title: Efficacy and safety of the Gardos channel blocker, senicapoc (ICA-17043), in patients with sickle cell anemia.
abstract: Senicapoc, a novel Gardos channel inhibitor, limits solute and water loss, thereby preserving sickle red blood cell (RBC) hydration. Because hemoglobin S polymerization is profoundly influenced by intracellular hemoglobin concentration, senicapoc could improve sickle RBC survival. In a 12-week, multicenter, phase 2, randomized, double-blind, dose-finding study, we evaluated senicapoc's safety and its effect on hemoglobin level and markers of RBC hemolysis in sickle cell anemia patients. The patients were randomized into 3 treatment arms: placebo; low-dose (6 mg/day) senicapoc; and high-dose (10 mg/day) senicapoc. For the primary efficacy end point (change in hemoglobin level from baseline), the mean response to high-dose senicapoc treatment exceeded placebo (6.8 g/L [0.68 g/dL] vs 0.1 g/L [0.01 g/dL], P < .001). Treatment with high-dose senicapoc also produced significant decreases in such secondary end points as percentage of dense RBCs (-2.41 vs -0.08, P < .001); reticulocytes (-4.12 vs -0.46, P < .001); lactate dehydrogenase (-121 U/L vs -15 U/L, P = .002); and indirect bilirubin (-1.18 mg/dL vs 0.12 mg/dL, P < .001). Finally, senicapoc was safe and well tolerated. The increased hemoglobin concentration and concomitant decrease in the total number of reticulocytes and various markers of RBC destruction following senicapoc administration suggests a possible increase in the survival of sickle RBCs. This study is registered at http://clinicaltrials.gov as NCT00040677.
authors.affiliation: Division of Hematology/Oncology, University of North Carolina at Chapel Hill, CB no. 7305, 3009 Old Clinic Bldg, Chapel Hill, NC 27599-7305, USA. kataga@med.unc.edu
authors.forename: Kenneth I
authors.initials: KI
authors.lastname: Ataga
authors.forename: Wally R
authors.initials: WR
authors.lastname: Smith
authors.forename: Laura M
authors.initials: LM
authors.lastname: De Castro
authors.forename: Paul
authors.initials: P
authors.lastname: Swerdlow
authors.forename: Yogen
authors.initials: Y
authors.lastname: Saunthararajah
authors.forename: Oswaldo
authors.initials: O
authors.lastname: Castro
authors.forename: Elliot
authors.initials: E
authors.lastname: Vichinsky
authors.forename: Abdullah
authors.initials: A
authors.lastname: Kutlar
authors.forename: Eugene P
authors.initials: EP
authors.lastname: Orringer
authors.forename: Greg C
authors.initials: GC
authors.lastname: Rigdon
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Stocker
mesh_terms: D000081:Acetamides / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use*; D000293:Adolescent; D000328:Adult; D000755:Anemia, Sickle Cell / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D026902:Potassium Channel Blockers / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D014320:Triphenylmethyl Compounds / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use*
chemical_list: D000081:Acetamides; D026902:Potassium Channel Blockers; D014320:Triphenylmethyl Compounds; C472774:senicapoc