Mitapivat Sustains Reduction in Iron Burden in Pyruvate Kinase Deficiency

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Mitapivat treatment was linked to long-term improvements in key markers of iron homeostasis and erythropoiesis in an analysis of the phase 3 ACTIVATE trial.

Mitapivat treatment exhibited clinically meaningful long-term improvements in key systemic markers of iron homeostasis and iron overload in patients with pyruvate kinase (PK) deficiency, according to new research.1

In February 2022, the US Food and Drug Administration (FDA) approved mitapivat, a first-in-class, oral, allosteric activator of red blood cell wild-type and mutant PK enzyme, for the treatment of hemolytic anemia in adults with PK deficiency.2

Results from this analysis of the phase 3 ACTIVATE trial and its long-term extension (LTE) study revealed mitapivat treatment had clinically meaningful and durable improvements in liver iron concentration (LIC) by magnetic resonance imaging (MRI), suggesting its impact on the iron burden faced by this population.1

“Mitapivat is the first disease-modifying pharmacotherapy shown to have beneficial effects on iron overload in adult patients with PK deficiency through its multimodal action, including modulating the erythroferrone-hepcidin axis,” wrote the investigative team, led by Eduard J. van Beers, center for benign hematology, thrombosis and hemostasis, University Medical Center Utrecht, Utrecht University.

A rare, hereditary disease, PK deficiency is characterized by mutations in the PKLR gene that can result in chronic hemolytic anemia, ineffective erythropoiesis, and serious complications.3 Iron overload is a common complication of PK deficiency, regardless of age, genotype, or transfusion history. Results from the ACTIVATE clinical trial program showed improvements in hemoglobin, hemolysis, and transfusions with mitapviat in 2 global phase 3 trials.

In this analysis, investigators evaluated the drug’s effect on iron overload and ineffective erythropoiesis in adults with PK deficiency not regularly transfused (≤4 transfusion episodes) in ACTIVATE and its LTE study.1

All participants included in the LTE received mitapivat throughout ACTIVATE/LTE (baseline to week 96: mitapivat-to-mitapivat [M/M] arm) or were switched from placebo (baseline to W96) to mitapivat (W24 to 96; placebo-to-mitapivat [P/M] arm). Those in the M/M arm maintained optimized treatment dosage from ACTIVATE while the P/M arm received an initial twice-daily 5 mg dose and could sequentially increase their dose to 20 or 50 mg.

Key markers of iron overload and erythropoiesis evaluated up to Week 96 for both the M/M and P/M arms included hepcidin, erythroferrone, soluble transferrin receptor (sTfR), LIR by MRI, ferritin, erythropoietin, and reticulocyte percentage. A total of 80 patients were included in the ACTIVATE/LTE analysis, with 40 included in each of the M/M and P/M groups, respectively.

Ultimately, 78 participants were treated with mitapivat following 2 study discontinuations, with 43 (55.1%) matching the criteria for iron overload at baseline (median LIC by MRI, 6.50 mg Fe/g dw). Upon analysis, investigators identified sustained directional improvements in markers of iron homeostasis and erythropoiesis associated with iron overload from week 24 to 96 in those treated with mitapivat in the LTE study.

In the M/M arm, these sustained improvements were observed in hepcidin (mean, 4770 ng/L [95% CI, -1532.3 to 11,072.3]), erythroferrone (mean, -9835 ng/L [95% CI, -14,328.4 to -5341.3]), sTfR (mean, -56.0 mmol/L [95% CI, -84.8 to -27.2]), and erythropoietin (mean, -32.85 [95% CI, -54.65 to -11.06]) levels from week 24 to 96. Those treated with placebo experienced relatively unchanged markers from baseline but showed improvements similar to the M/M arm after transitioning to mitapivat in the LTE.

Further, the mean changes from baseline in LIC by MRI were –2.0 mg Fe/g dw (95% CI, -4.8 to -0.8) in the M/M arm and –1.8 mg Fe/g dw (95% CI, -4.4 to 0.80) in the P/M arm at week 96. The change from baseline in LIC was additionally evaluated in a subgroup of mitapivat-treated patients with iron overload at baseline. Treatment with mitapivat showed meaningful and sustained improvements in LIC by MRI (mean change from baseline, Week 24, -0.8 mg Fe/g 230 dw [95% CI, -6.9 to 5.3]; Week 96, -3.3 mg Fe/g dw [95% CI, -6.4 to -0.3]) in this population.

van Beers and colleagues cited the importance of these data, given the serious consequences and additional disease burden faced by patients with PK deficiency and iron overload at baseline.

“The results presented here further highlight the importance of the assessment of LIC by MRI,” investigators wrote. “As the gold standard for the assessment of liver iron burden in patients with PK deficiency, this method ensures that iron burden is appropriately assessed and that patients receive optimal management.”


  1. van Beers EJ, Al-Samkari H, Grace RF, et al. Mitapivat improves ineffective erythropoiesis and iron overload in adult patients with pyruvate kinase deficiency. Blood Adv. Published online February 8, 2024. doi:10.1182/bloodadvances.2023011743
  2. Agios announces FDA approval of PYRUKYND® (mitapivat) as first disease-modifying therapy for hemolytic anemia in adults with pyruvate kinase deficiency. Agios Pharmaceuticals, Inc. February 17, 2022. Accessed February 13, 2024.
  3. Al-Samkari H, Galacteros F, Glenthoj A, et al. Mitapivat versus placebo for pyruvate kinase deficiency. N Engl J Med. 2022;386(15):1432-1442