| Reference | 1. Br J Haematol. 2011 Apr;153(1):92-104. doi: 10.1111/j.1365-2141.2010.08520.x. Epub 2011 Feb 17.<br />
Improvements in haemolysis and indicators of erythrocyte survival do not correlate with acute vaso-occlusive crises in patients with sickle cell disease: a phase III randomized, placebo-controlled, double-blind study of the Gardos channel blocker senicapoc (ICA-17043).<br />
Ataga KI(1), Reid M, Ballas SK, Yasin Z, Bigelow C, James LS, Smith WR, Galacteros F, Kutlar A, Hull JH, Stocker JW; ICA-17043-10 Study Investigators.<br />
Collaborators: Abdul-Rachid N, Bernstein J, Kline R, Bayreder A, Buitrago J, Adams-Graves P, Dugdale M, Ataga K, Orringer EP, Jones SK, Strayhorn DH, Asogbade M, Thein SL, Ballas S, McRay M, Lusardi M, Barbosa J, Grana N, Lukas C, Ayala I, Vrchoticky T, Kerr K, Aung L, Bellevue R, D'Augustine J, Nejamin L, Swinson GI, McMillion B, Bessman J, Whitehead RP, Suleman K, Willis M, Valencia-Stephens L, Crawford P, Hirsch SJ, Bigelow C, Herrin V, Hamilton RD, Blinder M, Field J, Carlos T, Redner R, Charles K, Seemungal TA, Leelah N, Ajayi TA, CHingos J, Pham DC, Walker RA, Rana FN, Mignone J, Villegas AE, Cohen A, Sha M, Rogers-Phillips E, Sabnani I, Cruz J, Leedy D, O'Brien F, MacLean J, Daeschner C, Grossi M, Dampier C, Luck L, Mba N, Meier M, Rockstein M, Cahill M, Moore A, DeCastro L, Jonassaint JC, Zimmerman S, Greenberg C, Friedman D, Laubach J, Whitlatch N, Pawloski JR, Anders C, Lanasa M, Palmer J, Zafar Y, Haith K, Figueiredo MS, Neto FM, Cavalheiro Rde C, Vicari P, Flug F, Appel B, Diamond S, Gregory J, Halpern S, Harlow P, Harris MB, Steele CS, Terrin B, Galacteros F, Anoosha H, Marie-Odette B, Dora B, Godder K, Gullquist S, Dunn NL, Massey GV, Laver J, Khan A, Hall E, Mauck A, Shockey D, Casper R, Temple B, Russell EC, Brunner T, Greist A, Shapiro A, Riley R, Hummel K, Muhammad A, Miller-Rice L, Parameswaran R, Guillaume E, Jaffe E, Wilson C, Hagar W, Stewart K, Hoehner C, Edwards S, Styles LA, Hagston N, Parikh N, Altman A, Gillan E, Steven K, Peluso E, Harrison J, Saidi P, Philipp C, Rose S, Michaels L, Drachtman R, Hassel K, Nuss R, Haynes J, Pack-Mabien A, Hussein A, Bronte L, Cohen J, Restrepo M, Bankston S, Glasser R, Lewis MS, Cano R, Franco S, Grosman D, Abraham A, Domenech G, Perez AT, Jackson S, Cavalier ME, Disco D, Peterson J, Rackoff E, Bergman S, Johnson S, Debenham E, Jeroudi K, Springer MA, Todd L, Bass PF 3rd, Joiner C, Balsa V, Kalinyak K, Gruppo R, Malik P, Palumbo J, Kalfa T, Lagory D, Nordheim T, Johnson V, Terry A, Wilson D, Hodgson M, Boyd P, Hackworth L, Kelly P, Smith F, Norman A, Godfrey D, Chan E, Juneja H, Ellent D, Brown D, Wu KK, Ghelani D, Kassim A, Winslow L, Nilson D, Klintworth S, Knupp C, Liles D, Krishnamurti L, Gunawardena SW, Windsor BA, Sakara AA, Lindsey CL, Kutlar A, Wells L, Daitch L, McKie K, McKie V, Natarajan K, Lanzkron S, David M, Roane Y, Lobo CL, Moura PG, Cerqueira Eda C, Queiroz AM, Queiroz AP, Loew T, DiPaola J, Goldman F, O'Dorisio MS, Radhi M, Tannous R, Vibhakar R, Hohl R, Holida M, McMillan S, McCaffrey R, Churchil WH, Okam MM, Mandell E, Souza M, Connors JM, Miller S, Rey K, Rao SP, Moore R, Langevin AM, Carpenter S, Britton H, Shah S, Mueller B, Mahoney DH, McClain K, Airewele G, Bryant R, Onyekwere O, DeGannes C, Castro O, Pefkarou A, Escalon EA, Warman R, Khatib ZA, Fort JA, Reid M, Cunningham-Myrie CA, Cumming V, Parshad-Asnani M, Knight-Madden J, Madden W, Lewis N, Saccente S, Becton D, Stein KC, Saylors RL, Samaik S, Whitten-Shurney WJ, Chitlur M, Strother K, Henderson OG, Saunthararajah Y, Labotka R, Molokie R, Saraf S, Sidhwani S, Gowhari M, Scher C, Kahn MJ, Hemenway CS, Rozans MK, Schorin MA, Schilelr G, Territo MC, Paquette R, Mariano da Rocha Silla L, Fogliatto LM, Friedrisch JR, Lehugteur DS, Smith W, Aiusiku I, White L, Smith-Whitley K, Kwiatkowski J, Ohene-Frempong K, Solomon W, Gillette P, Egan S, Kamenova B, St James L 3rd, Tanner-St James C, Blair-Britt L, Nesbitt CC, Iskander RS, Mather N, Styles L, Stewart K, Truskier MG, Edwards S, Hagar RW, Subramanian-Srinivsan U, Swerdlow P, Ortega J, Littsey L, Jett AR, Tebbi C, Wynn T, Obzut D, Rossbach HC, Telfer P, Kaya B, Uddon M, Vats T, Gonzales CE, Frankel LS, Villella A, Blumer JL, Berman BW, Gibbons J, Lemon E, Viswanathan K, Boruchov D, Khalil M, Kalavar MR, Naik S, Dumlao TL, Arora A, Warrier R, Gardner R, Yu L, Velez M, Singleton T, Wolff S, Posey L, Woods G, Neville K, Sarcone S, Stegenga K, Routhieaux J, Roath G, Wright L, Bhatia S, Wun T, Yasin Z, Pruemer J, Palascak J, Gupta A, Pancoast J, Naheleh Z, Jazieh AR, Zakarija A, Green D, Herman C, Soff G.<br />
