An expert review of voxelotor for the treatment of hemolytic anemia in patients with sickle cell disease: ‘bridging the gap between laboratory data and patient related outcomes’

ABSTRACT

Introduction

Until recently, the treatment of sickle cell disease (SCD) for a long time has been limited to hydroxycarbamide alone. SCD is characterized by hemoglobin (Hb) polymerization, hemolysis, and ischemia. Voxelotor, a first-in-class Hb modulator that increases Hb-oxygen affinity and reduces RBC polymerization, is approved for the treatment of hemolytic anemia in SCD patients.

Areas Covered

This review is to examine the evidence supporting the laboratory and clinical benefits of voxelotor in SCD. The search keywords were as follows: hemolytic anemia, SCD, voxelotor/GBT 440. A total 19 articles were reviewed. Most studies report voxelotor’s significant reduction in hemolysis; however, data related to positive effects on clinical outcomes, namely Vaso-occlusive crisis (VOCs), are sparse. We note the ongoing trials that have different endpoints related to the brain, kidney, and skin. Additional information from real-life post-marketing observational studies may shed more light on the benefits of voxelotor in SCD. Further research is required with the view to using related outcomes as end points e.g. VOCs, renal impairment. This is need to be undertaken in sub Saharan Africa, the epicentre of SCD.

Expert Opinion

Our recommendation remains to offer and optimize hydroxycarbamide therapy and consider voxelotor in situations with severe anemia and related sequelae affecting the brain or kidney.

KEYWORDS:

• Sickle cell disease
• anemia
• hemolysis
• vaso-occlusive crisis (VOC)
• GBT440
• voxelotor

Article highlights

• SCD is a monogenic disorder characterized by red cell hemolysis and anemia, resulting in unrelenting pain and end-organ damage such as stroke and leg ulcers; it is a condition for which disease-modifying treatment has been limited to hydroxycarbamide and blood transfusion only for decades now.

• now. Recent new therapies that have been FDA approved for use in SCD patients include L-glutamine, voxelotor, and crizanlizumab.

• Voxelotor is a first in class Hemoglobin (Hb) modulator that reduces sickle hemoglobin polymerization, currently approved for treatment of hemolytic anemia in SCD patients over the age of 12 years; this approval followed the release of the results of the HOPE Trial – a randomized, placebo-controlled trial that showed voxelotor was effective for reducing hemolysis markers and increasing hemoglobin levels in adults and adolescents. The open-label HOPE-KIDS 1 trial supported the use of voxelotor in children aged 4 to 12 years.

• Although there is evidence of voxelotor’s effect on red cell hemolysis in SCD patients, there are scarce data on its effect on other clinical outcomes such as VOC and end organ damage (e.g. brain, kidneys, skin). There is a need for further research in order to understand how voxelotor improves clinical outcomes

• Our current recommendation is to optimize hydroxycarbamide therapy before considering voxelotor therapy in selected patients – pending further data.

Acknowledgments

We would like to thank Prof Biree Andemariam for their advice on the structure of the manuscript.

Declaration of interest

BPD Inusa has received education funding (paid to Guy’s and St Thomas NHS Foundation Trust for the benefit of the Academy for Sickle Cell and Thalassaemia (ASCAT)) from Novartis Plc., Agios, Forma, and Global Therapeutics, and honoraria from Novartis, Global Therapeutics, Agios, and Forma/Novo-Nordisk. BPD Inusa has also received funding from the European Union’s Horizon 2020 Research and Innovation program under the Marie Sklowdowska-Curie grant agreement no. 824021. N Archer has received research funding from Global Blood Therapeutics, Novartis, and Agios. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.