Phase II Study of ABT‐122, a Tumor Necrosis Factor– and Interleukin‐17A–Targeted Dual Variable Domain Immunoglobulin, in Patients With Psoriatic Arthritis With an Inadequate Response to Methotrexate

Abstract

ObjectiveTo investigate the safety and efficacy of ABT‐122, a tumor necrosis factor (TNF)– and interleukin‐17A (IL‐17A)–targeted dual variable domain immunoglobulin, in patients with active psoriatic arthritis (PsA) who have experienced an inadequate response to methotrexate.MethodsPatients (n = 240) were randomized to receive ABT‐122 (120 or 240 mg every week), adalimumab (40 mg every other week), or placebo in a 12‐week double‐blind, parallel‐group study. The primary efficacy end point was the proportion of patients achieving ≥20% improvement in disease activity according to the American College of Rheumatology response criteria (ACR20) at week 12. Secondary and exploratory 12‐week end points included 50% improvement (ACR50) and 70% improvement (ACR70) response rates, and proportion of patients meeting the Psoriasis Area and Severity Index (PASI) response criteria for ≥75% (PASI75) and ≥90% (PASI90) improvement in skin scores among those with ≥3% of their body surface area affected by psoriasis.ResultsIn both ABT‐122 dose groups, ACR20 response rates at week 12 (64.8–75.3%) were superior to that in patients receiving placebo (25.0%) (P < 0.001) but similar to that in patients receiving adalimumab (68.1%). ACR50 and ACR70 response rates were also superior in both ABT‐122 dose groups (36.6–53.4% and 22.5–31.5%, respectively) compared to the placebo group (12.5% and 4.2%, respectively) (P < 0.05). Among eligible patients in the placebo, adalimumab, ABT‐122 120 mg every week, and ABT‐122 240 mg every week treatment groups, PASI75 responses were achieved in 27.3%, 57.6%, 74.4%, and 77.6% of patients, respectively, whereas PASI90 responses were achieved in 18.2%, 45.5%, 48.8%, and 46.9% of patients, respectively. Frequencies of treatment‐emergent adverse events, including infections, were similar across all treatment groups, causing no discontinuations. No serious infections or systemic hypersensitivity reactions were reported with ABT‐122.ConclusionDual neutralization of TNF and IL‐17A with ABT‐122 had efficacy and safety that was similar to, and not broadly differentiated from, that of adalimumab over a 12‐week treatment course in patients with PsA.

ABT‐122, a Bispecific Dual Variable Domain Immunoglobulin Targeting Tumor Necrosis Factor and Interleukin‐17A, in Patients With Rheumatoid Arthritis With an Inadequate Response to Methotrexate

“…The lack of a placebo control group (i.e., patients who were receiving methotrexate only) did not allow for direct assessment of the magnitude of the response to ABT‐122. It is conceivable that a higher dose of ABT‐122 might have improved its efficacy; however, in a separate study conducted in patients with psoriatic arthritis, even ABT‐122 at a dosage of 240 mg every week was not associated with significant differentiation from adalimumab at 40 mg every other week . The proportions of anti‐TNF activity versus anti–IL‐17A activity of ABT‐122 are fixed, which is unavoidable with a dual inhibitor, thereby precluding the evaluation of different ratios of anti‐TNF and anti–IL‐17A activity on efficacy outcomes.…”

A bispecific soluble receptor fusion protein that targets TNF‐α and IL‐21 for synergistic therapy in inflammatory arthritis

“…A dual target inhibitor of IL-6R and TNFR2 was shown to inhibit synovial fibroblast proliferation and migration, osteoclastogenesis, and disease severity more effectively than single-target drugs. 46,47 Although IL-17 is a major pathogenic cytokine that can act on various inflammatory cells such as fibroblasts and macrophages, IL-21, which is also overproduced in Th17, Tfh, and Tph cells, may play a key role in the activity of antibody-secreting B cells and Tfh cells. A fusion protein targeting TNF and IL-17A was shown to be more effective than etanercept alone in a CIA mouse model.…”

The Role of the IL-23/IL-17 Pathway in the Pathogenesis of Spondyloarthritis

“…ABT-122 is an IgG1 dual-variable domain immunoglobulin (DVD-Ig) that was engineered to bind to and neutralize human TNF and IL-17A. It is built on an adalimumab backbone by adding IL-17A binding domains [ 139 , 140 , 141 ]. Although the dual inhibition of TNF and IL-17A was expected to provide greater effects compared to adalimumab, which targets only TNF, two phase 2 clinical studies have failed to demonstrate the superiority of ABT-122 for the treatment of PsA compared to adalimumab at 12 weeks [ 141 , 142 ].…”