Preliminary clinical trial of senicapoc for hereditary xerocytosis due to heterozygous KCa3.1 missense variant V282M

1. A clinical trial of senicapoc to treat KCa3.1 V282M-associated Hereditary Xerocytosis did not consistently meet primary clinical endpoints. 2. Patch-clamp reevaluation of recombinant KCa3.1 V282M revealed reduced inhibitory potency of senicapoc, in contrast to previous report. Hereditary xerocytosis (HX, also known as Dehydrated Stomatocytosis) is an autosomal dominant hemolytic anemia characterized by dehydrated erythrocytes with increased cation leak and decreased osmotic fragility. HX is caused by heterozygous mutations in the PIEZO1 or KCNN4 genes. Most HX mutations are missense mutations with mutation-specific gain-of-function properties in heterologous expression assays and in affected erythrocytes. The nM potency KCa3.1 inhibitor, senicapoc, has been tested in humans with sickle cell disease and several lung diseases. Oral administration of senicapoc has achieved KCa3.1 target engagement across multiple animal species, in multiple mouse models of human disease, and in humans without significant drug toxicity. We hypothesized that patients with HX attributed to KCa3.1 gain-of-function would benefit from senicapoc treatment. We therefore undertook an exploratory clinical trial of senicapoc in four HX patients of a previously studied single family, each heterozygous for KCa3.1 variant V282M. Senicapoc treatment lowered serum bilirubin in all four subjects, but lowered reticulocyte count in only one subject. None of the four subjects met the endpoints for increased blood hemoglobin content, decreased serum LDH, decreased MCHC or improved serum haptoglobin, despite LC/MS-confirmed compliance. Indeed, revisiting electrophysiological analysis demonstrated greatly reduced senicapoc sensitivity of the KCa3.1 HX variant V282M. We conclude that senicapoc treatment did not improve anemia in four members of a single family with HX attributed to the heterozygous KCa3.1 variant V282M, consistent with reduced sensitivity of this channel pore mutant to inhibition by senicapoc. (ClinicalTrials.gov ID# NCT04372498).