ASH Annual Meeting and Exposition
ASH Annual Meeting and Exposition
December 10, 2016
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AG-348 safe, tolerable in congenital hemolytic anemia

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SAN DIEGO — Six months of daily therapy with a novel activator of the glycolytic enzyme pyruvate kinase appeared safe and tolerable in adults with a rare hemolytic anemia, according to findings of the DRIVE PK trial presented at the ASH Annual Meeting and Exposition.

Pyruvate kinase (PK) deficiency is a congenital hemolytic anemia caused by deficiency of the glycolytic enzyme red cell pyruvate kinase (PK-R). Rachael F. Grace, MD, director of the Hematology Clinic at Dana-Farber Boston Children's Cancer and Blood Disorder Center and assistant professor of pediatrics at Harvard Medical School, and colleagues evaluated AG-348 (Agios), an orally available, small molecule, allosteric activator of PK-R that has demonstrated an ability to activate wild-type and a range of mutated enzymes in vitro. The drug also increases PK activity and restores adenosine triphosphate levels in red blood cells.

“Pyruvate kinase deficiency is a rare hemolytic anemia that occurs in the neonatal period,” Grace said. “It can lead to lifelong hemolytic anemia.”

The analysis included 17 patients who received 50 mg of AG-348 and 17 patients who received 300 mg twice daily for 6 months. Safety and tolerability were the primary endpoints; pharmacokinetics of the study drug was a secondary outcome.

Results indicated that two patients experienced serious adverse events. Thirteen patients experienced at least one adverse event of any kind. There were two events of grade 3 or higher in the 50-mg arm, and six events of grade 3 or higher in the 300-mg arm. Ten patients required dose reductions.

The most frequent adverse events were nausea (n = 11), headache (n = 8) and insomnia (n = 8). Grade 3 adverse events included hypertension ( n= 1), hypertriglyceridemia (n = 1), insomnia (n = 2) and anemia (n=1).

Analysis of hormone levels indicated a downward trend in estradiol in both dosing arms, according to Grace. However, the hormone levels remain in the physiologic range.

“These data remain early and the clinical significance to patients is unclear,” she said.

Other findings showed that 47% of the cohort experienced an increase in hemoglobin. Three patients had dose reductions because their hemoglobin values exceeded the protocol-mandated maximum.

“Hemoglobin response and response maintenance are seen across a range of doses,” Grace said.

Five patients who were homozygous for R479H were nonresponders, she added.

Pharmacodynamic results indicated an increase in PK-R.

“These data suggest a positive correlation between hemoglobin change and change in glycolytic flux,” Grace said.

AG-348 is a novel first-in-class drug that improves anemia in patients with PK deficiency, Grace said.

“Daily dosing with this drug for up to 6 months is well tolerated,” she said. “We observed rapid and durable increases in hemoglobin in 47% of patients. Hemoglobin increase is linked to activation of the glycolytic pathway.” – by Rob Volansky

For more information:

Grace RF, et al. Abstract #402. Presented at: The ASH Annual Meeting and Exposition; Dec. 2-6, 2016; San Diego.

Disclosures: Grace reports being a scientific advisor and receiving research funding from Agios Pharmaceuticals. Please see the abstract for a list of all other researchers’ relevant financial disclosures.