Fontolizumab in moderate to severe Crohn's disease: a phase 2, randomized, double-blind, placebo-controlled, multiple-dose study.
BACKGROUND
The safety and efficacy of fontolizumab, a humanized anti-interferon gamma antibody, was investigated in patients with Crohn's disease (CD). Elevated gut mucosal levels of interferon gamma, a key cytokine involved in the inflammatory process of CD, are associated with disease symptoms.


METHODS
A total of 201 patients with Crohn's Disease Activity Index (CDAI) scores between 250 and 450 were randomized to receive an initial intravenous dose of 1.0 or 4.0 mg/kg fontolizumab or placebo, followed by up to 3 subcutaneous doses of 0.1 or 1.0 mg/kg fontolizumab or placebo every 4 weeks. Clinical response at day 29, the primary efficacy endpoint, was defined as a decrease in the CDAI of at least 100 points from baseline levels.


RESULTS
Of 201 patients, 135 (67%) completed the study. Day 29 response rates were similar in all treatment groups (31%-38%). At subsequent timepoints a significantly greater proportion of patients in the 1.0 mg/kg intravenous / 1.0 mg/kg subcutaneous fontolizumab group had clinical response and significantly greater improvement in the CDAI score compared with patients who received placebo. All fontolizumab groups had significant improvement in C-reactive protein levels. The overall frequency of adverse events was similar in all groups (58%-75%); most events were related to exacerbation of CD. There was a low frequency (5.2%) of neutralizing antibodies to fontolizumab.


CONCLUSIONS
Although a strong clinical response to fontolizumab was not observed, significant decreases in C-reactive protein levels suggest a biological effect. Fontolizumab was well tolerated, and further studies to assess its efficacy are warranted.
Reinisch
Walter
W
Clinic of Internal Medicine III, Department of Gastroenterology and Hepatology, University of Vienna, Vienna, Austria. walter.reinisch@meduniwien.ac.at
de Villiers
Williem
W
Bene
László
L
Simon
László
L
Rácz
István
I
Katz
Seymour
S
Altorjay
István
I
Feagan
Brian
B
Riff
Dennis
D
Bernstein
Charles N
CN
Hommes
Daniel
D
Rutgeerts
Paul
P
Cortot
Antoine
A
Gaspari
Michael
M
Cheng
May
M
Pearce
Tillman
T
Sands
Bruce E
BE
D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D003424:Crohn Disease / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D007262:Infusions, Intravenous; D055104:Infusions, Subcutaneous; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D055815:Young Adult
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D005765:Gastrointestinal Agents; C505731:fontolizumab