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

Published online

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Wun, T; Styles, L; DeCastro, L; Telen, MJ; Kuypers, F; Cheung, A; Kramer, W; Flanner, H; Rhee, S; Magnani, JL; Thackray, H

Published Date

  • 2014

Published In

Volume / Issue

  • 9 / 7

Start / End Page

  • e101301 -

PubMed ID

  • 24988449

Pubmed Central ID

  • 24988449

Electronic International Standard Serial Number (EISSN)

  • 1932-6203

Digital Object Identifier (DOI)

  • 10.1371/journal.pone.0101301

Language

  • eng

Conference Location

  • United States