ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1609

AMG 811 (anti-IFN-gamma) Treatment Leads To a Reduction In The Whole Blood IFN-Signature and Serum CXCL10 In Subjects With Systemic Lupus Erythematosus:   Results Of Two Phase I Studies

David A. Martin1, Andrew Welcher2, Michael Boedigheimer2, Zahir Amoura3, Alan Kivitz4, Jill P. Buyon5, Jorge Sanchez-Guerrero6, Juanita Romero-Diaz7, Alla Rudinskaya8, Kevin M. Latinis9, S Cohen10, Cynthia Aranow11, Mike Damore2, Winnie Sohn2, Kit Chiu2, Christine Wang12, Naren Chirmule2, Barbara Sullivan2 and James Chung2, 1Medical Sciences, Amgen, Seattle, WA, 2Amgen, Thousand Oaks, CA, 3Department of Internal Medicine 2. Referal center for SLE/APS, CHU Pitié-Salpêtrière, Paris, France, 4Altoona Center for Clinical Research, Duncansville, PA, 5Medicine, Division of Rheumatology, NYU School of Medicine, New York, NY, 6UHN Toronto Western Hospital, Toronto, ON, Canada, 7Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico, 8Danbury Hospital, Danbury, CT, 9Latinis Rheumatology, Leawood, KS, 10Metroplex Clinical Research Center, Dallas, TX, 11The Feinstein Institute, Manhasset, NY, 12Biostatistics, Amgen, Thousand Oaks, CA

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: , ,

Session Information

Title: Systemic Lupus Erythematosus - Clinical Aspects II: Central Nervous System Manifestations, Therapeutics

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Interferon-gamma (IFN-g) is a major pro-inflammatory cytokine that modulates the function of several important populations of immune cells including B cells, T cells, and macrophages. Several lines of evidence from animal models and in humans suggest increased levels of Type I and/or Type II IFN are associated with inflammatory disorders including systemic lupus erythematosus (SLE). Although some information is available on the effect of blocking Type I IFNs from human trials in SLE, little is known about the role of Type II. AMG 811 is a human IgG1 monoclonal antibody that selectively targets and neutralizes human IFN- g. The safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple dose administration of AMG 811 was assessed in SLE subjects. The studies were not powered to assess efficacy. 

Methods:

Mild, stable SLE subjects were administered AMG 811 or placebo in single (SD) (n=26) or multiple doses (MD) (n=28) ranging from 2 mg to 180 mg SC or 60 mg IV.  Adverse events, laboratory tests and disease activity were assessed.  Serum AMG 811 concentrations were measured using an enzyme-linked immunosorbent assay, and anti-AMG 811 antibodies were measured using an immunoassay. Whole blood immunophenotyping parameters were measured by flow cytometry.   Whole blood RNA and serum proteins were analyzed pre- and post-dosing by microarray and ELISA, respectively.

Results:

In the SD cohorts there were no withdrawals due to adverse events and few adverse events were reported by more than a single subject receiving either AMG 811 or placebo.   In the MD cohorts the number of subjects reporting treatment emergent adverse events was similar between placebo (7/8) and AMG 811 (18/20).  AMG 811 displayed linear pharmacokinetics and properties consistent with a typical IgG1 antibody. Immunogenicity to AMG 811 was low in both SD (1/18) and MD (none observed) cohorts.  There were no detectable changes in expression of MHC I or II on circulating immune cells following AMG 811 treatment.  AMG 811 led to a dose dependent and reversible modulation of the expression of many genes associated with IFN-g signaling and that are differentially expressed in lupus patients. The list of impacted genes and the magnitude of modulation following AMG 811 treatment in SLE subjects suggests that the lupus ‘interferon signature’ is not solely derived from Type 1 IFNs.  Levels of several serum proteins were elevated at baseline relative to healthy individuals, including CXCL10 (IP-10), which has been associated with increased disease activity and to correlate with future SLE flare.   Treatment with AMG 811 led to dose-related and reversible reduction in CXCL10 in both single- and multiple-dose settings.

Conclusion:

AMG 811 demonstrated acceptable safety and favorable PK profiles in single and multiple dose studies in mild SLE subjects.  AMG 811 administration impacted IFN-associated gene expression. AMG 811 reduced serum CXCL10 levels in a dose and concentration dependent manner. No impact of AMG 811 on disease activity was observed in these mild, stable SLE patients.  These data support further evaluation of AMG 811 as a therapeutic for SLE, including subjects with active lupus nephritis.

Disclosure:

D. A. Martin,

Amgen,

3;

A. Welcher,

Amgen,

3;

M. Boedigheimer,

Amgen,

3;

Z. Amoura,
None;

A. Kivitz,

AbbVie, Amgen, AstraZeneca, BMS, Celgene, Genentech, Janssen, Pfizer, UCB,

2,

BMS, Genentech, UCB,

5,

BMS,

8;

J. P. Buyon,
None;

J. Sanchez-Guerrero,

GlaxoSmithKline,

5,

Bristol-Myers Squibb,

5,

Genentech and Biogen IDEC Inc.,

5;

J. Romero-Diaz,
None;

A. Rudinskaya,
None;

K. M. Latinis,

Human Genome Sciences, Inc.,

8,

Genentech and Biogen IDEC Inc.,

8,

GlaxoSmithKline,

8;

S. Cohen,

Amgen, Biogen Idec, Bristol-Myers Squibb, Centocor, Genentech, Johnson Johnson, Pfizer, Merck, Roche,

2;

C. Aranow,

GlaxoSmithKline,

2,

Amgen,

5,

Bristol-Myers Squibb,

5,

Human Genome Sciences, Inc.,

2,

GlaxoSmithKline,

5,

Pfizer Inc,

2,

Eli Lilly and Company,

2,

UCB,

2,

Dynavax,

2,

Genentech and Biogen IDEC Inc.,

2;

M. Damore,

Amgen,

3;

W. Sohn,

Amgen,

3;

K. Chiu,

Amgen,

3;

C. Wang,

Amgen,

3;

N. Chirmule,

Amgen,

3;

B. Sullivan,

Amgen,

3;

J. Chung,

Amgen ,

1,

Amgen,

3.

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