A lack of objective metrics in
Sickle Cell Disease (SCD) makes it difficult to assess individual patient
therapy options or assess the effects of
therapy. This is further complicated by mechanisms of action involving multiple interconnected effects, that combine to relieve SCD symptoms. In 2019, based on the increase in
hemoglobin concentration observed in the HOPE trial, the Food and Drug Administration approved
voxelotor (Oxbryta®, Global Blood
Therapeutics) for SCD patients 12 years and older. The main mechanism of action for
voxelotor was increased
hemoglobin-
oxygen affinity, but other mechanisms may apply. In this study, we assessed the effect of
GBT1118, an
Oxbryta analog, on
hypoxia-induced lethal and sub-hemolytic red blood cell (RBC) membrane damage using RBC Mechanical Fragility (MF), a metric of existing membrane damage and prospective
hemolysis. RBC MF was measured non-invasively using a proprietary system comprising an electromagnetic bead mill and fiberoptic spectrophotometry detection. Three cycles of severe
hypoxia (<5% oxygenated
hemoglobin) with follow-up reoxygenation resulted in a significant increase in RBC MF for all SCD (Hb-S >60%) samples. Supplementation with
GBT1118 caused no significant changes in pre-
hypoxia RBC MF. However, following
GBT1118 treatment, cell stability showed significantly less degradation, as evidenced by a significantly smaller RBC MF increase after three cycles of
hypoxia-reoxygenation. These findings indicate that
GBT1118 prevents
hypoxia-induced membrane damage in sickled RBC, in part by alternative mechanisms not associated with induced changes in
hemoglobin-
oxygen affinity.