FRI0188 Safety, Tolerability, and Pharmacodynamics of ABT-122, A Dual TNF- and IL-17–Targeted Dual Variable Domain (DVD)-IG™ in Patients with Rheumatoid Arthritis
Authors: R.M. Fleischmann, F. Wagner, A.J. Kivitz, H.T. Mansikka, N. Khan, J. Liu, F. Hong, M. Ruzek, R.J. Padley
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> TNF and IL-17 independently contribute to the pathophysiology of RA, synergistically inducing inflammatory mediators and joint destruction. Selective dual neutralization of TNF and IL-17 confers superior protection vs inhibition of either alone in mouse RA models. ABT-122 is a novel dual variable domain immunoglobulin (DVD-Ig™) targeting both human TNF and IL-17A and hypothesized to provide greater clinical responses in RA patients (pts). <h3>Objectives</h3> Investigate safety, tolerability, and exploratory pharmacodynamics of multiple doses of ABT-122 in pts with stable RA <h3>Methods</h3> Two phase 1, placebo (PBO)-controlled, multiple-dose studies randomized 43 pts with stable RA receiving stable methotrexate (7.5–25 mg/wk). Pts received subcutaneous PBO, ABT-122 1 mg/kg every other wk (4 doses), or ABT-122 0.5, 1.5, or 3 mg/kg weekly (8 doses), and were evaluated through 45 d after last dose. Serum for inflammation markers and chemokines, based on preclinical studies with dual TNF and IL-17 neutralization, was collected at baseline (BL) through d 92 and analyzed by multiplex assays. <h3>Results</h3> No clinically significant safety findings were observed. Rates of treatment-emergent AEs were similar in the ABT-122 and PBO groups, with no evidence of a dose response. There were no AE or serious AE trends, systemic hypersensitivity reactions, or dose-limiting toxicities with ABT-122. Infections were reported, as expected in RA, with no apparent patterns related to etiology, type, or dose with ABT-122 vs PBO, and no pt discontinued the study owing to infection. There were no clinically significant laboratory, vital sign, or ECG abnormalities. CXCL9 and CXCL10 decreased within 3 d of ABT-122 administration (−25% and −30% vs BL, respectively) relative to PBO. Maximal decreases occurred by d 15 (−60% and −45% for CXCL9 and CXCL10, respectively) and persisted through 14 d after last dose. CCL23 decreased following ABT-122, with maximal decreases (−30%) at d 64, and continued through d 92. Consistent with TNF inhibition, soluble E-selectin decreased following ABT-122, persisting through d 92 for the 3 mg/kg group. <h3>Conclusions</h3> ABT-122 demonstrated a well-tolerated safety profile in RA pts through 8 wk of dosing up to 3 mg/kg, consistent with the prior first-in-human study in healthy subjects. Because CXCL9, CXCL10, and CCL23 are involved in lymphocyte and myeloid cell recruitment into inflamed tissues, decreases in these chemokines indicate that ABT-122 rapidly modulates potential pathophysiologic pathways in RA pts, with evidence for persistent effects after cessation of dosing. These results suggest that dual neutralization of TNF and IL-17 may provide an opportunity to control inflammation and its clinical manifestations in RA and other immune-mediated inflammatory diseases. <h3>Acknowledgement</h3> The design, study conduct, analysis, and financial support of the clinical trials were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the content. All authors had access to all relevant data. Katherine Groschwitz and John Fincke of Complete Publication Solutions, LLC, provided medical writing support. ABT-122 is an investigational product. <h3>Disclosure of Interest</h3> R. Fleischmann Grant/research support from: AbbVie, Consultant for: AbbVie, F. Wagner: None declared, A. Kivitz Grant/research support from: AbbVie, H. Mansikka Shareholder of: AbbVie, Employee of: AbbVie, N. Khan Shareholder of: AbbVie, Employee of: AbbVie, J. Liu Shareholder of: AbbVie, Employee of: AbbVie, F. Hong Shareholder of: AbbVie, Employee of: AbbVie, M. Ruzek Shareholder of: AbbVie, Employee of: AbbVie, R. Padley Shareholder of: AbbVie, Employee of: AbbVie