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Enzyme that’s new focus for cancer treatment

June 4, 2017
  • Data presented this weekend at big cancer meeting is promising
  • Small co. Incyte leads research with drug inhibiting enzyme

For a fetus in the womb, it’s an enzyme that means life, a shield from a mother’s immune system that would otherwise fight the embryo as an infection. Gone rogue, it can mean death — protecting malignant tumors from attacks by the body’s defenses.

That enzyme, IDO, is now the target of the next wave of cancer research.

Leading the pack with an experimental drug that inhibits IDO — thus removing the cloud that protection around a tumor — is Incyte Corp. The small firm from Wilmington, Delaware, has attracted four of the biggest makers of cancer treatments to collaborate on studies, including Merck & Co.

While it’s early stage, the hope is to create a two-pronged combined attack: an IDO inhibitor would lay a tumor bare, enabling infection-fighting cells that have been reinvigorated by existing therapies to give the kill shot.

“We actually feel pretty strongly that it’s likely this will be the standard of care for the treatment of melanoma in the next couple of years,” said Jason Luke, assistant professor of medicine at the University of Chicago Medicine, who focuses on early drug development. “It’s the combination that’s closest to prime time.”

Promising Results

The IDO approach was the talk of the town among doctors and investors this weekend at the largest gathering of cancer researchers in the world, the American Society of Clinical Oncology meeting in Chicago. The first results in a meaningful number of patients, presented Saturday, looked promising. They confirmed earlier research that adding Incyte’s epacadostat to oncology drugs like Merck’s Keytruda boost their effectiveness without significantly increasing side effects, the typical trade-off of such cocktails.

The results of the final study needed for approval to market an epacadostat combination with Keytruda for melanoma are expected next year.

The field of therapies that unleash the immune system’s own defenses to fight tumors, known as immuno-oncology, has exploded in the past three years. It gave hope to patients when rounds of chemotherapy had failed, and created blockbusters like Keytruda. While very effective for certain patients, though, immunotherapies only work on fewer than half of them.

To improve success rates, drugmakers turned to combining their immune-boosting therapies with other treatments — a massive undertaking across the industry with almost 2,000 drug cocktails under study, according to Michael Schmidt, a biotechnology analyst at Leerink Partners in Boston. If successful, IDO drugs could create a market worth $3 billion to $5 billion annually, Schmidt said.

Among the main challenges, however, would the price. New cancer medications cost $100,000 to $150,000 annually per patient. Putting two or three of the drugs into a single combination therapy could cause prices to skyrocket.

“The issue is how on Earth are we actually going to pay for it,” said Sam Fazeli, an analyst at Bloomberg Intelligence in London. “You have to make a significant difference on a patient’s responsiveness or the duration of their response. Only time will tell.”

1998 Study

The idea to inhibit IDO was sparked by a 1998 study in Science that examined the interplay between the immune system’s infection-fighting T-cells and tryptophan, an essential amino acid that provides the T-cells with fuel. The enzyme indoleamine, or IDO, can break down tryptophan, starving the T-cells and causing them to stop working.

Embryos exploit this system by expressing IDO and avoiding the activation of the mother’s infection-fighting T-cells, explaining what researchers dubbed the “paradox of fetal survival.” Five years later, Belgian investigators found that most human tumors also express IDO, enabling them to grow unhindered.

Incyte’s first efforts failed: IDO inhibitors alone failed to kill off cancer cells. The company turned to partners — Merck, Bristol-Myers Squibb Co., Switzerland’s Roche Holding AG and U.K.’s AstraZeneca Plc.

Secret Sauce

“We became somewhat promiscuous,” said Steven Stein, Incyte’s chief medical officer. “I don’t know the secret sauce of why everyone wants to date us, but I come back to the fundamentals,” he said. “If the data is positive, everyone can use it and advance the field and their own commercial interests.”

Besides the study combining epacadostat with Keytruda in melanoma, Incyte and Merck are trying the cocktail in four other tumor types, including lung, bladder and kidney cancers. Merck, Bristol-Myers and Roche are separately developing their own IDO inhibitor. And Roche is also working with NewLink Genetics Corp., a small drugmaker based in Iowa that has an IDO experimental drug.

“It’s an important aspect of the fight against cancer that companies can work with each other,” said Herve Hoppenot, Incyte’s chief executive officer.

Still, researchers and the industry alike caution that it’s still early.

“This is the beginning of a very long journey,” said Bob Abraham, group head of oncology research and development at New York drug giant Pfizer Inc., which is also getting into the race. “The next big thing is very difficult to pin down at this point.”

Luke, the University of Chicago Medicine oncologist, agrees.

“We’ve all been here in cancer before where we were hopeful and it didn’t pan out,” said Luke, a proponent of IDO inhibitors and one of its early users. “We have to prove it. In oncology, it isn’t true until it’s true.”


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