Phase 1 study of the E-selectin inhibitor GMI 1070 in patients with sickle cell anemia

Ted Wun, Lori Styles, Laura DeCastro, Marilyn J Telen, Frans Kuypers, Anthony Cheung, William Kramer, Henry Flanner, Seungshin Rhee, John L Magnani, Helen Thackray, Ted Wun, Lori Styles, Laura DeCastro, Marilyn J Telen, Frans Kuypers, Anthony Cheung, William Kramer, Henry Flanner, Seungshin Rhee, John L Magnani, Helen Thackray

Abstract

Background: Sickle cell anemia is an inherited disorder of hemoglobin that leads to a variety of acute and chronic complications. Abnormal cellular adhesion, mediated in part by selectins, has been implicated in the pathophysiology of the vaso-occlusion seen in sickle cell anemia, and selectin inhibition was able to restore blood flow in a mouse model of sickle cell disease.

Methods: We performed a Phase 1 study of the selectin inhibitor GMI 1070 in patients with sickle cell anemia. Fifteen patients who were clinically stable received GMI 1070 in two infusions.

Results: The drug was well tolerated without significant adverse events. There was a modest increase in total peripheral white blood cell count without clinical symptoms. Plasma concentrations were well-described by a two-compartment model with an elimination T1/2 of 7.7 hours and CLr of 19.6 mL/hour/kg. Computer-assisted intravital microscopy showed transient increases in red blood cell velocity in 3 of the 4 patients studied.

Conclusions: GMI 1070 was safe in stable patients with sickle cell anemia, and there was suggestion of increased blood flow in a subset of patients. At some time points between 4 and 48 hours after treatment with GMI 1070, there were significant decreases in biomarkers of endothelial activation (sE-selectin, sP-selectin, sICAM), leukocyte activation (MAC-1, LFA-1, PM aggregates) and the coagulation cascade (tissue factor, thrombin-antithrombin complexes). Development of GMI 1070 for the treatment of acute vaso-occlusive crisis is ongoing.

Trial registration: ClinicalTrials.gov NCT00911495.

Conflict of interest statement

Competing Interests: H.F., J.M., and H.T. are employees and have equity interest in Glycomimetics, Inc., which owns the patents to GMI 1070. W.K. has equity interest in Kramer Consulting, LLC, but has no commercial interest in GMI 1070. S.R. is an employee of Rho, Inc., but has no commercial interest in GMI 1070. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Enrollment Summary.
Figure 1. Enrollment Summary.
Figure 2. Change in absolute neutrophil count…
Figure 2. Change in absolute neutrophil count from baseline.
Figure 3. Change in total white blood…
Figure 3. Change in total white blood cell count (WBC) from baseline.
Figure 4. Change in total white blood…
Figure 4. Change in total white blood cell count (WBC) in the two subjects with marked leukocytosis.
Figure 5. Observed and model-predicted plasma concentrations…
Figure 5. Observed and model-predicted plasma concentrations of GMI-1070 after intravenous infusion.
Figure 6. Mean change in RBC velocity…
Figure 6. Mean change in RBC velocity as measured by computer-assisted intravital microscopy.

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