Voxelotor (previously GBT440) is an investigational oral therapy being developed by Global Blood Therapeutics for the treatment of sickle cell anemia.

The U.S. Food and Drug Administration granted voxelotor fast track, orphan drug, rare pediatric disease, and breakthrough therapy designations for the treatment of sickle cell anemia.

In addition, the European Medicines Agency (EMA) has included voxelotor in its priority medicines (PRIME) program, and the European Commission (EC) has granted the medicine orphan drug designation for the treatment of sickle cell anemia.

How voxelotor works

Red blood cells contain a protein called hemoglobin that binds oxygen. This enables the transport of oxygen around the body. Sickle cell anemia is caused by a genetic mutation in the HBB gene that provides instructions for making a component of hemoglobin. The mutation results in the formation of an abnormal hemoglobin molecule called sickle hemoglobin or HbS.

HbS has a propensity to polymerize or stick together, forming long, rigid rods within red blood cell. This causes red blood cells to become stiff and elongated into a sickle or crescent shape instead of adopting their normally round and flexible shape. As a result, they cannot flow properly in the blood vessels, reducing oxygen delivery to different tissues in the body. 

Voxelotor has the potential to selectively bind to hemoglobin, and increase its affinity for oxygen. It also inhibits hemoglobin polymerization and prevents red blood cells from becoming deformed. This should restore normal red blood cell function and oxygen delivery. It should also help reduce the risk of pain crises caused by sickle cells blocking blood vessels.

Voxelotor in clinical trials

Voxelotor is currently being evaluated in four clinical trials for the treatment of sickle cell anemia.

A randomized, placebo-controlled, double-blind Phase 1 clinical trial (NCT02285088), with a Phase 2 extension study (NCT03041909) was completed in February 2018.

These studies aimed to assess the safety, tolerability, pharmacokinetics (movement in the body), and pharmacodynamics (effect on the body) of voxelotor in healthy volunteers and people with sickle cell anemia.

The initial trial enrolled 133 participants to receive voxelotor or a placebo daily for up to 118 days, at a single site in London, England. Five patients enrolled in the open-label extension study to continue receiving voxelotor daily for up to six months.

The full results have not been announced yet but initial results showed an increase in hemoglobin with a profound and durable reduction in hemolysis or the rupturing of red blood cells, and sickle cells in the blood. These data, together with prior data, support the safety and tolerability profile of voxelotor.

A case report of one patient completing both trials has been published in the journal Hematology Reports. Treatment with voxelotor cleared the patent’s jaundice after one week, including scleral icterus, where the eyes appear yellow, and markedly improved his perceived quality of life.

Voxelotor is now being investigated in two clinical trials as part of the GBT HOPE program to further demonstrate its safety and capacity to modify the course of the disease The Phase 2 study, HOPE-KIDS 1 (NCT02850406) aims to recruit up to 41 patients, ages 12-17, at several U.S.-based sites.

A pivotal Phase 3 study, GBT_HOPE (NCT03036813), is recruiting up to 400 patients, ages 12 to 65, worldwide. 

Other details

The most common adverse events associated with the use of voxelotor are headaches. No treatment-related serious adverse events have been reported.

Voxelotor is also being studied as a potential therapy to treat hypoxemia (low levels of oxygen in the blood) in patients with idiopathic pulmonary fibrosis (IPF).


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