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

Division of Hematology/Oncology, University of North Carolina at Chapel Hill, CB no. 7305, 3009 Old Clinic Bldg, Chapel Hill, NC 27599-7305, USA.
Blood (Impact Factor: 10.45). 04/2008; 111(8):3991-7. DOI: 10.1182/blood-2007-08-110098
Source: PubMed


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 as NCT00040677.

  • Source
    • "Decades ago, a critical evaluation of the therapeutic potential of clotrimazole was prevented by side effects. Today, more potent and specific small-molecule inhibitors exist for both channels and at least for KCa3.1 clinical trials in sickle cell disease show that orally applicable K þ channel inhibitors may be safe in humans (Ataga et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Rheumatoid arthritis synovial fibroblasts (RA-SFs) show an aggressive phenotype and support joint inflammation and tissue destruction. New druggable targets in RA-SFs would therefore be of high therapeutic interest. The present study shows that the intermediate-conductance, calcium-activated potassium channel KCa3.1 (KCNN4) is expressed at the mRNA and protein level in RA-SFs, is functionally active, and has a regulatory impact on cell proliferation and secretion of pro-inflammatory and pro-destructive mediators. Whole-cell patch-clamp recordings identified KCa3.1 as the dominant potassium channel in the physiologically relevant membrane voltage range below 0 mV. Stimulation with transforming growth factor β1 (TGF-β1) significantly increased transcription, translation, and channel function of KCa3.1. Inhibition of KCa3.1 by the selective, pore-blocking inhibitor TRAM-34, (and, in part by siRNA) significantly reduced cell proliferation, as well as expression and secretion of pro-inflammatory factors (IL-6, IL-8, and MCP1) and the tissue-destructive protease MMP3. These effects were observed in non-stimulated and/or TGF-β1-stimulated RA-SFs. Since small molecule-based interference with KCa3.1 is principally well tolerated in clinical settings, further evaluation of channel blockers in models of rheumatoid arthritis may be a promising approach to identify new pharmacological targets and develop new therapeutic strategies for this debilitating disease. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Full-text · Article · Dec 2014 · Journal of Cellular Physiology
  • Source
    • "Importantly, KCa3.1 knockout mice are viable, of normal appearance, produce normal litter sizes, and exhibit rather mild phenotypes [13]. High doses of TRAM-34 administered to rodents over many weeks are well tolerated [13] and the orally available KCa3.1 blocker, ICA-17043, has been administered to humans in phase 2 and 3 trials of sickle cell disease with minor side effects [40]. There is therefore the potential for the rapid investigation of KCa3.1 blockade in clinical trials of IPF and other fibrotic lung diseases. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a common, progressive and invariably lethal interstitial lung disease with no effective therapy. We hypothesised that KCa3.1 K(+) channel-dependent cell processes contribute to IPF pathophysiology. KCa3.1 expression in primary human lung myofibroblasts was examined using RT-PCR, western blot, immunofluorescence and patch-clamp electrophysiology. The role of KCa3.1 channels in myofibroblast proliferation, wound healing, collagen secretion and contraction was examined using two specific and distinct KCa3.1 blockers (TRAM-34 and ICA-17043 [Senicapoc]). Both healthy non fibrotic control and IPF-derived human lung myofibroblasts expressed KCa3.1 channel mRNA and protein. KCa3.1 ion currents were elicited more frequently and were larger in IPF-derived myofibroblasts compared to controls. KCa3.1 currents were increased in myofibroblasts by TGFβ1 and basic FGF. KCa3.1 was expressed strongly in IPF tissue. KCa3.1 pharmacological blockade attenuated human myofibroblast proliferation, wound healing, collagen secretion and contractility in vitro, and this was associated with inhibition of TGFβ1-dependent increases in intracellular free Ca(2+). KCa3.1 activity promotes pro-fibrotic human lung myofibroblast function. Blocking KCa3.1 may offer a novel approach to treating IPF with the potential for rapid translation to the clinic.
    Full-text · Article · Dec 2013 · PLoS ONE
  • Source
    • "PF-05416266 or ICA-17043) was recently deposited in the NCATS (National Center for Advancing Translational Sciences) library and would be available for investigator initiated clinical trials. Similar to our academic tool compound TRAM-34, which exhibits an excellent selectivity over other ion channels and did not induce any toxicity in a 28-day toxicity study in mice and in a 6-months toxicity study in rats [28], Senicapoc was safe and well tolerate in a Phase-1 clinical trial in healthy volunteers [47], and was afterwards found to not induce any adverse events in over 500 sickle cell anemia patients taking Senicapoc for up to two years in Phase-2 and Phase-3 clinical trials [48]. Triarylmethane-type KCa3.1 blockers accordingly seem to be relatively safe, although the potential of toxicity arising through drug-drug interactions during combination therapy cannot be excluded, and Senicapoc could be added to existing transplantation treatment regiments in patients at risk for developing or already exhibiting AV. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Allograft vasculopathy (AV) remains one of the major challenges to the long-term functioning of solid organ transplants. Although its exact pathogenesis remains unclear, AV is characterized by both fibromuscular proliferation and infiltration of CD4(+) memory T cells. We here tested whether two experimental immunosuppressants targeting K(+) channels might be useful for preventing AV. PAP-1 inhibits the voltage-gated Kv1.3 channel, which is overexpressed on CCR7(-) memory T cells and we therefore hypothesize that it should suppress the memory T cell component of AV. Based on its previous efficacy in restenosis and kidney fibrosis we expected that the KCa3.1 blocker TRAM-34 would primarily affect smooth muscle and fibroblast proliferation and thus reduce intimal hyperplasia. Using immunohistochemistry we demonstrated the presence of Kv1.3 on infiltrating T cells and of KCa3.1 on lymphocytes as well as on proliferating neointimal smooth muscle cells in human vasculopathy samples and in a rat aorta transplant model developing chronic AV. Treatment of PVG rats receiving orthotopically transplanted aortas from ACI rats with TRAM-34 dose-dependently reduced aortic luminal occlusion, intimal hyperplasia, mononuclear cell infiltration and collagen deposition 120 days after transplantation. The Kv1.3 blocker PAP-1 in contrast did not reduce intima hyperplasia despite drastically reducing plasma IFN-γ levels and inhibiting lymphocyte infiltration. Our findings suggest that KCa3.1 channels play an important role in the pathogenesis of chronic AV and constitute an attractive target for the prevention of arteriopathy.
    Full-text · Article · Nov 2013 · PLoS ONE
Show more