Health Science Reviews

By Lesego Mahlasi

Sickle cell disease (SCD) is one of the most common hereditary blood disorders worldwide. It is marked by the presence of sickle haemoglobin, which disrupts red blood cell (RBC) activity. A point mutation in the B-globin gene on chromosome 11 causes sickle haemoglobin (HbS) to replace normal haemoglobin (HbA). When oxygen levels are low, HbS molecules polymerise, forming long fibers that deform red cells into stiff, sickle-shaped cells. These abnormal red cells block vessels and undergo haemolysis, resulting in vaso-occlusion, chronic anaemia, inflammation, and organ damage. This phenomenon appears acutely as painful crises, infections, acute chest syndrome, and strokes. Long-term effects include lower quality of life and premature death(1–3).

HbS polymerisation is the central molecular event underpinning the clinical consequences of SCD; hence, disrupting this process may have symptom-modifying effects. Voxelotor is a treatment that directly reduces haemoglobin polymerisation. It binds to haemoglobin and stabilises RBC in an oxygenated state, resulting in increased oxygen transport to organs, decreased haemolysis, and fewer anaemias(4). This phase 3 HOPE trial intends to assess the efficacy and safety of voxelotor in adolescents and adults with sickle cell disease, building on the Howard J phase 1/2 trial that showed haematologic improvements in SCD(2).

The HOPE trial aims to address the following question: Can voxelotor safely and effectively raise haemoglobin levels and prevent haemolysis in SCD adolescents and adults?(1).

The study is a randomised controlled trial conducted across 12 different countries.  274 participants with SCD, ages 12 to 65, were randomly assigned to one of three groups: voxelotor 1500mg, voxelotor 900mg, or placebo.  Participants had a Hb level ranging from 5.5 to 10.5g/dL and had experienced at least one to ten vaso-occlusive crises within the previous 12 months.  Participants taking hydroxyurea were accepted provided their dose had been constant for more than three months.  The researchers eliminated people who had recently been hospitalised or transfused, as well as those who were on regular transfusion therapy.  Prior to randomisation, individuals were grouped based on critical criteria such as hydroxyurea use, geographic region, and age group(1).

The major outcome examined is the percentage of participants who had more than a 1 g/dL increase in haemoglobin by week 24 of the experiment.  To better understand the therapy’s effects, other outcomes were assessed, including haemoglobin level changes in haemolysis markers, and the frequency of vaso-occlusive crisis(1).

The study outcomes were fantastic in terms of demonstrating voxelotor’s disease-modifying potential. The study found that the 1500 mg dose of Voxelotor significantly improved haemoglobin levels, with a mean increase of 1.1 g/dL at 24 weeks. The 1500 mg group also showed significant reductions in haemolysis markers like indirect bilirubin and reticulocytes. There were no significant differences in the frequency of vaso-occlusive crises between the three groups. The proportion of participants who had adverse events was similar between the voxelotor and placebo groups(1).

In conclusion, the trial demonstrates voxelotor’s disease-modifying efficacy, as it caused sustained improvements in haemoglobin levels while effectively reducing anaemia.  The treatment was well tolerated by participants, confirming its safety.  The drug reinforces the importance of directly treating the underlying pathophysiology of SCD.

Some questions I ponder regarding voxelotor

• Does combining it with agents such as hydroxyurea produce better effects?
• Does voxelotor reduce organ damage or mortality?
• What are the potential downside effects of increasing haemoglobin affinity for oxygen?

References

1.          Vichinsky E, Hoppe CC, Ataga KI, Ware RE, Nduba V, El-Beshlawy A, et al. A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease. New England Journal of Medicine [Internet]. 2019 Aug 8;381(6):509–19. Available from: http://www.nejm.org/doi/10.1056/NEJMoa1903212

2.          Howard J, Hemmaway CJ, Telfer P, Layton DM, Porter J, Awogbade M, et al. A phase 1/2 ascending dose study and open-label extension study of voxelotor in patients with sickle cell disease. Blood [Internet]. 2019 Apr 25;133(17):1865–75. Available from: https://ashpublications.org/blood/article/133/17/1865/275910/A-phase-12-ascending-dose-study-and-openlabel

3.          Han J, Saraf SL, Gordeuk VR. Systematic Review of Voxelotor: A First‐in‐Class Sickle Hemoglobin Polymerization Inhibitor for Management of Sickle Cell Disease. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy [Internet]. 2020 Jun 19;40(6):525–34. Available from: https://accpjournals.onlinelibrary.wiley.com/doi/10.1002/phar.2405

4.          Barak M, Hu C, Matthews A, Fortenberry YM. Current and Future Therapeutics for Treating Patients with Sickle Cell Disease. Cells [Internet]. 2024 May 16;13(10):848. Available from: https://www.mdpi.com/2073-4409/13/10/848