Voxelotor for Sickle Cell Disease

Voxelotor (previously called GBT440), is being developed as an oral, once-daily therapy for patients with sickle cell disease (SCD). Voxelotor is designed to work by helping hemoglobin, the molecules inside red blood cells, hold onto more oxygen as the red blood cells travel through the body. This keeps red blood cells in their normal shape and helps stop sickling.

In our ongoing clinical development program, we are evaluating the impact of voxelotor on abnormal polymerization of deoxy-hemoglobin, the underlying mechanism of red blood cell sickling. We believe that this mechanism is potentially relevant for all patients with SCD and have designed a clinical program targeted at the treatment of SCD patients across all ages and genotypes.

In recognition of the critical need for new treatments, the U.S. Food and Drug Administration (FDA) has granted voxelotor both Fast Track, Orphan Drug and Rare Pediatric Disease designations for the treatment of patients with SCD. The European Medicines Agency (EMA) has included voxelotor in its Priority Medicines (PRIME) program, and the European Commission (EC) has designated voxelotor as an orphan medicinal product for the treatment of patients with SCD.

About SCD

Sickle cell disease (SCD) is a chronic, inherited blood disorder that impacts hemoglobin, a protein found in red blood cells (RBCs) that carries oxygen throughout the body. The disease is caused by a genetic mutation in the beta-chain of hemoglobin, which results in the formation of abnormal hemoglobin known as sickle hemoglobin (HbS). 

In its deoxygenated state, HbS has a propensity to polymerize, or bind together into long, rigid rods within an RBC, much like a "sword within a balloon." As a consequence, the normally round and flexible RBC becomes rigid and elongated into a “sickled” shape. Polymerization causes the destruction of RBCs, known as hemolytic anemia. In addition, sickled RBCs, which do not flow properly in the bloodstream, clog small blood vessels and reduce blood flow to the organs. This results in inadequate oxygen delivery, or hypoxia, to all body tissues.

Sickle Cell Disease (SCD)

Who SCD Affects:
There are 90,000 to 100,000 SCD patients in the U.S., 60,000 SCD patents in Europe, and millions worldwide. SCD is a congenital disease, and symptoms and organ damage begin within the first years of life. This makes newborn screening (required in all states in the U.S.) and pediatric development of new therapeutics critical. Approximately one in 365 African American children in the U.S. is born with SCD and the global incidence of SCD is estimated to be 250,000 to 300,000 births annually. The disease is concentrated in populations of African, Middle Eastern and South Asian descent.

Among children with SCD, roughly 10–15 percent will suffer an overt stroke. Many more will experience one or more silent strokes, which are associated with brain damage and cognitive impairment.

The Need for New SCD Treatments:
SCD represents a global health problem and new treatment options are desperately needed.

Beginning in early childhood, SCD patients suffer unpredictable and recurrent episodes or crises of severe pain due to hypoxia (inadequate oxygen delivery to body tissues) and hemolytic anemia (the destruction of RBCs). This can lead to multi-organ damage and early death. A recent publication noted that in the United States, SCD results in a decrease of approximately 25 to 30 years in life expectancy.

SCD is also associated with high treatment costs. One study estimated that in the United States, the average annual cost for the care of an adult patient with the most common genotype of SCD exceeds $200,000. This equates to cumulative lifetime costs in excess of $8.0 million over an assumed 50-year lifespan, driven primarily by hospital admissions, physician fees, clinic and emergency department visits, and the costs of diagnostic procedures and outpatient consultations.

Clinical Studies

Our Phase 3 HOPE (Hemoglobin Oxygen Affinity Modulation to Inhibit HbS PolymErization) Study is active but no longer enrolling patients. The HOPE Study is evaluating whether voxelotor is effective in reducing the damage sickle cell disease causes to red blood cells and therefore, decrease the day-to-day symptoms in adults and adolescents who have the disease.

We are also studying voxelotor in patients 6-17 years of age in the Phase 2a HOPE-KIDS 1 Study.

For more information about our sickle cell disease clinical study program visit www.GBTSickleCell.com.

Click here to access information about the Phase 3 HOPE Study on ClinicalTrials.gov.

Click here to access information on the Phase 2a HOPE-KIDS 1 Study on ClinicalTrials.gov.

