Review Examines Immunogenicity Rates in Patients Taking Innovator Biologics, Biosimilars

The potential immunogenicity of biosimilar agents is an important consideration in the treatment decision-making process, and a new systematic review of immunogenicity associated with biological therapies in chronic inflammatory diseases, published in BioDrug, explores the frequency of immunogenicity and its potential impact on efficacy and safety. The review was conducted by Vibeke Strand, MD, of the Division of Immunology and Rheumatology at Stanford University School of Medicine in Portola Valley, California, and colleagues. Dr Strand, a leading expert on rheumatology, recently contributed to The Center for Biosimilars™ Peer Exchange® titled "Clinician and Managed Care Insights on Biosimilars for Inflammatory Diseases."

The researchers conducted literature searches through November 2016 for eligible studies of randomized clinical trials (RCTs), non-RCTs, and observational studies of patients treated for rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, nonradiologic axial spondyloarthritis, psoriasis, Crohn’s disease, and ulcerative colitis. Approved innovator biologics and biosimilar agents included in the studies were abatacept, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, secukinumab, tocilizumab, ustekinumab, and the infliximab biosimilar CT-P13.

A total of 32,584 publications were initially identified in the literature—27,560 were reviewed in the first screening, and 1148 were reviewed in the second screening. After excluding publications with risks of bias, 443 studies were selected for analysis.

The researchers found that the proportions of patients who developed treatment-induced anti-drug antibodies (ADAbs) varied widely across agents. They note, however, that comparisons of immunogenicity across agents should be conducted with caution due to fundamental difference in molecular structure, number of studies reporting ADAbs for individual agents, disease states included, study designs, and assay methods.

The highest overall rates of patients developing ADAbs were reportedly associated with the following products:

• Infliximab (0%-83%)
• Adalimumab (0%-54%)
• CT-P13 (21%-52%)

The lowest rates of patients developing ADAbs were reported with the following products:

• Secukinumab (0%-1%)
• Ustekinumab (1%-11%)
• Etanercept (0%-13%)
• Golimumab (0%-19%)

Most ADAbs were neutralizing, except those to abatacept and etanercept. ADAb-positive (ADAb+) versus ADAb-negative patients had lower rates of clinical response to abatacept, golimumab, infliximab, rituximab, ustekinumab, and CT-P13. Higher rates of infusion-related reactions were reported in infliximab and CT-P13—treated ADAb+ patients. Background immunosuppressive and antiproliferative agents reduced biologic immunogenicity across diseases.

In conclusion, the analysis found that ADAbs were detected in as many as 50% of patients treated with commonly used tumor necrosis factor inhibitor antibodies and in a lower proportion of patients receiving other biologics.

Across chronic inflammatory disease states, immunogenicity rates were highest (>50%) in studies of adalimumab, infliximab, and CT-P13, and lowest (<20%) in studies of secukinumab, golimumab, etanercept, and ustekinumab. Although of less importance, some evidence suggests an elevated risk of hypersensitivity reactions in ADAb+ patients, particularly with infliximab. However, considerable variability in immunogenicity was seen between studies of the same and different agents, the researchers note.

“The persistent presence of ADAbs decreases biologic activity via interference with epitope bindings and/or formation of immune complexes, which results in lower serum levels of the biologic and consequently possible loss of clinical response,” the authors conclude. Monitoring ADAbs and biologic concentrations may provide essential information to clinicians that can potentially improve treatment management decisions as well as outcomes and reduce risks and costs. “Such assessment is not currently routine in rheumatology practice,” the researchers said, “but heightened awareness of the immunogenic potential of biologics and the putative clinical consequences has been achieved among gastroenterologists who treat [inflammatory bowel disease].”