ORLANDO – An experimental agent that restores plasticity to red blood cells significantly improved hematologic parameters and reduced the deformation of red blood cells from sickle cell disease, suggest preliminary results from a phase I/II randomized clinical trial.

The drug, labeled GBT440, was well tolerated over one month, with no serious drug-related adverse events and no evidence of tissue hypoxia, said Dr. Claire Hemmaway from Queens Hospital in Essex, United Kingdom.

“We have emerging data with 28 days of dosing, and this supports the hypothesis that this drug inhibits polymerization of sickle hemoglobin, improves hemolysis, reduces red blood cell damage even in the micro-circulation, and improves oxygen delivery. Longer-term dosing is clearly required and this will define the optimal hematologic effects and the clinical benefit of this drug,” she said at the American Society of Hematology annual meeting.

Although its mechanism of action is not completely understood, GBT440 is a small-molecule hemoglobin modifier which is known to increase hemoglobin oxygen affinity. This first-in-class agent has been shown in both in vitro and in vivo studies to be a strong and direct anti-sickling agent. The drug has also been shown to inhibit polymerization of hemoglobin S, the central event in sickle cell disease, Dr. Hemmaway said.

“We hypothesized that patients on GBT440 will see a reduction in the red cell damage, see a reduction in hemolysis, and an improvement in the anemia, and with an inhibition of the formation of the sickle cells we’ll also see an improvement in blood flow, and this could potentially modify the course of sickle cell disease in our patients,” she said at a briefing prior to her presentation of the data in an oral abstract session.

To test the safety and efficacy of the drug, the investigators enrolled 64 healthy volunteers and 16 patients with homozygous HbSS sickle-cell disease into a phase I/II randomized, double-placebo controlled, parallel group trial.

The patients all had baseline hemoglobin levels from 6 to 10 g/dL, and had not had a vaso-occlusive crisis or transfusion with 30 days of screening.

The study was divided into parts, with part A testing single ascending doses, and part B testing multiple ascending doses compared with placebo on a 6:2 randomization basis.

As of July 24 2015, 54 healthy volunteers had completed the study, two were discontinued due to mild-to-moderate rash and/or headache, and eight were still on follow-up.

Eight patients with sickle cell disease completed part A, and eight were on follow-up in part B. No patients dropped out of the study, although one had a dose reduction from 700 mg to 400 mg because of abdominal discomfort.

Patients and volunteers generally tolerated the drug well, with generally mild adverse events, no deaths, and just one serious adverse event, an acute painful crisis in a patient on placebo.

The drug was shown to increase hemoglobin in both healthy volunteers and patients, reduce reticulocytosis, and improve biomarkers of hemolysis and inflammation. The hematologic effects correlate with GBT440 blood levels, Dr. Hemmaway said.

“You can see dramatic reductions in the reticulocyte counts, which maximally are reduced by more than 50%, and these are maintained over 28 days. The reduction in reticulocyte counts suggests an improvement in red cell life span,” she said.

One patient who received a 700 mg daily oral dose of GBT440 had evidence of a complete absence of sickled cells 28 days after starting on therapy, she noted.

The investigators have not been able to determine whether the hematologic improvements seen in the study correlate with symptomatic improvements, because they have only 28 days of dosing data and the results are still blinded, Dr. Hemmaway said.

A pediatric hematologist who was not involved in the study said that the early results offer hope for patients.

“I think many of us in the field continue to come back to the painful reality that as of today there is only one FDA-approved medication for sickle cell disease. That fundamentally is something that I think many of us are extremely troubled by, especially at a meeting like this where we see so many other opportunities in other conditions,” commented Dr. Alexis Thompson, a professor of hematology at the Robert H. Lurie Children’s Hospital of Chicago, Illinois.

Although the data are early, they are encouraging enough to justify moving forward with a phase II trial, which is planned to start in early 2016.

“I think the person who is going to be the ultimate beneficiary from many of these advances will be a child who can look forward to not only a longer lifespan but a lifespan that is less hampered by the complications of this disease,” she said.

Dr. Thompson moderated the briefing in which Dr. Hemmaway presented the data.

The study is supported by Global Blood Therapeutics. Dr. Hemmaway had no relevant disclosures. Several co-investigators are employees of the company. Dr, Thompson had no disclosures relevant to the study.

ASH: Novel GBT440 reduces sickle cells, improves hematologic parameters