Mechanism of Action

Abstracts & Presentations

60th American Society of Hematology Annual Meeting & Exposition (2018)

46th Annual National Sickle Cell Disease Association of America Convention (2018)

23rd Congress of the European Hematology Association (2018)

Foundation for Sickle Cell Disease Research’s 12th Annual Symposium (2018)

American Thoracic Society International Conference (2018)

American Society of Pediatric Hematology/Oncology Conference (2018)

59th American Society of Hematology Annual Meeting & Exposition (2017)

SCDAA 45th Annual National Convention (2017)

Academy for Sickle Cell and Thalassemia 11th Annual Conference (2017)

22nd Congress of the European Hematology Association (2017)

58th American Society of Hematology Annual Meeting & Exposition (2016)

European Hematology Association’s (EHA) 21st Congress (2016)

10th Sickle Cell Disease Research and Educational Symposium (2016)

57th American Society of Hematology (ASH) Annual Meeting (2015)

56th American Society of Hematology (ASH) Annual Meeting (2014)

55th American Society of Hematology (ASH) Annual Meeting (2013)


Development and Validation of an Oxygen Dissociation Assay, a Screening Platform for Discovering and Characterizing Hemoglobin Oxygen Affinity Modifiers
M Patel, V Siu, A Silva-Garcia, Q Xu, Z Li, D Oksenberg
Drug Design, Development and Therapy. 2018 June 1; Volume 12; 1599-1607.

Impact of Voxelotor (GBT440) on Unconjugated Bilirubin and Jaundice in Sickle Cell Disease: A Patient Case Report
P Telfer, I Agodoa, K Fox, L Burke, T Mant, M Jurek, M Tonda, J Lehrer-Graiwer
Hematology Reports. 2018 May 22; Volume 10 (2); 50-52.

GBT440 Reverses Sickling of Sickled Red Blood Cells Under Hypoxic Conditions In Vitro
K Dufu, D Oksenberg
Hematology Reports. 2018 May 14; Volume 10 (2); 35-39.

Case Series of Patients with Severe Sickle Cell Disease Treated with Voxelotor (GBT440) by Compassionate Access
G Blyden, K Bridges, L Bronte
American Journal of Hematology. 2018 May 12; Volume 93 (8); E188-E190.

GBT440 Improves Red Blood Cell Deformability and Reduces Viscosity of Sickle Cell Blood Under Deoxygenated Conditions
K Dufu, M Patel, D Oksenberg, P Cabrales
Clinical Hemorheology and Microcirculation. 2018 Apr 13; Preprint; 1-11.

Voxelotor (GBT440), a First‐in‐Class Hemoglobin Oxygen‐affinity Modulator, Has Promising and Reassuring Preclinical and Clinical Data
J Estepp
American Journal of Hematology. 2018 Jan 20; Volume 93 (3); 326-329.

Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin
B Metcalf, C Chuang, K Dufu, M Patel, A Silva-Garcia, C Johnson, Q Lu, J Partridge, L Patskovska, Y Patskovsky, S Almo, M Jacobson, L Hua, Q Xu, S Gwaltney, C Yee, J Harris, B Morgan, J James, D Xu, A Hutchaleelaha, K Palanan, D Oksenberg, Z Li
ACS Medical Chemistry Letters. 2017 Jan 23; Volume 8 (3); 321–326.

GBT440 Inhibits Sickling of Sickle Cell Trait Blood Under In Vitro Conditions Mimicking Strenuous Exercise
K Dufu, J Lehrer-Graiwer, E Ramos, D Oksenberg
Hematology Reports. 2016 Sep 28; Volume 8 (3); 37-41.

GBT440, a Novel Sickle Haemoglobin Polymerisation Inhibitor, Increases Haemoglobin Oxygen Affinity and Results in a Rapid Improvement in Haemolysis and Anaemia
P Telfer, J Lehrer-Graiwer, M Tonda, E Ramos
European Medical Journal. 2016 Jul; Volume 4 (1); 63-64.

GBT440 Increases Haemoglobin Oxygen Affinity, Reduces Sickling and Prolongs RBC Half‐Life in a Murine Model of Sickle Cell Disease
D Oksenberg, K Dufu, M. Patel, C. Chuang, Z Li, Q Xu, A Silva‐Garcia, C Zhou, A Hutchaleelaha, L Patskovska, Y Patskovsky, S Almo, U Sinha, B Metcalf, D Archer
British Journal of Haematology. 2016 Jul 5; Volume 175 (1); 141-153.