Sickle cell disease (SCD) is caused by mutation of beta-globin chain alleles, with the involvement of at least one sickle mutation. Sickling of red cells leads to hemolytic anemia, vaso-occlusions, and inflammation. Voxelotor (GBT440) is a hemoglobin modulator that prevents polymerization by increasing the affinity of hemoglobin with oxygen. We performed a systematic review to evaluate the efficacy and safety of voxelotor in SCD patients.


PRISMA guidelines were followed to perform the literature search and selection of articles for this systematic review. A search was performed using databases including PubMed, Cochrane, Web of Science, Embase, and We used the following keywords, "Voxelotor" OR "Benzaldehydes" OR "GBT440" AND "Sickle Cell Anemia" from the inception of literature till 04/25/2020. Out of 475 articles, we screened and included three clinical trials and a case series measuring the efficacy (i-e, change in Hemoglobin (Hb), Hb modification, etc.) and safety (adverse events) in clinical terms (N=359). We excluded case reports, pre-clinical studies, review articles, and meta-analysis.


We included data on 359 patients, with 12-67 years of age. In Blyden et al. 2018, authors presented a case series of 7 patients with advanced SCD treated with 700 mg-1500 mg voxelotor. With treatment, vaso-occlusive episodes related hospitalizations decreased by 67%, hemoglobin levels, and markers of hemolysis improved in all patients.

Authors in Hutchaleelaha et al. 2019 randomly assigned 24 participants to a once-daily dose of 900 mg, 600 mg, 300 mg voxelotor, and placebo for 15 days. With treatment, hemoglobin modification was maximum in the 900 mg voxelotor group. Headache and diarrhea were the only adverse events related to voxelotor treatment. No grade 3 adverse events were reported.

In phase I/II trial by Howard et al. 2019, (n=54) 38 patients were followed for 28 days, and 16 patients were followed for >90 days. The compliance for study drug was 91%. In the 28-day cohort, treatment with 1000 mg of voxelotor showed maximum improvement in hemoglobin level, reticulocyte count, and unconjugated bilirubin. In >90-day cohort, the improvement in hemoglobin, unconjugated bilirubin, and reticulocyte count were statistically significant in favor of 900 mg voxelotor treatment as compared to placebo (p<0.05). LDH showed variability with treatment. Vaso-occlusive episodes seen in voxelotor groups were reported when the treatment was on hold or after the last dose. No grade ≥3 adverse events were reported.

In a randomized placebo-controlled phase III clinical trial by Vichinsky et al. 2019, two doses of voxelotor 1500 mg (N=90) and 900 mg (N=92) were compared with placebo (N=92). 12-65 years old SCD patients were followed for 24 weeks. After treatment, improvement in hemoglobin was statistically significant in favor of 1500 mg voxelotor vs. placebo. Moreover, markers of hemolysis, reticulocyte count, and indirect bilirubin levels were also significantly improved in favor of 1500mg voxelotor treatment vs. placebo. The incidence of vaso-occlusive crisis episodes was similar in 1500 mg, 700 mg, and placebo groups (p>0.05). Treatment-related adverse events were seen in 94%, 93%, and 89% of participants in 1500mg, 700mg, and placebo groups, respectively. (Table 1)

There are 6 ongoing clinical trials registered on (n=665) to determine the efficacy and safety of high doses of voxelotor and its use in children below 12 years. (Table 2)


Voxelotor has an acceptable safety profile in sickle cell disease patients of 12 years or older. Voxelotor has shown a dose-dependent improvement in hemoglobin levels and markers of hemolysis, which is associated with a reduction in end-organ damage. Moreover, the increase in hemoglobin was not associated with an increase in vaso-occlusive crisis episodes, in contrast to the other hemoglobin modulator (senicapoc). Additional large prospective multicenter randomized clinical trials are needed to confirm these results.


Anwer:Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.

Author notes


Asterisk with author names denotes non-ASH members.