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Responses to the treatment of non-ankylosing spondylitis…

Responses to Cosentyx (secukinumab) among people with ankylosing spondylitis (AS) and other inflammatory diseases are not significantly affected by a person’s genetic background, a new study suggests.

The results challenge the existing hypothesis that variable responses to treatment in clinical practice may be driven primarily by genetic variation.

“These results were surprising, as it was thought that genetics could have a strong effect on whether a person responds to anti-IL17. [Cosentyx] Treatment,” Luke Jostins-Dean, PhD, of the Kennedy Institute of Rheumatology at the University of Oxford, England, and one of the study’s corresponding authors, said in a university press release. “The results cast doubt on whether genetics play a role in patient response to anti-IL17 therapy. [Cosentyx] and genetics can be used to predict who will benefit most from this treatment.”

Lesson, “Response to anti-IL17 therapy in inflammatory disease is not significantly affected by genetic background,” was published in American Journal of Human Genetics. Conducted and funded as part of the Oxford Big Data Institute-Novartis Collaboration for AI in Medicine. Novartis is the developer of Cosentyx, an antibody that targets interleukin-17a (IL-17), an inflammation signaling molecule involved in a wide range of inflammatory and autoimmune diseases. It is approved in the US for a number of such diseases, including AS, nonradiographic axial spondyloarthritis, plaque psoriasis, and certain types of arthritis.

Responses to medication vary widely. While some patients see a rapid reduction and improvement in symptoms, others may see no response at all. For example, response rates to Cosentyx in AS are about 60.5%, but only 30.7% of those with rheumatoid arthritis respond.

The issue is not specific to Cosentyx. Biological treatments for these inflammatory diseases generally produce unusual responses, the scientists said. For this reason, it is often difficult to predict which patients will respond to which medications.

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Assessment of the effect of genetic variation on treatment response

A prevailing theory is that genetic variation may explain variable treatment responses. If these genetic factors were better understood, they could be supported as biomarkers to predict treatment responses, leading an international group of researchers to investigate whether genetic patterns can predict responses to Cosentyx among more than 5,000 people who have participated in 19 clinical trials of Cosentyx. The trial included people with AS, psoriasis, psoriatic arthritis, and rheumatoid arthritis.

The researchers used the data to conduct a genome-wide association study (GWAS). Through this analysis, they look for correlations between specific genetic changes and recorded changes in disease activity that a person has had while on Cosentyx or placebo in the trial.

In AS patients, the primary clinical outcome measure was the AS disease activity score and c-reactive protein (ASDAS-CRP).

As part of the analysis, 4,063 people were treated with Cosentyx and 1,151 were given a placebo. Among 754 people with AS across four clinical trials, the median age was 42 and 33% were women.

Across the genome, no genetic factors have been identified that predict an individual’s response to treatment for any of the four diseases.

Reviewing the HLA gene family

The researchers also examined the leukocyte antigen (HLA) gene family. HLA genes are very important for the functioning of the immune system and many changes in this family of genes are associated with the risk of many inflammatory diseases. In AS, variation in the HLA B27 gene is associated with disease risk.

But no relationship was seen between HLA genes and Cosentyx responses. Furthermore, risk scores based on genetic variants associated with the risk of developing 11 inflammatory diseases did not correlate with Cosentyx responses.

“We found that the genetic predictors that put patients at risk of the disease do not seem to affect how easy these patients are,” said Jostins-Dean.

A secondary analysis using other clinical measures of disease activity also showed no relationship.

Overall, the results provide “strong evidence to support the claim that genetic heterogeneity is not a major driver of response to anti-IL17 therapy,” the researchers wrote. “We have to consider the possibility that genetics may not play a major role in response to other biological treatments.”

While it is possible that certain genetic variants may predict treatment responses, these may have been rare to identify in this study and a large number of patients would be needed to detect them.

Scientists believe that both clinical trials and real-world data will be needed to map genetics of treatment responses. This study could be a “starting point” for a larger analysis, they suggest.

However, “despite the adverse effects … the study adds to our deeper understanding of autoimmune diseases and where precision medicine can best be used,” Jostins-Dean said. “The study also raises the question of what else may be causing variable responses to anti-IL17 therapy, if not genetics.”

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