Drug Development

FDA slaps a hold on Agios’ PK drug, forcing the biotech to kill it in favor of an internal rival

Agios CEO David Schenkein

Agios CEO David Schenkein

A few days ago, Agios $AGIO was trying to decide whether it should take AG-348 or AG-519 into a pivotal trial for rare cases of pyruvate kinase (PK) deficiency. But now the FDA has made the decision for Agios, handing down a clinical hold on AG-519 that persuaded the biotech to scrap the program altogether.

The hold, Agios CEO David Schenkein tells me, was triggered by an earlier case of cholestatic hepatitis that was reported at ASH a little more than a week ago. One of the patients in a bioavailability study taking a 300 mg dose was hit by the liver disease. And even though “she’s improving” while Agios was also “likely to move to 50 mg or lower (for the pivotal), one can’t be sure we wouldn’t have seen this again.”

That case of cholestatic hepatitis — which can damage the liver — rattled investors at the time, badly denting the biotech’s shares. And Agios took a 20% hit on its share price in after-market trading today.

AG-348 has more data, but analysts have been questioning whether a more potent 519 could make for a better gamble than a drug with a waning impact. Investigators also recorded evidence of aromatase inhibition for AG-348, says Schenkein, but without clinical impact. AG-348, he adds, “is a terrific drug with compelling data.”

It also has the kind of risk/benefit profile that is worth a pivotal gamble, he adds, as opposed to what they have now in 519. Not all analysts are likely to buy off on that without question.

“Follow-on compound AG-519 appears to be slightly more potent, at least based on pharmacodynamics (PD) markers while lacking aromatase inhibition of AG-348,” noted Leerink’s Michael Schmidt in an ASH update, as Agios shares slid on the reaction. “One drug-related serious adverse event (SAE) of cholestatic hepatitis at a high dose level is being investigated, but the dose expected to move into Ph III is expected to be significantly lower according to mgmt.”

PK deficiency is a rare inherited disease that triggers the accelerated destruction of red blood cells. The biotech’s lead programs are AG-120 and AG-220 for cancers with IDH1 and IDH2 mutations.

“We share the FDA’s commitment to patient safety and believe this is the right decision to ultimately help people with PK deficiency,” said Schenkein in a statement. “As the lead compound in our PKR program, AG-348 has demonstrated clear proof of concept with robust, rapid and sustained increases in hemoglobin in patients with PK deficiency. Based on our clinical experience with DRIVE PK, we are developing a registration path for AG- 348 in adult PK deficiency patients and plan to discuss this strategy with regulators.”

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