MRI scan of a PML patient displaying prominent brain lesions (indicated by white signal). [Image credit: Daniel S. Reich, National Institute of Neurological Disorders and Stroke (NINDS)]
Biogen’s Tysabri (natalizumab), the first humanized monoclonal antibody for multiple sclerosis (MS), sparked optimism among MS patients following its FDA approval in 2004. The drug offered significant benefits, reducing relapses for patients resistant to other treatments. This was a significant milestone in the treatment of MS, but the journey of natalizumab and PML soon took a concerning turn.
Within a year, alarming reports surfaced: A number of patients were developing progressive multifocal leukoencephalopathy (PML), a rare and often fatal brain infection. The suspected culprit? Natalizumab’s immunomodulatory effect, which suppressed the immune cells fighting the JC (John Cunningham) virus, which is involved in inducing PML.
“PML is a rare demyelinating disorder of the brain caused by a polyomavirus. This particular virus is ubiquitous; we find it in all populations,” said Dr. Joseph Berger, a renowned neurologist and co-author of a recent commentary on PML in Frontiers in Neuroscience.
“Once you reach adulthood, about 60 to 70% of us have been infected by this virus, as evidenced by seroepidemiologic studies,” Berger noted. “Yet, PML was a back-of-the-textbook disorder until recently — meaning, in medical school, you barely learn about it. It was not something that was particularly common or well known.”
In the mid-2000s, NEJM documented multiple early case reports, including a case involving a recipient of the drug with Crohn’s disease.
Consequently, Biogen and its distributor Elan withdrew natalizumab from the market in 2005. Given the drug’s significant benefits in patients unaffected by PML and strong patient advocacy from patients, it was reintroduced with explicit warnings in 2006. This marked a complex portion in the saga of natalizumab and PML, with an aim to balance the drug’s benefits with the potentially fatal risk it presented.
The hurdle of mitigating risks while maximizing benefits
“The issue is, natalizumab is a very effective drug, and it’s particularly effective in individuals that have failed other treatments. So there’s a desire to continue the treatment beyond two years, but the question is how do you mitigate the risk of PML,” Berger said.
A study published in Frontiers in Neurology points in a new direction. This research confirmed a strong link between four genetic mutations and the development of PML. As Dr. Eli Hatchwell, lead author and chief scientific officer at Population Bio UK, explained, “Our findings could enable a genetic test to predict PML risk, enabling personalized treatment decisions.” This discovery suggests genetic testing could become a standard of care, a viewpoint supported by Dr. Lawrence Steinman, the inventor of Tysabri.
The study actually identified 19 genetic variants linked to an increased risk of PML, but the four within the C8B, LY9 (also known as SLAMF3), FCN2 and STXBP2 genes exhibited the most significant association with PML risk. The Frontiers in Neurology study found that carriers of any one of these variants have an elevated risk of developing PML compared to a control group of patients also exposed to the drugs but without these variants.
The hurdle of mitigating natalizumab and PML risks
Despite the potential of genetic testing, Berger underscores the persisting risk of PML for many individuals, even those testing negative for the associated genetic markers. Hatchwell likens this to the BRCA test used in predicting breast cancer risk. “If a woman tests negative, that doesn’t mean she won’t develop breast cancer. Similarly, a negative PML test isn’t completely reassuring,” Hatchwell explained. This fact points to the complex challenge in considering natalizumab and PML risk, using the drug to its full potential while minimizing the risk of potentially severe adverse effects.
Berger calls for continued vigilance and careful patient management, shedding light on the potential for individuals to transition from JC virus antibody negative to positive over time. Consequently, he supports the use of drugs like natalizumab in such cases, albeit for a limited duration given the looming risk of PML.
Genetic tests are a tool but not definitive predictors of PML risk
Genetic tests are not definitive predictors but risk indicators, Hatchwell said. They’re potent tools, yet they require a comprehensive understanding of each patient’s medical history and current health status to be fully effective.
Berger expresses reservations about the applicability of the genetic test for PML risk associated with other drugs. He highlights fingolimod, the MS drug with the second-highest incidence rate for PML. “The risk of developing PML with fingolimod is substantially lower, an order of magnitude difference, in fact. This makes identifying risk mitigation strategies for this drug particularly challenging,” Berger noted. While the genetic test might provide another layer to risk mitigation strategies, its influence on overall risk might be limited, given the small fraction of patients it flags.
Berger estimates that the genetic test discussed in the Frontiers in Neurology study, focusing on the four key variants in the C8B, LY9 (SLAMF3), FCN2, and STXBP2 genes, would identify about 10% of the population that is at risk for PML. “So while it may help remove a portion of the population at high risk of developing PML, and thus lower the rates of PML, there will still be a large number of individuals at risk. That said, we have seen the incidence rates of natalizumab-associated PML fall substantially with the widespread adoption of risk mitigation strategies.”
Sizing up genetic testing’s benefits
Despite the potential benefits, Berger remains skeptical of the test’s usefulness in mitigating risk associated with other drug-related PML cases. “With other drugs, the numbers are just too small,” he said. “For instance, with a drug like ocrelizumab, there are only two cases that hadn’t been treated with something else. Determining whether these genetic tests will be valuable in such populations will be incredibly difficult. It’s a bit of a guessing game at this point.”
Hatchwell points out that while the study findings do indicate a correlation between these genetic variants and an increased risk of PML, further research is essential to fully unravel the relationship between these genes and the JC virus. Researchers remain hopeful about identifying other genetic variants that may contribute to PML risk.
Berger believes that while the genetic test could contribute to risk management, its impact might be limited. “So you’re only identifying a small sliver of the at-risk population,” he said. “If these four genes were present in 70% or 80% of the population developing PML, it would be a different story, but as it stands, it’s a very small number in my view.”
The need for more clarity on PML
“We also need to know what puts individuals at risk. I mean, why are there so many people that have this virus yet, even in the face of immunosuppression, never go on to develop PML. And we also have to have effective treatments for the disease,” Dr. Berger said.
This graph illustrates the number of PML cases attributed to different drug types, as reported in the FDA Adverse Event Reporting System (FAERS). Note, the 2023 figures are a projection for the full year based on Q1 data.
PML also affects patients treated for conditions like blood cancers, inflammatory bowel disease, Crohn’s disease, rheumatoid arthritis, lupus, and organ transplant recipients. As immunosuppressant therapies increase, drug-induced PML cases have risen, with FDA reports more than doubling since 2011, culminating in 522 cases reported in 2022 alone, according to the FDA Adverse Event Reporting System (FAERS).
While the genetic test may not be a comprehensive strategy, it signifies a step towards more nuanced patient care.
The road to better patient stratification and management
Despite these challenges, the potential for genetic testing to mitigate PML risks presents a promising avenue, but Hatchwell and Berger stress that this is only the beginning. It is vital to continue pushing the boundaries of medical innovation, encouraging open debate, and ensuring patients are well-informed. “The hope is that we can stratify patients into low, medium and high risk of PML, and that will guide therapy,” Hatchwell suggested.
The ultimate goal is to move towards precision medicine, Hatchwell said, where treatment decisions are tailored to the individual based on their unique genetic makeup and personal health factors. The study is a small step in that direction, he added, offering the potential for more personalized risk assessment and management for PML.
Our next article will delve deeper into the emerging research on genetic risk factors for PML, providing more detail on how this research could influence treatment strategies and patient outcomes.