Jonathan W. Stocker

Improvements in haemolysis and indicators of erythrocyte survival do not correlate with acute vaso‐occlusive crises in patients with sickle cell disease: a phase III randomized, placebo‐controlled, double‐blind study of the gardos channel blocker senicapoc (ICA‐17043)

Red blood cell (RBC) hydration is regulated in part by the Ca2+‐activated K+ efflux (Gardos) channel. Senicapoc selectively blocks potassium efflux through the Gardos channel, reducing RBC dehydration and haemolysis, and increasing haemoglobin levels in sickle cell disease (SCD). This randomized, placebo‐controlled trial was designed to determine the safety and clinical efficacy of senicapoc in SCD patients. One hundred and forty‐five patients were randomized to receive senicapoc and 144 patients to receive placebo for 52 weeks. Consistent with a previous study, patients in the senicapoc group had significantly increased haematocrit, haemoglobin, and decreased numbers of both dense erythrocytes and reticulocytes when compared to the placebo group. The unblinded Data Monitoring Committee terminated this study early due to a lack of efficacy when it determined that, despite improvements in anaemia and haemolysis, no significant improvement in the rate of sickle cell painful crises was observed in patients treated with senicapoc compared to those on placebo (0·38 vs. 0·31, respectively). Comparisons of the times to first, second and third crises between the senicapoc and placebo groups were not statistically significant. Nausea and urinary tract infections occurred more frequently in the senicapoc group than placebo. Serious adverse events were similar in the two groups.

Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease

Background The up‐regulation of P‐selectin in endothelial cells and platelets contributes to the cell–cell interactions that are involved in the pathogenesis of vaso‐occlusion and sickle cell–related pain crises. The safety and efficacy of crizanlizumab, an antibody against the adhesion molecule P‐selectin, were evaluated in patients with sickle cell disease. Methods In this double‐blind, randomized, placebo‐controlled, phase 2 trial, we assigned patients to receive low‐dose crizanlizumab (2.5 mg per kilogram of body weight), high‐dose crizanlizumab (5.0 mg per kilogram), or placebo, administered intravenously 14 times over a period of 52 weeks. Patients who were receiving concomitant hydroxyurea as well as those not receiving hydroxyurea were included in the study. The primary end point was the annual rate of sickle cell–related pain crises with high‐dose crizanlizumab versus placebo. The annual rate of days hospitalized, the times to first and second crises, annual rates of uncomplicated crises (defined as crises other than the acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism) and the acute chest syndrome, and patient‐reported outcomes were also assessed. Results A total of 198 patients underwent randomization at 60 sites. The median rate of crises per year was 1.63 with high‐dose crizanlizumab versus 2.98 with placebo (indicating a 45.3% lower rate with high‐dose crizanlizumab, P=0.01). The median time to the first crisis was significantly longer with high‐dose crizanlizumab than with placebo (4.07 vs. 1.38 months, P=0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P=0.02). The median rate of uncomplicated crises per year was 1.08 with high‐dose crizanlizumab, as compared with 2.91 with placebo (indicating a 62.9% lower rate with high‐dose crizanlizumab, P=0.02). Adverse events that occurred in 10% or more of the patients in either active‐treatment group and at a frequency that was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain. Conclusions In patients with sickle cell disease, crizanlizumab therapy resulted in a significantly lower rate of sickle cell–related pain crises than placebo and was associated with a low incidence of adverse events. (Funded by Selexys Pharmaceuticals and others; SUSTAIN ClinicalTrials.gov number, NCT01895361.)

Novel inhibitors of the Gardos channel for the treatment of sickle cell disease.

Sickle cell disease (SCD) is a hereditary condition characterized by deformation of red blood cells (RBCs). This phenomenon is due to the presence of abnormal hemoglobin that polymerizes upon deoxygenation. This effect is exacerbated when dehydrated RBCs experience a loss of both water and potassium salts. One critical pathway for the regulation of potassium efflux from RBCs is the Gardos channel, a calcium-activated potassium channel. This paper describes the synthesis and biological evaluation of a series of potent inhibitors of the Gardos channel. The goal was to identify compounds that were potent and selective inhibitors of the channel but had improved pharmacokinetic properties compared to 1, Clotrimazole. Several triarylamides such as 10 and 21 were potent inhibitors of the Gardos channel (IC50 of <10 nM) and active in a mouse model of SCD. Compound 21 (ICA-17043) was advanced into phase 3 clinical trials for SCD.

