When David Schenkein left Genentech to lead Agios Pharmaceuticals in 2009, part of the draw was the fact that the Cambridge, MA-based startup was positioning itself as a trailblazer in a raw field of oncology—cancer metabolism. The idea, essentially, was to starve tumors by blocking the enzymes that help them gobble up nutrients.
Five years and many millions of dollars later, the company has produced the first evidence in humans that the idea might yield viable treatments for cancer—though there is, of course, still a long road ahead and many hurdles to clear before it will know for sure.
Agios (NASDAQ: [[ticker:AGIO]]) today is announcing the first clinical data on its lead experimental cancer metabolism drug, AG-221, at the American Association for Cancer Research’s annual meeting in San Diego. To be clear, this is an interim look at a small, early trial—a Phase 1 study that’s designed mainly to assess the drug’s safety and side effects and to determine the maximum dose that patients can handle. And Agios is only reporting data from seven patients in the study, each of whom has acute myeloid leukemia.
But six of those seven responded to AG-221—and three of them had no trace of cancer in their blood after 28 days of treatment. This is despite the fact that they only received the lowest two of four planned dosages of AG-221. Also encouraging is the fact that the company so far hasn’t run into toxicities that would keep it from ramping up the dosage.
“It’s unusual,” says Eytan Stein, the study’s lead investigator and an attending physician at Memorial Sloan-Kettering Cancer Center. “[But] it’s extremely early. I am cautiously optimistic, certainly this seems like a drug that has great clinical potential, but there’s always that possibility that the next 10 patients aren’t going to respond at all.”
AG-221 targets an enzyme known as isocitrate dehydrogenase-2, or IDH2, which is part of the molecular machinery that generates energy within cells. Researchers say that when IDH2 is mutated in cancer, it ends up producing a byproduct called 2-hydroxyglutarate, or 2HG, that flips a genetic switch in immature bone marrow cells turning them into cancer cells rather than the blood cells they were supposed to become.
By binding to the mutated IDH2, AG-221 is designed to stop this process from happening and allow the normal maturation of the marrow cells to resume. In other words, rather than killing cancer cells, the drug is theoretically stopping them from being born in the first place. “That’s very different than the way we think about any other kind of AML but perhaps it could serve as a paradigm of what we really need to do to attack other genetic subsets of AML,” Stein says. (About 10 to 15 percent of the patients with AML have the IDH2 mutation, he adds.)
This approach, if it proves successful, could offer a dramatically different treatment option for patients with AML, a fast-moving type of blood cancer. The typical treatment for the disease is chemotherapy, which essentially nukes the blood system, destroying cancer cells and healthy cells alike and leaving people weak, sick, and prone to infections.
“Certainly the hope is that [the Agios drug] won’t have the kind of immunosuppressive effects that chemotherapy has,” Stein says. “Theoretically what should happen is the patient should never feel worse than they felt before, they should just start feeling better. And that’s actually what we’ve seen in the patients that responded to the drug. They gain weight, they have an appetite, they don’t have infections. So that’s very encouraging.”
AML patients also often wind up needing bone marrow transplants, which carry their own set of risks. In an absolute best-case scenario, AG-221 would
