Figure 3.
Improvements of efficacy parameters in the dose-finding period and the fixed-dose extension period of treatment with mitapivat treatment in patients with SCD (intention-to-treat analysis). (A) Hb level increases were sustained over time in patients with SCD compared with baseline (n = 9 BL-W24; n = 8 W32; n = 7 at W40 and W52). (B-D) The increase in Hb level is accompanied by decreases of laboratory markers of hemolysis: (B) ARC, (C) Total bilirubin, and (D) LDH toward the upper limit of normal. (E) Five of 9 patients (56%) with SCD showed a mean increase in Hb level ≥1 g/dL in the fixed-dose extension period from baseline (solid, light blue, horizontal reference line). (F-G) Oxygen gradient ektacytometry showed in 4 of 8 patients (50%) with SCD a mean decrease in PoS of ≥10% in the fixed-dose extension period from baseline (solid, light blue, horizontal reference line), which indicates that initiation of RBC sickling occurs at lower PO2 levels. Notably, fixed-dose extension period data are missing for 1 patient, a week 52 visit (n = 1 patient), and 4 visits from week 24 to week 52 (n = 2 patients). (H) Treatment with mitapivat increased Hb-oxygen affinity in patients with SCD, reflected by a decreases in P50 from baseline (red) to the end of the dose-finding period (darkest blue), week 24 of the fixed-dose extension period (middle blue), and week 52 of the fixed-dose extension period (lightest blue) toward P50 values of untreated healthy controls (Ctr; gray; n = 45). (I) The ATP:2,3-DPG ratio increased upon treatment with mitapivat, also compared with untreated healthy controls (Ctr; gray; n = 40). Means are presented. Error bars represent standard errors of the mean. Dashed, gray, horizontal reference lines represent LLN, ULN or 0% change from baseline as indicated. Dashed, gray, vertical reference lines separate untreated healthy controls (on the left) with different timepoints of the treated patients (on the right). ARC, absolute reticulocyte count; BL, baseline; D56/W0, day 56 of the dose-finding period corresponding with W0 of the fixed-dose extension period; F, female; LLN, lower limit of normal; ULN, upper limit of normal; W, study visit week of the fixed-dose extension period.

Improvements of efficacy parameters in the dose-finding period and the fixed-dose extension period of treatment with mitapivat treatment in patients with SCD (intention-to-treat analysis). (A) Hb level increases were sustained over time in patients with SCD compared with baseline (n = 9 BL-W24; n = 8 W32; n = 7 at W40 and W52). (B-D) The increase in Hb level is accompanied by decreases of laboratory markers of hemolysis: (B) ARC, (C) Total bilirubin, and (D) LDH toward the upper limit of normal. (E) Five of 9 patients (56%) with SCD showed a mean increase in Hb level ≥1 g/dL in the fixed-dose extension period from baseline (solid, light blue, horizontal reference line). (F-G) Oxygen gradient ektacytometry showed in 4 of 8 patients (50%) with SCD a mean decrease in PoS of ≥10% in the fixed-dose extension period from baseline (solid, light blue, horizontal reference line), which indicates that initiation of RBC sickling occurs at lower PO2 levels. Notably, fixed-dose extension period data are missing for 1 patient, a week 52 visit (n = 1 patient), and 4 visits from week 24 to week 52 (n = 2 patients). (H) Treatment with mitapivat increased Hb-oxygen affinity in patients with SCD, reflected by a decreases in P50 from baseline (red) to the end of the dose-finding period (darkest blue), week 24 of the fixed-dose extension period (middle blue), and week 52 of the fixed-dose extension period (lightest blue) toward P50 values of untreated healthy controls (Ctr; gray; n = 45). (I) The ATP:2,3-DPG ratio increased upon treatment with mitapivat, also compared with untreated healthy controls (Ctr; gray; n = 40). Means are presented. Error bars represent standard errors of the mean. Dashed, gray, horizontal reference lines represent LLN, ULN or 0% change from baseline as indicated. Dashed, gray, vertical reference lines separate untreated healthy controls (on the left) with different timepoints of the treated patients (on the right). ARC, absolute reticulocyte count; BL, baseline; D56/W0, day 56 of the dose-finding period corresponding with W0 of the fixed-dose extension period; F, female; LLN, lower limit of normal; ULN, upper limit of normal; W, study visit week of the fixed-dose extension period.

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