P1565: mitapivat improves ineffective erythropoiesis and reduces iron overload in patients with pyruvate kinase deficiency

Background: Pyruvate kinase (PK) deficiency is a rare hereditary disease resulting in chronic hemolytic anemia, which is associated with serious complications, including iron overload (FeO). Ineffective erythropoiesis is linked to FeO in patients (pts) with hemolytic anemias. Mitapivat (AG-348), an oral, allosteric activator of the red blood cell PK enzyme (PKR), has demonstrated improvement in hemoglobin, hemolysis, and transfusion burden in pts with PK deficiency. Aims: Assess effect of mitapivat on markers of erythropoiesis and FeO in pts (≥18 years [yrs]) with PK deficiency enrolled in 2 phase 3 studies, ACTIVATE (NCT03548220) and ACTIVATE-T (NCT03559699), and their long-term extension (LTE) study (NCT03853798). Methods: In ACTIVATE (double-blind, placebo [PBO]-controlled study), 80 adult pts with PK deficiency who were not regularly transfused (≤4 transfusion episodes in prior yr; none in prior 3 months) were randomized 1:1 to receive mitapivat or PBO. In ACTIVATE-T (open-label, single-arm study), 27 adult pts with PK deficiency who were regularly transfused (≥6 transfusion episodes in prior yr) were treated with mitapivat. Pts completing either trial (24 weeks [wks] [ACTIVATE], 40 wks [ACTIVATE-T]) were eligible to continue in the LTE, where all received mitapivat. Erythropoiesis markers included erythropoietin (EPO), erythroferrone, reticulocytes, and soluble transferrin receptor (sTfR). Markers of FeO included hepcidin, iron, transferrin saturation (TSAT), ferritin, and liver iron concentration (LIC) by magnetic resonance imaging. Pts from ACTIVATE were categorized into mitapivat-to-mitapivat arm (M/M) or PBO-to-mitapivat arm (P/M). The ACTIVATE-T/LTE analysis includes pts who achieved transfusion-free status in ACTIVATE-T. The ACTIVATE/LTE analysis assessed change in markers from baseline (BL) over time in both study arms. Results: 80 pts were included in the ACTIVATE/LTE analysis (M/M=40; P/M=40). Pts in both arms had abnormal BL erythropoiesis markers consistent with underlying ineffective erythropoiesis, and abnormal BL markers of FeO. In the M/M arm, mean (SD) EPO, erythroferrone, reticulocytes, and sTfR decreased from BL to Wk 24 of mitapivat treatment: –32.9 IU/L (62.47), –9834.9 ng/L (13081.15), –202.0 109/L (246.97), and –56.0 nmol/L (82.57), respectively, they remained stable or increased in the P/M arm on PBO. 24 wks after starting mitapivat in the LTE (Wk 48 post BL), pts in the P/M arm had comparable beneficial decreases in mean (SD) EPO, erythroferrone, reticulocytes, and sTfR: –11.6 IU/L (30.74), –9246.1 ng/L (8314.17), –283.7 109/L (374.27), and –38.7 nmol/L (48.37), respectively. Improvements in hepcidin, iron, TSAT, and LIC were also observed with mitapivat treatment; ferritin remained stable (Table). Mean (SD) hepcidin increased in the M/M arm at Wk 24 and in the P/M arm 24 wks after starting mitapivat (Wk 48 post BL). At Wk 24, mean (SD) iron and TSAT, and median (Q1, Q3) LIC decreased in the M/M arm, while they increased on PBO. In the P/M arm, iron, TSAT, and LIC decreased 24 wks after starting mitapivat (Wk 48 post BL). Transfusion-free responders from ACTIVATE-T (n=6) also experienced improvements in markers of erythropoiesis and FeO in the LTE. Image:Summary/Conclusion: These data indicate that activation of PKR with mitapivat improves markers of ineffective erythropoiesis and iron homeostasis in PK deficiency, thereby decreasing FeO in these pts. Mitapivat is the only approved pharmacotherapy in PK deficiency, and may have the potential to improve iron metabolism and reduce FeO in pts with this condition.