Author information:<br />
(1)University of North Carolina, Chapel Hill, NC, USA.<br />
Red blood cell (RBC) hydration is regulated in part by the Ca(2+) -activated K(+) efflux (Gardos) channel. Senicapoc selectively blocks potassium efflux through the Gardos channel, reducing RBC dehydration and haemolysis, and increasing haemoglobin levels in sickle cell disease (SCD). This randomized, placebo-controlled trial was designed to determine the safety and clinical efficacy of senicapoc in SCD patients. One hundred and forty-five patients were randomized to receive senicapoc and 144 patients to receive placebo for 52 weeks. Consistent with a previous study, patients in the senicapoc group had significantly increased haematocrit, haemoglobin, and decreased numbers of both dense erythrocytes and reticulocytes when compared to the placebo group. The unblinded Data Monitoring Committee terminated this study early due to a lack of efficacy when it determined that, despite improvements in anaemia and haemolysis, no significant improvement in the rate of sickle cell painful crises was observed in patients treated with senicapoc compared to those on placebo (0·38 vs. 0·31, respectively). Comparisons of the times to first, second and third crises between the senicapoc and placebo groups were not statistically significant. Nausea and urinary tract infections occurred more frequently in the senicapoc group than placebo. Serious adverse events were similar in the two groups.<br />
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2. Expert Opin Investig Drugs. 2009 Feb;18(2):231-9. doi: 10.1517/13543780802708011 .<br />
Senicapoc (ICA-17043): a potential therapy for the prevention and treatment of hemolysis-associated complications in sickle cell anemia.<br />
Ataga KI(1), Stocker J.<br />
Author information:<br />
(1)Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Room 3149, Physicians Office Building, CB# 7305, Chapel Hill, NC 27599-7305, USA. [email protected]<br />
Sickle cell disease (SCD) is characterized by hemolytic as well as vaso-occlusive complications. The development of treatments for this inherited disease is based on an understanding of its pathophysiology. Polymerization of sickle hemoglobin is dependent on several independent factors, including the intracellular hemoglobin concentration. The hydration state (and intracellular hemoglobin concentration) of the sickle erythrocyte depends on the loss of solute and osmotically obliged water through specific pathways. Senicapoc (also known as ICA-17043) is a potent blocker of the Gardos channel, a calcium-activated potassium channel of intermediate conductance, in the red blood cell. Preclinical studies and studies in transgenic models of SCD show that inhibition of potassium efflux through the Gardos channel is associated with an increased hemoglobin level, decreased dense cells and decreased hemolysis. Senicapoc is well tolerated when administered to SCD patients and produces dose-dependent increases in hemoglobin and decreases in markers of hemolysis. Despite the lack of a reduction in the frequency of pain episodes, the increasing recognition that hemolysis contributes to the development of several SCD-related complications suggests that by decreasing hemolysis, senicapoc may yet prove to be beneficial in this disease.<br />
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3. Blood. 2008 Apr 15;111(8):3991-7. doi: 10.1182/blood-2007-08-110098. Epub 2008 Jan 11.<br />
Efficacy and safety of the Gardos channel blocker, senicapoc (ICA-17043), in patients with sickle cell anemia.<br />
Ataga KI(1), Smith WR, De Castro LM, Swerdlow P, Saunthararajah Y, Castro O, Vichinsky E, Kutlar A, Orringer EP, Rigdon GC, Stocker JW; ICA-17043-05 Investigators.<br />
Collaborators: Adams-Graves P, Larkin A, Adler B, Johnson-Telfair A, Ataga KI, Orringer EP, Jordison-Jones S, Ballas S, Bellamy G, Bigelow C, Anderson A, Carlos T, Roundtree-Schmotzer A, Castro O, Taylor-Thomas S, Claster S, Smith A, De Castro LM, Jonassaint J, Kutlar A, Wells L, Lanzkron S, Dobs A, Ramirez G, Rivera J, Saunthararajah Y, Dorn L, Smith WR, White L, Solomon W, Fryd S, Swerdlow P, Pemberton P, Udden M, Ambriz E, Vichinsky E, Edwards S, Woods C, Weaver C.<br />
Author information:<br />
(1)Division of Hematology/Oncology, University of North Carolina at Chapel Hill, CB no. 7305, 3009 Old Clinic Bldg, Chapel Hill, NC 27599-7305, USA. [email protected]<br />
Comment in<br />
Blood. 2008 Apr 15;111(8):3918-9.<br />
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.<br />
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