Efficacy and safety of the Gardos channel blocker, senicapoc (ICA-17043), in patients with sickle cell anemia

Kenneth 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. Stacker

Research output: Contribution to journalArticle

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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 gl 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 (-1.18mg/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 NCT00040677I.

Original languageEnglish (US)
Pages (from-to)3991-3997
Number of pages7
JournalBlood
Volume111
Issue number8
DOIs
StatePublished - Apr 15 2008

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Sickle Cell Anemia
Safety
Hemoglobins
Blood
Erythrocytes
Placebos
Cells
Reticulocyte Count
Sickle Hemoglobin
senicapoc
Reticulocytes
Hemolysis
L-Lactate Dehydrogenase
Bilirubin
Polymerization
Hydration
Cell Survival
Therapeutics
Survival
Water

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Ataga, K., Smith, W. R., De Castro, L. M., Swerdlow, P., Saunthararajah, Y., Castro, O., ... Stacker, J. W. (2008). Efficacy and safety of the Gardos channel blocker, senicapoc (ICA-17043), in patients with sickle cell anemia. Blood, 111(8), 3991-3997. https://doi.org/10.1182/blood-2007-08-110098

Efficacy and safety of the Gardos channel blocker, senicapoc (ICA-17043), in patients with sickle cell anemia. / Ataga, Kenneth; Smith, Wally R.; De Castro, Laura M.; Swerdlow, Paul; Saunthararajah, Yogen; Castro, Oswaldo; Vichinsky, Elliot; Kutlar, Abdullah; Orringer, Eugene P.; Rigdon, Greg C.; Stacker, Jonathan W.

In: Blood, Vol. 111, No. 8, 15.04.2008, p. 3991-3997.

Research output: Contribution to journalArticle

Ataga, K, Smith, WR, De Castro, LM, Swerdlow, P, Saunthararajah, Y, Castro, O, Vichinsky, E, Kutlar, A, Orringer, EP, Rigdon, GC & Stacker, JW 2008, 'Efficacy and safety of the Gardos channel blocker, senicapoc (ICA-17043), in patients with sickle cell anemia', Blood, vol. 111, no. 8, pp. 3991-3997. https://doi.org/10.1182/blood-2007-08-110098
Ataga, Kenneth ; Smith, Wally R. ; De Castro, Laura M. ; Swerdlow, Paul ; Saunthararajah, Yogen ; Castro, Oswaldo ; Vichinsky, Elliot ; Kutlar, Abdullah ; Orringer, Eugene P. ; Rigdon, Greg C. ; Stacker, Jonathan W. / Efficacy and safety of the Gardos channel blocker, senicapoc (ICA-17043), in patients with sickle cell anemia. In: Blood. 2008 ; Vol. 111, No. 8. pp. 3991-3997.
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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 gl 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 (-1.18mg/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 NCT00040677I.",
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AU - Vichinsky, Elliot

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