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

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.

• Authors: Kennedy R Lees, Hans-Christoph Diener, Kjell Asplund, Michael Krams, UK-279,276-301 Study Investigators
• Journal: Stroke (Stroke) Vol. 34 Issue 7 Pg. 1704-9 (Jul 2003) ISSN: 1524-4628 [Electronic] United States
• PMID: 12805489 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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