High-dose Evrysdi’s side effects may be due to how it affects genes

Combining low-dose Evrysdi with branaplam may reduce side effects: Cell study

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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The side effects that some patients experience on Evrysdi (risdiplam), an approved treatment for spinal muscular atrophy (SMA), may be due to how the therapy alters the activity of thousands of genes when given at high doses, according to a new study in cell models.

Findings also suggest that combining Evrysdi with similar therapies at low doses may minimize potential off-target effects of treatment.

“While the recent approval of [Evrysdi] for the treatment of SMA is welcome news, many concerns remain due to uncomfortable side effects including rash, fever, diarrhea, joint pain (arthralgia), ulcers of the mouth area and urinary tract infections,” the researchers wrote. “It is likely that some of these side effects could be attributed at least in part to the off-target effects we report here.”

The study, “Diverse targets of SMN2-directed splicing-modulating small molecule therapeutics for spinal muscular atrophy,” was published in Nucleic Acids Research. The work was funded by the National Institutes of Health.

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SMA is caused by mutations in the gene SMN1, which provides instructions for making the SMN protein. A second “backup” gene, called SMN2, also provides instructions for making this protein, but due to a slight difference in its genetic code, less SMN protein is made when the SMN2 gene is “read.”

Evrysdi is an oral small molecule that works as a splicing modulator — in simplest terms, the therapy alters how the SMN2 gene is “read,” which allows more SMN protein to be produced from that gene. The treatment is approved in the U.S. for all types of SMA in patients of all ages. It’s sold by Roche, which was not involved in this study.

Another splicing modulator with the same general mechanism of action, called branaplam, was tested in SMA clinical trials, but Novartis discontinued development of the therapy in 2021.

While Evrysdi and branaplam aim to change activity of the SMN2 gene, these small molecules may also have off-target effects that change the activity of other genes in cells.

Overall, our results supported the benefits of the combined treatments using lower concentrations of the compounds on SMN2 … splicing with seemingly minimized off-target effects.

Scientists used cell lines to test how treatments affect global gene activity

In this study, a team of scientists at Iowa State University conducted experiments using cell lines to test how these therapies affect global gene activity.

“The study was aimed at capturing and comparing the broad spectrum of off-target effects caused by these compounds,” they wrote.

Results showed that high levels of either therapy led to substantial genetic dysregulation. High doses of Evrysdi changed the activity of more than 10,000 genes, with 3,670 showing a change in gene expression of more than twofold. High doses of branaplam changed the activity of more than 2,000 genes, 10% of which showed gene expression changes of over twofold.

In contrast, fewer than 600 genes had altered activity when the lowest dose of Evrysdi was used, and one of the genes had a change of at least twofold. Low doses of branaplam “produced changes in the expression of only a handful of genes,” the researchers said.

The scientists conducted a battery of cellular tests to validate these findings, with detailed testing to outline some of the changes in gene splicing and activity at the molecular level. They noted that most changes seen in branaplam were also seen with high doses of Evrysdi, but Evrysdi caused many other changes in gene activity that weren’t seen with the other compound.

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A graphic showing a scissor cutting or splicing a double-helix strand of DNA.

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Lower doses of combo therapy could boost therapeutic effect, reduce side effects

The team also conducted tests to further explore the molecular mechanism of the two therapies on the SMN2 gene and found they stopped being effective when specific regions of this gene were mutated. Because the same mutations affected both compounds, the researchers said, “it is likely that these compounds share common mechanisms of splicing regulation in these instances.”

The team also found that lower doses of Evrysdi and branaplam could be combined to boost the therapeutic effect on the SMN2 gene, while minimizing some of the off-target effects seen with higher therapy doses.

“Overall, our results supported the benefits of the combined treatments using lower concentrations of the compounds on SMN2 … splicing with seemingly minimized off-target effects,” the researchers concluded.

“Our findings are significant for devising the effective dosing regimens as well as for developing the next generation of small molecule therapeutics for the treatment of SMA,” they added.