P1545: durability of hemoglobin response and reduction in transfusion burden is maintained over time in patients with pyruvate kinase deficiency treated with mitapivat in a long-term extension study

Background: Mitapivat (AG-348), a first-in-class, oral, allosteric activator of red blood cell (RBC) PK enzyme, demonstrated improvements in hemoglobin (Hb) and markers of hemolysis and hematopoiesis (ACTIVATE, NCT03548220), and reduction in transfusion burden (ACTIVATE-T, NCT03559699) in patients (pts) with PK deficiency. Aims: Report data from ACTIVATE, ACTIVATE-T, and their long-term extension (LTE) study (NCT03853798). Methods: In the double-blind, placebo (PBO)-controlled ACTIVATE study (12-week [wk] dose-optimization period [5/20/50 mg twice daily [BID]]; 12-wk fixed-dose period [FDP]), 80 pts (≥18 years [yrs]) with PK deficiency who were not regularly transfused (≤4 transfusion episodes in prior yr; none in prior 3 months [mos]) were randomized 1:1 to mitapivat or PBO. Primary endpoint was Hb response (≥1.5 g/dL increase in Hb from baseline [BL] sustained at ≥2 assessments at Wks 16, 20, and 24 in the FDP). In the single-arm, open-label ACTIVATE-T study (16-wk dose-optimization period [5/20/50 mg BID]; 24-wk FDP), 27 pts (≥18 yrs) with PK deficiency who were regularly transfused (≥6 transfusion episodes in prior yr) were treated with mitapivat. Primary endpoint was transfusion response (≥33% reduction in number of RBC units transfused during the FDP, compared with pt’s individual historical transfusion burden standardized to 24 wks). Secondary endpoint was achieving transfusion-free status (no transfusions in FDP). Pts who completed the FDP of ACTIVATE/ ACTIVATE-T were eligible to continue in the LTE, where all received mitapivat. The ACTIVATE/LTE analysis assessed duration of Hb response in 2 cohorts: 1) pts assigned to mitapivat who achieved a Hb response and continued to the LTE (mitapivat-to-mitapivat arm [M/M]); 2) pts assigned to PBO who switched to mitapivat in the LTE (PBO-to-mitapivat arm [P/M]) and then met Hb response criteria. The ACTIVATE-T/LTE analysis assessed transfusion response in the LTE, and transfusion-free duration among pts from ACTIVATE-T who achieved transfusion-free status. Results: In ACTIVATE, 40% of pts treated with mitapivat (N=40) achieved a Hb response; in the LTE, pts randomized to PBO in ACTIVATE showed similar improvements in Hb levels after switching to mitapivat. These improvements were sustained with continued treatment (Figure 1a). All 16 pts assigned to mitapivat in ACTIVATE who achieved Hb responses continued to the LTE; 15 M/M pts were evaluable for Hb assessment in the LTE. 13/15 M/M pts (86.7%) maintained ≥1.5 g/dL Hb increase from BL up to 19.5 mos at all time points; 2 pts maintained ≥1 g/dL Hb increase from BL at all time points. None of the pts assigned to PBO in ACTIVATE (N=40) had a Hb response; 17 P/M pts had sufficient time (24 wks of treatment) in the LTE for Hb response assessment. 6/17 pts (35%) achieved Hb responses in the LTE, and all maintained Hb responses during follow-up. In ACTIVATE-T (N=27), 37% of pts achieved a transfusion response and 22% of pts achieved transfusion-free status. In the LTE, 9 pts (33.3%) met criteria for a transfusion response. All 6 pts who achieved transfusion-free status in ACTIVATE-T maintained the status in the LTE up to 21.9 mos (Figure 1b). One additional pt, who met the primary endpoint, but was not transfusion free in ACTIVATE-T, did not receive any transfusions in the LTE. Image:Summary/Conclusion: Mitapivat improved Hb and reduced transfusion burden in pts with PK deficiency over time, demonstrating the consistency and long-term durability of treatment with mitapivat.