A critical evaluation of crizanlizumab for the treatment of sickle cell disease

ABSTRACT

Introduction

P-selectin is a key adhesion molecule in the pathogenesis of sickle cell disease, including acute painful event(s). Many of the mediators activated in prototypical pain crisis are also involved in other complications seen in this population. Crizanlizumab is a monoclonal antibody approved in the US in 2019 for patients of all genotypes of sickle cell disease. By blocking P-selectin, it effectively prevents acute painful event(s) and has a manageable safety profile.

Areas covered

In this review, we provide an overview of the (i) biology of P-selectin in sickle cell disease, (ii) various agents inhibiting P-selectin, (iii) pharmacology of crizanlizumab, (iv) preclinical and clinical data on crizanlizumab, and (v) its potential for other indications, ongoing studies, regulatory status, and cost issues. Further, we describe its position among other approved agents in sickle cell disease and project future directions as well.

Expert opinion

Crizanlizumab holds great promise in modulating the natural history of sickle cell disease and may have pleotropic effects. Studies are ongoing to define its role in preventing other sickle cell-related complications, non-sickle cell inflammatory states, and thrombotic disorders.

KEYWORDS:

• Crizanlizumab
• sickle cell disease
• pain crisis
• P-selectin
• SEG101

Article highlights

• Frequent vaso-occlusive crises presenting as acute painful event(s) and resulting ischemic tissue damage is a hallmark of sickle cell disease.

• Crizanlizumab is a monoclonal antibody that blocks P-selectin, thus blocking intercellular adhesion driven microvascular vaso-occlusion. It has no effect on hemolysis.

• The SUSTAIN study confirmed the safety and effectiveness of crizanlizumab in preventing acute painful event(s). The study was not powered for evaluating its role in other complications of sickle cell disease.

• Hydroxyurea and crizanlizumab can be safely combined with additive efficacy to prevent acute painful event(s).

• Crizanlizumab is now approved for use in USA in patients with all genotypes of sickle cell disease age 16-65.

• Infusion related reactions mediated by complement activation, in a pattern seen with other monoclonal antibodies have been observed. Management is largely supportive.

• Crizanlizumab may be effective in preventing or delaying many complications seen in sickle cell disease, especially those that are related to repeated vaso-occlusion. However, this remains to be investigated.

Acknowledgments

Thanks to Novartis for allowing use of the image on mechanism of action of crizanlizumab.

Disclosure statement

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.