Evidence and Gaps in Clinical Outcomes of Voxelotor in Sickle Cell Disease: A Systematic Literature Review
Authors: Yassin Mohamed A 
Published: December 2024

Background:. Prior to 2017, hydroxyurea was the only pharmaceutical disease-modifying therapy available for the management of SCD However, recent advances in pharmacotherapy have led to the development of novel disease-modifying therapies that target cellular adhesion, inflammation, oxidant injury, vascular tone, and haemoglobin polymerisation. In 2017, L-glutamine was approved by the US Food and Drug Administration (FDA) for oral administration in adults and paediatric patients aged above 5 years with SCD. In 2019, the FDA approved crizanlizumab for adult and paediatric patients aged 16 years and above with SCD and approved voxelotor for adults and paediatric patients ≥12 years of age with SCD .
The objective of this review r is to summarise the safety and efficacy outcomes of Voxelotor in the treatment of SCD, based on data from clinical trials and real-world settings and to identify any differences or gaps in clinical outcome data from clinical trials and real-world settings through a systematic literature review approach.
methodology:
We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The Evidence-Based Medicine (EBM) Reviews-Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Embase (2017-2024), and Ovid MEDLINE(R) ALL were the electronic databases searched for clinical trials, observational studies, case series, and case reports published in English. The key terms used in searches included: “sickle cell disease”, “sickle cell anaemia”, “voxelotor”, “”real-world studies“, ”clinical trials“, and ”HbSS“. The search included all articles published up to 31 May 2024. Studies on gene therapies and haematopoietic stem-cell transplantation were excluded.
Results and discussion:
Pivotal clinical trials, including the HOPE and HOPE-KIDS 1, primarily assessed the effect of voxelotor treatment on Hb levels and haemolysis markers in patients with SCD. In the HOPE trial, voxelotor demonstrated a significant increase in haemoglobin levels by 1 g/dL in 51% of participants and a reduction in haemolysis indicators; similarly, the HOPE-KIDS 1 study revealed a notable increase in haemoglobin by 1 g/dL in 47% of paediatric patients, along with a decrease in haemolysis markers for children diagnosed with HbSS or HbSβ0 thalassemia. However, these 2 key clinical trials did not assess the impact of voxelotor on clinical outcomes such as VOC or health-related quality of life in patients with SCD. Nevertheless, the post hoc analysis and long-term follow-up of the HOPE trial assessed a few additional clinical outcomes. The 72-week analysis of the HOPE trial reported that patients with SCD who achieved Hb above 10 g/dL with voxelotor experienced fewer VOCs compared with those who achieved lower Hb levels and were treated with placebo
Real-world studies have demonstrated clinical benefits related to the use of voxelotor beyond increasing Hb levels or reducing haemolysis markers. In a retrospective study of a US national claims database of 3128 patients with SCD aged ≥12 years, voxelotor markedly reduced the mean annualised VOC rate from 10.9 to 8.4 (p&lt;0.001). The mean annualised rate of VOC hospitalisations and all-cause hospitalisations decreased from 10.9 to 8.4 (p&lt;0.001) and from 7.4 to 4.6 (p&lt;0.001), respectively. Voxelotor led to a lower need for blood transfusions, with the average yearly transfusion rate falling from 7.0 to 3.3 (p&lt;0.001). Furthermore, the study findings indicated a reduction in the average number of outpatient appointments for patients taking voxelotor, from 24.8 to 22.5 visits (p=0.006), and a decrease in the average prescribed opioid duration, from 312 to 272 days (p&lt;0.001) .
Other beneficial effects of voxelotor reported in observational studies included improvement in health-related quality of life and kidney function. In a retrospective analysis, treatment of 5 patients with SCD with CKD stages I-III resulted in a reduction in urine albumin concentration, in addition to a reduction in Hb levels and absolute reticulocyte counts .
Voxelotor is well tolerated with a few minor side effects, as reported in the HOPE and HOPE-KIDS 1 trials, with the most common ones being headache, diarrhoea, and abdominal pain. Most observational studies also reported similar findings.