Voxelotor (<scp>GBT</scp>440), a first‐in‐class hemoglobin oxygen‐affinity modulator, has promising and reassuring preclinical and clinical data
Authors: Jeremie H. Estepp
Journal: American Journal of Hematology (2018)

Concern: "…it seems uncertain whether the 30% modification by GBT440 would actually be protective for HbS polymerization under in vivo conditions." The kinetics of deoxy-sickle hemoglobin (deoxy-HbS) polymerization are unusual. Prior to polymerization, there is a delay period (inversely proportional to the 30th power to the deoxy-HbS concentration) followed by rapid progression of polymer formation.4 This translates to dramatic increases in the delay time with small reductions in deox-HbS concentrations. In in vitro studies, voxelotor modified HbS (voxelotor-HbS) maintains an oxyhemoglobin state under hypoxic conditions and delays polymerization of unmodified HbS and imparts similar delay times as fetal hemoglobin (HbF) (Figure 1).3 The Hebbel model assumed a left shift of the p50 to 18 mm Hg for 30% voxelotor-HbS,5 however, the p50 at 1000 mg per day is more modest than this at 28 mm Hg with 27% modification.6, 7 In adults with SCD who received 500 mg (n = 10) or 700 mg of voxelotor for 28 days, irreversibly sickled cells were reduced, and five individuals continued 700 mg for 90 days and had a sustained reduction in irreversibly sickled cells and irreversibly sickled cells present at 28 days was sustained (Figure 2).8 Voxelotor-modified HbS delays polymerization of unmodified HbS with similar delay times as HbF. Graphs (n = 2, in duplicate) showing polymerization delay times elicited by voxelotor-HbS (A) or HbF (B) mixed with various percentages of unmodified HbS. The total Hb concentration per reaction is 50 µmol/L. Adapted3 from Okensberg BJH 2016 [Color figure can be viewed at wileyonlinelibrary.com] Relative change from baseline of irreversibly sickled cells at days 28, 60, and 90 with adult participants treated with placebo (n = 2) and 700 mg of Voxelotor (n = 6). Horizonal line indicates median values and the error bars represent the 25th-75th percentiles. *Day 90 has 5 of 6 subjects treated with voxelotor. Adapted9 from Lehrer 21st Congress of EHA 2016 [Color figure can be viewed at wileyonlinelibrary.com] Concerns: (1) Are the increases in hemoglobin seen in patients treated with GBT440 a pyrrhic victory? (2) Does a 30% GBT-HbS modification with a starting hemoglobin of 8 g/dL reduce the oxygen delivery potential to being the equivalent to a hemoglobin of 5.6 g/dL? These concerns are based on the idea of "Functional Oxygen Content" (FOC), where the FOC is what remains of hemoglobin's total oxygen content after the contribution from an extreme-affinity component is subtracted out.5 The assumption is that the voxelotor–HbS complex (the therapeutic goal for voxelotor is to modify 20%-30% of HbS) with increased affinity for oxygen decreases (or eliminates) its ability to deliver oxygen to peripheral tissues in the setting of low capillary pO2. In the setting of acute hypoxia, serum erythropoietin (EPO) levels begin to rise within hours and peak around day #3, and this rise in EPO is closely followed by a wave of reticulocytosis beginning on day #2 of hypoxia.10 In children with SCD, after 16 weeks of 900 mg of voxelotor, the median (IQR) change in hemoglobin compared to baseline was +1.1 g/dL (0.2-1.6 g/dL), and 55% (n = 6/11) of children had an increase of greater than 1 g/dL.8 A similar magnitude in the rise of hemoglobin was observed in adults.10 As Hebbel and Hedlund explain, this magnitude of rise in hemoglobin would be insufficient to mitigate a functional oxygen delivery loss of the 20%-30% of voxelotor-Hb. The hematologic response following initial exposure to voxelotor is provided in Figure 3. After four days of receiving 500 mg (n = 10), adults with SCD have stable to slightly lower EPO levels compared to baseline, no change in reticulocyte counts, and increases in hemoglobin values.11 After 28 days of voxelotor, higher hemoglobin levels and lower reticulocyte percentages compared to baseline are observed in the setting of stable to slightly lower EPO levels11 and this relationship persists for up to 90 days with exposure to voxelotor.9 Relative change from baseline of hemoglobin (g/dL) and reticulocytes (%) at days 4, 8, 15, 22, 25, and 28 with adult participants treated with placebo (n = 8), 500 mg (n = 10), and 700 mg (n = 12) of voxelotor. Horizonal line indicates median values and the error bars represent the 25th-75th percentiles. Adapted11 from Lehrer-Graiwer ASH 2015 [Color figure can be viewed at wileyonlinelibrary.com] Concern: In a hypoxemic patient the P50 left-shifting effect of GBT440 could be dangerously deceptive. The drug modified tetramers would reassuringly bolster measured oxygen saturation measures, but this would not translate to oxygen delivery benefit. Giving GBT440 to any patient with hypoxia would be highly inadvisable. Concern: A rising hemoglobin in response to GBT440 may reflect successful inhibition of polymerization, but this may need not be the case. Indeed, an argument can be made that the drug effect would tend to favor inhibition of the polymerization-independent pathway to sickle RBC destruction previously described that supposedly accounts for two-thirds of hemolysis. Both adults1, 8 and children8 and children treated with voxelotor see reductions in hemolysis with lower levels of unconjugated bilirubin, lactate dehydrogenase, and reticulocytes. The initial drop in bilirubin occurs as early as day #4 after exposure to voxelotor, which corresponds to when a rise in hemoglobin is observed and the reticulocyte count has not begun to decline. Concern: Cerebrovascular Jeopardy Without question, the further study on the effect of voxelotor on cerebrovascular blood flow and oxygen delivery to the brain are warranted. The data currently available is in twelve children who had normal baseline transcranial Doppler ultrasounds prior to and following 12 weeks of voxelotor and shows no evidence of an increase in cerebral blood flow velocity as predicted by the model proposed by Hebbel and Hedlund.5 Further evaluations are underway at St. Jude Children's Research Hospital in children enrolling in the ongoing HOPE-KIDS1 trial. Our working hypothesis, given the clinical data reported, is not that voxelotor places individuals with SCD at greater risk of cerebrovascular injury. To the contrary, we hypothesize voxelotor will be of benefit and reduce cerebrovascular blood flow and improve oxygen delivery. Hebbel and Hedlund should be commended for their expert commentary that is a thoughtful, well-crafted, and detailed hypothetical and theoretical model. Indeed, this thought experiment should be performed for all upcoming agents in this new therapeutic class. I suspect that the balance of oxygen-affinity to combat polymerization versus oxygen-delivery to peripheral tissues will be different for each compound. Nevertheless, the available preliminary preclinical and clinical data for voxelotor cannot be explained by the theoretical Hebbel and Hedlund model and suggests that Eaton and Bunn were correct when they cautioned the physiology of oxygen delivery to peripheral tissues is too complicated to be predicted based on biophysical studies with regards to oxygen affinity-shifting agents.12 The preliminary data for voxelotor is promising. I eagerly await data from the definitive trials. I remain hopefully optimistic. JHE receives funding support from Pfizer and Eli Lilly and Co and serves as a consultant for Daiichi Sankyo and Global Blood Therapeutics. Global Blood Therapeutics did not financially support the writing of this manuscript, nor did they have intellectual input in its design, format or construction.