This study was designed to evaluate one or two doses of fontolizumab at 4 or 10 mg/kg, doses expected to provide pharmacologically active concentrations based on in vitro assays. There was no significant difference in response between the three arms at day 28, with placebo resulting in a 33% response rate. On the other hand, the fontolizumab arms produced a 50% greater reduction in mean CDAI score compared with placebo, an advantage that was statistically significant as early as day 14 in the higher dose cohort. A subgroup analysis of approximately 50% of the study patients with an elevated CRP found that 20%, 44%, and 46% of placebo, 4, and 10 mg/kg fontolizumab patients, respectively, responded favourably to the study treatment at day 28. Although the difference was not statistically significant, both doses of fontolizumab were associated with a more favourable response than placebo.
Unlike infliximab, the target for fontolizumab, interferon γ does not exist as a membrane bound protein, and there is no in vitro evidence that target binding by fontolizumab would result in acute apoptosis of mucosal lymphocytes. Its onset of action might be more gradual, with maximum benefit observed after multiple dosing. Analysis of the patients in group II who received two doses of fontolizumab lends preliminary evidence that this might indeed be the case. On day 56, four weeks after the second dose of study drug, the response rates in the fontolizumab arms were doubled compared with placebo: 35% in the placebo versus 69% and 67% in the 4 and 10 mg/kg fontolizumab groups, respectively. This effect was enhanced for patients with an elevated baseline CRP who received two doses, where the day 56 response rate was 17% for placebo compared with 82% for the 4 mg/kg cohort (p<0.01) and 77% for the 10 mg/kg fontolizumab cohort (p<0.01).
This clear reduction in placebo response rate and a neutral to increased impact on the fontolizumab subset is consistent with a true anti‐inflammatory effect of this molecule. Further corroboration of a direct anti‐inflammatory effect of fontolizumab comes from analysis of median change from baseline in CRP value. There were statistically significant reductions in the 10 mg/kg cohort of patients in group II compared with the placebo group on days 28, 42, 56, and 84. It is interesting to note that the effect on CRP was greatest in the 10 mg/kg cohort whereas 4 mg/kg appeared at least as active in terms of CDAI related parameters. This discrepancy may be due to the fact that CDAI does not always correlate well with CRP.
One of the primary end points of this study was safety, especially as 10 mg/kg fontolizumab had never been administered to patients with CD. Based on animal studies and cases of humans with non‐functional interferon γ receptors, the predicted toxicities are increased susceptibility to intracellular infections with microbacteria. Patients in this study were required to have no clinical or radiographic evidence of prior tuberculosis. All three arms were similarly well tolerated. There was no evidence of infusion reactions after one or two doses, and no clinical evidence of infectious complications of interferon γ inhibition. One patient died in his sleep 35 days after the second dose of 4 mg/kg fontolizumab. The cause of death was presumed to be unrelated to fontolizumab, but results of larger randomised studies will be required to rule out an unexpected drug related aetiology.
Long term use of other biological agents has been limited by immunogenicity. In this study, one or two doses of fontolizumab resulted in detection of neutralising anti‐fontolizumab antibodies in only 4.4% of patients. These antibodies were of low titre, transient (appearing typically at two weeks and becoming undetectable in subsequent sampling), and with no clinical or detectable pharmacokinetic impact. If confirmed in larger studies, with longer term dosing, the low level immunogenicity of this molecule could be of significant clinical benefit for chronic or even intermittent dosing.
In vitro bioassays of fontolizumab indicate maximal activity in the concentration range 10–100 μg/ml.12
Pharmacokinetic analysis from this study reveals an elimination half life of 18 days, a peak concentration of 120 μg/ml after two doses of 4 mg/kg fontolizumab, and a trough concentration of 17 μg/ml at four weeks after the second dose. The corresponding peak and tough concentrations for the 10 mg/kg dose were 224 μg/ml and 40 μg/ml, respectively. As a consequence of the long elimination half life, a clinically convenient dosing interval of every four weeks was sufficient to maintain the desired drug level in both the 4 and 10 mg/kg dose groups. Both doses thus provide sustained pharmacologically active concentrations over the dosing period, consistent with the similar levels of clinical activity between doses. Given the equivalent tolerability of both doses, the 10 mg/kg dose may allow for the development of regimens with longer, more convenient, dosing intervals.
This study has described the clinical and biological activity of fontolizumab at either one or two doses of 4 or 10 mg/kg. The favourable side effect profile, long half life, and low immunogenicity suggest that more sustained dosing, and more adequately powered studies, should be considered. The 10 mg/kg dose could offer the option of dosing every 6–8 weeks.