Oxbryta (Voxelotor)

Oxbryta (voxelotor), formerly known as GBT440,  is an oral daily therapy developed by Global Blood Therapeutics (GBT) for the treatment of sickle cell disease (SCD).

It was approved conditionally by the U.S. Food and Drug Administration (FDA) in November 2019 to treat adults and adolescents, ages 12 and older, with SCD, thereby becoming the first approved therapy targeting the underlying cause of SCD. GBT is planning to file an application with the FDA requesting the expansion of Oxbryta’s current label to include children as young as 4.

Oxbryta is under regulatory review in Europe to treat SCD in individuals 12 and older. In December 2020, GBT launched an early access program for Oxbryta in Europe and other areas outside the U.S. to treat patients 12 and older who have no alternative treatment options and are unable to access the medication through clinical trials.

How does Oxbryta work?

Oxbryta is a small molecule that addresses the underlying cause of SCD, which is the clumping and sticking of faulty hemoglobin molecules into rigid, long rods that deform red blood cells into a sickle or crescent-like shape. Hemoglobin is the protein inside red blood cells that is responsible for oxygen transport.

Red blood cell sickling destroys red blood cells (hemolysis), lowers hemoglobin levels, and blocks small blood vessels, triggering vaso-occlusive crises (VOCs).

The therapy works by binding to hemoglobin and increasing its affinity to oxygen, preventing its clumping and the subsequent sickling and destruction of red blood cells. As such, the therapy is expected to restore normal red blood cell function and oxygen delivery to tissues, reducing anemia, hemolysis, and VOCs.

Oxbryta in clinical trials

A placebo-controlled Phase 1/2 trial (NCT02285088) and its open-label extension study (NCT03041909) evaluated Oxbryta’s safety, tolerability, pharmacokinetics, and pharmacodynamics in 133 healthy volunteers and people with SCD.

Pharmacokinetics refers to the therapy’s movement into, through, and out of the body, while pharmacodynamics pertains to its effects on the body.

Participants, recruited at a single site in London, U.K., were assigned randomly to receive either Oxbryta (500–1,000 mg) or a placebo daily for up to 118 days (nearly four months). Five patients then enrolled in the extension study to continue treatment for up to six months.

Data from both trials showed the therapy was well-tolerated and resulted in an increase in hemoglobin levels and in a profound and durable reduction in hemolysis and sickled cells in SCD patients.

Those and previous positive findings supported Oxbryta as a potential disease-modifying therapy for SCD, and prompted GBT to launch a pivotal Phase 3 trial, called HOPE (NCT03036813). The global study assessed the safety and effectiveness of Oxbryta (900 mg or 1,500 mg oral tablets) against a placebo in 274 adults and adolescents, ages 12 to 65, with SCD.

Top-line results from the first six months of treatment showed that 51% of the 90 patients receiving 1,500 mg of Oxbryta — the now-approved dose — achieved a hemoglobin response, defined as a hemoglobin raise of at least 1 gram per deciliter (g/dL), compared with 7% of those on a placebo.

The higher dose also significantly lowered the levels of bilirubin and reticulocytes — two biomarkers of hemolysis.

Notably, these benefits were seen regardless of concurrent use of hydroxyurea, a standard treatment to reduce VOCs frequency and the need for blood transfusions.

HOPE’s longer-term data, of nearly 1.5 years of treatment, confirmed the six-month findings and revealed that Oxbryta also was superior to a placebo at lowering VOCs frequency and at easing, or fully healing, painful leg ulcers. The therapy continued to be generally safe and well-tolerated.

The GBT-sponsored Phase 2 HOPE-KIDS 1 study (NCT02850406) is evaluating Oxbryta’s safety, pharmacokinetics, and early effectiveness in up to 155 children and adolescents, ages 9 months to 17 years, with SCD. The study is divided into four parts (A to D), each involving children of different ages assigned to receive single or multiple doses of the therapy, given at the 1,500 mg approved dose or a weight-based equivalent dose.

Recently presented interim data covered the first 45 children, ages 4–11, treated with Oxbryta for at least six months in group C (which includes children ages–17). The therapy was found to result in similar rises in hemoglobin levels and reductions in hemolysis to those observed in older patients who received the approved dose in HOPE.

If confirmed at one year of treatment, these findings are expected to support GBT’s planned request to expand the use of Oxbryta in the U.S. to children as young as 4.

HOPE-KIDS 1, now underway in the U.S., U.K., and Lebanon, is still enrolling patients for its part C, and has started recruitment of 30 infants and young children, ages 9 months to 3 years, for its part D. The trial is expected to finish by December 2022.

GBT also launched the international, placebo-controlled Phase 3 HOPE-KIDS 2 study (NCT04218084) to serve as a confirmatory trial for Oxbryta’s full approval in the U.S. The study is currently recruiting up to 224 children, ages 2–14, with SCD at sites across the U.S., Africa, and Europe.

The trial’s main goal is to assess whether Oxbryta is superior to a placebo at reducing the risk of stroke — as assessed through a non-invasive ultrasound that detects changes in brain blood flow — in pediatric patients after 24 weeks of treatment. Of note, children with SCD are at a higher risk of stroke due to disease-associated increased blood flow in certain brain arteries.

Secondary goals include other stroke risk evaluations and changes in the levels of hemoglobin and markers of hemolysis over time. The trial is expected to conclude in March 2026.

A multicenter Phase 4 study, called ActIVe (NCT04400487), also is investigating Oxbryta’s effects on physical activity and sleep quality, as measured by a validated wrist-worn device, in up to 50 SCD patients, ages 12–55, living in the U.S. Enrollment is ongoing and the study is anticipated to end by February 2023.

Other details

Oxbryta received fast track, orphan drug, rare pediatric disease, and breakthrough therapy designations in the U.S. for the treatment of SCD. It also was granted priority medicine and orphan drug designations in Europe and promising innovative medicine designation in the U.K. for the same indication. These designations are meant to accelerate the therapy’s development and regulatory review.

The most common adverse events, or side effects, associated with the use of Oxbryta are headaches, diarrhea, abdominal pain, nausea, fatigue, rash, and fever.


Last updated: June 18, 2021


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