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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.
Perspective
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Michael M. Millenson, MD, FACP
Pyruvate kinase deficiency is an extremely rare condition and not something on the radar screen of most general, adult hematologists/oncologists. Patients with this condition are usually diagnosed in childhood, or identified after working up an affected family member, and the severity of hemolysis can be quite variable. The genetics also are fairly complicated, with two distinct genes and several associated isoforms described. Affected individuals can either be homozygous for the same mutation or double heterozygotes for two different pyruvate kinase gene defects. In short, this is not a major public health issue, with estimates of frequency on the order of 50 cases per million in the general population based on the genetics. However, because of the variability in clinical severity, the actual number of affected individuals is quite small. It is noteworthy that the study by Grace and colleagues was an international effort involving multiple centers in the United States, Canada, France and Italy, and yet only included 25 patients.
All of that said, this report is significant in that it demonstrates a proof of concept that an orally administered small molecule drug can act in a novel way to improve enzyme functioning, resulting in real benefits for affected patients. AG-348 (Agios) is an allosteric activator of red cell pyruvate kinase, the dominant isoform in red cells, and appears to restore adenosine triphosphate levels in red blood cells of affected individuals, consistent with enzyme activation. Indeed, a high percentage of patients with missense mutations (68%) had a hemoglobin increase of greater than 1.0 gm/dL, with the hope that this could lead to transfusion independence in a significant subset of patients. If so, this could indeed be considered a disease-modifying intervention, representing a significant improvement for patients whose main option for management at present is chronic transfusion support. Clearly we need to see the safety and efficacy data in a larger number of treated patients, and we also need to get a better sense of the durability of responses. Nonetheless, this novel approach appears to offer hope for patients with this rare condition, and may serve as a paradigm for therapeutic development in other diseases.
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