Oxbryta (voxelotor) for sickle cell disease

Last updated May 22, 2024, by Andrea Lobo, PhD
Fact-checked by Inês Martins, PhD

What is Oxbryta for sickle cell disease?

Oxbryta (voxelotor) is an oral therapy conditionally approved in the U.S. for children and adults with sickle cell disease (SCD), 4 and older.

It is used to prevent red blood cell sickling and destruction, and to reduce blood viscosity caused by the production of a faulty version of hemoglobin — the protein in red blood cells that’s responsible for oxygen transport. Oxbryta’s conditional approval was based on early data showing it can significantly increase levels of hemoglobin.

The therapy was originally developed by Global Blood Therapeutics, which is now a Pfizer subsidiary.

Therapy snapshot

How does Oxbryta work?

In sickle cell disease, mutations in the HBB gene result in the production of a faulty version of hemoglobin called hemoglobin S. This abnormal form of hemoglobin tends to clump together to form long, rigid chains inside red blood cells that cause these cells to take on the sickle-like shape that’s characteristic of the disease.

The misshapen red blood cells usually are very fragile and die prematurely compared to those with a normal oval shape, a process called hemolysis. They are also stiff and sticky and have difficulty passing through small blood vessels, sometimes blocking blood flow and inducing painful episodes known as vaso-occlusive crises (VOCs).

Oxbryta, formally known as GBT440, is a small molecule designed to prevent hemoglobin S from forming rigid chains inside red blood cells. It does that by increasing the molecule’s affinity for oxygen, which makes it less prone to clump up inside cells.

This helps red blood cells maintain their normal shape, which is expected to reduce hemolysis, restore red blood cell function and oxygen delivery to tissues, and ease the frequency and severity of VOCs.

Who can take Oxbryta?

Oxbryta was conditionally approved by the U.S. Food and Drug Administration (FDA) in November 2019 for SCD patients, 12 and older, becoming the first approved therapy that targets the underlying cause of the disease.

The FDA extended that accelerated approval in December 2021 to include children as young as 4.

Both approvals were made under the accelerated approval pathway, based on early evidence that Oxbryta resulted in rapid and sustained increases in hemoglobin levels in SCD patients. Continued approval for this indication, however, may require confirmation of its clinical benefits in future trials.

The therapy is also approved in the European Union, either alone or in combination with the standard SCD treatment hydroxyurea, for patients 12 and older.

Who should not take Oxbryta?

Oxbryta is contraindicated for anyone who has experienced a serious allergic reaction to voxelotor or other ingredients in the medication.

How is Oxbryta administered?

Oxbryta is a once-daily medication available in two forms: oral tablets and tablets for oral suspension. Tablets come in two dosage strengths while only one is available for the oral suspension formulation:

• The 300 mg film-coated tablets are oval and purple, and imprinted with “G 300” on one side.
• The 500 mg film-coated tablets are oval and yellow, and have “GBT 500” imprinted on one side.
• The tablets for oral suspension have 300 mg of the active ingredient, and are round and yellow and imprinted with “300 D” on one side.

While film-coated tablets should be swallowed whole, the tablets for oral suspension are designed to be mixed in a clear liquid, such as water, clear soda, apple juice, clear electrolyte drinks, clear flavored drinks, or clear sports drinks. The liquid mixture should be swirled until the tablet breaks apart but it will not be completely dissolved.

The medication can be taken with or without food, but none of the tablets should be cut, crushed, or chewed.

Oxbryta should be given to patients, 12 and older, at a recommended daily dose of 1,500 mg. In turn, doses for children 4 to 12 are based on weight:

• 1,500 mg daily for patients weighing 40 kg (about 88 lbs) or more
• 900 mg each day for patients weighing 20-40 kg (44-88 lbs)
• 600 mg a day for children weighing 10-20 kg (22-44 lbs).

Still, dosage adjustments may be needed for certain groups of patients. For example, lower doses are recommended for SCD patients with severe liver impairment, while higher doses should be given to patients who need to take strong or moderate CYP3A4 inducers, which increase Oxbryta’s metabolism and reduce its levels in the bloodstream. However, St. John’s wort — an herbal supplement and CYP3A4 inducer — should not be taken during treatment with Oxbryta.

Oxbryta may be given with or without hydroxyurea. If a dose is missed, the medication should be resumed as usual the following day.

Oxbryta in clinical trials

Oxbryta’s accelerated approvals for SCD were mainly based on data from two clinical trials: the HOPE Phase 3 trial (NCT03036813) in patients 12 and older, and the HOPE Kids 1 Phase 2a trial (NCT02850406) in children and adolescents, 9 months to 17 years old.

HOPE trial

The international HOPE trial enrolled 274 people with SCD, ages 12 to 65, who had experienced between one and 10 vaso-occlusive crises in the year before screening.

