Oxbryta (voxelotor) for sickle cell disease

Last updated Jan. 10, 2025, by Andrea Lobo, PhD
Fact-checked by Joana Carvalho, PhD

What is Oxbryta for sickle cell disease?

Oxbryta (voxelotor), which is now withdrawn from the market due to safety concerns, was an oral small molecule conditionally approved in the U.S. for children and adults with sickle cell disease (SCD), ages 4 and older.

It was 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 that showed it could significantly increase hemoglobin levels.

Pfizer has voluntarily decided to withdraw the therapy from all markets and discontinue all global clinical trials and expanded access programs while the review of safety data is ongoing. The decision was based on clinical data that suggested the benefits of Oxbryta no longer outweighed its potential risks. Specifically, data indicated some patients started having more vaso-occlusive crises after starting treatment with Oxbryta, with 16 deaths having been reported in patients who received the therapy in post-marketing clinical studies.

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

Therapy snapshot

How does Oxbryta work?

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

The misshapen red blood cells usually are very fragile and die prematurely compared with more the normal, oval-shaped ones as part of 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, or VOCs.

Oxbryta, formally named 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 was expected to reduce hemolysis, restore red blood cell function and oxygen delivery to tissues, and ease the frequency and severity of VOCs.

Who could take Oxbryta?

Oxbryta was conditionally approved by the U.S. Food and Drug Administration (FDA) in November 2019 for SCD patients, ages 12 and older, becoming the first approved therapy too target 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 required confirmation of its clinical benefits in subsequent trials, however.

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

Who should not take Oxbryta?

Oxbryta was contraindicated, or not recommended, for anyone who’d experienced a serious allergic reaction to voxelotor or other ingredients in the medication.

How was Oxbryta administered in sickle cell disease?

Oxbryta was a once-daily medication available in two forms: oral film-coated tablets and tablets for oral suspension. The tablets came in two dosage strengths, while only one was available for the oral suspension formulation. They were:

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

While film-coated tablets were to be swallowed whole, the oral suspension tablets were 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 would be swirled until the tablet broke apart, but not completely dissolved. The medication was to be taken with or without food, but none of the tablets should be cut, crushed, or chewed.

Oxbryta’s recommended daily dose was 1,500 mg for patients, ages 12 and older. For children ages 4 to 12, the doses were based on weight:

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

Dose adjustments might have been needed for certain patients. For example, lower doses were recommended for SCD patients with severe liver impairment, while higher doses were advised for those who needed to take strong or moderate CYP3A4 inducers, which increase Oxbryta’s metabolism and reduce its levels in the bloodstream. St. John’s wort, an herbal supplement and CYP3A4 inducer, shouldn’t be taken during treatment with Oxbryta.

Oxbryta was able to be given with or without hydroxyurea. If a dose had been missed, the medication should be resumed as usual the following day.

Oxbryta in sickle cell disease clinical trials

Oxbryta’s accelerated approvals for SCD were mainly based on data from two clinical trials: the Phase 3 HOPE trial (NCT03036813) in patients ages 12 and older, and the Phase 2a HOPE Kids 1 trial (NCT02850406) in children and adolescents, ages 6 months to 17 years.

HOPE trial

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

The 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 (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, defined as an increase in hemoglobin levels of more than 1 g/dL after six months. Secondary measures included assessing changes in hemoglobin levels and 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 saw 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 with 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 was deemed generally safe and well tolerated and also helped 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) where all were to 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, along with a low frequency of VOCs (1.1 events per year).

The extension study has been terminated following Pfizer’s disclosure of clinical data indicating the overall benefits of Oxbryta no longer outweighed its potential risks.

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 evaluable patients achieving a hemoglobin response. Those increases were observed as early as two weeks after starting treatment.

The children also had similar hemolysis marker reductions as those 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 open-label extension study (NCT04188509) that sought to assess the long-term safety and efficacy of the medication in this population.

Both studies were terminated due to emerging clinical data indicating the treatment’s risk profile in SCD patients exceeded the benefits observed in previous studies, which are currently being evaluated.

The therapy had also been made available under an expanded access protocol (NCT04724421) for children ages 6 months to 11 years who had no alternative treatment options and weren’t eligible for any Oxbryta clinical trial. This program is also no longer available for the same reasons.

HOPE Kids 2 trial

The Phase 3 HOPE Kids 2 trial (NCT04218084), now also terminated, was testing Oxbryta in 236 children with SCD, ages 2 to 14, who weighed at least 10 kg (about 22 pounds) and were at risk of stroke.

The patients, mainly enrolled in sub-Saharan Africa, were randomly assigned to a weight-based dose of Oxbryta or a placebo, given once daily for about two years.

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

Secondary measures included other parameters related to the brain’s blood flow, as well as changes in hemoglobin levels and markers of hemolysis, and the incidence of VOCs.

However, eight patients treated with Oxbryta died along with two in the placebo group, all in sub-Saharan Africa. Most fatal cases in the treatment group described the incidence of infections, including three patients who developed severe malaria and two who had sepsis.

RESOLVE trial

Also terminated is the Phase 3 RESOLVE trial (NCT05561140), which was assessing Oxbryta’s impact on leg ulcers in 88 SCD patients, ages 12 and older. The study was being conducted in Kenya, Nigeria, and Brazil, and the patients were allowed to continue treatment with hydroxyurea.

Eight out of nine deaths were reported in the study’s open-label portion, a rate that was deemed to be higher than anticipated. In four of these cases, malaria was either considered the cause of death or a contributing factor. Two more new deaths have been reported in a recent update, bringing the total number of deaths in the study to 11.

RETRO and PROSPECT registry studies

RETRO (NCT04930328) and PROSPECT (NCT04930445) were registry studies that were being carried out to evaluate the effects of Oxbryta in a real-world setting for SCD patients.

Results from interim analyses of the two studies indicated an increase in the incidence of VOCs following treatment with Oxbryta. In RETRO, an exploratory interim analysis based on data from 140 patients showed the incidence of acute pain crises increased from 33.6% before treatment with Oxbryta to 68.7% after treatment. In PROSPECT, an exploratory analysis based on data from 161 patients indicated the number of VOCs per patient-year increased from 0.49 before treatment to 2.71 after treatment.

Common side effects of Oxbryta

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

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

Allergic reactions

Oxbryta was associated with serious allergic reactions that might manifest in the form of a generalized rash, hives, shortness of breath, face swelling, and higher than normal levels of immune cells called eosinophils. Some patients experienced these symptoms along with internal organ involvement.

If an allergic reaction occurred, treatment with Oxbryta was to have been discontinued and patients should have received appropriate medical care.

Use in pregnancy and breastfeeding

No data were available about the use of Oxybryta in pregnant women. Animal studies suggested the medication does not cause harm to the developing fetus, but may cause harm to the mother. Thus, treatment with Oxbryta should have only been considered during pregnancy, in consultation with a healthcare provider, if its benefits outweighed the potential risks.

It remains unknown whether Oxbryta could pass into human breast milk, or whether it could have any harmful effects on nursing infants or on milk production. The medication was found in the milk of treated rats, however, and may carry potential risks to breastfed children. Therefore, breastfeeding wasn’t recommended during treatment,and for at least two weeks after the last dose.

Patients who were or planned to become pregnant, and those who were breastfeeding or planned to, were advised to discuss the risks and their options during treatment with their healthcare team.

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