Background/Purpose:  Baseline differences in rheumatoid arthritis (RA) disease characteristics and molecular profile across populations may be a reflection of genetic variations and environmental factors such as regional differences in treatment paradigm, access to biologics, diet and lifestyle. These differences may influence response to treatment. The objective of this study was to compare baseline and post treatment molecular profiles of RA patients across geographic regions that were inadequate responders (IR) to conventional DMARDs and anti-TNFs and were treated with sirukumab, a monoclonal antibody that binds IL6.

Methods:  Serum samples were taken at baseline, Week 4, and Week 24 in two phase 3 studies of sirukumab in RA: SIRROUND-D (DMARD-IR), and SIRROUND -T (anti-TNF-IR).

Results are reported (from SIRROUND -D|-T) for patients from Asia-Pacific (AP), Europe (EU), and North America(NA), respectively, in the following dose groups: sirukumab 100mg q2w (n=49|33, 98|36, 24|67) and sirukumab 50mg q4w (n=40|21, 103|40, 25|67). Serum was analyzed using the SomaLogic SOMAscan^TM platform (376 analytes). Analytes significantly and differentially expressed in baseline RA samples versus independently collected demographically-matched healthy control serum samples were used to derive a serum composite score for each sample set via a log2-transformation of the median of normalized values for the analytes. mRNA from whole blood samples was isolated and profiled using the Affymetrix HT HG-U133+ PM Array. Gene set variation analysis was used to evaluate enrichment of an in vitro derived IL-6 gene signature in each sample and compared across geographic regions. Results: The following analytes, elevated in baseline serum samples from RA patients versus healthy controls, formed the basis of the serum composite score: annexin I, BLC/CXCL13, BPI, CRP, IL6, IP-10/CXCL10, LEAP1/hepcidin, MMP1, MMP3, PBEF, PHI, SAA, SP-D, TIMP-3. At baseline, the serum composite score, as well as individual RA-associated analytes, such as CXCL13, MMP3, and SP-D, were significantly elevated in patients from AP compared with EU or NA. Patients from AP also showed higher enrichment for the in vitro-derived IL-6 gene expression signature at baseline. After 4 and 24 weeks of treatment, the serum composite score and IL-6 gene signature was significantly decreased in all patients from both sirukumab treatment arms compared with placebo. However, stronger pharmacodynamic effects and significantly greater down regulation of both the serum composite score and IL-6 gene signature were observed in AP patients at both 4 and 24 weeks post treatment. These molecular changes were associated with higher baseline RA disease severity and CRP levels observed in patients from the AP region.

Conclusion:  RA-related inflammatory proteins and the IL-6 gene signature are significantly elevated at baseline and more extensively down-regulated post sirukumab treatment in both DMARD-IR and TNFi-IR patients from the AP region compared with the rest of world. These differences and their implications with respect to RA disease activity and clinical treatment options will be explored in subsequent analyses.

« Back to 2016 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/distinct-baseline-serum-molecular-profile-and-pharmacodynamic-effects-of-sirukumab-an-anti-il-6-cytokine-monoclonal-antibody-in-asian-pacific-patients-with-active-rheumatoid-arthritis-despit/