UK-279,276, a neutrophil inhibitory glycoprotein, in acute stroke: tolerability and pharmacokinetics

Stroke. 2003 Jul;34(7):1704-9. doi: 10.1161/01.STR.0000078563.72650.61. Epub 2003 Jun 12.

Abstract

Background and purpose: UK-279,276, a recombinant glycoprotein, binds selectively to the CD11b/CD18 integrin on neutrophils and has the potential to modulate the neuroinflammation associated with acute stroke. After preclinical evidence of neuroprotection, UK-279,276 has entered clinical development. The purposes of this study were to evaluate the safety and tolerability of UK-279,276 and to examine its pharmacokinetics and pharmacodynamics (binding to neutrophil CD11b) in patients with acute stroke.

Methods: This was a multicenter, double-blind, dose-escalation study in 176 patients randomized to a single intravenous dose of UK-279,276 (6 cohorts: 0.06, 0.1, 0.2, 0.5, 1.0, 1.5 mg/kg) or placebo (3:1 randomization within each cohort) within 12 hours of stroke onset.

Results: Age and stroke severity were well balanced across groups, with a mean age of 70 years (range, 39 to 92 years) and moderate baseline stroke severity (mean Scandinavian Stroke Scale score, 36.5 to 43.2; mean National Institutes of Health Stroke Scale score, 6.3 to 8.5). UK-279,276 was well tolerated at doses up to 1.5 mg/kg. There was no evidence of a relationship between dose of UK-279,276 and adverse events or clinical chemistry or hematology laboratory tests, or of an increased incidence of infection-related adverse events with the study drug. A dose-dependent UK-279,276-specific IgG antibody response was observed in patients treated with the 1.0- and 1.5-mg/kg doses. UK-279,276 displayed nonlinear pharmacokinetics across the dose range investigated. The duration of CD11b saturation was dose dependent, with >80% saturation achieved for at least 7 days after treatment with UK-279,276 1.0 and 1.5 mg/kg.

Conclusions: UK-279,276 was well tolerated in acute stroke patients at single doses up to 1.5 mg/kg. Further clinical investigation of UK-279,276 is ongoing.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Adult
  • Aged
  • Aged, 80 and over
  • CD11b Antigen / drug effects
  • CD11b Antigen / metabolism
  • Cell Adhesion / drug effects
  • Cohort Studies
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Glycoproteins / adverse effects
  • Glycoproteins / immunology
  • Glycoproteins / pharmacokinetics*
  • Helminth Proteins / adverse effects
  • Helminth Proteins / immunology
  • Helminth Proteins / pharmacokinetics*
  • Humans
  • Immunoglobulin G / blood
  • Injections, Intravenous
  • Male
  • Membrane Proteins / adverse effects
  • Membrane Proteins / immunology
  • Membrane Proteins / pharmacokinetics*
  • Middle Aged
  • Neuroprotective Agents / adverse effects
  • Neuroprotective Agents / immunology
  • Neuroprotective Agents / pharmacokinetics*
  • Neutrophils / drug effects
  • Recombinant Proteins / adverse effects
  • Recombinant Proteins / immunology
  • Recombinant Proteins / pharmacokinetics
  • Severity of Illness Index
  • Stroke / diagnosis
  • Stroke / drug therapy*
  • Stroke / physiopathology
  • Treatment Outcome

Substances

  • CD11b Antigen
  • Glycoproteins
  • Helminth Proteins
  • Immunoglobulin G
  • Membrane Proteins
  • Neuroprotective Agents
  • Recombinant Proteins
  • UK279276
  • NIF protein, Ancylostoma caninum