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