Genetic marker helps predict which MS therapy will work: Study
Biomarker gauges benefit of glatiramer acetate, interferon
Researchers have identified a genetic biomarker that predicts whether people with relapsing forms of multiple sclerosis (MS) will respond to glatiramer acetate (sold as Copaxone, among others) therapy.
A study based on an analysis of more than 3,000 MS patients showed that those who carry a form of the HLA gene called HLA-A*03:01 benefit significantly more from glatiramer acetate treatment than from interferon-beta therapies.
“Our study shows for the first time that a genetic marker is linked to the treatment success of an MS medication,” Nicholas Schwab, PhD, the study’s lead author and a professor at the University of Münster, said in a university news story. “This allows us to predict before starting therapy whether glatiramer acetate or interferon is likely to be the better choice.”
The discovery was detailed in the study, “HLA-A∗03:01 as predictive genetic biomarker for glatiramer acetate treatment response in multiple sclerosis: a retrospective cohort analysis,” published in eBioMedicine.
Glatiramer acetate is an established first-line treatment for adults with relapsing forms of MS, especially those with mild to moderate disease activity. The therapy helps reduce relapse rates to a similar degree as interferon beta therapies, a group of other first-line MS therapies sold under several brand names.
Cell response hints at relapse risk
While both glatiramer acetate and IFN-beta medications have relatively mild side effects and are well tolerated, it’s difficult to determine which patients would respond better to one therapy or another.
“There is currently no validated predictive treatment response biomarker for [glatiramer acetate] – or any other MS medication, for that matter,” the researchers wrote.
The team of scientists in Germany, France, and the U.S. examined T-cell responses in people treated with glatiramer acetate to identify potential biomarkers of treatment effectiveness.
They first analyzed T-cell receptors in the blood of 1,627 MS patients, 204 of whom were treated with glatiramer acetate. T-cell responses to glatiramer acetate were found in patients who carried two forms, or alleles, of HLA genes: HLA-A*03:01 and HLA-DRB1*15:01. HLA genes encode proteins that help the immune system distinguish the body’s own cells from foreign invaders.
The scientists validated those findings in a separate group of 72 MS patients before and after glatiramer acetate treatment. Both HLA-A*03:01 and HLA-DRB1*15:01 sequence patterns predicted previous glatiramer acetate therapy in two additional groups of 1,322 people.
To determine whether these two HLA alleles are also associated with glatiramer acetate’s efficacy, the researchers reviewed clinical data from 1,987 MS patients treated with glatiramer acetate or IFN-beta, from five separate groups.
Among HLA-A∗03:01 carriers, which made up 29%-49% of all patients, glatiramer acetate reduced the risk of relapse by 33% compared with IFN-beta in one group and by 34% in another. In another group, glatiramer acetate lowered the risk of first relapse by 63% over IFN-beta in HLA-A∗03:01 carriers.
HLA-A∗03:01 carriers also had fewer MRI lesions during glatiramer acetate treatment and had lower levels of neurofilament light, a marker for nerve damage. None of these benefits were seen in HLA-DRB1*15:01 carriers.
In HLA-A∗03:01 carriers previously treated with glatiramer acetate, the MS Severity Score and the Expanded Disability Status Scale (EDSS) score were also lower, indicating less severe disease, compared with carriers who were not given the treatment. Over time, patients with this HLA allele showed slower increases in EDSS scores than those treated with IFN-beta (0.42 points vs. 0.47 points per year).
The discovery is “a significant advance for personalised MS treatment,” said Heinz Wiendl, MD, a professor at the university and spokesperson for the German Competence Network on Multiple Sclerosis, which co-designed the study,
“Our study identifies HLA-A∗03:01 as a predictive and genetic treatment biomarker for MS, enabling caregivers and patients to make a personalised decision before initiation of treatment,” the scientists wrote. “Application of the biomarker offers one third of patients with MS … an efficacious treatment with a beneficial safety profile, superior to its comparator IFN.”
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