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Blood, 15 April 2008, Vol. 111, No. 8, pp. 3991-3997.
Prepublished online as a Blood First Edition Paper on January 11, 2008; DOI 10.1182/blood-2007-08-110098.
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Submitted August 30, 2007
Accepted December 14, 2007
Efficacy and safety of the Gardos channel blocker, Senicapoc (ICA-17043), in patients with sickle cell anemia
Kenneth I Ataga*, Wally R Smith, Laura M De Castro, Paul Swerdlow, Yogen Saunthararajah, Oswaldo Castro, Elliot Vichinsky, Abdullah Kutlar, Eugene P Orringer, Greg C Rigdon, and Jonathan W Stocker
Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC, United States
Division of Hematology/Oncology, Virginia Commonwealth University Medical Center, Richmond, VA, United States
Division of Hematology/Oncology, Duke University Medical Center, Durham, NC, United States
Division of Hematology/Oncology, Wayne State University, Detroit, MI, United States
Division of Hematology/Oncology, University of Illinois, Chicago, IL, United States
Division of Hematology/Oncology, Howard University, Washington, D.C., United States
Division of Hematology/Oncology, Children's Hospital of Oakland, Oakland, CA, United States
Division of Hematology/Oncology, Medical College of Georgia, Augusta, GA, United States
New Product Development, Icagen, Inc., Research Triangle Park, NC, United States
* Corresponding author; email: kataga{at}med.unc.edu.
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 II, 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); and high-dose (10 mg/day) senicapoc. For the primary efficacy endpoint (change in hemoglobin from baseline), the mean response to high-dose senicapoc treatment exceeded placebo (0.68 g/dL vs. 0.01 g/dL, P<0.001). Treatment with high-dose senicapoc also produced significant decreases in such secondary endpoints as: percentage of dense RBCs (-2.41 vs. -0.08, P<0.001); reticulocytes (-4.12 vs. -0.46, P<0.001); lactate dehydrogenase (-121 U/L vs. -15 U/L, P=0.002); and indirect bilirubin (-1.18 mg/dL vs. 0.12 mg/dL, P<0.001). 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.
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