Change in hemolysis markers from baseline in study subjects. Hemolysis markers, (A) LDH, (B) total bilirubin, (C) ARC, and (D) AST, were measured at steady state (baseline); after 14 ± 3 days of treatment on 5 mg BID, 20 mg BID, 50 mg BID, and 100 mg BID of mitapivat; at the end of taper (1 ± 3 days after the last dose of mitapivat); and at EOS (4 weeks ± 3 days after the last dose of mitapivat). A total of 16 subjects escalated to the 50-mg BID dose, and 9 of 10 subjects completed up to the 100-mg BID dose level. End of taper data were unavailable for 1 subject who self-discontinued treatment without undergoing a taper; EOS data were excluded for 1 subject because of intervening blood transfusion. Mean change was calculated from baseline, defined as the most recent measurement prior to start of study drug and reported as absolute change. Error bars correspond to SDs. A linear mixed effects model using age and sex as covariates was created for each variable (referred to as the basic model; supplemental Materials). No significant changes from baseline were identified for LDH (A) and AST (D). ∗There was a significant absolute reduction in (B) total bilirubin level compared with baseline at the 20-, 50-, and 100-mg BID dose levels of mitapivat (P = .001, <.0001, and <.0001, respectively). (C) Reduction in ARC compared with baseline was significant at the 50- and 100-mg BID dose levels of mitapivat (P = .002 and .05, respectively), as denoted by ∗.