Novel Gardos-channel blocker preserves sickle RBC hydration

An increase in the survival of sickle red blood cells may be possible with senicapoc (ICA-17043), a new Gardos-channel inhibitor.

In a 12-week, phase-2, randomized, double-blind, dose-finding study, researchers at the University of North Carolina at Chapel Hill and other institutions studied senicapoc to determine its effect on hemoglobin level and markers of hemolysis in patients with sickle cell anemia.

Researchers randomly assigned 90 patients to placebo, low-dose (6 mg/day) senicapoc or high-dose (10 mg/day) senicapoc. Change in hemoglobin in those assigned to high-dose senicapoc exceeded placebo (0.68 g/dL vs. 0.01 g/dL, P<.001), according to researchers.

High-dose senicapoc also reduced the percentage of dense red blood cells (–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). – by Stacey L. Adams

Blood. 2008;doi:10.1182/blood-2007-08-110098.

The most striking finding here is that the hemoglobin rose on a high-dose Gardos-channel inhibitor, suggesting less hemolysis in these patients. The primary endpoint in this study was an increase in hemoglobin, which rose by 0.68 g/dL in the high-dose subgroup; this was statistically significant. The presumption is that because you have fewer very dense sickle red cells, you are having less hemolysis. This study reported other indirect, statistically significant reflections of diminished hemolyisis, including a marked diminution in lactate dehydrogenase and in reticulocytosis in these patients.

I don’t think this was the homerun that they had wanted—and the phase 3 study with this agent, looking at pain crises, was reportedly stopped early because it didn’t show a benefit. However, pain crises and hemolysis may be two different ends of the pathophysiological spectrum. That is, there may be some disorders of the vascular bed in sickle cell disease that relate directly to the hemolysis piece and not to the vaso-occlusive piece. Decreasing hemolysis may not affect pain crises, but it may affect some of these other long-term (and often severe) side effects of sickle cell disease. It may be that, in the future, these Gardos-channel inhibitors will be used successfully to diminish the hemolytic consequences of sickle cell disease.

– Jane Little, MD

Assistant Professor in the Department of Medicine at Albert Einstein College of Medicine at Yeshiva University in Bronx, N.Y.