ASH Clinical News Advances in Hematology Research & Patient Care: Hi | Page 14

CLINICAL NEWS

Hemoglobin Modifier GBT440: A New Option for Patients
with Sickle Cell Disease
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
Claire Hemmaway, MD, the lead hematology consultant at Queens
patients had discontinued, but one patient in part B of the study
Hospital in Essex, United Kingdom, and colleagues explored the
had a dose reduction from 700 mg to 400 mg (due to abdominal
safety, pharmacokinetics, pharmacodynamics, and potential efficacy
discomfort).
of GBT440 in a prospective, randomized, placebo-controlled, douIn terms of safety (the trial’s primary endpoint), GBT440 was
ble-blind, parallel-group phase I/II study of healthy volunteers and
“generally well tolerated,” the authors reported, with mostly mild
SCD patients. The study was presented at the ASH annual meeting
AEs and no deaths. One serious AE (an acute painful crisis) oclast month.
curred in a patient taking placebo.
GBT440 works by increasing hemoglobin oxygen affinity, the
The most common AEs associated with GBT440 were headauthors explained, and has been shown to be a potent and direct
ache and sickle cell crisis; all instances of reported sickle cell crises
anti-sickling agent with high specificity for hemoglobin in in vitro
occurred after discontinuation of the study drug.
and in vivo studies. “This drug is potentially disease-modifying for
“GBT440 showed dose-proportional pharmacokinetics,” Dr.
patients with sickle cell disease,” Dr. Hemmaway said in a discusHemmaway and colleagues observed, with a terminal half-life of
sion of the results. “We hypothesized that [GBT440] should rapidly
1.5 to three days and a dose-dependent increase in hemoglobin
interrupt red blood cell hemolysis, improve anemia, and potentially
oxygen affinity in both healthy volunteers and SCD patients.
become a safe and effective long-term therapy.”
GBT440-treated patients showed increased hemoglobin, hematocrit,
The study was conducted in two parts: part A tested single
and erythrocyte counts with corresponding decreases in LDH,
ascending doses and part B multiple ascending doses of study drug
unconjugated bilirubin, reticulocytes, and erythropoietin levels
with 6:2 randomization (GBT440:placebo).
(TABLE 1).
Doses administered were:
When the researchers analyzed peripheral blood smears, they also
• Part A: 100-2,800 mg in healthy volunteers and 1,000 mg in
observed a marked reduction in sickle cells among GBT440-treated
SCD patients
patients – decreasing by 56 percent and 46 percent in the 500 mg and
700 mg cohorts, respectively. Patients receiving placebo, however,
• Part B: 300-900 mg once-daily for 15 days in healthy volunteers
experienced a 14 percent increase in median sickle cell counts.
and 700 mg once-daily for 28 days in SCD patients
Overall, daily dosing with GBT440 “demonstrated proof of
mechanism with a dose-dependent increase in hemoglobin oxygen
Patients were monitored closely in a clinical research unit for the
a