Background/Purpose: Discoid Lupus Erythematosus (DLE) is the most common form of chronic cutaneous LE (CCLE) and develops in up to a quarter of SLE patients.   DLE inflammation typically involves hair follicles and the epidermis leading to scaring, atrophy, telangiectasias and/or dyspigmentation.  Patients with DLE have an IFN signature in the blood and the skin, and the level of gene expression correlates with cutaneous disease activity.  Skin biopsies of DLE lesions show elevated mRNA levels of interferon gamma and  provide rationale for a therapeutic trial of AMG 811, a human IgG1 monoclonal antibody that selectively neutralizes human IFN-g.

Methods: This multi-center, randomized, double-blind, placebo-controlled, two-period, crossover study in which 16 subjects with DLE received AMG 811 and placebo in one of two sequences [ie, AMG 811 followed by placebo (n=9) on day 85 or placebo followed by AMG 811 on day 85 (n=7)].   The primary objectives were to evaluate the safety, tolerability and immunogenicity of a single subcutaneous (SC) dose of AMG 811.  Secondary objectives focused on the single-dose pharmacokinetic (PK) profile of AMG 811 and changes from baseline in the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) score following a single SC dose of either AMG 811 or placebo.  Adverse events, safety laboratory tests and disease activity were assessed. Serum AMG 811 concentrations were measured by ELISA, and anti-AMG 811 antibodies were measured by an immunoassay.  Skin biopsies were obtained from lesional and non-lesional areas pre-dose and from lesional areas on day 15 and 57.   T cell and macrophage infiltrate in the skin was quantitated by laser scanning cytometry.  Whole blood and skin RNA and serum proteins were analyzed by microarray and ELISA, respectively.

Results: During the study all but one DLE subject (9/9 AMG 811 and 6/7 placebo) experienced treatment-emergent adverse events.  AMG 811 displayed linear pharmacokinetics and no immunogenicity to AMG 811 was observed.   Changes in the CLASI scores were similar between subjects that received AMG 811 and placebo over the first 85 days, and there was no beneficial effect on disease activity seen in placebo subjects receiving AMG 811 on day 85.  IFN-g modulated genes were elevated in both blood and lesional skin, indicating the presence of an interferon signature.  In blood AMG 811 led to a dose dependent modulation of the expression of genes previously shown to be modulated by AMG 811 in subjects with SLE.  Histopathology and RNA transcript analysis revealed substantial intra- and inter-subject heterogeneity between skin biopsies from DLE subjects at baseline and following AMG 811 treatment.   The number of CD3+ T cells and CD68+ macrophages were elevated in the lesional skin compared to non-lesional and there was no apparent reduction following AMG 811. 

Conclusion: AMG 811 demonstrated acceptable safety and favorable PK profiles in this single dose study of DLE subjects but there was no apparent clinical benefit.  Evidence of a pharmacodynamic effect in the blood (e.g. inhibition of IFN-g) was apparent; however, heterogeneity in skin samples prevented definitive conclusions about the effects of AMG 811 in diseased skin.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-phase-i-single-dose-crossover-study-to-evaluate-the-safety-tolerability-pharmacokinetics-pharmacodynamics-and-clinical-efficacy-of-amg-811-anti-ifn-gamma-in-subjects-with-discoid-lupus-erythem/