With New Data, Agios Plots Quick Turn into Key Late-Stage Trials

Xconomy Boston — 

Agios Pharmaceuticals has already established itself as a star of the 2013 biotech IPO class. Since going public last year, the company has increased its value nearly six fold—from $18 per share to $105 as of Friday—and shown early signs that two different drugs might have an impact on a deadly blood cancer known as acute myeloid leukemia, or AML.

So far, those signals have been seen in very small sample sizes, just handfuls of patients. But the Cambridge, MA-based Agios (NASDAQ: AGIO) is revealing more clinical results today at the American Society of Hematology’s annual meeting in San Francisco, and they are encouraging enough for the company to take an unusually large step forward into a “registration trial”—the last required before regulatory approval.

If all goes according to plan, it would make for one of the quicker drug development paths for a cancer drug in recent memory. And what’s more, Celgene, Agios’s development partner, would foot the bill.

Agios is reporting the latest clinical data for AG-221, a drug for patients with blood cancers such as AML and a specific genetic mutation. It’s the same Phase 1 trial we wrote about in April, but Agios continues to see a high response rate to its therapy, even with more patients on its drug. All of them are very sick with advanced hematological malignancies such as AML, and hadn’t responded to prior treatment.

The company says 25 of the 45 patients (56 percent) it could evaluate for efficacy have achieved “objective responses,” meaning their leukemia was reduced. Fifteen of those patients had the cancer totally cleared from their blood, with some of those responses lasting as long as eight months.

“For a relapsed/refractory AML population, those are numbers that I would say we never see,” says Eytan Stein, the study’s lead investigator and an attending physician at Memorial Sloan-Kettering Cancer Center in New York. “The fact that that percentage has remained relatively constant suggests that this is a real effect, that this number is real.”

A key yardstick in Phase 1 trials is safety. With more people now exposed to AG-221, Agios says the side effects, or adverse events, remain mainly mild or moderate—nausea, fever, diarrhea, and fatigue.

There have been severe adverse events, however. Agios reports 13 patients suffered 21 total SAEs that were possibly related to AG-221. The company notes that the deaths of two patients—one who had sepsis and one with an abnormal heart rhythm—were “possibly” related to AG-221.

Stein says investigators haven’t seen any signs tying cardiovascular toxicity to the drug, and that it’s common for patients with AML to develop septic shock because the cancer destroys their immune-boosting white blood cells.

“There’s nothing unusual about those two cases that you wouldn’t necessarily see in a general AML population,” he says. “I’ve treated a lot of patients with this drug now, and my personal experience is that it is extremely well tolerated—you really don’t hear much of anything.”

Agios continues to enroll more patients in the Phase 1 study, will test higher doses, and report more of its findings next year. But even with that effort ongoing, Agios says the efficacy and safety data it now has give it confidence to start a global registration trial for AG-221 in 2015. (It’s also considering starting a similar trial in early 2016 for its other AML drug, AG-120).

That decision puts Agios on an unusually fast track. It filed papers with the FDA (a so-called investigational new drug application, or IND) to begin its first trial in June 2013, and dosed the first patient in that study two months later. Just two years afterwards, it’s gearing up for a late-stage study.

By comparison, it takes an average of 8 years for a cancer drug to go from the start of its first trial to approval. Notable exceptions include Novartis’s imatinib (Gleevec), which went from IND to approval in around three years; and Pfizer’s crizotinib (Xalkori), which went from IND to approval in six years. Pharmacyclics’ ibrutinib (Imbruvica), Millennium Pharmaceuticals’s bortezomib (Velcade), and Plexxicon/Genentech’s vemurafenib (Zelboraf) each took about five years or less to go from IND to FDA approval.

To be clear, AG-221 isn’t guaranteed to join that group. There are many questions yet to answer about AG-221’s safety in the long term, effectiveness, and durability. While some responses have lasted upwards of eight months at this point, for instance, investigators and regulators will want to see how much longer they last, and how many patients relapse into active disease.

“Hopefully this is a treatment that will last for years and years, but that will always remain an open question,” Stein says.

But the expressway is open to Agios if the data hold up. The FDA has granted a fast-track designation for AG-221, which would speed the agency’s review of the drug once it has completed a pivotal trial.

AG-221 targets an enzyme called isocitrate dehydrogenase-2 (IDH2). That enzyme helps generate energy within cells, but when it’s mutated in cancer, it creates a byproduct that flips a genetic switch in immature bone marrow cells. Those cells then don’t develop properly, and start multiplying wildly, rather than becoming the blood cells they were supposed to become.

By binding to mutated IDH2, AG-221 is supposed to block the byproduct and allow bone marrow cells to mature normally. As such, it works very differently than chemotherapy, which kills cancer and healthy cells alike.

If it works, it would represent a paradigm shift in the treatment of AML—a fast-moving blood cancer whose only cure is a bone marrow transplant that is only available to a small number of patients. Between 9 and 13 percent of patients with AML have the IDH2 mutation.

Here’s a rundown of the data Agios is reporting today. The company enrolled 73 patients in its study, but 28 couldn’t be evaluated because they became too sick or their disease was too advanced.

“These patients are so ill that it is difficult to evaluate them before they’ve gotten a month of therapy,” Stein says.

Of the 45 evaluable patients:

—Six responders have no trace of cancer in their system (complete remissions).

—Nine responders have no trace of leukemia, but their blood levels haven’t returned to normal yet.

—None of the six with a complete remission have relapsed.

—Ten responders had partial remissions, meaning some of their leukemia is gone.

—90 percent of the responders have been on therapy for at least three months; four responders have been on AG-221 for at least six months, with some on treatment as long as seven or eight months, according to Stein.

—Ten patients have stable disease; Stein says that for many of these patients, the number of “blasts,”—abnormal, immature cells that are a hallmark of leukemia—in their blood have decreased. Their platelet counts, however, haven’t returned to normal.

AG-221 is part of Agios’s partnership with Summit, NJ-based Celgene (NASDAQ: CELG). Celgene holds worldwide rights to the drug, and is paying all of its development costs; Agios would get milestones and royalties on the drug if it continues forward. Agios does hold U.S. rights to AG-120, however, and full rights to a third drug, AG-348, for an inherited form of anemia known as pyruvate kinase deficiency. Agios will be reporting data from the first study of AG-348 at ASH as well.

Separately, while Agios looks to start a registrational trial in AML, South San Francisco, CA-based Sunesis Pharmaceuticals {NASDAQ: SNSS) recently finished one with its drug voxarosin. The trial’s lead investigator is presenting the data at ASH today, as well. Although the trial didn’t meet its primary endpoint of extending the lives of patients with relapsed or refractory disease, subgroups of patients in the trial saw greater benefit. Sunesis plans to ask regulators in the U.S. and E.U. for approval.