A dose escalating, placebo controlled, double blind, single dose and multidose, safety and tolerability study of fontolizumab, a humanised anti-interferon gamma antibody, in patients with moderate to severe Crohn's disease.
BACKGROUND
This study was designed to evaluate the safety of fontolizumab, a humanised anti-interferon gamma antibody, in patients with moderate to severe Crohn's disease (CD).


METHODS
Forty five patients with a CD activity index (CDAI) of 250-450 were randomised in a double blind, placebo controlled, dose escalating fashion to receive single doses of fontolizumab (0.1, 1.0, and 4.0 mg/kg) or placebo. By day 29, patients with clinical response were re-randomised to receive three additional doses of one half their initial fontolizumab dose or placebo at four weekly intervals. Primary objectives were safety and tolerability. Secondary outcomes included assessments of immunogenicity, clinical activity, and potential pharmacodynamic surrogates.


RESULTS
Treatment was generally well tolerated. There were slightly more reports of chills, flu-like syndrome, asthenia, nausea, and vomiting in the 1.0 mg and 4.0 mg/kg fontolizumab cohorts. Two serious adverse events rated as worsening of CD occurred under fontolizumab. Antibodies to fontolizumab were confirmed in one patient. No differences in clinical activity parameters were noted between any of the active treatment groups and placebo, with the placebo group having a particularly favourable outcome (60% response and 40% remission). By day 29, a more enhanced decrease in median Crohn's disease endoscopic index of severity (p = 0.02) and serum C reactive protein (p<0.001) was observed in the 4.0 mg/kg (n = 14) fontolizumab cohort compared with placebo (n = 10). Pharmacodynamic effects were observed by immunohistochemistry.


CONCLUSIONS
Fontolizumab was well tolerated with minimal immunogenicity at doses of up to 4.0 mg/kg in patients with CD. A biological activity of fontolizumab is suggested.
Universitaetsklinik Innere Medizin IV, Abteilung Gastroenterologie and Hepatologie, Vienna, Austria. walter.reinisch@meduniwien.ac.at
W
W
Reinisch
D W
DW
Hommes
G
G
Van Assche
J-F
JF
Colombel
J-P
JP
Gendre
B
B
Oldenburg
A
A
Teml
K
K
Geboes
H
H
Ding
L
L
Zhang
M
M
Tang
M
M
Cheng
S J H
SJ
van Deventer
P
P
Rutgeerts
T
T
Pearce
D000328:Adult; D000368:Aged; D000906:Antibodies / Q000097:blood; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology; D061067:Antibodies, Monoclonal, Humanized; D002097:C-Reactive Protein / Q000378:metabolism; D003424:Crohn Disease / Q000188:drug therapy* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D016896:Treatment Outcome
D000906:Antibodies; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D005765:Gastrointestinal Agents; D006684:HLA-DR Antigens; C505731:fontolizumab; D007371:Interferon-gamma; D002097:C-Reactive Protein