Simple Genetic Test Identifies Patients Vulnerable to Severe Side Effect of MS Drugs

Several medications prescribed for conditions ranging from multiple sclerosis and blood cancers to rheumatoid arthritis have been associated with a rare but often deadly neurological disorder known as progressive multifocal leukoencephalopathy (PML). PML destroys the cells responsible for creating myelin, the protective substance surrounding nerve cells in the brain. It's triggered by a virus present in as many as 85% of adults but only becomes active when the immune system is significantly weakened. Now, a simple genetic test makes it possible to identify individuals at a tenfold higher risk of developing PML, allowing them to consider safer treatment alternatives.

Researchers from Population Bio, Inc. (New York, NY, USA) conducted the most extensive study so far to examine the relationship between medications that heighten PML risk and specific genetic predispositions. They analyzed data from the Food and Drug Administration Adverse Event Reporting System (FAERS) and identified 81 drugs, along with another 18 from the same drug class not reported to FAERS, that are linked to the development of PML. A majority of these drugs are used as immunosuppressant disease-modifying therapies. The researchers evaluated whether these medications mentioned the risk of PML on their labels, either as a Serious Adverse Event (SAE) or featuring a Boxed Warning, the FDA's most severe label caution. They noted that the majority of PML cases are associated with two drugs, natalizumab (used for MS) and rituximab (used for cancer and rheumatoid arthritis), both of which carry a Boxed Warning. Surprisingly, they discovered that two commonly used blood cancer drugs, daratumumab and venetoclax, have no PML risk warning on their labels.

The researchers found that recently-identified genetic variants in four specific genes (C8B, FCN2, LY9 and STXBP2) increased an individual's susceptibility to PML by tenfold if they are taking one of these high-risk medications. These genetic variants are critical players in immune functions and disorders that activate the JC virus, which is dormant in most people. If the JC virus becomes active in someone with a weakened immune system, it can lead to PML. A free genetic test is now available for patients contemplating the use of such medications. If they possess one of these genetic variants, alternative treatment options that do not carry a PML risk should be considered, according to the team.

“The increased risk of drug-induced PML in patients testing positive is higher than already-known genetic associations that are used to guide treatments, like BRCA1/2 for breast cancer, yet many neurologists and oncologists may have limited awareness of how many drugs have been linked to PML,” said Peggy S. Eis, PhD, lead author of the study and chief technology officer at Population Bio, Inc. “There are no treatments to cure PML, so prevention is the best defense, including knowing your genetic risk. Even though the chance of developing PML is very low for some of these drugs, patients should still be screened given the ease and low cost of doing so relative to the avoidable potential consequences for those who do test positive. Clearly, warning labels on some of these drugs need to be updated and can now include a requirement for genetic testing before these drugs are prescribed.”

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Population Bio, Inc. 

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