Rheological Impact of GBT1118 Cessation in a Sickle Mouse Model

Abstract

In sickle cell disease (SCD), higher whole blood viscosity is a risk factor for vaso-occlusive crisis, avascular necrosis, and proliferative retinopathy. Blood viscosity is strongly impacted by hemoglobin (Hb) levels and red blood cell (RBC) deformability. Voxelotor is a hemoglobin S (HbS) polymerization inhibitor with anti-sickling properties that increases the Hb affinity for oxygen, thereby reducing HbS polymerization. In clinical trials, voxelotor increased Hb by an average of 1g/dl, creating concern that this rise in Hb could increase viscosity, particularly when the drug was cleared. To investigate this potential rebound hyperviscosity effect, we treated SCD mice with GBT1118, a voxelotor analog, and stopped the treatment to determine the effect on blood viscosity and RBC deformability under a range of oxygen concentrations. GBT1118 treatment increased Hb, improved RBC deformability by increasing the elongation index under normoxic (EImax) and hypoxic conditions (EImin), and decreased the point of sickling (PoS) without increasing blood viscosity. The anti-sickling effects and improvement of RBC deformability balanced the effect of increased Hb such that there was no increase in blood viscosity. Forty-eight hours after ceasing GBT1118, Hb declined from the rise induced by treatment, viscosity did not increase, and EImin remained elevated compared to control animals. Hb and PoS were not different from control animals, suggesting a return to native oxygen affinity and clearance of the drug. RBC deformability did not return to baseline, suggesting some residual rheological improvement. These data suggest that concerns regarding viscosity rise above pre-treatment levels upon sudden cessation of voxelotor are not warranted.

Effects of GBT1118, a voxelotor analog, on intestinal pathophysiology in sickle cell disease

“…The median splenic weight was 1.9 g (range 1.69–3.49) in mice fed with the control chow, whereas the median splenic weight was 1.36 g (range 1.25–1.55) in the GBT1118‐treated mice ( p = 0.004). Our findings of lesser splenomegaly and higher Hb concentrations are, therefore, consistent with a previous study in mice showing reduced haemolysis with subsequent increase in the haemoglobin when the mice were treated with GBT1118 18 …”

“…GBT1118 has been incorporated into the chow for laboratory animals and can, therefore, be administered to mice without any oral gavages. This strategy of incorporating the GBT1118 into chow has previously been shown to provide the dose of the Hb allosteric modifier that resulted in a Hb occupancy of around 30% in mice, comparable to that obtained in voxelotor‐treated patients 18 . GBT1118 improved oxygen delivery to hypoxic tissues in various mouse models of hypoxic tissue injury 19,20 .…”

“…This strategy of incorporating the GBT1118 into chow has previously been shown to provide the dose of the Hb allosteric modifier that resulted in a Hb occupancy of around 30% in mice, comparable to that obtained in voxelotor-treated patients. 18 GBT1118 improved oxygen delivery to hypoxic tissues in various mouse models of hypoxic tissue injury. 19,20 It also protects SCD mice from renal damage due to chronic haemolysis and haemoglobinuria by reducing the urine reactive oxygen species.…”

“…Our findings of lesser splenomegaly and higher Hb concentrations are, therefore, consistent with a previous study in mice showing reduced haemolysis with subsequent increase in the haemoglobin when the mice were treated with GBT1118. 18 F I G U R E 4 Recovery of intestinal abnormalities 3 weeks following VOC. Recovery was faster in small intestinal permeability to FITC-Dextran 4k (A), iFABP (B), microbial density (C) and serum LPS (D) in mice treated with GBT1118 than in mice fed with control chow.…”

“…GBT1118, an analogue of voxelotor, has been designed for use in the transgenic sickle cell disease mice to investigate the effects of voxelotor. It has better pharmacokinetic properties 18 than voxelotor. GBT1118 has been incorporated into the chow for laboratory animals and can, therefore, be administered to mice without any oral gavages.…”