The human anti-IL-1 beta monoclonal antibody ACZ885 is effective in joint inflammation models in mice and in a proof-of-concept study in patients with rheumatoid arthritis

Abstract

Introduction: IL-1beta is a proinflammatory cytokine driving joint inflammation as well as systemic signs of inflammation, such as fever and acute phase protein production.

Methods: ACZ885, a fully human monoclonal antibody that neutralizes the bioactivity of human IL-1beta, was generated to study the potent and long-lasting neutralization of IL-1beta in mechanistic animal models as well as in a proof-of-concept study in patients with rheumatoid arthritis (RA).

Results: The mouse IL-1 receptor cross-reacts with human IL-1beta, and it was demonstrated that ACZ885 can completely suppress IL-1beta-mediated joint inflammation and cartilage destruction in mice. This observation prompted us to study the safety, tolerability and pharmacodynamic activity of ACZ885 in RA patients in a small proof-of-concept study--the first to be conducted in humans. Patients with active RA despite treatment with stable doses of methotrexate were enrolled in this dose escalation study. The first 32 patients were split into four cohorts of eight patients each (six were randomly assigned to active treatment and two to placebo). ACZ885 doses were 0.3, 1, 3 and 10 mg/kg, administered intravenously on days 1 and 15. To explore efficacy within 6 weeks of treatment, an additional 21 patients were randomly assigned to the 10 mg/kg cohort, resulting in a total of 20 patients dosed with 10 mg/kg and 15 patients treated with placebo. There was clinical improvement (American College of Rheumatology 20% improvement criteria) at week 6 in the 10 mg/kg treatment group; however, this did not reach statistical significance (P = 0.085). A statistically significant reduction in disease activity score was observed after 4 weeks in the 10 mg/kg group. Onset of action was rapid, because most responders exhibited improvement in their symptoms within the first 3 weeks. C-reactive protein levels decreased in patients treated with ACZ885 within 1 week. ACZ885 was well tolerated. Three patients receiving ACZ885 developed infectious episodes that required treatment. No anti-ACZ885 antibodies were detected during the study.

Conclusion: ACZ885 administration to methotrexate-refractory patients resulted in clinical improvement in a subset of patients. Additional studies to characterize efficacy in RA and to determine the optimal dose regimen appear warranted.

Trial registration: ClinicalTrials.gov identifier NCT00619905.

Figure 1

Study design. Sequential dose-escalation, randomized, double-blind, placebo controlled study design with an extension at the highest dose level. ACZ885 was administered intravenously on days 1 and 15 (arrows). Safety data generated up to day 20 in each cohort were reviewed before escalating to the next higher dose level. Independent observer efficacy assessments were made at day 1, before dosing, and day 43, in addition to weekly investigator assessments up to Day 43. The end of study was on day 113. After safety review of the first six patients at 10 mg/kg, an extension cohort was started, which included 14 patients on ACZ885 and seven patients on placebo (pbo).

Figure 2

Blocking of IL-1 in mouse models of arthritis. (a) Inhibition of swelling. Mice were given different doses of ACZ885 or a control anti-CD25 antibody (CHI621, 12 mg/kg) intraperitoneally before injection of 10,000 3T3-huIL-1β cells into the right hind knee joint. Swelling was measured 3 days after cell injection (as described in Materials and methods) and is expressed as the ratio between the right (treated) and left (untreated) joint. The results presented represent the mean ± standard error or the mean (SEM; n = 5). **P < 0.01 by analysis of variance followed by Dunnett's test for multiple comparisons post hoc. NS, not significant. (b) Proteoglycan (PG) synthesis by chondrocytes in explanted patellae was measured by incorporation of ³⁵S labelled sulphate in isolated cartilage from treated (right) and untreated (left) knee joints. The results are given as the ratio of ³⁵S incorporation between right and left knee cartilage and represent the mean ± SEM (n = 5). Statistical analysis of the treated groups versus the control group (CHI621) was performed by analysis of variance followed by Dunnett's test for multiple comparisons post hoc. *P < 0.05; **P < 0.01. ED₅₀, dose needed to achieve a mean of 50% effect. (c) Histology was analyzed at day 3 after local injection of 3T3-hIL-1β producing cells. Section of a mouse knee joint treated with isotype control antibody or AC885 are shown. Hematoxylin and eosin staining, original magnification (200×). Quantitative evaluation of the slides was done as described in Materials and methods and is presented in the graph. n = 5 joints per group; all comparisons between active and control were significant (P < 0.05, Mann-Whitney U-test).

Figure 3

Reduction in disease activity and CRP levels following ACZ885 therapy in RA patients. (a) Mean disease activity (Disease Activity Score using 28 joint counts [DAS28]) levels over time. Baseline adjusted mean and standard error of the mean (SEM) from the repeated measures analysis are presented for patients treated with ACZ885 10 mg/kg (n = 20) and placebo (n = 15). P values for comparison of ACZ885 10 mg/kg versus placebo at each time point are presented. (b) Geometric mean C-reactive protein (CRP) levels over time. Baseline adjusted mean and SEM from the repeated measures analysis are presented after transformation back onto the original scale for patients treated with ACZ885 10 mg/kg (n = 20) and placebo (n = 15). P values for comparison of ACZ885 10 mg/kg versus placebo at each time point are presented. Normal range of CRP was 0 to 8.4 mg/l.