GBT021601 improves red blood cell health and the pathophysiology of sickle cell disease in a murine model

Abstract

The pathophysiologic mechanism of sickle cell disease (SCD) involves polymerization of sickle haemoglobin (HbS) following deoxygenation in the microvasculature, leading to red blood cell (RBC) sickling and decreased RBC health, deformability and survival. 1,2 These abnormalities drive haemolysis, anaemia, vascular inflammation and microvasculature occlusions, resulting in clinical complications, such as fatigue, painful vaso-occlusive crisis, reduced quality of life, considerable end-organ damage and premature death. 1,2 Voxelotor is a first-in-class polymerization inhibitor approved by the US Food and Drug Administration for the treatment of SCD in patients aged ≥4 years and in Great Britain, the European Union, the United Arab Emirates, Kuwait, and Oman in patients aged ≥12 years. Voxelotor is a reversible covalent modifier of Hb that allosterically increases Hb-O 2 affinity, thereby increasing the proportion of oxygenated Hb in all RBCs. 3,4 GBT021601 is a potent second-generation HbS polymerization inhibitor with the same mechanism of action as voxelotor. Herein, we present the in vitro characterization of GBT021601 using blood

More of the same? Voxelotor spawns a successor, but on what success does it build?

“…The diminished oxygen unloading is dramatically displayed in figure 1I of Ref. [9] (And lest the reader interpret Figure 6C as indicative of ample oxygen transport, it must be noted that what is shown is a calculation which combines pumping rate with oxygen content, and thus describes oxygen carried in the circulation, which is not oxygen delivered to the tissues given reluctance of the modified HbS to deliver its oxygen. )…”

“…This motivates the therapeutic approach of restraining T-state formation so as to block polymer formation, which is the premise of voxelotor, and its successor GBT021601. 9 By binding to the terminus of the α chain, the drug obstructs one of the salt bridges that stabilize the T structure, and by stretching across to the other α chain, also occludes its symmetry-related partner. (It is a bit of a misnomer to say that the R-state has become more stable.)…”

“…Into this complicated state of affairs, a successor drug to voxelotor has now been developed. 9 This new agent binds to the same α chain terminus target, thus disrupting the same salt bridge. To no surprise, then, the outcome is virtually identical in terms of shifted p50.…”