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Researchers say the small molecule GBT440 could be a disease-modifying agent for patients with sickle cell disease (SCD).
Preclinical data showed that GBT440 can reduce sickling, extend the circulating half-life of red blood cells (RBCs), and decrease excessive erythropoiesis in SCD.
GBT440 binds specifically to hemoglobin and is designed to inhibit sickle hemoglobin (HbS) polymer formation.
“One promising strategy for preventing red blood cell sickling and subsequently modifying sickle cell disease over the long term involves inhibiting polymerization of HbS in red blood cells,” said David R. Archer, PhD, of Emory University School of Medicine in Atlanta, Georgia.
“This can be achieved by increasing the proportion of oxygenated HbS in those cells. We believe our preclinical results provide strong evidence that GBT440 inhibits HbS polymerization and red blood cell sickling, which is important because it addresses the underlying pathophysiology of sickle cell disease and has the potential to change its devastating clinical course.”
Dr Archer and his colleagues reported these results in the British Journal of Haematology. The research was supported by Global Blood Therapeutics, Inc., the company developing GBT440.
The researchers reported that, in vitro, GBT440 dose-dependently increased the affinity of HbS for oxygen, delayed polymerization of HbS, and reduced the number of sickled RBCs in whole blood from SCD patients.
In an animal model of SCD, GBT440 inhibited RBC sickling, prolonged the half-life of RBCs, and reduced reticulocyte counts.
The researchers said the drug also exhibited favorable pharmacokinetic properties in various animal species, suggesting the potential for once-daily oral dosing in SCD patients.
“Our preclinical work has developed a foundation of evidence that GBT440 is a potent inhibitor of the polymerization of HbS,” said Ted W. Love, MD, chief executive officer of Global Blood Therapeutics, Inc.
“We continue to build on these data with our ongoing phase 1/2 study, which has shown that GBT440 was well-tolerated over 90 days of dosing and that all SCD patients who received multiple doses of GBT440 exhibited improvements in one or more clinical markers of hemolysis and anemia. Our next step is to initiate a pivotal trial in adults with SCD later this year.”
