After FDA Hold, Agios Quickly Scraps One Anemia Drug, Turns to Another

Xconomy Boston — 

Agios Pharmaceuticals has been developing two experimental drugs for anemia. For a couple of years, the company has said it would eventually move the better one forward and leave the other behind. As it turns out, the FDA has made the decision an easy one.

Agios (NASDAQ: AGIO) said this afternoon it has scrapped AG-519, an experimental drug the company has been developing for a rare form of anemia called pyruvate kinase (PK) deficiency. Agios made the decision after the FDA told the company yesterday AG-519 would be placed on “clinical hold,” meaning clinical testing of the drug would be suspended. Cambridge, MA-based Agios reported earlier this month that one healthy volunteer in a Phase 1 trial had liver inflammation after taking AG-519.

“It was pretty clear from [the FDA’s] vantage point that AG-519 no longer has a risk-benefit ratio in this disease that was favorable,” Agios CEO David Schenkein told Xconomy.

The decision doesn’t affect Agios’s other experimental drug for PK deficiency, AG-348, which is currently in a Phase 2 trial and could advance into late-stage testing soon. Schenkein wouldn’t say when that would happen; the plan is subject to ongoing discussions with regulators. Agios is exploring a potentially “accelerated” approval path, on less evidence than is typically required, for AG-348. “Once we have that strategy we’ll articulate it,” he says.

Agios is best known for its work in blood cancers. Two experimental drugs the company has developed for subsets of patients with acute myelogenous leukemia have posted encouraging results in early testing. One of those drugs, enasidenib, could be headed for an FDA review this month, according to plans laid out by Agios’s partner Celgene. And Agios has said it might follow a similar path with AG-120, another AML drug that isn’t far behind enasidenib.

The AG-120 plan is important to Agios, because it will only earn milestones and royalty payments on enasidenib from Celgene. By comparison, Agios owns full rights to AG-120 and the two anemia drugs.

PK deficiency disease causes the body to improperly kill red blood cells, leading to anemia. Durably boosting oxygen-carrying hemoglobin in patients with severe cases of PK deficiency—as AG-348 and AG-519 are meant to do—could help them avoid blood transfusions or complications like fatigue, jaundice, or a life-threatening accumulation of iron in their organs. There are no treatments approved specifically for PK deficiency, which affects less than 1 percent of the population, according to the National Organization for Rare Disorders.

Both AG-348 and AG-519 target an enzyme, PKR, that is defective in the red blood cells of people with PK deficiency. The drugs bind to the defective enzyme and repair it, which should boost patients’ levels of oxygen-carrying hemoglobin.

So far, both have shown early promise in increasing the hemoglobin levels of some patients. But safety concerns have emerged as well. While AG-519 appeared, as Leerink Partners analyst Michael Schmidt wrote in a recent research note, “slightly more potent” than AG-348, it also appeared more dangerous. In June, Agios reported that a patient developed thrombocytopenia, or low platelets, after taking the drug for 14 days. Then, at the American Society of Hematology’s annual meeting earlier in December, Agios disclosed the case of drug-induced liver inflammation, which can lead to liver damage or other problems. The “totality of the data” Schenkein says, combined with the FDA’s feedback, were enough for Agios to scrap AG-519.

Agios hasn’t seen the same safety problems with AG-348 so far, but it hasn’t been worry-free. AG-348 binds not just to its target but also to an enzyme that affects sex hormones. This hasn’t led to a health issue for patients so far, but considering AG-348 is a pill meant to be taken for life, it’s important to watch for emerging problems.”It just means we have to study it in more detail going forward,” Schenkein says. He adds the company might lower the dose of AG-348 in further testing, as that might lead to a milder impact on sex hormones.

Most other side effects—the most frequent being headache, nausea, and insomnia—have been considered mild. The drug has been tested in 124 patients and healthy volunteers since Agios began testing it in 2014. The longest patients have been treated is “well beyond six months,” Schenkein says. By comparison, AG-519 hadn’t even been tested in PK deficiency patients yet before safety issues emerged.

Schenkein acknowledges, however, that Agios has much to prove with AG-348.

“Obviously in drug development we won’t know for a period of time, but this gives us confidence that this is the right molecule to move forward,” he says.