Agios’ PK deficiency data tees up decision on pivotal trial

red blood cells
Red blood cells

Agios Pharmaceuticals has moved closer to starting a pivotal clinical trial of one of its wholly owned treatments for pyruvate kinase (PK) deficiency. The latest data drop tees Agios up to discuss a pivotal trial with regulators before deciding which of its two candidates to advance into a late-phase study in the indication.

AG-348 is the more advanced of the two assets, having already shown it can increase hemoglobin in patients with a condition that causes the premature death of red blood cells. But Agios thinks the similarity of AG-519 to AG-348 and data generated to date give it the option to move the follow-up candidate straight from healthy volunteers into a pivotal trial.

With Agios seeing both assets as viable for further development following the release of new efficacy data on AG-348 and healthy volunteer results on AG-519 this weekend, the company has a decision to make.

“One will go into pivotal, the other will stay as the backup,” Agios CEO David Schenkein said at an event at the 2016 American Society of Hematology Annual Meeting and Exposition (ASH).

Agios has more data on AG-348. The oral activator of PKR increased hemoglobin by more than 1.0 g/dL in almost half of participants in a 32-person trial. When patients without a missense mutation were removed from the analysis, the proportion of responders rose to 58%. The responder rate is down 10 percentage points on earlier data updates.

AG-348 was generally well tolerated, with most adverse events rated grade 2 or below. Potential causes for concern include grade 3 cases of hemolysis and anemia in one patient after they stopped treatment, although Agios thinks it now understands and can mitigate this risk.

“There is going to be hemolysis if you abruptly stop the drug. When the dose is gradually decreased, the patients don’t have hemolysis. It’s avoidable,” Dr. Rachael Grace of Dana-Farber Boston Children's Cancer and Blood Disorder Center said. Dr. Grace is the principal investigator on the study.

When Agios last posted data on AG-519 in June, one case of grade 2 thrombocytopenia prompted investors to wipe 15% off the company’s share price. That event, which resolved itself spontaneously within a week of the last dose, remains the only case of thrombocytopenia. The new concern is a case of drug-related cholestatic hepatitis that occurred after the data cutoff.

Despite these adverse events, Agios regards AG-519 as well tolerated, although it acknowledges it lacks long-term data on the drug. This has implications for the next steps.

“If 519 were to be taken forward into a pivotal trial, the long-term safety profile would need to be further delineated,” Agios CMO Chris Bowden said.

Whether Agios thinks it is worth carrying out this work when AG-348 is good to go remains to be seen. Potency is one factor in favor of AG-519. “On a milligram per milligram basis, 519 is a more potent drug,” Agios CSO Scott Biller said.

Shares in Agios fell more than 10% in early trading.