Sickle Cell Disease (SCD)

Oxbryta® (voxelotor), previously known as GBT440, is an oral daily prescription medicine developed by Global Blood Therapeutics (GBT) that is indicated for the treatment of sickle cell disease (SCD) in patients aged 12 years and older.1 The active pharmaceutical ingredient of Oxbryta is voxelotor, a hemoglobin S (HbS) polymerization inhibitor. Oxbryta was approved under accelerated approval by the US Food and Drug Administration (FDA) in 2019.1 Previously, the FDA granted voxelotor Fast Track, Orphan Drug (both in 2015), Rare Pediatric Disease (in 2017) and Breakthrough Therapy (in 2018) designations.2

Get full prescribing information for Oxbryta on MPR’s monograph page.

Mechanism of Action

Voxelotor is an oral inhibitor of hemoglobin S polymerase that is used in the therapy of sickle cell disease. Voxelotor has been associated with rare instances of mild-to-moderate serum enzyme elevations during therapy, but has not been linked to instances of idiosyncratic acute liver injury.. Credit: PubChem

Sickle cell disease is a rare, genetic blood disorder characterized by the presence of sickle- or rigid crescent-shaped red blood cells (RBCs).3 The formation of these abnormal RBCs results from the polymerization of deoxygenated HbS. Sickle RBCs have damaged membranes and are more adhesive.2 By interacting with other cells, the sickle RBCs may lead to vaso-occlusive crises (VOCs) with blockage of blood flow and consequent organ damage.2,4 Symptoms associated with SCD include severe pain in the bones and chest, infections, and anemia due to hemolysis of the abnormal RBCs.3

Voxelotor is a hemoglobin modulator that binds to the α-globin chains of hemoglobin and modulates hemoglobin-oxygen affinity, stabilizing the RBCs in an oxygenated state and ultimately inhibiting HbS polymerization in a dose-dependent manner.1,4,5 The use of voxelotor is considered for patients who do not respond to or do not tolerate standard hydroxyurea therapy, as well as for patients who have a worsening anemia.6 Nonclinical studies point to a potential improvement in RBC deformability and a reduction in blood viscosity following voxelotor administration.1

Administration and Usage

Oxbryta is available as 500 mg tablets, and the recommended dose is 1500 mg taken orally once a day. The tablets should be swallowed without crushing, cutting, or chewing. Oxbryta may be administered simultaneously with standard hydroxyurea. Drug intake may lead to serious hypersensitivity reactions with rash and urticaria. Common adverse reactions may include headache, diarrhea, abdominal pain, nausea, fatigue, rash, and pyrexia.1 

Efficacy and Safety in Clinical Trials

The safety, tolerability, pharmacokinetics, and pharmacodynamics of voxelotor were first evaluated in a placebo-controlled phase 1 clinical trial, NCT02285088, and in an open-label, phase 2, single-arm study, NCT03041909, that included 5 participants with SCD who were previously enrolled in the phase 1 study.7 In the first study, patients were randomized to receive voxelotor or a placebo once a day for up to 118 days. In the extension study, the safety and tolerability of the drug were assessed for up to 6 months. These trials reported that voxelotor was well tolerated and that an improvement of hemoglobin levels and reductions in hemolysis and sickle cells were observed, supporting its use as a disease-modifying therapy in SCD.7

The efficacy and safety of voxelotor in SCD was further evaluated in the phase 3 trial, HOPE (NCT03036813).8 This was a randomized, double-blind, placebo-controlled, multicenter trial that enrolled 274 patients. Participants aged 12 to 65 years were randomized to receive a once-daily oral dose of either voxelotor (1500 mg), voxelotor (900 mg), or a placebo for 24 weeks. The primary endpoint was the percentage of patients who showed a hemoglobin response.8

The results of this study revealed that 51% of the patients treated with 1500 mg of voxelotor showed a hemoglobin increase of more than 1 g/dL at week 24 compared to 7% in the placebo-treated group. Validated natural history studies suggest that by significantly increasing hemoglobin levels, the rates of multiorgan failure and death can decrease.8 Additionally, when compared to the placebo group at week 24, voxelotor-treated patients had significant reductions in hemolysis markers, specifically the indirect bilirubin level and percentage of reticulocytes. These effects were observed regardless of hydroxyurea treatment or anemia severity at baseline. No increased incidence rate of VOCs was observed with drug administration despite the increased hemoglobin levels, suggesting that blood viscosity was not affected by drug administration.8

A phase 2 clinical trial, HOPE Kids (NCT02850406), is currently ongoing to evaluate the safety, efficacy, and pharmacokinetics of voxelotor in children aged 9 months to 17 years.9 GBT is also conducting a phase 3 clinical trial as a confirmation trial for full approval of voxelotor in the United States (HOPE Kids 2, NCT04218084).10 Lastly, the effects of voxeletor on daily physical activity and sleep quality in patients with SCD is the focus of the phase 4 trial ActIVe (NCT04400487).11


1. Oxbryta. Package insert. Global Blood Therapeutics, Inc.; 2021. Accessed November 9, 2021.

2. Lehrer-Graiwer J, Yokoshima L, Tong B, Love TW. Accelerated approval of Oxbryta® (voxelotor): a case study on novel endpoint selection in sickle cell disease. Contemp Clin Trials. 2020;98:106161. doi:10.1016/j.cct.2020.106161

3. Sickle cell disease. National Organization for Rare Disorders (NORD). Accessed November 9, 2021.

4. Darbari DS, Sheehan VA, Ballas SK. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management. Eur J Haematol. 2020;105(3):237-246. doi:10.1111/ejh.13430

5. Rai P, Ataga KI. Drug therapies for the management of sickle cell disease. F1000Res. 2020;9:F1000 Faculty Rev-592. doi:10.12688/f1000research.22433.1

6. Ali MA, Ahmad A, Chaudry H, et al. Efficacy and safety of recently approved drugs for sickle cell disease: a review of clinical trials. Exp Hematol. 2020;92:11-18.e1. doi:10.1016/j.exphem.2020.08.008

7. Howard J, Hemmaway CJ, Telfer P, et al. A phase 1/2 ascending dose study and open-label extension study of voxelotor in patients with sickle cell disease. Blood. 2019;133(17):1865-1875. doi:10.1182/blood-2018-08-868893

8. Vichinsky E, Hoppe CC, Ataga KI, et al.; HOPE Trial Investigators. A phase 3 randomized trial of voxelotor in sickle cell disease. N Engl J Med. 2019;381(6):509-519. doi:10.1056/NEJMoa1903212

9. Study to evaluate the effect of GBT440 in pediatrics with sickle cell disease (HOPE Kids). August 1, 2016. Updated May 13, 2021. Accessed November 9, 2021.

10. Study to evaluate the effect of GBT440 on TCD in pediatrics with sickle cell disease (HOPE Kids 2). January 6, 2020. Updated August 18, 2021. Accessed November 9, 2021.

11. Actigraphy improvement with voxelotor (ActIVe) study (ActIVe). May 22, 2020. Updated November 5, 2021. Accessed November 9, 2021.

Reviewed by Kyle Habet, MD, on 11/15/2021.