A new study has shown that pyruvate kinase activators (PKAs), such as AG946 and mitapivat (AG348), may increase hemoglobin-oxygen affinity in red blood cells (RBC) and reduces RBC sickling in patients with sickle cell disease (SCD).

The study, published in the British Journal of Haematology, supports continued exploration of PKAs in clinical trials as a potential approach to reducing vaso-occlusive crises (VOCs) and/or decreasing the severity of anemia in these patients.

“A recent phase 1 and phase 2 open-label study in patients with SCD confirmed that mitapivat decreased 2,3-DPG, increased the haemoglobin-oxygen affinity and decreased sickling tendency,” the authors wrote. “The present study investigated the ex vivo effects of mitapivat and AG946 on the properties of RBCs in patients with SCD.”

The researchers collected blood samples from nontransfused adults and children with SCD. The RBCs were treated with mitapivat, AG346, or vehicle for 4 hours. A subgroup of RBCs was treated with cumene hydroperoxide to mimic increased oxidative stress. Then, hemoglobin-oxygen affinity, RBC deformability and sickling tendency, and RBC senescence properties were assessed.

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The results showed that AG946 and mitapivat reduced RBC sickling tendency and increased hemoglobin-oxygen affinity ex vivo, and this effect occurred even in the context of increased oxidative stress. Both PKAs reduced p50.

There was a slight increase in intracellular Ca+ in the cells treated with AG946, which the authors suspect was due to the fact that PKA molecules are calcium dependent, but there was no effect of this increase on RBC senescence.

The results demonstrate the encouraging potential of PKAs to reduce RBC sickling tendency, thereby reducing the frequency of VOCs, and to improve hemoglobin-oxygen affinity, leading to less severe anemia in patients with SCD. Given that a recent phase 1 clinical trial on healthy adults showed that AG946 had a favorable safety profile, the authors conclude that PKAs merit continued evaluation as a treatment for this condition.  


Joly P, Nader E, Ketels F, et al. Effects of pyruvate kinase activators on red blood cell properties in sickle cell disease. Br J Haematol. Published online June 5, 2023. doi:10.1111/bjh.18916.