Voxelotor: A Novel Treatment for Sickle Cell Disease

Abstract

Objective: To review the pharmacological characteristics, clinical evidence, and place in therapy of voxelotor for the treatment of sickle cell disease (SCD). Data Sources: A comprehensive literature search of PubMed (1966 to April 2020) was conducted. Key search terms included GBT440, sickle cell, and voxelotor. Other sources were derived from bibliographies of articles, product labeling, manufacturer’s website, and news releases. ClinicalTrials.gov was searched for additional studies. Study Selection and Data Extraction: All English-language articles identified from the data sources were reviewed and evaluated. Case reports/series and phase 1 through 3 clinical trials were included. Data Synthesis: SCD is an inherited disorder associated with significant morbidity and early mortality. Three medications approved for SCD reduce SCD-associated complications but do not selectively ameliorate the underlying disease. Voxelotor is a novel agent that targets the pathophysiology of SCD. A phase 3 trial reported an increase in mean Hb level from baseline for voxelotor compared with placebo (1.1 vs −0.1 g/dL; P < 0.001). Voxelotor is generally well tolerated, with common adverse effects including headache, diarrhea, nausea, and arthralgia. Relevance to Patient Care and Clinical Practice: Voxelotor may be considered for patients with SCD who have continued anemia and hemolysis despite being on maximum tolerated dose of hydroxyurea or in those who are hydroxyurea intolerant. Voxelotor is costly; therefore, both cost and benefit should be weighed before prescribing. Conclusion: Voxelotor appears to be safe and effective as monotherapy or in combination with hydroxyurea for patients with SCD who are 12 years of age and older.

First case of DRESS (drug reaction with eosinophilia and systemic symptoms) associated with voxelotor

“…There is an ongoing open label extension study of the HOPE trial examining treatment-related adverse effects over a 5-year time period (NCT 03573882) and a phase 2 open label dose escalation study of doses of 1500 to 3000 mg/d of voxelotor (NCT 04247594). 10 This case highlights the importance of prompt recognition of possible DRESS in patients started on voxelotor in order to mitigate or prevent long term effects in this vulnerable population as well as the need for long-term studies of the safety profiles of voxelotor and any new medications approved in rare diseases.…”

How do we monitor hemoglobin S in patients who undergo red blood cell exchange and take voxelotor?

“…The majority of adult hemoglobin is composed of hemoglobin A (HbA), which is a tetramer composed of two alpha and two beta globin chains. Hemoglobin S (HbS) is the result of an autosomal recessive point mutation leading to the substitution of glutamic acid with valine on the beta chain of hemoglobin 1,5 . SCD occurs in individuals who are homozygous for HbS (HbSS) or who inherit HbS with an additional hemoglobinopathy (for example, hemoglobin C or beta thalassemia) 1 .…”

“…Voxelotor is a small molecule which acts by reversibly binding to an alpha chain of hemoglobin. This stabilizes oxygenated hemoglobin and prevents hemoglobin polymerization 1,5 . In theory, by decreasing the sickling of RBCs, the overall lifespan of RBCs should be increased and a decrease in adverse events due to sickled cells should be seen 1,5 .…”

“…This stabilizes oxygenated hemoglobin and prevents hemoglobin polymerization 1,5 . In theory, by decreasing the sickling of RBCs, the overall lifespan of RBCs should be increased and a decrease in adverse events due to sickled cells should be seen 1,5 . A phase 3 randomized controlled trial reported that, at 24 weeks, patients who received 1500 mg voxelotor daily (orally) showed greater reductions in indirect bilirubin ( p < .001) and reticulocyte percent ( p < .001) as compared to placebo.…”

Functional foods: promising therapeutics for Nigerian Children with sickle cell diseases

“… 1500mg once daily. Voxelotor is available as a 500-mg oral tablet, and its estimated cost is $138.89 per tablet [ 76 ] while its annual cost is $84,000 [ ICER ]. Headache, diarrhea, nausea, and arthralgia …”