Hemoglobin Modifier GBT440: A New Option for Patients with Sickle Cell Disease

Patients with sickle cell disease (SCD) who received GBT440, a novel oral small molecule hemoglobin modifier, had a reduction in sickle cells, a reduction in hemolysis, and an improvement in anemia, according to preliminary data from an early-phase ongoing trial.

Claire Hemmaway, MD, the lead hematology consultant at Queens Hospital in Essex, United Kingdom, and colleagues explored the safety, pharmacokinetics, pharmacodynamics, and potential efficacy of GBT440 in a prospective, randomized, placebo-controlled, double-blind, parallel-group phase I/II study of healthy volunteers and SCD patients. The study was presented at the ASH annual meeting last month.

GBT440 works by increasing hemoglobin oxygen affinity, the authors explained, and has been shown to be a potent and direct anti-sickling agent with high specificity for hemoglobin in in vitro and in vivo studies. “This drug is potentially disease-modifying for patients with sickle cell disease,” Dr. Hemmaway said in a discussion of the results. “We hypothesized that [GBT440] should rapidly interrupt red blood cell hemolysis, improve anemia, and potentially become a safe and effective long-term therapy.”

The study was conducted in two parts: part A tested single ascending doses and part B multiple ascending doses of study drug with 6:2 randomization (GBT440:placebo).

Doses administered were:

  • Part A: 100-2,800 mg in healthy volunteers and 1,000 mg in SCD patients
  • Part B: 300-900 mg once-daily for 15 days in healthy volunteers and 700 mg once-daily for 28 days in SCD patients

Patients were monitored closely in a clinical research unit for the first four days of treatment, so researchers could identify any potential side effects and monitor how GBT440 is absorbed at each dose. After the initial four days, patients were able to leave the unit and come back for periodic checks.

Sixty-four healthy volunteers and 16 SCD patients had been enrolled in the study at the time of presentation. Among healthy volunteers, 54 had completed the study, two had discontinued due to non-serious adverse events (AEs; headache and rash), and eight were in follow-up; among SCD patients, eight had completed part A of the study and eight were in part B follow-up. None of the SCD patients had discontinued, but one patient in part B of the study had a dose reduction from 700 mg to 400 mg (due to abdominal discomfort).

In terms of safety (the trial’s primary endpoint), GBT440 was “generally well tolerated,” the authors reported, with mostly mild AEs and no deaths. One serious AE (an acute painful crisis) occurred in a patient taking placebo.

The most common AEs associated with GBT440 were headache and sickle cell crisis; all instances of reported sickle cell crises occurred after discontinuation of the study drug.

“GBT440 showed dose-proportional pharmacokinetics,” Dr. Hemmaway and colleagues observed, with a terminal half-life of 1.5 to three days and a dose-dependent increase in hemoglobin oxygen affinity in both healthy volunteers and SCD patients. GBT440-treated patients showed increased hemoglobin, hematocrit, and erythrocyte counts with corresponding decreases in LDH, unconjugated bilirubin, reticulocytes, and erythropoietin levels (TABLE).

When the researchers analyzed peripheral blood smears, they also observed a marked reduction in sickle cells among GBT440-treated patients – decreasing by 56 percent and 46 percent in the 500 mg and 700 mg cohorts, respectively. Patients receiving placebo, however, experienced a 14 percent increase in median sickle cell counts.

Overall, daily dosing with GBT440 “demonstrated proof of mechanism with a dose-dependent increase in hemoglobin oxygen affinity without causing tissue hypoxia,” the authors concluded. These results, they added, support further clinical investigation of GBT440. The current ongoing trial aims to enroll 128 patients, and the trial is now enrolling research subjects who will take GBT440 for as long as 90 days.

“Our expanding experience with GBT440 shows that it is a promising and well-tolerated investigational treatment,” Dr. Hemmaway said. “These results are exciting because patients with SCD desperately need a mechanism-based treatment option that can transform their disease.”


Lehrer-Graiwer J, Howard J, Hemmaway CJ, et al. GBT440, a potent anti-sickling hemoglobin modifier reduces hemolysis, improves anemia and nearly eliminates sickle cells in peripheral blood of patients with sickle cell disease. Abstract #542. Presented at the 2015 ASH Annual Meeting, December 7, 2015; Orlando, Florida.

TABLE. Changes in Pharmacodynamic/Pharmacokinetic Measures in GBT440-Treated Versus Placebo-Treated Patients
Mean Change at Day 28
GBT440 Placebo
Hemoglobin (g/dL) 0.8 (0.2) –0.5 (0.4)
Percent of sickle cells in peripheral blood –83 (9) 19 (4)
Erythrocyte count (1012/L) 0.5 (0.1) –0.1 (0.2)
Reticulocyte count (%) –2.2 (1) 0.8 (1.6)
LDH (percent change from baseline) –12 (7) –9 (1)
Unconjugated bilirubin (percent change from baseline) –25 (10) –9.6 (16)
Erythropoietin (U/L) –29 (16) 21 (33)