LAUSR

Sickle cell disease (SCD) is a common inherited disorder, which is caused by a mutation in the haemoglobin β subunit gene that results in the formation of sickle haemoglobin (HbS). On deoxygenation, HbS polymerizes, that leads to the formation of sickle cells, which then causes painful vaso-occlusive crisis (VOC), chronic haemolytic anaemia, progressive organ damage, bone pain, decreased quality of life (QoL), and early death. Although allogeneic bone marrow transplantation can cure SCD, its use is restricted by the toxicity and limited availability of suitable donors. Until recently, the therapeutic approach to SCD has remained dependent on old drugs with limitations. Hydroxycarbamide is one of these drugs, and it was first tested in SCD in 1984. Then, the United States Food and Drug Administration (US FDA) and the European Medicines Agency (EMA) have approved hydroxycarbamide for the treatment of SCD in 1998 and 2007, respectively. Long-term daily hydroxycarbamide treatment increases the foetal haemoglobin (HbF) levels, which leads to a decrease in the frequency of VOCs, the number of red blood cell (RBC) transfusions, and mortality rates together with the improvement in QoL. While long-term hydroxycarbamide treatment generally is not associated with serious adverse events (AEs), myelosuppression is a predictable, dose-dependent, and reversible AE of daily hydroxycarbamide therapy, which may cause delays in reaching the maximum tolerated dose (MTD). Recently, Dong et al. published in the British Journal of Clinical Pharmacology, a strategy that they had developed using pharmacokinetic (PK) modelling to overcome the delay in dose titration of hydroxycarbamide therapy for children with SCD and achieve maximum tolerated dose (MTD) more quickly. As alterations in renal function may occur in SCD, the impact of renal function on hydroxycarbamide exposure in SCD patients was recently evaluated by Pressiat and colleagues in the British Journal of Clinical Pharmacology. The PK results of this study showed that systemic exposure to hydroxycarbamide is correlated with renal function, and patients with a high estimated glomerular filtration rate (eGFR) presented a higher renal clearance of hydroxycarbamide, resulting in a need for higher doses. Conversely, patients with a low eGFR required a dose reduction. A recently approved drug, crizanlizumab, was shown to reduce the incidence of VOCs in patients with SCD. This is a monoclonal antibody that binds to P-selectin, blocking its interaction with its ligand, P-selectin glycoprotein ligand-1 (PSGL-1). By binding P-selectin on the surface of activated endothelium and platelets, it blocks the interaction between endothelial cells, platelets, sickled RBCs, and leukocytes, inhibiting platelet aggregation and maintaining normal blood flow. Although it may reduce the risk of thrombosis and prevents the development of VOCs, this treatment does not address the underlying cause of the disease nor fully ameliorates disease manifestations. Apart from these treatment options, voxelotor (previously GBT440) is a first-in-class oral Hb modulator that increases Hb-oxygen affinity, thereby reducing Hb polymerization and sickling of RBCs, targeting the underlying mechanism of SCD. GBT440-001 is a phase 1/2 randomized, double-blind, placebo-controlled, single and multiple ascending dose study of voxelotor in adult healthy volunteers and patients with SCD. In the GBT440-001 trial, 38 patients with SCD received 28 days of voxelotor 500, 700, or 1000 mg per day or placebo; 16 patients received 90 days of voxelotor 700 or 900 mg per day or placebo. All patients who received voxelotor for ≥28 days experienced increase in Hb and reduction in haemolysis and percentage of sickled RBCs. Voxelotor was well tolerated with no serious treatment-related AEs (TRAEs) and no evidence of tissue hypoxia. Voxelotor pharmacokinetics in whole blood and plasma showed that approximately 99% of the voxelotor in blood was within the RBCs, which provides evidence Received: 28 December 2020 Revised: 16 January 2022 Accepted: 23 January 2022