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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.

Alten R, Gram H, Joosten LA, van den Berg WB, Sieper J, Wassenberg S, Burmester G, van Riel P, Diaz-Lorente M, Bruin GJ, Woodworth TG, Rordorf C, Batard Y, Wright AM, Jung T - Arthritis Res. Ther. (2008)

Bottom Line: A statistically significant reduction in disease activity score was observed after 4 weeks in the 10 mg/kg group.ACZ885 was well tolerated.ACZ885 administration to methotrexate-refractory patients resulted in clinical improvement in a subset of patients.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Internal Medicine II, Rheumatology, Schlosspark-Klinik Teaching Hospital Charité University Medicine Berlin, Heubnerweg, D-14059 Berlin, Germany.

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.

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Related in: MedlinePlus

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).
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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).

Mentions: The initial dose escalation phase of the study consisted of four cohorts (Figure 1). In each cohort six patients were randomly assigned to receive ACZ885 and two patients were randomly assigned to receive placebo. In the first cohort, patients randomly assigned to ACZ885 received 0.3 mg/kg intravenously on days 1 and 15. Safety data from a minimum of six out of eight patients in this cohort up to day 20 were reviewed prior to proceeding with the study and starting the next higher dose. Patients randomly assigned to ACZ885 in the second cohort received 1 mg/kg, in the third cohort 3 mg/kg, and finally in the fourth cohort 10 mg/kg. Safety data from the 10 mg/kg cohort were found to raise no concern that might prevent proceeding with the study, so this cohort was extended to increase the sample size, such that in total 20 patients received 10 mg/kg intravenous on days 1 and 15, and a total of 15 patients received placebo. Thus, a total of 53 patients with RA were enrolled.


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.

Alten R, Gram H, Joosten LA, van den Berg WB, Sieper J, Wassenberg S, Burmester G, van Riel P, Diaz-Lorente M, Bruin GJ, Woodworth TG, Rordorf C, Batard Y, Wright AM, Jung T - Arthritis Res. Ther. (2008)

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).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2483458&req=5

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).
Mentions: The initial dose escalation phase of the study consisted of four cohorts (Figure 1). In each cohort six patients were randomly assigned to receive ACZ885 and two patients were randomly assigned to receive placebo. In the first cohort, patients randomly assigned to ACZ885 received 0.3 mg/kg intravenously on days 1 and 15. Safety data from a minimum of six out of eight patients in this cohort up to day 20 were reviewed prior to proceeding with the study and starting the next higher dose. Patients randomly assigned to ACZ885 in the second cohort received 1 mg/kg, in the third cohort 3 mg/kg, and finally in the fourth cohort 10 mg/kg. Safety data from the 10 mg/kg cohort were found to raise no concern that might prevent proceeding with the study, so this cohort was extended to increase the sample size, such that in total 20 patients received 10 mg/kg intravenous on days 1 and 15, and a total of 15 patients received placebo. Thus, a total of 53 patients with RA were enrolled.

Bottom Line: A statistically significant reduction in disease activity score was observed after 4 weeks in the 10 mg/kg group.ACZ885 was well tolerated.ACZ885 administration to methotrexate-refractory patients resulted in clinical improvement in a subset of patients.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Internal Medicine II, Rheumatology, Schlosspark-Klinik Teaching Hospital Charité University Medicine Berlin, Heubnerweg, D-14059 Berlin, Germany.

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.

Show MeSH
Related in: MedlinePlus