New insight into how Biogen's Tecfidera works may lead to better MS therapies

blue illustration of neurons
Scientists propose that Tecfidera regulates the microRNA miR-21, which is necessary to produce harmful T cells in multiple sclerosis. (Colin Behrens)

Biogen’s top-selling Tecfidera (dimethyl fumarate) has proven to be an effective treatment for multiple sclerosis, bringing in $4.27 billion in sales in 2018, but its exact mechanism of action remains a mystery. Now scientists from the City University of New York and the Icahn School of Medicine at Mount Sinai have identified a possible mechanism of action, providing information that they believe could lead to better drugs for MS and other autoimmune diseases.

MS happens when brain-homing T cells mistakenly attack the central nervous system. In their paper, which is featured on the March cover of the journal Brain, the CUNY-Mount Sinai team suggested that Tecfidera—after it is metabolized by the body—works via a particular DNA region to reduce the development of these harmful immune cells.

During the study, the researchers analyzed 35 patients who were given Tecfidera and 16 who were treated with Teva’s Copaxone. They collected blood samples from all the participants and measured their levels of brain-homing T cells by looking at the cytokine receptors CCR4 and CCR6, which are important for T-cell trafficking and have been implicated in MS development.


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In patients on Tecfidera, the researchers recorded lower levels of brain-homing T cells compared with other groups. They then analyzed how the drug achieved that immuno-modulating effect on the epigenetic level, meaning they studied how Tecfidera alters gene expression of T cells without changing the underlying DNA sequence.

They found that Tecfidera hyper-"methylates" a genomic site in CD4 T cells that encodes miR-21, a microRNA that is believed to be critical for producing MS-related T cells. Methylation is an epigenetic process whereby DNA's structure—and hence its activity—is changed. The researchers treated CD4 T cells in vitro and observed DNA methylation at miR-21 that was dose-dependent.

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The CUNY-Mount Sinai team believes their findings offer “useful insight into how we might leverage the metabolic-epigenetic interplay between cells and their environment to create new immune-modulating therapies for diseases like MS,” Patrizia Casaccia, M.D. Ph.D., the study’s senior author, said in a statement.

Figuring out why some T cells turn on the body is a priority for researchers studying MS and other autoimmune diseases. Researchers at the Georgia Institute of Technology, for example, said last year that they discovered a mechanism in the body that prevents precursor cells from maturing into harmful T cells—a signaling process that could be a potential target for autoimmune diseases.

The new insight into Tecfidera may benefit more than just MS research, the CUNY-Mount Sinai scientists argue. It could boost efforts to find new therapies for other immune-mediated diseases that are dependent on miR-21 overexpression. The authors noted in the study that psoriasis, systemic lupus erythematosus and inflammatory bowel disease have all been linked to miR-21.

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