Because CD is widely regarded as a Th‐1 type immune mediated inflammatory disorder, IFN‐γ provides a rational therapeutic target.4,5,6
Here we present results from the first study with a humanised anti‐IFN‐γ antibody, fontolizumab, in patients with moderate to severe CD. The results suggest safety and biological activity of single and multiple doses of fontolizumab in these patients.
Fontolizumab was well tolerated in the range 0.1–4.0 mg/kg as a single dose and in the range 0.05–2.0 mg/kg for three additional monthly doses. Most AEs were mild to moderate in intensity. Flu‐like syndrome and chills were reported predominantly from the higher dose groups of fontolizumab. Notably, no increased susceptibility to infections was observed. Whether drug related or not, the events were not immunogenic in origin because they occurred with the initial dose, and in only one of 35 tested patients was an anti‐fontolizumab antibody response detected. In this case, the anti‐antibody response was transient, without neutralising capacity, and did not influence the pharmacokinetic profile of fontolizumab in this one patient. Therefore, the excellent safety profile and low immunogenicity observed favour fontolizumab as a reasonable candidate for long term use.
Rates of remission (60%), response (60%), and enhanced response (40%) at day 29 after a single dose of placebo in our study were among the highest reported in the literature in placebo controlled randomised trials in patients with moderate to severe CD.18
This is worth mentioning, especially considering the short term evaluation and high baseline CDAI scores of the patients, since short study duration and high entry CDAI scores have been described as predictors of low placebo remission rates.18
Against the background of the high placebo rate, an overall difference between the four treatment groups in any secondary end points based on CDAI could not be detected.
Although not designed to allow definite conclusions about clinical efficacy, the study provides evidence of the biological activity of fontolizumab. Recently, a high CRP serum level
10 mg/l, indicative of inflammation, has been shown to correlate with a lower placebo response compared with TNF‐α inhibitors.19,20
Stratifying our patients according to CRP
10 mg/l increased rates of enhanced response, and remission became apparent for the high dose fontolizumab groups compared with the placebo and 0.1 mg/kg fontolizumab groups. Furthermore, assessment of the exposure‐response relationship revealed a positive correlation between CDAI score and serum fontolizumab area under the concentration curve (AUC), as well as between CDEIS score and serum fontolizumab AUC (data not shown), indicating dose dependent clinical activity. The decrease observed in CDEIS with 4.0 mg/kg fontolizumab is notable as this assessment tool is an objective score of mucosal involvement. As no dose limiting toxicity was observed in the present study, a higher dose level with longer duration of treatment may be further explored to optimise the dose regimen.
To evaluate the biological effects of fontolizumab at the lesion site, several biomarkers were analysed on biopsy specimens using immunohistochemistry. Stat1 is a major transcription factor activated by IFN‐γ that regulates genes, including those coding for chemokines (IP10, MIG, I‐TAC, and MCP‐1), inducible nitric oxide synthetase, MHC class II, and intercellular adhesion molecule 1.21
These molecules play important roles in recruitment of activated phagocytes and lymphocytes into intestinal lesions, and their expression has been shown to correspond with overall inflammatory activity.22,23,24,25
Therefore, Stat1 activation may contribute to many of the pathophysiological features observed in inflammatory bowel disease, and indeed expression, phosphorylation, and nuclear translocation of Stat1 are increased in the lesional mucosa of patients with CD.26
Expression of the chemokine receptor CXCR3 as well as its ligands, IP‐10 and MIG, has also been observed in the inflamed mucosa from patients with CD.22,27
Particularly expressed on Th1 cells, CXCR3 may be involved in the continuous migration of activated T lymphocytes into mucosal lesions in CD. In patients examined from the 4 mg/kg fontolizumab group, treatment was associated with decreased expression of HLA‐DR, Stat1, and CXCR3. Additionally, there was a profound decrease in the total number of T cells (CD3) and proliferating activities (Ki67) in the inflamed mucosa following treatment. Results from this small group of patients suggest that fontolizumab inhibits lesional IFN‐γ mediated gene transcription.
There is a potential advantage of targeting IFN‐γ for the treatment of CD. Neutralisation of IFN‐γ may interrupt the cytokine cascade that leads to TNF‐α upregulation, resulting in decreased TNF‐α and IFN‐γ levels.12,13
Inhibition of IFN‐γ reduces induction of class II MHC molecule expression and blocks the maturation of naive T cells into TH
1 cells. In fact, some of the clinical effects of anti‐TNF‐α therapy have been attributed to downregulation of IFN‐γ. In targeting a distinct pathway, fontolizumab may be effective in patients who do not respond to anti‐TNF‐α therapies.
In conclusion, fontolizumab was generally well tolerated and minimally immunogenic in patients with moderate to severe CD. Biological and clinical responses were evident in patients treated with single dose fontolizumab and in multiple dose maintenance of remission.