GBT440 is a novel, small molecule haemoglobin oxygen affinity modifier. In vitro data has shown that by increasing sickle haemoglobin (HbS) oxygen affinity, GBT440 can delay HbS polymerisation and inhibit red blood cell sickling. By acting on the fundamental pathophysiologic mechanism in sickle cell disease (SCD), GBT440 has the potential to inhibit polymerisation, decrease red blood cell damage, and prevent the downstream clinical complications caused by haemolysis and vaso-occlusion. The GBT440-001 study was designed with the objective of understanding pharmacokinetics, pharmacodynamics, and safety, as well as to determine the effect on haemolysis and irreversibly sickled cells.
GBT440-001 is a randomised, placebo-controlled, double-blind, single and multiple ascending dose study evaluating GBT440 in both healthy subjects and patients with SCD. Data presented at EHA included 46 SCD patients at three dose levels including 6 patients who completed 700 mg/day for 90 days, 12 patients who completed 700 mg/day for 28 days, 10 patients who completed 500 mg/day for 28 days, 6 patients who completed 1,000 mg/day (administered as 500 mg twice a day for 28 days), and 12 patients who received placebo.
The 90-day results with GBT440 700 mg/day (n=6) showed a durable reduction in haemolysis from baseline to Day 90, as evidenced by a rapid and sustained reduction in bilirubin starting as early as Day 4 and continuing through Day 90 (median decrease of >35% compared with an increase of approximately 20% with placebo). A median 1.1 g/dL increase in haemoglobin was observed with GBT440 treatment compared with 0.2 g/dL decrease with placebo. A median decrease of approximately 20% in reticulocyte count, compared with an approximately 20% increase with placebo, suggested that the observed increase in haemoglobin is due to a decrease in haemolysis. A sustained reduction in irreversibly sickled cells was observed, with a median decrease of approximately 70% within 90 days compared to an increase of approximately 15% with placebo. Results from cohorts dosed for 28 days showed similar trends.
GBT440 was well-tolerated in all 28 and 90-day cohorts. There have been no drug-related serious or severe adverse events. The majority of adverse events were Grade 1 or 2 in severity and appeared in similar if not higher frequency in the placebo arms as compared to GBT440-treated arms. This data was presented in a moderated poster session at EHA, as well as in an educational session on novel SCD therapeutics. The results generated great interest among haematologists and investigators because of the large unmet need in SCD and the paucity of experimental drugs that directly target the underlying mechanism of disease and therefore have the potential to chronically control symptoms and disease progression. Many SCD investigators expressed interest in participating in future studies with this compound. These results suggest that GBT440 is rapidly and durably inhibiting HbS polymerisation in vivo at well- tolerated doses, and that a meaningful reduction in haemolysis and anaemia is achieved. Given that the mechanism of action of GBT440 addresses the underlying pathophysiology of sickling, these results suggest the potential of GBT440 to modify the course of this devastating disease over time. Future clinical studies to investigate GBT440’s potential clinical benefit in longer duration studies are being planned.