title: Phase 1 study of the E-selectin inhibitor GMI 1070 in patients with sickle cell anemia.
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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00911495.
authors.affiliation: Division of Hematology Oncology, University of California Davis School of Medicine, Sacramento, California, United States of America; Clinical and Translational Sciences Center, UC Davis School of Medicine, Sacramento, California, United States of America; Department of Pathology and Laboratory Medicine, UC Davis School of Medicine, Sacramento, California, United States of America; VA Northern California Health Care System, Sacramento, California, United States of America.
authors.forename: Ted
authors.initials: T
authors.lastname: Wun
authors.affiliation: Children's Hospital and Research Institute Oakland, Oakland, California, United States of America.
authors.forename: Lori
authors.initials: L
authors.lastname: Styles
authors.affiliation: Division of Hematology and Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Laura
authors.initials: L
authors.lastname: DeCastro
authors.affiliation: Division of Hematology and Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Marilyn J
authors.initials: MJ
authors.lastname: Telen
authors.affiliation: Children's Hospital and Research Institute Oakland, Oakland, California, United States of America.
authors.forename: Frans
authors.initials: F
authors.lastname: Kuypers
authors.affiliation: Department of Pathology and Laboratory Medicine, UC Davis School of Medicine, Sacramento, California, United States of America.
authors.forename: Anthony
authors.initials: A
authors.lastname: Cheung
authors.affiliation: Kramer Consulting LLC, North Potomac, Maryland, United States of America.
authors.forename: William
authors.initials: W
authors.lastname: Kramer
authors.affiliation: GlycoMimetics, Inc, Gaithersburg, Maryland, United States of America.
authors.forename: Henry
authors.initials: H
authors.lastname: Flanner
authors.affiliation: Rho, Inc., Chapel Hill, North Carolina, United States of America.
authors.forename: Seungshin
authors.initials: S
authors.lastname: Rhee
authors.affiliation: GlycoMimetics, Inc, Gaithersburg, Maryland, United States of America.
authors.forename: John L
authors.initials: JL
authors.lastname: Magnani
authors.affiliation: GlycoMimetics, Inc, Gaithersburg, Maryland, United States of America.
authors.forename: Helen
authors.initials: H
authors.lastname: Thackray
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000755:Anemia, Sickle Cell / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D001783:Blood Flow Velocity / Q000187:drug effects; D019040:E-Selectin / Q000032:analysis / Q000378:metabolism*; D005260:Female; D006017:Glycolipids / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D006801:Humans; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D019040:E-Selectin; D006017:Glycolipids; C553182:rivipansel