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: 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, Jonathan W Stocker, ICA-17043-05 Investigators
• Journal: Blood (Blood) Vol. 111 Issue 8 Pg. 3991-7 (Apr 15 2008) ISSN: 0006-4971 [Print] United States
• PMID: 18192510 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Acetamides
• Potassium Channel Blockers
• Trityl Compounds
• senicapoc

Topics

• Acetamides (adverse effects, blood, therapeutic use)
• Adolescent
• Adult
• Anemia, Sickle Cell (drug therapy)
• Female
• Humans
• Male
• Middle Aged
• Potassium Channel Blockers (adverse effects, blood, therapeutic use)
• Time Factors
• Treatment Outcome
• Trityl Compounds (adverse effects, blood, therapeutic use)