Brief Report: Pharmacodynamics, Safety, and Clinical Efficacy of AMG 811, a Human Anti-Interferon-γ Antibody, in Patients With Discoid Lupus Erythematosus

Abstract

Objective: Interferon-γ (IFNγ) is implicated in the pathogenesis of discoid lupus erythematosus (DLE). This study sought to evaluate a single dose of AMG 811, an anti-IFNγ antibody, in patients with DLE.

Methods: The study was designed as a phase I randomized, double-blind, placebo-controlled crossover study of the pharmacodynamics, safety, and clinical efficacy of AMG 811 in patients with DLE. Patients received a single subcutaneous dose of AMG 811 (180 mg) or placebo. The patients in sequence 1 received AMG 811 followed by placebo, while those in sequence 2 received placebo followed by AMG 811. Pharmacodynamic end points included global transcriptional analyses of lesional and nonlesional skin, IFNγ blockade signature (IGBS) transcriptional scores in the skin and blood, keratinocyte IFNγ RNA scores, and serum levels of CXCL10 protein. Additional end points were efficacy outcome measures, including the Cutaneous Lupus Erythematosus Disease Area and Severity Index, and safety outcome measures.

Results: Sixteen patients with DLE were enrolled in the study (9 in sequence 1 and 7 in sequence 2). AMG 811 treatment reduced the IGBS score (which was elevated in DLE patients at baseline) in both the blood and lesional skin. The keratinocyte IFNγ RNA score was not affected by administration of AMG 811. Serum CXCL10 protein levels (which were elevated in the blood of DLE patients) were reduced with AMG 811 treatment. The AMG 811 treatment was well tolerated but did not lead to statistically significant improvements in any of the efficacy outcome measures.

Conclusion: AMG 811 treatment led to changes in IFNγ-associated biomarkers and was well tolerated, but no significant clinical benefit was observed in patients with DLE.

Trial registration: ClinicalTrials.gov NCT01164917.

Figure 1

Changes in biomarker expression with AMG 811 treatment. A, Interferon‐γ (IFNγ) blockade signature (IGBS) scores in nonlesional skin at baseline and in lesional skin of patients with discoid lupus erythematosus (DLE) at baseline and on days 15 and 57 after treatment with AMG 811 or placebo (in period 1). ∗ = P = 0.0063 versus AMG 811–treated lesional samples at baseline. B, Keratinocyte IFNγ RNA score in lesional skin of DLE patients at baseline and on days 15 and 57 after AMG 811 treatment compared with nonlesional DLE skin and normal healthy control skin. Results are shown as box plots, where the horizontal line within the boxes represents the median, the boxes represent the first and third quartiles, and the bars outside the boxes represent the minimum and maximum values. C, Serum CXCL10 protein concentrations in healthy volunteers (HV) and untreated patients with DLE. Results are shown as irregular box plots, where the horizontal line within the boxes represents the median, the notches represent an estimate of the uncertainty about the median, the boxes represent the first and third quartiles, and the dashed bars represent the lower and upper ends of the farthest observed data point within 1.5 times the interquartile range; the plus signs represent outliers. D, Baseline‐adjusted mean serum CXCL10 protein concentrations in DLE patients treated with AMG 811 or placebo. The dashed horizontal line represents the mean baseline value. † = P _adjusted = 0.0038 for the intraday (day 15) comparison between AMG 811 and placebo. 95% CI = 95% confidence interval.

Figure 2

Clinical efficacy as measured by the Cutaneous Lupus Erythematosus Disease Area and Severity Index disease activity (CLASI‐A) score. The mean total CLASI‐A scores (A) and median percentage change in CLASI‐A scores (B) at baseline (BL) predose and on postdose days 15, 29, 57, and 85 (end of study [EOS]) are shown for patients who received placebo followed by AMG 811 (sequence 2) in period 1, patients who received AMG 811 followed by placebo (sequence 1) in period 1, and patients who received AMG 811 followed by placebo (sequence 2) in period 2. 90% CI = 90% confidence interval.