/TDO dual inhibitors, and TDO-selective inhibitors,” said Barry McGuinness, IOmet’s senior research scientist. The biotech has raised around $25 million from its investors to date and thus has enough funding to move its IDO1/TDO pipeline forward and into first-in-human studies during the first half of 2016.

Another potential attraction offered by the IDO and TDO approach is that the enzymes can be targeted with a small molecule, thus reducing costs relative to use of antibodies. There’s rising industry speculation that, given the number of novel antibodies coming to the market, combination therapies could face pricing pressure in the future. Thus the small molecule approach associated with IDO1/TDO inhibition offers a big cost of goods advantage to companies developing immuno-oncology combination therapies.

“Small molecules work inside cells and are cheap to produce; antibodies work on the cell surface and tend to be more expensive to manufacture, so there’s an economic case as well for trying to combine an antibody with a small molecule,” he said in an interview.

Because some cancers express more TDO than IDO, the combination approach with dual IDO/TDO inhibitors should also benefit patients across multiple cancer types, he said.

“For example, colorectal cancer patients might end up with a secondary metastases appearing in the liver, which is a very rich TDO environment. So if a colorectal cancer patient was treated with an IDO1 inhibitor only, you might successfully treat the cancer in the colorectal area but metastases could form in the liver, which is a TDO-rich environment – so you’d need a TDO inhibitor to potentially treat that. So there’s a real rationale for dual inhibitors here to control the kynurenine regardless of whether it’s produced by IDO1 or TDO.”

Trill has big expectations for IOmet’s IDO1/TDO inhibitors.

“Where we can see other rival compounds out there and where we can see data, we have some very significant advantages over those, and our belief is that we can be first in class with the bona fide dual inhibitors of both those enzymes – we can be first in class with the TDO specific, and at the next generation of the IDO1 we can be best in class because we think we can be better than the companies that are already out there in the clinic ahead of us.”

Asked what he and his management’s response might be to an eventual takeover approach, Trill replied: “We’re very excited by what we have, so we’re just focused on the tasks ahead. But clearly, if you get the development right, then people become interested in what you have. We’re a company with investors like anyone else, so that would be a discussion we’d have further down the track.”