A 48-Week Open-Label Study of Senicapoc (ICA-17043), a Gardos Channel Blocker, in Patients with Sickle Cell Disease.

The Gardos channel, a calcium-activated potassium channel that spans the membrane of red blood cells (RBCs), is a key pathway in RBC dehydration affecting the intracellular concentration of hemoglobin S (Hb S). Inhibition of the Gardos channel in patients with sickle cell disease (SCD) may prevent the formation of dehydrated sickle RBCs, decrease Hb S polymerization, and reduce symptoms. In a Phase II 12-week, randomized, double-blind, placebo-controlled, dose-finding study in 90 patients with SCD, senicapoc (ICA-17043), a novel Gardos channel blocker, demonstrated statistically significant and beneficial hematologic effects including increased hemoglobin levels and decreased indicators of hemolysis. Patients from this study were eligible to enroll in a 48-week, open-label extension study in which all patients received an oral daily dose (10 mg) of senicapoc. Safety assessments included clinical laboratory data, physical exams, vital signs, ECGs, and ophthalmologic exams. Of 56 eligible patients, 44 enrolled in the open-label study. Because all patients received active drug, no formal efficacy comparisons to placebo were available. Within-subject comparison versus baseline levels from the double-blind phase indicated that the beneficial effects of senicapoc were maintained during the open-label study. Patients demonstrated increases in hemoglobin (+6%), hematocrit (+6%), and RBC count (+6%), and decreases in dense cells (−24%), reticulocytes (−19%), indirect bilirubin (−30%), and lactate dehydrogenase (−18%). Senicapoc was generally well tolerated during the open-label extension study. No deaths occurred, and there were no serious adverse events attributable to senicapoc. Twelve of 44 patients discontinued from the 48-week treatment period. Two patients discontinued due to adverse events considered possibly or probably related to study medication (elevation in gamma glutamyl transferase [GGT] level and interstitial nephritis, respectively). Two additional patients discontinued due to adverse events (sickle cell crisis and pain) not considered related to study medication. Of the 8 remaining patients, 1 was lost to follow-up, and 7 discontinued for administrative reasons. The most common adverse events (≥10% of patients) during treatment included sickle cell pain crisis, arthralgia, back pain, headache, upper respiratory tract infection, limb pain, increased GGT, pyrexia, and rash. The only adverse events that occurred in 2 or more patients and considered possibly related to study medication were GGT elevation, rash, and headache. In conclusion, senicapoc 10 mg once daily for 48 weeks appears to be safe and well tolerated in patients with SCD. Hematologic and clinical laboratory data collected in this safety extension study are consistent with the beneficial hematological effects observed during the Phase II double-blind study.