Patients were randomly assigned to receive Oxbryta at one of two doses (900 mg or 1,500 mg) or a placebo, once-daily for up to 72 weeks, or about 1.5 years. Patients on a stable hydroxyurea dose were also allowed to continue that treatment during the trial, and 65% did so.

The trial’s main goal was to determine the proportion of participants with a hemoglobin response, which is defined as an increase in hemoglobin levels of more than 1 g/dL after six months. Secondary measures included total changes in hemoglobin levels and in hemolysis markers after six months, and the average number of VOCs per year after 1.5 years.

Both Oxbryta doses resulted in a significantly higher proportion of patients achieving a hemoglobin response compared with the placebo, but the 1,500 mg dose tended to provide the greatest benefits. After six months, 51% of patients receiving that dose achieved a hemoglobin response, versus 7% on the placebo.

These patients also experienced a significantly greater increase in total hemoglobin levels and a higher reduction in the levels of bilirubin and reticulocytes — two biomarkers of hemolysis — after six months.

Final 1.5-year results from the trial confirmed that Oxbryta, at its approved dose, led to significant and sustained increases in hemoglobin levels and reductions in hemolysis markers compared to a placebo. It also reduced the annual number of VOCs by 15% and led to more patients having their clinical status rated as “moderately improved” or “very much improved” by their clinician (74% vs. 47%).

Oxbryta treatment was deemed generally safe and well tolerated, and also helped to heal painful leg ulcers, a common complication of SCD.

A total of 178 patients who completed HOPE chose to join an open-label extension study (NCT03573882), in which all receive 1,500 mg of Oxbryta daily for up to five years. After a median treatment duration of 2.4 years, patients showed durable hemoglobin responses and reductions in hemolysis markers, as well as a low frequency of VOCs (1.1 events per year).

HOPE Kids 1 trial

The open-label HOPE Kids 1 trial was a four-part study that tested Oxbryta in children and adolescents in different age ranges. One group included children ages 4 to 11, who received Oxbryta for up to 48 weeks (or nearly one year).

Initial findings from the first 45 patients in that group showed treatment with a weight-based dose of Oxbryta resulted in a mean increase in hemoglobin levels of 1 g/dL after six months, with 47% of patients achieving a hemoglobin response. Those increases were observed as early as two weeks after starting treatment.

These children also experienced similar reductions in hemolysis markers as observed in older patients, and the therapy was well tolerated in this age group.

Participants younger than 18 who participated in HOPE Kids 1 or other Oxbryta clinical trials were given the option to enter an ongoing open-label extension study (NCT04188509), which is testing the long-term safety and efficacy of the medication in this patient population. The study is expected to conclude in 2028.

Treatment is also available under an expanded access protocol (NCT04724421) for children 6 months to 11 years old who have no alternative treatment options and are not eligible for any Oxbryta clinical trial.

Ongoing trials

A Phase 3 trial, called HOPE Kids 2 (NCT04218084), is now ongoing at about 50 sites globally to serve as a confirmatory trial to support Oxbryta’s full approval for children and adolescents with SCD.

The trial enrolled a total of 236 children, ages 2 to 14 and weighing at least 10 kg (22 lbs), and randomly assigned them to a weight-based dose of Oxbryta or a placebo, given once daily for about two years.

The study’s main goal is to assess whether Oxbryta can reduce problems with blood flow (and thus, stroke risk) in the children’s brains after six months of treatment. This will be assessed with a noninvasive test called a transcranial doppler ultrasound.

Secondary measures include other parameters related to the brain’s blood flow, as well as changes in hemoglobin levels and in markers of hemolysis, and the incidence of VOCs. The trial is expected to finish in early 2025.

Common side effects of Oxbryta

The most common side effects associated with Oxbryta in clinical trials include:

• headache
• diarrhea
• abdominal pain
• nausea
• rash
• fever
• vomiting.

Allergic reactions

Oxbryta can cause serious allergic reactions that may appear as a generalized rash, hives, shortness of breath, face swelling, and higher-than-normal levels of immune cells called eosinophils. Some patients have experienced these symptoms along with internal organ involvement.

If an allergic reaction occurs, treatment with Oxbryta should be discontinued and patients should receive appropriate medical care. The medication should not be restarted in patients who experience these symptoms.

Use in pregnancy and breastfeeding

No data are available about the use of Oxybryta in pregnant women. Animal studies suggest the medication does not cause harm to the developing fetus, although it may cause harm to the mother. Thus, treatment with Oxbryta should only be considered during pregnancy, in consultation with a healthcare provider, if its benefits outweigh the potential risks.

It’s currently not known if Oxbryta can be found in human milk, or whether it affects milk production or the breastfed infant. However, the medication has been found in the milk of treated rats, and may carry potential risks to breastfed children. Therefore, breastfeeding is not recommended during treatment, and for at least two weeks after the last dose.

Patients who are pregnant or plan to conceive, and those who are breastfeeding or plan to, should talk with their healthcare team about these risks and their options during treatment.

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