Dose-escalation study of ICA-17043 in patients with sickle cell disease.

Study Objective. To determine the dose tolerance, safety, and pharmacokinetics of a single oral dose of ICA‐17043 in patients with sickle cell disease.

Senicapoc (ICA-17043): a potential therapy for the prevention and treatment of hemolysis-associated complications in sickle cell anemia.

Sickle cell disease (SCD) is characterized by hemolytic as well as vaso-occlusive complications. The development of treatments for this inherited disease is based on an understanding of its pathophysiology. Polymerization of sickle hemoglobin is dependent on several independent factors, including the intracellular hemoglobin concentration. The hydration state (and intracellular hemoglobin concentration) of the sickle erythrocyte depends on the loss of solute and osmotically obliged water through specific pathways. Senicapoc (also known as ICA-17043) is a potent blocker of the Gardos channel, a calcium-activated potassium channel of intermediate conductance, in the red blood cell. Preclinical studies and studies in transgenic models of SCD show that inhibition of potassium efflux through the Gardos channel is associated with an increased hemoglobin level, decreased dense cells and decreased hemolysis. Senicapoc is well tolerated when administered to SCD patients and produces dose-dependent increases in hemoglobin and decreases in markers of hemolysis. Despite the lack of a reduction in the frequency of pain episodes, the increasing recognition that hemolysis contributes to the development of several SCD-related complications suggests that by decreasing hemolysis, senicapoc may yet prove to be beneficial in this disease.

The trials and hopes for drug development in sickle cell disease

Although sickle cell disease (SCD) is highly prevalent worldwide, it is a rare disease in the United States and Europe. Over the past decade, there has been an increased understanding of the pathophysiology of SCD. While multiple drugs have been tested, only one drug, hydroxycarbamide, is approved by the relevant regulatory agencies specifically for this disease. Due to the combination of an improved understanding of disease pathophysiology, governmental support and the success of several recently approved drugs for other orphan diseases, there is an increased interest in the development of targeted drugs for SCD. Novel drugs that are currently being evaluated include haemoglobin F inducers, anti‐sickling agents, anti‐oxidants, anti‐adhesive agents, anti‐inflammatory agents, anticoagulants and anti‐platelet agents. In addition to the evaluation of acute pain crisis as a study endpoint, clinical trials employing other SCD‐related complications, exercise capacity, as well as patient reported outcomes are warranted and necessary in order to advance the development of these novel therapeutic agents. Finally, despite the availability of multiple biomarkers, many of these are of limited clinical value in SCD and require further assessment in prospective studies to validate their prognostic importance before they are acceptable as surrogate endpoints.

Anti-haemolytic effect of senicapoc and decrease in NT-proBNP in adults with sickle cell anaemia

