UK-279,276, a neutrophil inhibitory glycoprotein, in acute stroke: tolerability and pharmacokinetics.
OBJECTIVE
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.
Lees
Kennedy R
KR
University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, G11 6NT, UK. k.r.lees@clinmed.gla.ac.uk
Diener
Hans-Christoph
HC
Asplund
Kjell
K
Krams
Michael
M
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D039481:CD11b Antigen / Q000187:drug effects / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006023:Glycoproteins / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics*; D015801:Helminth Proteins / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007275:Injections, Intravenous; D008297:Male; D008565:Membrane Proteins / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics*; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics*; D009504:Neutrophils / Q000187:drug effects; D011994:Recombinant Proteins / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics; D012720:Severity of Illness Index; D020521:Stroke / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D016896:Treatment Outcome
D039481:CD11b Antigen; D006023:Glycoproteins; D015801:Helminth Proteins; D007074:Immunoglobulin G; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; C476006:UK279276; C086581:NIF protein, Ancylostoma caninum