PD in patients with SCD. Mean RBC 2,3-DPG and ATP concentrations in the MAD (A,C), and OL (B,D) cohorts. Values were normalized by dividing the Hb value at each time point to adjust for a dilution effect from increased Hb (A-D). The P50 value as a function of intracellular 2,3-DPG concentration in the MAD (excluding placebo patients) and OL cohorts 24 hours after the last dose (E). Scatterplot at baseline (BL) and EOT for P50 in the OL cohort (Median BL and EOT values shown in green and blue diamonds, respectively) (F); each data point corresponds to data from 1 patient. Paired BL and EOT data points from each patient are connected by a line. In the MAD cohorts (A,C), P values were based on Wilcoxon signed rank tests to test the changes at EOT from BL. In the OL cohort (B,D), PD values with statistical significance compared with BL were identified with an asterisk (∗P < .05) at their scheduled visits, based on MMRM, which included PD values as dependent variable, and a fixed effect of scheduled visit during the treatment period with compound symmetry covariance matrix to model the within patient variance-covariance errors; the EOT P values were derived from Wilcoxon signed rank tests. Statistical tests were not performed for the visits after EOT. P values in the scatterplot are from a Wilcoxon matched-pairs signed rank test (F). One MAD1 (300 mg) patient was excluded from 2,3-DPG, ATP, and P50 analyses because the patient only took 1 dose of study drug on day 1. ATP, adenosine triphosphate; CFB, change from baseline; 2,3-DPG, 2,3-diphosphoglycerate; EOT, end of treatment; Hb, hemoglobin; MAD, multiple ascending dose; MMRM, mixed model for repeated measurement; OL, open-label; P50, oxygen tension at which Hb is 50% saturated; PD, pharmacodynamic; SCD, sickle cell disease; SD, standard deviation; RBC, red blood cell.
