Efficacy and Safety of the Gardos Channel Inhibitor, ICA-17043, in Patients with Sickle Cell Anemia.

The rate and extent of hemoglobin S (HbS) polymer formation in the circulating sickle erythrocyte (RBC) is strongly influenced by the intracellular concentration of HbS. ICA-17043 (bis(4-fluorophenyl)phenyl acetamide) is a novel Gardos channel inhibitor that specifically blocks Ca ++ -dependent K + efflux from the human RBC. By limiting the loss of K + , Cl − , and water, this drug preserves the hydration status of the RBC, prevents increases in HbS concentration and thereby inhibits HbS-polymerization. We hypothesized that ICA-17043 could decrease both the hemolytic rate and vaso-occlusive complications of sickle cell anemia (SCA). In a recently completed multicenter, parallel-group, randomized, double-blind, dose-range-finding study, we examined the efficacy and safety of ICA-17043 in patients with SCA. In this 12-week study, 90 patients were randomized into 3 arms: placebo; low dose ICA-17043 (6 mg); and high dose ICA-17043 (10 mg). The primary outcome variable was the change in hemoglobin (Hb) from baseline to the end of the study. A total of 90 subjects were enrolled in this study, 80 of whom completed the 12-week treatment period. Using an intent-to-treat analysis, we found a significant increase from baseline of the total Hb when the subjects in the high dose arm (0.68 ± 0.11 g/dL, S.E.) were compared to those in the placebo arm (0.01 ± 0.12 g/dL), p In addition to the increase in Hb (as well as similar increases in hematocrit and RBC count), statistically significant decreases were noted after 12 weeks on 10 mg of ICA-17043 vs. placebo in the following variables: a) dense RBC (% with Hb >41 g/dL) [−2.41 vs. −0.08, p