Atlas Venture

The immuno-oncology sector has yet another player. Kyn Therapeutics just made its debut after almost two years of gestation at Atlas Venture with three immuno-metabolism platforms and $49 million in first-round funding.

Explaining the rationale behind the new company, CEO Mark Manfredi told us that “the dramatic successes of checkpoint inhibitors have made their deficiencies and opportunities for improvement a hot topic in the industry, and a major driver for investment.”

“We believe immuno-metabolism is the next big area for immuno-oncology therapeutics, as it has the potential to generate broad-spectrum immune stimulation either alone or in combination with checkpoint inhibitors.”

Kyn comes out of stealth mode with a pair of preclinical programs targeting the kynurenine pathway, which is implicated in a number of diseases including cancer, as well as ARY-007, a prostaglandin E2 (EP4) receptor antagonist licensed from Japan’s AskAt Inc. that will be developed alongside affiliate company Arrys Therapeutics.

ARY-007 has already been through human trials outside of cancer and will be Kyn’s first clinical candidate, starting phase 1b trials next year, said Manfredi. The company has a big-hitting rival for the program, however, as Bristol-Myers Squibb has just licensed an EP4 receptor antagonist from longtime immuno-oncology partner Ono Pharma for $40 million upfront.

“The literature has increasingly evidenced a broad-ranging immunosuppressive function for this receptor, through multiple cellular mechanisms,” said the CEO. “Once we understood this, it was an obvious choice to assess in the cancer immunotherapy setting.”

Kyn’s kynurenine pathway candidates are further back in development but have “substantial” preclinical data showing they can improve anti-tumor immune responses, according to Manfredi.

The first focuses on Kynase—an enzyme that degrades kynurenine directly and addresses both IDO (indoleamine 2,3-dioxygenase) and TDO (tryptophan 2,3-dioxygenase) immunosuppression pathways—and grew out of work the University of Texas at Austin.

There’s no shortage of other groups working on IDO—with BMS, Incyte and NewLink currently leading the charge—but fewer have focused on TDO. Kyn’s approach of targeting Kynase may lead to “efficacy in tumors that overexpress either IDO, TDO or both [and] therefore … could address a broader patient population than IDO inhibitors alone,” according to Manfredi. Added to that, its candidates seem to be much stronger at blocking kynurenine than IDO inhibitors in clinical trials.

The third pillar of Kyn’s portfolio is an in-house program geared towards developing aryl hydrocarbon receptor (AHR) antagonists that aim to block immunosuppression activated by various metabolites, including kynurenine.

The IDO/TDO and AHR programs are closely linked. In cancer cells, IDO and TDO stimulate the formation of kynurenine, which in turn activates AHR receptors and leads to an increase in immunosuppressive T cells in the tumor microenvironment. Moreover, AHR can also be activated by ligands other than kynurenine.

“In terms of clinical development, immunometabolism-based therapies are the next most advanced area within immuno-oncology,” he said, adding, “We think there is a lot of potential for our candidates in multiple solid tumors, but we’re not ready yet to talk specifics.”

“We also have a potential aid to efficiency in that the pathways we are exploring have several biomarkers—including the target metabolites themselves—that could lend themselves to patient enrichment approaches to study design.”

The $49 million in series A funding from Atlas and OrbiMed will be split two ways, with Arrys allocated $21 million for the EP4 project—which is subcontracted to Kyn—and the remaining $28 million going to the IDO/TDO and AHR programs, which should have lead development candidates selected in the next 12 to 18 months.

“We expect to add about 5 to 8 new employees internally over the next 12 months,” Manfredi told us. “Several of those employees will focus on candidate optimization and preclinical studies but we will also grow our internal clinical program management expertise.”

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