Background/Purpose: Tumor necrosis factor (TNF) and interleukin 17 (IL-17) appear to independently contribute to the pathophysiology of rheumatoid arthritis (RA), synergistically inducing inflammatory mediators leading to joint destruction. Selective dual neutralization of TNF and IL-17 confers superior protection compared with inhibition of either target in a mouse collagen-induced arthritis model. ABT-122 is a novel dual variable domain immunoglobulin (DVD-Ig™) targeting both human TNF and IL-17A, hypothesized to provide greater clinical responses in RA patients (pts). The objective of this study was to investigate the safety and efficacy of ABT-122 in RA pts with inadequate response to methotrexate (MTX).  

Methods: Two hundred twenty-two pts were enrolled in this 12-week (wk) phase 2, randomized, double-blind, active-controlled, parallel group, study in active RA pts receiving concomitant MTX. Pts were randomized in a 1:1:1:1 ratio to receive ABT-122 (60 mg every other wk [eow], 120 mg eow, 120 mg every wk [ew]) or adalimumab (ADA, 40 mg eow) subcutaneously. The primary efficacy endpoint was the American College of Rheumatology (ACR) 20 response at wk 12. Additional secondary efficacy endpoints included responses of ACR50/70, low disease activity (LDA) and clinical remission (CR) based on DAS28 (hsCRP) or CDAI. The analysis presented here used non-responder imputation for missing data.  

Results: ACR20 responses for ABT-122 demonstrated dose-dependence, with numerically higher responses for the 120 mg ew dose compared with 40 mg eow ADA. These ACR20 responses were consistent with the secondary efficacy endpoints suggesting that ABT-122 at doses ≥120 mg eow has efficacy at least comparable to ADA 40 mg eow (Table 1). Treatment-emergent adverse events (AEs) were similar across all treatment groups with the majority being of mild or moderate severity. Across all treatment groups, there were no discernable differences in serious AEs or discontinuations; infection rates were similar for all treatment groups with no serious infections reported. There were no systemic hypersensitivity reactions reported with ABT-122. There were no dose-limiting or clinically-concerning laboratory abnormalities.

Conclusion: Efficacy data showed at least comparable efficacy of ABT-122 at doses ≥120 mg eow to 40 mg eow ADA in RA pts on concomitant MTX over 12 wks. With dual inhibition of TNF- and IL-17, there were no observed increases in safety findings. These results demonstrate that dual inhibition of TNF and IL-17 with a DVD-Ig provides an acceptable safety profile at the doses tested. Dual inhibition cannot be differentiated from TNF inhibition alone based on this dataset.