Genetics not found to influence Cosentyx treatment responses
Finding challenges idea that varying responses driven by genetic variation
The responses to Cosentyx (secukinumab) among people with ankylosing spondylitis (AS) and other inflammatory diseases aren’t significantly impacted by a person’s genetic background, a recent study suggests.
The findings challenge an existing hypothesis that the variable responses to the therapy in clinical practice could largely be driven by genetic variation.
“These results were surprising, as it was predicted that genetics might strongly influence whether someone responds to anti-IL17 [Cosentyx] therapy,” 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 a doubt on whether genetics plays a role in a patient’s response to anti-IL17 therapy [Cosentyx] and whether genetics could be used to predict who would benefit the most from these treatments.”
The study, “Response to anti-IL17 therapy in inflammatory disease is not strongly impacted by genetic background,” was published in The American Journal of Human Genetics. It was 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 inflammatory signaling molecule implicated in a wide range of inflammatory and autoimmune diseases. It’s approved in the U.S. for a number of such diseases, including AS, nonradiographic axial spondyloarthritis, plaque psoriasis, and certain types of arthritis.
Responses to the medication vary widely. While some patients see a fast and strong reduction 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 to it.
The issue isn’t specific to Cosentyx. Biological treatments for these inflammatory diseases yield irregular responses in general, the scientists said. For this reason, it’s often difficult to predict which patients might respond to which medications.
Testing effect of genetic variation on treatment response
An existing theory is that genetic variation may explain variable treatment responses. If these genetic underpinnings were better understood, they could be leveraged as biomarkers to predict treatment responses, leading an international team of researchers to investigate whether genetic patterns could predict responses to Cosentyx among more than 5,000 people who’d participated in 19 Cosentyx clinical trials. The trials involved people with AS, psoriasis, psoriatic arthritis, and rheumatoid arthritis.
The researchers used the data to conduct a genome-wide association study (GWAS). With this analysis, they looks for correlations between particular genetic changes and the recorded changes in disease activity a person had while on Cosentyx or a placebo in the trial.
For AS patients, the main clinical outcome measure was the AS disease activity score with 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 were identified that could predict a person’s response to treatment in any of the four diseases.
Examining HLA gene family
The researchers also examined the human leukocyte antigen (HLA) gene family. HLA genes are critical for immune system function and multiple variations in this family of genes are linked to the risk of a number of 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. Moreover, calculated risk scores based on variation in genes associated with the risk of developing 11 different inflammatory diseases didn’t correlate with Cosentyx responses.
“We found that the genetic predictors that put patients at risk of the disease did not seem to impact how easy these patients were to treat,” Jostins-Dean said.
Secondary analyses using other clinical measures of disease activity also showed no relationships.
Altogether, the findings offer “strong evidence to support the claim that genetic heterogeneity is not a large driver of response to anti-IL17 therapy,” the researchers wrote. “We should consider the possibility that genetics may not play a major role in response to other biological therapies as well.”
While it’s still possible that certain genetic variants can predict treatment responses, these may have been too rare to be identified in this study and a larger numbers of patients would be needed to detect them.
The scientists believe both clinical trial and real-world data will be needed to map the genetics of therapy responses. This study could be a “starting point” for larger analyses, they suggested.
Still, “despite the negative results … the study adds to our deepening understanding of inflammatory and autoimmune diseases and where precision medicine can be best applied,” Jostins-Dean said. “The study also raises the question of what else could be causing the variable responses to anti-IL17 therapy, if it isn’t genetics.”