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, Jonathan W Stocker, ICA-17043-05 Investigators, Patricia Adams-Graves, Anita Larkin, Brian Adler, Adrena Johnson-Telfair, Kenneth I Ataga, Eugene P Orringer, Susan Jordison-Jones, Samir Ballas, Gwen Bellamy, Carolyn Bigelow, Arleen Anderson, Timothy Carlos, Amy Roundtree-Schmotzer, Oswaldo Castro, Sally Taylor-Thomas, Susan Claster, Anna Smith, Laura M De Castro, Jude Jonassaint, Abdullah Kutlar, Leigh Wells, Sophie Lanzkron, Adrian Dobs, Gloria Ramirez, Julie Rivera, Yogen Saunthararajah, Louise Dorn, Wally R Smith, Larry White, William Solomon, Susanne Fryd, Paul Swerdlow, Pam Pemberton, Mark Udden, Eunice Ambriz, Elliot Vichinsky, Sandie Edwards, Christy Woods, Cynthia Weaver, 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, Patricia Adams-Graves, Anita Larkin, Brian Adler, Adrena Johnson-Telfair, Kenneth I Ataga, Eugene P Orringer, Susan Jordison-Jones, Samir Ballas, Gwen Bellamy, Carolyn Bigelow, Arleen Anderson, Timothy Carlos, Amy Roundtree-Schmotzer, Oswaldo Castro, Sally Taylor-Thomas, Susan Claster, Anna Smith, Laura M De Castro, Jude Jonassaint, Abdullah Kutlar, Leigh Wells, Sophie Lanzkron, Adrian Dobs, Gloria Ramirez, Julie Rivera, Yogen Saunthararajah, Louise Dorn, Wally R Smith, Larry White, William Solomon, Susanne Fryd, Paul Swerdlow, Pam Pemberton, Mark Udden, Eunice Ambriz, Elliot Vichinsky, Sandie Edwards, Christy Woods, Cynthia Weaver
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 https://ichgcp.net/clinical-trials-registry/NCT00040677" title="See in ClinicalTrials.gov">NCT00040677.
Source: PubMed