Sickle cell disease (SCD) is a serious and life-threatening genetic disorder where the red blood cells, which carry oxygen around the body, develop abnormally and become rigid and shaped like a crescent (sickle shape). These cells die early, leaving a shortage of healthy red blood cells (anaemia) and block the flow of oxygen through the body resulting in pain, fatigue, strokes, organ damage, and other serious complications.

Currently, the only known cure for SCD is bone marrow transplant but is expensive and getting compatible donors is difficult. However, SCD can be controlled by use of various medications and supplements. Before 2017, the only known medication approved for preventing the painful episodes was hydroxyurea. Hydroxyurea works by increasing the amount of hemoglobin F in the blood which reduces the quantity of the sickled red blood cells. In the US, the recently approved treatment options include L-glutamine, voxelotor, and crizanlizumab-tmca.  

GBT021601 works by increasing oxygen binding capacity thus reducing sickling of red blood cells. Treatment with GBT021601 has also led to significant reductions in sickle cell counts in the peripheral blood, which supports the potential for voxelotor to serve as a disease-modifying therapy for SCD. 

This study will be conducted in multiple sites globally, the main purpose is to evaluate the long-term effects of GBT021601. The study will include participants aged 6 months and older with SCD who have participated in a GBT021601 study and meet eligibility criteria.

Sickle cell disease (SCD) is a serious and life-threatening inherited hemoglobin (Hb) disorder caused by a single amino acid substitution in the beta (β)- globin gene (β^s c.20A>T; rs334). Patients with SCD endure chronic hemolytic anaemia and acute and recurrent clinical events that vary in frequency and severity, the most common being VOCs. . Vaso-occlusive crises are caused by activation of the endothelial cells, neutrophils, monocytes and platelets by the sickled red blood cells leading to aggregation and adhesion of these cells to one another and to the endothelial cells leading to clot formation and blockage of the microvascular channels. Despite current standards of care, including hydroxyurea (HU), blood transfusion, and supportive care with analgesia, patients with SCD continue to suffer serious morbidity and premature mortality. There exists a significant unmet medical need for safe and effective therapies for the treatment of SCD that result in both an improvement in anaemia and reduction in sickle cell–related crises.

Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative therapy for SCD. HSCT in children with SCD is associated with overall and event-free survival rates of 95% and 92%, respectively. However, HSCT use is limited by the paucity of suitable donors, the risk of graft-versus-host disease, infections, infertility, and other long-term transplant-related complications. Moreover, HSCT is generally available only in high-income countries and not commonly used in older patients with significant morbidity (Kassim, 2017). This study will look at the molecule GBT021601. The objectives of the study are to evaluate the long-term safety and frequency of SCD-related complications of daily dosing of GBT021601 in participants with SCD, to evaluate the effects of long-term use of GBT021601 on hemolytic anemia, to evaluate the the long-term effects of GBT021601 treatment on inflammation, erythropoietin levels, quality of life assessments, and SCD- specific biomarkers and to evaluate the pharmacokinetic parameters of long term exposure to GBT021601.

GBT021601 is an HbS polymerization inhibitor being developed by GBT for the treatment of SCD. GBT021601 increases hemoglobin-oxygen (Hb-O₂) affinity and stabilizes hemoglobin (Hb) in the oxy-hemoglobin (oxyHb) state thereby inhibiting polymerization of HbS in RBCs. By addressing this underlying mechanism of SCD, GBT021601 has the potential to be a disease-modifying therapy, leading to improved anemia, reduced hemolysis and the potential to reduce the end-organ damage resulting from chronic hemolytic anemia.

This is a multicenter, global, open-label extension study to evaluate the long-term safety, tolerability, and sickle cell disease (SCD) related complications of participants who have been treated with GBT021601.

The study will be conducted at up to 50 global sites, and up to approximately 500 participants will be enrolled. It would be available to eligible participants enrolled in a prior GBT-sponsored GBT021601 clinical study (originating study) and these participants must meet the entry criteria for this study to be eligible for enrollment. In Kenya, the study will be conducted at KEMRI-CRDR Siaya and Nairobi sites. Eligible participants will receive GBT021601 administered orally daily if they continue to receive clinical benefit that outweighs risk, as determined by the Investigator, until the participant has access to GBT021601 from an alternative source.

The results of this study will be important in defining new additional treatment for SCD.