P1473: clinically relevant hemoglobin response in adults with pyruvate kinase deficiency treated with mitapivat – a sub-analysis of the activate trial

Topic: 28. Enzymopathies, membranopathies and other anemias Background: Mitapivat, an oral, allosteric activator of pyruvate kinase (PK), is approved by the US FDA for the treatment of hemolytic anemia in adults with PK deficiency and by the EMA for the treatment of PK deficiency in adults. In the ACTIVATE trial (NCT03548220), mitapivat demonstrated improvements in hemoglobin (Hb) in patients (pts) who were not regularly transfused. 16/40 (40%) pts receiving mitapivat met the primary endpoint of Hb response (≥1.5 g/dL increase from baseline [BL] sustained at ≥2 scheduled assessments at weeks [wks] 16, 20, and 24 in the fixed-dose period) compared with 0 for placebo (PBO). Understanding Hb response using a clinically applicable definition of ≥1.0 g/dL improvement after mitapivat treatment may provide additional benefits. Aims: This analysis examined Hb, hemolysis, and disease-specific patient-reported outcome (PRO) responses to mitapivat during ACTIVATE and/or the long-term extension (LTE) (NCT03853798) in pts who had a ≥1.0 g/dL Hb increase. Methods: In the global, phase 3, randomized, PBO-controlled ACTIVATE trial, 80 pts were randomized 1:1 to receive mitapivat or PBO for a 12-wk dose-optimization period (5/20/50 mg twice daily), followed by a 12-wk fixed-dose period. This analysis included pts treated with mitapivat in ACTIVATE who continued into the LTE and had a clinically relevant Hb response defined as ≥1.0 g/dL increase from BL for at least 2 timepoints after the start of the fixed-dose period. Hemolysis was evaluated through bilirubin and reticulocyte analyses. Quality of life was evaluated by using the PRO measures, PK deficiency diary (PKDD) and PK deficiency impact assessment (PKDIA); for both, a lower score represents lower disease burden. The minimal clinically important change (MCIC) is defined as a reduction of 4.2 and 5.5 in PKDD and PKDIA scores, respectively. Results: 25/40 (62.5%) pts originally randomized to mitapivat in ACTIVATE/LTE met the criteria for having a clinically relevant Hb response (≥1.0 g/dL) which occurred as early as 20 wks and as late as 108 wks. Median (Q1, Q3) Hb improvement from BL to Wk 108 was 2.6 g/dL (1.17, 3.27; n=19) (Figure). This group included a subset of 9 pts who did not meet original protocol endpoint (≥1.5 g/dL increase in Hb). For this subset, median (Q1, Q3) Hb improvement from BL at Wk 108 was 1.07 g/dL (0.69,1.92; n=8). 19/25 pts meeting the criteria for clinically relevant Hb response had a ≥1.5 g/dL Hb increase on ≥2 timepoints after the start of the fixed-dose period, of which 16 achieved this by Wk 24; 3 pts achieved ≥1.5 g/dL Hb improvement after Wk 24 (up to Wk 120). Median (Q1, Q3) change from BL to Wk 108 in bilirubin was -30.1 µmol/L (-55.15, -19.20; n=17) and in reticulocyte % was -8.3% (-19.2%, -2.8%; n=18). Improvements in hemolysis markers were similar in the subset of 9 who did not meet original protocol endpoint. At Wk 108, mean (95% CI) changes from BL in PKDD and PKDIA scores were -7.2 (-11.1, -3.2; n=15) and -7.3 (-10.8, -3.8; n=17), respectively (Figure). For the subset of 9 pts, mean (95% CI) changes from BL in PKDD and PKDIA scores were -6.1 (-14.6, 2.3; n=4) and -6.2 (-15.5, 3.2; n=6), respectively. Summary/Conclusion: This analysis shows that a majority of pts treated with mitapivat in ACTIVATE/LTE (62.5%) achieved a clinically relevant Hb response, defined as a Hb increase of ≥1.0 g/dL, along with improvements in hemolysis and PROs, indicating beneficial effects to pts with PK deficiency. Further, some Hb responses ≥1.0 g/dL occurred after 6 months, indicating that certain pts may reach this threshold with continued treatment regardless of initial Hb response.Keywords: Hemolysis, Pyruvate kinase deficiency, Hemolytic anemia, Hemoglobin