Senicapoc and Dehydrated Stomatocytosis

Overview

Dehydrated stomatocytosis is a genetic disorder characterized by chronic hemolysis, variable anemia and erythrocyte dehydration. Causative mutations have been identified in either the Gardos (KCNN4) channel or the mechanosensitive channel PIEZO1. Senicapoc is a selective blocker of the Gardos channel that has been extensively studied in sickle cell disease and shown to be safe with limited side-effects. However, senicapoc did not meet the designated clinical endpoints in a pivotal phase 3 trial. The present study is an explanatory, proof-of-concept study of Senicapoc administered once daily in patients with familial dehydrated stomatocytosis caused by autosomal dominant V282 mutations in the Gardos (KCNN4) channel.

The proposed study is an explanatory, proof-of-concept study of Senicapoc administered once daily in patients with familial dehydrated stomatocytosis caused by the autosomal dominant V282 mutation in the Gardos (KCNN4) channel. The study population will include up to 6 members of the same family, all carrying the V282M mutation, and other V282 mutations with demonstrated in-vitro sensitivity to senicapoc, meeting study criteria for inclusion and exclusion. Patients will begin the study with a loading dose of 20 mg/day for 4 days followed by a dose of 10 mg once daily for the first 4 weeks of study. After 4 weeks at the initial dose, patients will be escalated to higher doses (in 3 steps of 10 mg every 4 weeks) to a maximal dose of 40 mg once daily. Patients who demonstrate response in the primary endpoints at the end of the efficacy study, and who have not been permanently discontinued due to Senicapoc-attributed serious adverse events (SAE), will be eligible for a 12-month study extension at the dose determined to be effective in the treatment efficacy study. Patients who meet inclusion criteria will be enrolled at visit 0, and if available, will be provided with the appropriated instrument to record daily pain scores and other QOL indicators. Treatment will begin at Visit 1, which will follow visit 0 after 2-3 weeks. After an effective dose and tolerated has been established in the dose escalation period, patients will be seen every two weeks until they reach 24 weeks of treatment. Patients will be seen for a potential maximum of 19 visits in the treatment efficacy phase of the study, with additional phone contacts after the first week of treatment and within a week from each dose escalation. At the end of the efficacy portion of the study, patients will be eligible to participate in a one-year optional open-label extension, provided that they have not been permanently discontinued from the study.