ASH Annual Meeting and Exposition

ASH Annual Meeting and Exposition

Perspective from Alexis A. Thompson, MD, MPH
December 08, 2015
4 min read

Hemoglobin modifier appears safe, effective for sickle cell disease

Perspective from Alexis A. Thompson, MD, MPH
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ORLANDO, Fla. — GBT440, a novel oral small molecule hemoglobin modifier, reduced hemolysis and improved anemia without causing tissue hypoxia among patients with sickle cell disease, according to results of a placebo-controlled, double blind study presented at the ASH Annual Meeting and Exposition.

Treatment with GBT440 (Global Blood Therapeutics) also substantially reduced sickle cells in the peripheral blood of patients, according to researchers.

GBT440 works by increasing hemoglobin oxygen affinity. Preclinical data indicated that the therapy is a potent anti-sickling agent with a high specificity for hemoglobin. Further, results suggested between 10% and 30% modification of hemoglobin could safely prevent sickle hemoglobin (HbS) polymerization.

“These data further support the promising potential of GBT440 as a disease-modifying treatment for patients with sickle cell disease,” Claire Jane Hemmaway, MD, the lead hematology consultant at Queens Hospital in Essex, United Kingdom, told HemOnc Today. “GBT 440 is designed to bind hemoglobin to prevent polymerization of sickle hemoglobin, stop red blood cell destruction and improve oxygen delivery to tissues. Our expanding experience in sickle cell patients is consistent with GBT440 having these effects in patients and also shows that the drug is very well tolerated.”

Hemmaway and colleagues sought to explore the safety, pharmacokinetics and pharmacodynamics, and efficacy of the therapy in 30 patients (aged 18 to 60 years) with the HbSS genotype of sickle cell disease, as well as in 64 healthy volunteers (aged 18 to 55 years). Patients with sickle cell disease had baseline hemoglobin levels between 6 g/dL and 10 g/dL and had not experienced a vaso-occlusive crisis or received blood transfusion within 30 days prior to entering the study.

“We hypothesized that a potent anti-sickling hemoglobin modifier should rapidly interrupt red blood cell hemolysis, improve anemia and potentially become a safe and effective long-term disease-modifying therapy,” Hemmaway and colleagues wrote.

Hemmaway and colleagues conducted the study in two parts. The first part assessed single ascending doses of GBT440 and the second part assessed multiple ascending doses with a 6:2 randomization of GBT440 to placebo. GBT440 was administered orally.

In the first part of the study, healthy volunteers received GBT440 doses between 100 and 2,800 mg and patients with sickle cell disease received a 1,000 mg dose.  In the second portion of the study, healthy volunteers received between 300-mg and 900-mg doses once daily for 15 days and the sickle cell cohorts received 500 mg and 700 mg once daily for 28 days.

As of Nov. 20, 2015, 64 healthy volunteers had completed the study. Two individuals discontinued because of mild adverse events (headache and rash).

Eight patients with sickle cell disease had completed the single ascending dose first part of the study and 30 patients with sickle cell disease — including 14 on 500-mg GBT440 or placebo, and 16 on 700-mg GBT440 or placebo — had completed the multiple dose second part of the study. There were no discontinuations by patients with sickle cell disease, although one patient had a dose reduction from 700 mg to 400 mg due to mild abdominal pain and one patient had a protocol-specified dose reduction from 500 mg to 200 mg due to an increase in hemoglobin of more than 2 g/dL, which was not associated with symptoms.

GBT440 appeared well tolerated — all adverse events were considered mild to moderate, and no instances of tissue hypoxia occurred. Although the safety data is blinded, no deaths occurred, and there were four serious adverse events all unrelated to study treatment. Three of the serious adverse events were sickle cell crises that all occurred after the 28-day treatment period.

Researchers observed dose-proportional pharmacokinetics, a terminal half-life of 1.6 days in patients with sickle cell disease and 3 days in healthy volunteers, a high partitioning into red blood cells (75-90:1) and a dose-dependent increase in hemoglobin oxygen affinity in the entire study population.

All patients with sickle cell disease who were in the multiple-dose cohort (16 men, 15 women; age range, 19-56 years) were evaluable at 28 days.

Compared with patients assigned placebo, patients treated with GBT440 experienced a greater median change from baseline to day 28 in hemoglobin (500 mg, 0.5 g/dL; 700 mg, 0.7 g/dL vs. placebo, –0.1 g/dL), erythropoietin levels (500 mg, –9 mU/mL; 700 mg, –18 mU/mL vs. placebo, +28 mU/mL), reticulocyte count (500 mg, –31%, 700 mg, –37% vs. placebo, +7%).

Patients who received GBT440 achieved a 20% and 12% reduction in lactate dehydrogenase and 31% and 43% reduction in unconjugated bilirubin. An analysis of peripheral blood smears showed a pronounced reduction in the number of sickle cells (–56% and –46%) for those treated with GBT440 compared with a 14% increase with placebo.

The researchers indicated that trends in these changes were noticeable as early as day 4, whereas there were no changes in the placebo group.

“These results are exciting because patients with sickle cell disease around the world desperately need a mechanism-based treatment option that can transform their disease,” Hemmaway said. – by Anthony SanFilippo


Lehrer-Graiwer J, et al. Abstract 542. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.

Disclosure: The study was funded by Global Blood Therapeutics. The researchers report employment with, stock or other ownership in, consultant/advisory roles with and travel accommodations from Aes-Rx, Agios, GlaxoSmithKline, Global Blood Therapeutics, Novartis, Pfizer and Quintiles.