Background/Purpose: TNF and IL-17 independently contribute to the pathophysiology of rheumatoid arthritis (RA) acting synergistically to induce mediators of inflammation and joint destruction. Selective dual neutralization of TNF and IL-17 confers superior protection vs inhibition of either alone in mouse arthritis models. ABT-122 is a novel dual variable domain immunoglobulin (DVD-Ig™) targeting both human TNF and IL-17A and is hypothesized to provide greater clinical responses in patients with RA.

Objective: Investigate safety, tolerability and exploratory pharmacodynamics of multiple doses of ABT-122 in subjects with stable RA

Methods: Two Phase 1, placebo-controlled, multiple dose studies randomized 43 subjects with stable RA while receiving stable doses of methotrexate (7.5–25 mg/wk). Subjects were subcutaneously administered either one of 4 dose regimens of ABT-122, 1 mg/kg every other week (4 doses), or 0.5, 1.5, or 3.0 mg/kg weekly (8 doses); or placebo and evaluated through 45 days following last dose. Serum samples for a panel of inflammation markers, and chemokines based on preclinical studies with dual TNF and IL-17 neutralization, were collected at baseline through day 92 and analyzed by multiplex assays.

Results: No clinically significant safety findings were observed in subjects with RA. Rates of treatment-emergent AEs were similar in ABT-122 and placebo treatment 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, consistent with expectations in RA, were reported with no apparent patterns related to etiology, type, or dose in rates with ABT-122 vs placebo and no subject discontinued the study due to infection. There were no clinically significant laboratory, vital sign, or ECG abnormalities. For CXCL9 and CXCL10, rapid decreases relative to placebo occurred within 3d of ABT-122 administration (−25% and −30% from baseline for CXCL9 and CXCL10, respectively). Maximal decreases occurred by d15 (−60% and −45% for CXCL9 and CXCL10, respectively) and persisted through 14d after last dose. Serum CCL23 also decreased following ABT-122 with maximal decreases (−30%) at d64 and continued through d92. Consistent with anti-TNF inhibition, soluble E-selectin levels decreased following ABT-122 , persisting through d92 for the 3.0 mg/kg group.

Conclusion: ABT-122 demonstrated a well tolerated safety profile in subjects with RA through 8 weeks of dosing up to 3 mg/kg, consistent with previous observations in the 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 patients, 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 subjects and in other immune-mediated inflammatory diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/safety-tolerability-and-pharmacodynamics-of-abt-122-a-dual-tnf-and-il-17-targeted-dual-variable-domain-dvd-igtm-in-subjects-with-rheumatoid-arthritis/