Voxelotor for the treatment of sickle cell disease

ABSTRACT

Introduction: The clinical manifestations of sickle cell disease (SCD) result from an inherited mutation in the beta-globin chain of hemoglobin (Hb) that causes Hb tetramers to polymerize when deoxygenated. The resulting erythrocyte deformation causes mechanical obstruction of blood flow by sickled cells, hemolysis, anemia and end-organ injury. While pain is the hallmark symptom of SCD, chronic organ injury as a result of anemia, inflammation and progressive vasculopathy play a major role in morbidity and mortality. Due to the complex pathophysiology of SCD, the need for an individualized, multi-modal pharmacologic approach is apparent. Until 2018, hydroxyurea was the only disease-modifying pharmacologic therapy approved for use in SCD. Since then, three new agents have been approved including voxelotor, the subject of this review.Areas covered: Published pre-clinical and clinical data are reviewed. Voxelotor is a first-in-class small-molecule agent that binds to Hb and increases oxygen affinity, preventing polymerization. Recent clinical trials have shown that it increases Hb concentration and reduces hemolysis in patients with SCD. This increase in Hb concentration may significantly impact morbidity and mortality from chronic organ injury.Expert opinion: The mechanism of action, published studies and current opinions on the clinical use of voxelotor in SCD are presented.

KEYWORDS:

• Sickle cell disease
• voxelotor
• anemia
• hemoglobin
• hemoglobinopathy

Article highlights

• Severe anemia is an independent risk factor for chronic end-organ injury and mortality in patients with sickle cell disease.

• Voxelotor is an orally administered agent that prevents sickling of erythrocytes by stabilizing hemoglobin in the relaxed state.

• The HOPE study showed that patients treated with voxelotor had a significant increase in hemoglobin concentration and decrease in markers of hemolysis. There was a numerical but not statistically significant change in the number of acute pain episodes experienced by patients treated with voxelotor.

• The long-term effects of voxelotor on end-organ function are yet to be determined.

• Voxelotor is now approved for use in the USA in patients with all sickle cell disease genotypes ages 12 and older.

• Voxelotor undergoes hepatic metabolism through CYP3A4 and dose may need to be adjusted in patients who take inhibitors (ketoconazole, fluconazole) or inducers (rifampin) of this enzyme as well as in patients with underlying hepatic dysfunction.

Declaration of interest

The authors conducted research supported by Global Blood Therapeutics, Inc. E Vichinksy is additionally supported by Bluebird Bio and Chiesi. The authors have no other relevant affiliations of 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

A reviewer of this manuscript has disclosed that they were in the Voxelotor Clinical Trial GBT-440-031 (closed) and GBT 440-034 (ongoing). Peer reviewers in this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.