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Déjà Vu for Agios as Second Drug Shines in Small Blood Cancer Study

Xconomy Boston — 

Agios Pharmaceuticals turned heads in April when it showed its first drug prospect might be able to treat a devastating blood cancer, acute myeloid leukemia (AML), in people who have a specific genetic mutation. It was the first shred of validation, in humans, for Agios’s work in a raw field of oncology—cancer metabolism—and the company’s shares have zoomed upwards ever since.

Today, Cambridge, MA-based Agios (NASDAQ: AGIO) has unveiled the first clinical data from its second drug, a compound called AG-120. These interim Phase 1 data are critical for Agios, because it owns the U.S. rights to AG-120, unlike the other drug that has already shown promise, known as AG-221. Each drug is designed to treat a different group of AML patients.

It’s important to emphasize that with today’s data, as with the data from AG-221 in April, these are early results from small patient samples.

But they are nonetheless unusual. Phase 1 trials are typically designed to test a drug’s safety and tolerability, find a maximum dose that patients can handle, and determine if a drug is hitting the right molecular target. A drug response, while often measured, isn’t necessarily anticipated—particularly a significant one.

Yet Agios today is reporting that 7 of 14 AML patients have indeed responded to AG-120, with some showing no trace of cancer in their blood after 28 days of treatment. What’s more, no toxicities have emerged to put a ceiling on the size of the dose patients can tolerate.

“When you design a study like this you don’t expect to see multiple complete remissions,” says Agios CEO David Schenkein (pictured above). “This molecule comes on the heels of AG-221, where we saw that activity, so now we were obviously hoping that we’d see this degree of activity [here as well]. But this has certainly exceeded our expectations.”

Agios will expand the trial significantly in the first half of 2015, with more patients taking a specific dose for a longer period of time. It’s déjà vu: after strong early results with AG-221, Agios pushed on with a similar expansion of that Phase 1 trial, as well.

Agios is also eyeing both drugs as treatments for newly-diagnosed AML patients, not just for those who haven’t responded to other therapies.

While the early returns are promising, Agios still doesn’t yet know how long these disease responses will hold up, whether these patients will relapse, if the next group of patients will respond in the same way, or even if some unexpected safety issues will pop up as the study numbers increase.

For now, the one severe side effect investigators saw with AG-120 occurred in one patient who was on the highest dose of the drug and suffered an irregular heartbeat, or “QT prolongation.”

The problem was resolved when the dose was reduced. The patient is still in complete remission and remains on the drug, according to Agios. “We don’t view it as a major issue at this time at all,” says Schenkein. “It’s pretty common in patients with AML because these patients are so sick and on so many other medications.”

But it’s the type of thing to keep an eye on. All of the other side effects have been mild to moderate in nature, and typical of patients with AML, Schenkein says.

AG-120 is designed to work very similarly to AG-221. Unlike chemotherapy, which kills cancer and healthy cells alike, these drugs are supposed to essentially stop the birth of new cancer cells. They target enzymes called isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2), respectively. Both enzymes help generate energy within cells. But when mutated in cancer, they create a byproduct that flips a genetic switch in immature bone marrow cells.

As a result, rather than becoming platelets or other blood cells they were meant to be, those bone marrow cells don’t develop properly, and start multiplying wildly. AG-120 and AG-221 aim to stop this process by binding to the mutated IDH1 (in the case of AG-120) or IDH2 (for AG-221) enzymes, leading cells to mature normally. Mutated IDH1 is found in about 6 to 10 percent of the patients with AML; Aberrant IDH2 is seen in between 9 to 13 percent, according to Schenkein.

If successful, Agios’s drugs could represent a paradigm shift in treatment for AML, a fast-moving blood cancer that affects about 18,000 people in the U.S. every year and kills most of them. AML patients typically get chemotherapy, which leaves people weak, sick, and prone to infections. The only cure is for the small number of AML patients (about 10 percent, says Schenkein) who are eligible for bone marrow transplants, which carry their own set of risks.

Because AG-120 forces budding cancer cells to grow properly instead of killing them and healthy cells alike, as chemotherapy does, in theory it shouldn’t create the side effects of chemo. What’s more, AG-120 is a pill (as is AG-221), which makes it possible—depending on how safe and effective the drug proves to be, of course—that AML patients could take it once or twice a day to manage their disease, turning what’s now often a death sentence into a chronic illness.

“Maybe it’ll be chronic therapy, or maybe we’ll actually eradicate the disease, either as a single agent or potentially in combination [with chemotherapy],” Schenkein says. “Our plan is to go fast and broad, and make the biggest impact we can in these diseases.”

The longer patients take the drug, the more Agios learns about the breadth and durability of that impact. All patients who responded to AG-120, for instance, remain on the drug today, and haven’t relapsed. Schenkein says the four that have had complete remissions have been on treatment anywhere from one month to more than five months.

All told, the company enrolled a group of IDH1-mutated patients with either AML or myelodysplastic syndrome (when the bone marrow doesn’t produce enough healthy blood cells). They all had previously failed at least one and up to five rounds of chemotherapy. Those patients, who were a median age of 73, were given AG-120 for 28 days, at doses of either 300 milligrams, 500 mg, or 800 mg once a day, or 100 mg twice a day.

Here’s a deeper breakdown of the 14 patients in the study (another three are enrolled but not long enough to evaluate):

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

—Two of the responders had “marrow complete remissions,” meaning the leukemia was cleared from their blood and bone marrow, but their blood count hadn’t returned to normal yet.

—One responder had a partial remission, meaning some of the leukemia is gone, but the patient now has a normal blood count.

—One patient has stable disease, meaning the leukemia hasn’t neither progressed nor gotten better.

—Seven did not respond to treatment, although all but one of the non-responders had “stable disease for a while,” says Schenkein, before they came off the drug (“for a variety of reasons—not side effects”) and the leukemia progressed.

Schenkein says AG-120 was particularly effective at higher doses, which might be “an early sign that with increasing doses we’re seeing more responses, but that will have to play out over time just a little bit more.”

Here’s more déjà vu: These data from AG-120 echo the first data from AG-221, which Agios released in April. Six of the first seven patients who could be evaluated responded to treatment, and three had no trace of cancer.

Shares shot up more than 30 percent, from $35.48 to $45.35, and they’ve continued to climb. Earlier today, shares closed around $84 apiece, near five times the IPO price when Agios went public in 2013. That’s a big boon for Agios development partner Celgene (NASDAQ: CELG), which held 15.12 percent of Agios as of an April proxy filing, second only to VC firm Third Rock Ventures (17.83 percent as of the filing).

The response rate to AG-221 has tailed off as patient numbers have increased, but it’s still promising. To date, 20 of 32 patients who could be evaluated for treatment with AG-221 have responded: Eight with complete remissions, and four have complete remissions but either their platelet or blood cell counts haven’t returned to normal yet.

Agios is updating the AG-221 results at the American Society of Hematology’s annual meeting in a few weeks.

While AG-120 is Agios’s second drug, its success is much more important to the company’s financial future than AG-221. Summit, NJ-based Celgene holds worldwide rights to AG-221 under a $130 million deal the two companies struck in 2009; Agios will only get milestone payments and royalties if it continues forward.

Celgene has an option to grab international rights to AG-120, but Agios has held onto U.S. rights, which means a much larger portion of the rewards if the drug proves successful.

Agios also has a separate early trial underway testing AG-120 in patients with solid tumors, and expects to produce data from that study at a medical conference next year.