P-Selectin Blockade in the Treatment of Painful Vaso-Occlusive Crises in Sickle Cell Disease: A Spotlight on Crizanlizumab

Abstract

Microvascular vaso-occlusion driven pain crisis is the hallmark of sickle cell disease with profound morbidity and increased mortality. Selectins, most notably P-selectins have an integral role in this phenomenon. P-selection was first identified in 1989. In 2019, after 3 decades of basic, translational, and clinical work with this pathway, the US Food and Drug Administration approved a P-selectin antibody, crizanlizumab to reduce frequency of pain crisis in patients more than 16 years with sickle cell disease. We review the fundamentals of P-selectin pathobiology, P-selectin blocking agents, clinical data with the use of crizanlizumab and prospects of this novel class of drugs in the context of other treatments for painful vaso-occlusive episodes.

Keywords: P-selectin; crizanlizumab; pain crisis; sickle cell disease.

Figure 1

Mechanism of action of crizanlizumab. Crizanlizumab is a monoclonal antibody that binds to P-selectin. Blockade of P-selectin may prevent cell–cell interactions between blood cells and endothelial cells, and thus eliminate or reduce vaso-occlusion. Figure reproduced with permission from© 2020 Novartis AG.

Figure 2

SCPC event-free patients in the high-dose crizanlizumab, low-dose crizanlizumab, and placebo subgroups in an ITT population with respect to the annualized crisis rate in the preceding year. Note: Data from Kutlar et al.