Latest News

Immunogenicity concerns for biosimilars so far don’t go beyond originator biologics


 

EXPERT ANALYSIS FROM THE ANNUAL PERSPECTIVES IN RHEUMATIC DISEASES

 

A key factor that impacts the efficacy and the toxicity of biologics used for rheumatic diseases is their immunogenicity, and this factor doesn’t appear to be any different for biosimilars in studies conducted so far.

In a meta-analysis of 63 studies of tumor necrosis factor (TNF) inhibitors, investigators including Daniel E. Furst, MD, professor of rheumatology at the University of Washington, Seattle, who also is affiliated with the University of California, Los Angeles, and the University of Florence, Italy, found that antidrug antibodies developed in 17% of patients (BioDrugs 2015;29:241-58).

“That doesn’t sound too bad, but does it differ by medication?” asked Dr. Furst, who spoke at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education. “For infliximab, 30% of the time, there are antidrug antibodies. So if that has a clinical effect, that’s a big deal. For certolizumab ... it’s only 6%, so there is a huge difference within the TNF inhibitors.” At the same time, antidrug antibodies developed in patients on adalimumab 23% of the time, followed by certolizumab (6%), golimumab (4%), and etanercept (2%).

Dr. Daniel E. Furst, professor of rheumatology at the University of Washington, Seattle, who also is affiliated with the University of California, Los Angeles, and the University of Florence, Italy.
Dr. Daniel E. Furst
The same meta-analysis found that the frequency of having immunogenicity differed among diseases as well. For example, antidrug antibodies developed in about 14% of patients with rheumatoid arthritis (RA), in 25% of patients with inflammatory bowel disease, and in 7% among patients with ankylosing spondylitis. “There are huge differences in the relative risk of having an antidrug antibody,” said Dr. Furst, director of research for Arthritis Associates of Southern California in Los Angeles. He also noted that the rate of drug response among patients who develop antidrug antibodies is decreased by about 50%. “So if you have the antibodies, it really makes a difference,” he said. “That differs by drug, and it differs by disease.”

One approach to circumventing the impact of antidrug antibodies on clinical response is by using immunosuppression, which in the meta-analysis had a 70% probability for decreasing antidrug antibodies. But this approach comes with a hitch, Dr. Furst said. The effect of immunosuppression on antidrug antibody positivity differs by disease. Immunosuppression had a 78% probability for decreasing antidrug antibody positivity in RA, 63% probability in inflammatory bowel disease, and 32% probability in ankylosing spondylitis. “That’s a wild mix of immunogenicity and the possibility that it’s going to affect the underlying response,” he said. The best studies in this area are of infliximab and adalimumab, which showed that antidrug antibodies in patients on infliximab reduced the probability of a clinical response by 54% and for adalimumab by 65%.

The same meta-analysis found that there were more antibodies to adalimumab than to certolizumab, golimumab, or etanercept, and also more antibodies to infliximab than to certolizumab, golimumab, or etanercept, but no difference between adalimumab and infliximab. “You’d think that maybe there is a difference between adalimumab and infliximab, but that’s not true,” Dr. Furst said. The apparent effect on the percentage of antidrug antibodies depends on what type of assay is used. For example, radioimmunoassay measures about 11% more antidrug antibodies, compared with enzyme-linked immunosorbent assay. Disease duration also matters. Each year of disease duration increases the antidrug antibodies by 1%.

What about the non-TNF inhibitors? A meta-analysis of five core trials of tocilizumab for RA found that the antidrug antibodies ranged from 1.7% at baseline to 2.3% during the respective trials (Clin Ther. 2010;32:1597-1609). “Anywhere along the way, the percentage of antidrug antibodies was about 1.5%,” said Dr. Furst, who was not involved with the study. “So as opposed to the TNF inhibitors, when you look at tocilizumab, this whole immunity question is probably a non-issue. The same is true for abatacept. With rituximab, the question is a little bit different. In one randomized, controlled trial, immunogenicity was 2.9%, while in the next it was 7.9%. In an open-label trial, it was 11.5%. So I think for rituximab we have to assume that you have some potentially important antidrug antibodies that might affect response.”

Studies have shown that antidrug antibodies do affect the pharmacokinetics of a biologic (and thereby clinical response) by producing lower trough levels of the biologic through an increase in its clearance. However, studies of infliximab and its biosimilars have not yielded any significant differences in clinical responses rates despite small differences in rates of antidrug antibodies or in rates of treatment-emergent adverse events, he said.

There has also been no difference in disease worsening in the only reported double-blind, randomized, switching study for infliximab and an infliximab biosimilar, the NOR-SWITCH study. However, the small numbers of patients in the study with certain diseases for which infliximab is indicated do not allow for conclusions to be drawn for specific diseases, Dr. Furst said.

Dr. Furst disclosed that he has received grant/research support from AbbVie, Actelion, Amgen, Bristol-Myers Squibb, Corbus, the National Institutes of Health, Novartis, and Roche/Genentech. He is also a consultant for AbbVie, Actelion, Amgen, Bristol-Myers Squibb, Cytori, Novartis, Pfizer, and Roche/Genentech. Global Academy for Medical Education and this news organization are owned by the same parent company.
   Comments ()

Recommended for You

News & Commentary

Quizzes from MD-IQ

Research Summaries from ClinicalEdge

Related Articles

Next Article: