Key Takeaways:
- Researchers have identified 99 drugs used for conditions ranging from multiple sclerosis to blood cancers that may cause a rare but often-fatal condition called Progressive Multifocal Leukoencephalopathy (PML).
- People who have one of four recently identified genetic variants are at 10 times the risk of developing PML if they take these drugs.
- A simple and free genetics test can identify those who are at higher risk.
- Many physicians who treat these patients may be unaware of how many of these commonly prescribed drugs increase the risk of PML, which has no cure.
- Drug warning labels should be updated to include genetic testing before prescribing one of these drugs.
PHILADELPHIA, Sept. 11, 2023 – Nearly 100 drugs for multiple sclerosis (MS), blood cancers, rheumatoid arthritis and other diseases may cause Progressive Multifocal Leukoencephalopathy (PML), a rare but often-fatal condition. A simple genetic test can determine who has a 10-fold higher risk for the condition so they can discuss safer treatment options with their physicians. The largest study to date on drugs that increase the risk for PML and the genetic link to the disease is being presented at the 148th Annual Meeting of the American Neurological Association (ANA).
Researchers analyzed the Food and Drug Administration Adverse Event Reporting System (FAERS) and found 81 drugs—plus 18 more not reported to FAERS but in the same drug class as PML-linked drugs—are linked to PML deadly brain disease. Most of them are immunosuppressant disease-modifying therapies. They assessed whether the drug label listed PML risk anywhere on the label and if so, whether it was only listed as a Serious Adverse Event (SAE) or carried a Boxed Warning, the FDA’s strongest drug label warning. They note that the largest number of PML cases have been associated with natalizumab (for MS) and rituximab (for cancer and rheumatoid arthritis), both of which have a Boxed Warning. But they also found two common blood cancer drugs (daratumumab and venetoclax) have no warning on their labels of the risk of developing PML.
The researchers recently identified genetic variants in four genes (C8B, FCN2, LY9, STXBP2) that increase by 10-fold a person’s risk of developing PML when taking one of these drugs. All four genetic variants play a key role in immune pathways and disorders related to activating the JC virus, which lies dormant in the vast majority of people. Once activated in a person who is immune compromised, the JC virus can infect the brain and cause PML. Using a free genetic test, those who are considering taking one of those drugs can learn if they have one of the genetic variants and, if so, may consider alternative treatments that aren’t linked to PML.
A growing number of PML cases have been reported in patients on therapies for conditions including MS, Crohn’s disease, psoriasis, lupus, blood cancers, and organ transplants heightening the importance of understanding the risk and options to help prevent future cases of this devastating drug-induced side effect.
“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., New York. “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.”
She noted that patients who are currently taking those drugs should also be tested and said surveys have found patients overwhelmingly want to be tested once they know a genetic test is available.
Those testing positive for one of the genetic variants may want to consider an alternative treatment that has not been associated with PML, such as an interferon-based therapy, glatiramer acetate or teriflunomide in MS patients. In some cases, despite testing positive for one of the genes, patients may choose to stay on PML-linked therapies because they are so effective. But having knowledge of their higher genetic risk, patients and their doctors can monitor more closely for PML, such as with more frequent brain MRIs.
The researchers will present updated findings from this largest-ever PML study of its kind, including an analysis of the FAERS data, a breakdown by drug class (such as target and mechanism of action) and indication. For example, 17 of the 99 drugs are used to treat MS. It will also provide further insights into the biology of the four genes linked to PML risk and immune biology regarding how PML infects the brain (all four genes are linked to viral defense mechanisms) as well as how the genes and processes overlap with infections from the Epstein-Barr virus (EBV). For example, the STXBP2 gene (one of the four genes associated with PML) is directly linked to a type of EBV-associated disease called hemophagocytic lymphohistiocytosis.
The test for the four genetic variants associated with PML is now available free in the U.S. at https://www.pmlrisktest.org/. The test sample can be taken at home and shipped to the lab for analysis.
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About the American Neurological Association (ANA)
From advances in stroke and dementia to movement disorders and epilepsy, the American Neurological Association has been the vanguard of research since 1875 as the premier professional society of academic neurologists and neuroscientists devoted to understanding and treating diseases of the nervous system. Its monthly Annals of Neurology is among the world’s most prestigious medical journals, and the ANA’s Annals of Clinical and Translational Neurology is an online-only, open access journal providing rapid dissemination of high-quality, peer-reviewed research related to all areas of neurology. The acclaimed ANA Annual Meeting draws faculty and trainees from the top academic departments across the U.S. and abroad for groundbreaking research, networking, and career development. For more information, visit www.myana.org or @TheNewANA1
Meeting Link: American Neurological Association Annual Meeting, September 2023
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