Dear Editor: The Gardos channel inhibitor senicapoc is proven to diminish haemolytic anaemia in a Phase II study conducted in adults with sickle cell anaemia (Ataga, et al 2008), and later confirmed in a Phase III study in sickle cell disease subjects as reported in a recent article in the British Journal of Haematology (Ataga, et al 2011). Brain natriuretic peptide is a hormone secreted by ventricular cardiomyocytes in response to stretch (Levin, et al 1998). The plasma level of its propeptide (NT-proBNP) provides a convenient biomarker of cardiac stress, correlating in sickle cell subjects with pulmonary hypertension proven by pulmonary artery catheterization, or estimated by noninvasive Doppler echocardiography (Machado, et al 2006). Increased NT-proBNP in sickle cell adults is associated with lower haemoglobin, high serum lactate dehydrogenase (LDH) and other laboratory variables (Machado, et al 2006, Mekontso Dessap, et al 2008, Mokhtar, et al 2010, van Beers, et al 2008, Voskaridou, et al 2007). Because senicapoc is proven to increase haemoglobin and decrease LDH in sickle cell anaemia (Ataga, et al 2008), we hypothesized that NT-proBNP levels would fall in sickle cell anaemia subjects who respond to senicapoc treatment with increased haemoglobin level. We obtained local regulatory approval to study coded plasma samples from the 2008 Phase II senicapoc trial (Ataga, et al 2008). We procured archived plasma samples from that trial, and measured NT-proBNP by the same standard clinical laboratory assay we have previously reported in sickle cell anaemia (Machado, et al 2006). In the 53 treated subjects, NT-proBNP levels declined by a nonsignificant degree. However, when the analysis was restricted to the 35 subjects (66%) who responded to senicapoc with a rise in total Hb of at least 5 gm/L, significant changes were observed in NT-proBNP and other markers. Subjects who responded to 6mg daily or 10mg daily were analyzed together as a single group. Among these 35 senicapoc responders, baseline NT-proBNP fell by 26% (geometric mean 97 vs. 72 ng/l, p<0.01, paired t-test, log transformed values; Fig. 1). Haemoglobin levels increased by 13% (mean 79 ± 2 vs. 89 ± 2 gm/L, mean ± SEM, p<0.001, paired t-test; Fig. 2A), as expected in this group defined by senicapoc-induced rise in haemoglobin. Serum LDH levels fell 22% (geometric mean 466 vs. 365 iu/l, p<0.001, paired t-test, log transformed values; Fig. 2B), serum bilirubin levels dropped 35% (67.2 vs. 44.5 µmol/l, p<0.001; Fig. 2C), and percentage reticulocytes declined (12.5 vs. 8.6%, p<0.001; Fig. 2D). These results suggest that senicapoc simultaneously diminished both haemolysis and NT-proBNP in a subgroup of subjects. Figure 1 NT-proBNP levels before and after senicapoc therapy. White bar indicates baseline plasma NT-proBNP level prior to initiating oral senicapoc therapy in 35 adults with sickle cell anaemia. The black bar indicates plasma NT-proBNP level on day 85 of senicapoc ... Figure 2 Indicators of haemolytic severity before and after senicapoc therapy. White bars indicate baseline values prior to initiating oral senicapoc therapy in 35 adults with sickle cell anaemia. The black bars indicate values on day 85 of senicapoc therapy in ... A limitation in our study is that only two-thirds of these senicapoc subjects had a sufficient increase in haemoglobin to observe the linked decrease in NT-proBNP, and inclusion of the senicapoc nonresponders obscures this NT-proBNP change. This study was also not prospectively designed to determine the efficacy of senicapoc in reducing NT-proBNP, and the results should be interpreted with caution. However, the findings support important concepts linking haemolytic anaemia to elevated pulmonary arterial pressure. A similar decline in NT-proBNP also has been reported in patients with another chronic haemolytic anaemia, paroxysmal nocturnal hemoglobinuria, in whom hemolysis was reduced by use of the drug eculizumab (Hill, et al 2010). We also have reported downward trends in NT-proBNP and significant decline in pulmonary artery systolic pressure estimated by Doppler echocardiography in several sickle cell anaemia patients in whom hydroxycarbamide produced robust increase in foetal haemoglobin and significant reduction in serum LDH (Olnes, et al 2009). Severity of chronic haemolytic anaemia is linked to high levels of the functional cardiac marker NT-proBNP, and three mechanistically different pharmacological interventions that attenuate intravascular hemolysis also reduced NT-proBNP in these two pathologically distinct haemolytic anaemias. Our result suggests that reducing hemolysis in sickle cell anaemia results in lower NT-proBNP, previously shown to serve in this population more as a biomarker of mean pulmonary artery pressure than of left ventricular dysfunction (Machado, et al 2006). Additional research directed at reducing hemolysis is warranted as a potential means to reduce NT-proBNP and improve pulmonary hypertension in sickle cell disease.