[Updated 12/14/2017, 9:23 am, see below.] Cancer immunotherapy drugs called checkpoint inhibitors, which unleash immune cells on tumors, have taken the oncology world by storm over the past few years. But they work for only a fraction of patients, and one possible reason is that tumors have many ways to hide from the attack. Kyn Therapeutics is designing drugs to block some of those escape routes, and today announced a $49 million Series A round from Atlas Venture and OrbiMed Advisors.
Kyn, based in Cambridge, MA and founded in 2016, is taking aim at a metabolic reaction in immune and cancer cells that tumors harness to keep the immune system quiet. The company is one of a few focusing on an emerging area of cancer immunotherapy: targeting the metabolism of cancer and immune cells to dial up more tumor-killing power from the immune system. The growing interest in this area stems from research from the last several years suggesting that the out-of-whack metabolism that fuels the relentless growth of cancer cells can also change the behavior of immune cells.
One of Kyn’s programs is focused on technology from the lab of co-founder George Georgiou, a University of Texas, Austin professor. Georgiou has studied the effect in animals of an enzyme that breaks down a molecule called kynurenine, which is made by cancer cells (and immune cells too) as part of their metabolism. When kynurenine binds to immune cells, it leads to a dampening of immune cell activity. Kyn is working on an enzyme that degrades kynurenine, as well as a small molecule that stops kynurenine from binding to immune cells by targeting a receptor called AHR. (Editor’s note for clarification: The small molecule is designed to prevent other substances, not just kynurenine, from binding to the AHR receptor, to lower immune suppression.)
CEO Mark Manfredi says the goal is to have an anti-kynurenine drug candidate ready for human testing by the middle of 2019.
Other companies are also targeting the kynurenine pathway, but in a different way: by inhibiting an enzyme that makes kynurenine, called IDO. IDO inhibitors have generated a lot of interest from Big Pharma because they might help boost the effects of checkpoint inhibitors. While some have yielded disappointing results in clinical trials, others have produced encouraging data—and lots of hype. Incyte Pharmaceuticals (NASDAQ:INCY) of Wilmington, DE, has an IDO1 inhibitor, epacadostat, that is being tested in combination with multiple FDA-approved checkpoint inhibitors in a variety of early and late-stage clinical trials. A Phase 3 study testing epacadostat with Merck’s checkpoint inhibitor pembrolizumab (Keytruda) in patients with metastatic melanoma should produce data in 2018, and could be the first big validation for IDO inhibitors.
Manfredi says his company will also test its anti-kynurenine enzyme along with checkpoint inhibitors (and as a single agent too), with the hope that Kyn’s drug will reduce the chances of tumors becoming resistant to checkpoint inhibitors. “We think there’s a natural combinability,” says Manfredi.
Manfredi adds that Kyn’s approach has advantages over IDO inhibitors like Incyte’s. He says that kynurenine is the part of the IDO pathway that suppresses immune responses. Blocking IDO, he says, won’t completely get rid of kynurenine, because the cancer cell has other ways of making the molecule. Kyn says that targeting kynurenine directly will wipe it out, and that could lead to better immune responses than IDO inhibitors can stir up.
There is, however, some debate in the scientific literature about how much kynurenine is involved in immune suppression, says Alex Muller, a professor at the Lankenau Institute for Medical Research in Wynnewood, PA, and an expert on the IDO pathway. Georgiou and his collaborators have found evidence that kynurenine is the main player in this immune suppression, but results from other animal studies suggest that the IDO pathway might be dialing down the immune system through another mechanism that Kyn isn’t targeting. That other mechanism—the depletion of an amino acid called tryptophan by IDO—is targeted, Muller says, by a drug being developed by NewLink Genetics (NASDAQ:NLNK) of Ames, IA. NewLink says it will soon test its IDO pathway inhibitor, indoximod, in combination with approved checkpoint inhibitors, in a Phase 3 trial in patients with advanced melanoma.
In the end, only clinical data from these companies will show which approach will prove most effective, says Muller. “It’s hard to be sure how it’s going to pan out,” he says.
Kyn is not the only drugmaker looking to tweak the metabolism of immune cells for cancer therapy. Agios Pharmaceuticals (NASDAQ:AGIO) of Cambridge, MA, is working with its longtime partner Celgene (NASDAQ:CELG), to find new drug targets in immune cell metabolism. Celgene agreed last year to pay Agios $200 million up front to lead this early R&D work. Agios already has one cancer metabolism drug on the market, enasidenib (Idhifa), for patients with acute myeloid leukemia and a specific gene mutation.
Calithera Biosciences of South San Francisco, CA, is developing an inhibitor of a metabolic enzyme called arginase. The experimental drug, now in Phase 1 testing, is also designed to lower immune suppression.
The new funding should get Kyn to its first human trial, which Manfredi says should happen the second half of next year, with another experimental drug. This one blocks the EP4 receptor, which is also implicated in immune suppression and is part of another immuno-metabolic pathway. The drug has already been tested in humans for osteoarthritis, and Manfredi says starting with this program will allow his company to get into the clinic relatively quickly.