ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2868

Pharmacodynamic Analysis of Whole Blood Gene Expression over 2 Years in a Phase IIIb Head-to-Head Trial of Abatacept and Adalimumab in Patients with RA

O Jabado1, MA Maldonado1, Michael Schiff2, Michael Weinblatt3, Roy Fleischmann4, William H. Robinson5, A Greenfield1 and SE Connolly1, 1Bristol-Myers Squibb, Princeton, NJ, 2University of Colorado, Denver, CO, 3Brigham and Women’s Hospital, Boston, MA, 4Metroplex Clinical Research Center Dallas, Dallas, TX, 5Stanford University, Palo Alto, CA

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: , , ,

Session Information

Date: Tuesday, November 7, 2017

Title: Rheumatoid Arthritis – Small Molecules, Biologics and Gene Therapy IV: Pharmacodynamic Markers and Therapeutic Intervention

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: The head-to-head AMPLE study compared the safety and efficacy of abatacept (co-stimulatory modulator) versus adalimumab (TNFα inhibitor) for treatment of RA over 2 years. The objective of this initial analysis was to determine molecular pharmacodynamic (PD) changes in whole blood associated with abatacept and adalimumab treatment; this is the first step toward defining predictive biomarkers of response. Methods: RNA was isolated from the whole blood of patients at baseline, Day 85, Year 1, and Year 2, then profiled using Affymetrix U219 GeneChip (628 patients, 2049 total samples). Differential expression between study arms over time was assessed using a linear model with clinical covariates and a multiple testing correction. Single-sample Gene Set Enrichment Analysis (ssGSEA)1 was used to calculate enrichment for gene modules derived from literature. Transcription profiling of naïve and activated immune cell types was used to generate immune gene signatures as a proxy for cell abundance measurements.2 Results: Differential gene expression analysis revealed many changes that fit with expected mechanisms of action (MoA). Genes that encode proteins associated with T-cell co-stimulation and antibody production were lower in the abatacept arm; genes transcribed in response to pro-inflammatory signals were lower in the adalimumab arm (Table). Some of the most differentially expressed genes have not been previously associated with RA (e.g. PI3/elafin, ALPL, PROK2, GBP5, ZNF683) or are poorly studied. Using immune cell type gene expression signatures as proxies for abundance, we found plasma cells, B cells and natural killer cells were all lower in the abatacept arms by Year 2; conversely, polymorphonuclear leukocytes were higher in the abatacept arm (Figure).

Conclusion: This first analysis shows PD differences consistent with the expected MoA of abatacept and adalimumab. Further analysis of this rich time course dataset may reveal predictive biomarkers of response and disease progression, and novel targets for therapeutics.

1. Subramanian A, et al. Proc Natl Acad Sci U S A 2005;102:15545–50.

2. Gaujoux R, et al. Bioinformatics 2013;29:2211–2.

Disclosure: O. Jabado, Bristol-Myers Squibb, 3; M. Maldonado, Bristol-Myers Squibb, 1,Bristol-Myers Squibb, 3; M. Schiff, AbbVie, BMS, Eli Lilly, JNJ, UCB, 5,AbbVie, BMS, 8; M. Weinblatt, Amgen, BMS, Crescendo Bioscience, UCB, DxtTerity, Sanofi, 2,Amgen, BMS, Crescendo Bioscience, UCB, AbbVie, Lilly, Pfizer, Roche, 5; R. Fleischmann, AbbVie, Amgen, Astellas, AstraZeneca, BMS, Celgene, EMD-Serono, Janssen, Eli Lilly, Merck, Novartis, Pfizer, Roche, Sanofi-Genzyme, UCB, 2,AbbVie, Amgen, BMS, Celgene, GSK, Janssen, Eli Lilly, Novartis, Pfizer, Roche, Sanofi-Genzyme, UCB, 5; W. H. Robinson, None; A. Greenfield, Bristol-Myers Squibb, 3; S. Connolly, Bristol-Myers Squibb, 3,Bristol-Myers Squibb, 1.

To cite this abstract in AMA style:

Jabado O, Maldonado M, Schiff M, Weinblatt M, Fleischmann R, Robinson WH, Greenfield A, Connolly S. Pharmacodynamic Analysis of Whole Blood Gene Expression over 2 Years in a Phase IIIb Head-to-Head Trial of Abatacept and Adalimumab in Patients with RA [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/pharmacodynamic-analysis-of-whole-blood-gene-expression-over-2-years-in-a-phase-iiib-head-to-head-trial-of-abatacept-and-adalimumab-in-patients-with-ra/. Accessed .

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