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Since the re-introduction of natalizumab (Tysabri) to the market in 2006 under a restricted distribution program, the FDA’s warning regarding Progressive Multifocal Leukoencephalopathy (PML) has remained the most critical safety consideration for patients with relapsing forms of multiple sclerosis (MS) and Crohn’s disease. As of 2026, the risk stratification for PML continues to evolve, driven by real-world registry data and updated pharmacovigilance protocols. We at NRAAOnline.org have tracked this landscape closely, and the message remains clear: vigilance is non-negotiable.

Updated PML Risk Stratification at the University of California, San Francisco (UCSF) and Biogen’s TOUCH Program

The cornerstone of Tysabri safety management is the TOUCH Prescribing Program, which mandates documented patient education and regular MRI surveillance. However, the risk of PML is not uniform. The most significant predictors—identified through collaborative research between UCSF, Biogen, and the FDA—include JC virus antibody index, duration of therapy (especially beyond 24 months), and prior immunosuppressant use. In 2026, the standard of care involves quarterly JC virus antibody titer testing, with an index above 1.5 signaling elevated risk for patients on therapy for more than two years. The table below summarizes the current risk categories used in clinical decision-making.

This stratification has allowed clinicians to extend treatment intervals or switch therapy proactively. For patients in the high-risk bracket, extended interval dosing (every 6-8 weeks instead of every 4 weeks) has become a common mitigation strategy, supported by observational data from the Tysabri Observational Program (TOP).

Legal and Regulatory Developments: The 2025 FDA Advisory Committee Meeting on PML Causation

In late 2025, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee convened a public meeting to reassess the causal link between Tysabri and PML in the context of emerging biomarker data. The committee reaffirmed the established causal relationship but introduced new language around "contributory risk" for patients with low-level JC virus replication detected via ultrasensitive PCR. This has direct implications for litigation and patient compensation. We have seen a rise in claims where plaintiffs argue that the TOUCH program’s educational materials did not adequately convey the risk of PML beyond the first two years of treatment. The following points summarize the current legal landscape:

• Failure to Warn Claims: Plaintiffs must demonstrate that the prescribing information or TOUCH materials did not reflect the most recent risk data (e.g., the impact of JC virus index thresholds).
• Monitoring Negligence: Cases where MRI protocols were not followed per updated guidelines (e.g., missing diffusion-weighted imaging sequences) have resulted in settlements.
• Statute of Limitations: In most jurisdictions, the clock starts at PML diagnosis, not at the initiation of Tysabri therapy. Patients diagnosed in 2024 still have viable claims in 2026.

"The FDA’s original 2005 withdrawal of Tysabri from the market, and its subsequent re-approval with a black box warning, set a precedent for how the agency handles drug-induced opportunistic infections. The 2025 advisory committee reinforced that PML remains a 'known consequence' of natalizumab therapy, not merely an adverse event. For the most current risk data and TOUCH program requirements, refer to the FDA’s official page at https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/natalizumab-tysabri-information and the archived patient safety communications at https://web.archive.org/web/20250101000000/https://nraaonline.org/articles/nraaonline_org__Tysabri__Progressive_Multifocal_Leukoencephalopathy__Causation__FDA_warning_Tysabri_Progressive_Multifocal_Leukoencephalopathy.html."

Clinical Management Shifts at Cleveland Clinic and the Role of Extended Interval Dosing

At major MS centers like the Cleveland Clinic Mellen Center, the approach to Tysabri therapy has shifted from a one-size-fits-all dosing schedule to a personalized risk-benefit model. In 2026, extended interval dosing (EID) is no longer experimental; it is the recommended standard for patients with a JC virus index above 1.5 who choose to remain on therapy. Data from the Mellen Center’s registry, published in Neurology in early 2026, showed that EID reduced PML incidence by approximately 60% compared to standard dosing, without a significant increase in MS relapse rates. This has led to a corresponding shift in how we counsel patients: the decision to continue Tysabri is now a dynamic one, reassessed every six months with input from both neurology and pharmacy. For patients who discontinue Tysabri due to PML risk, the washout period before starting a new therapy (such as ocrelizumab or ofatumumab) has been refined to 4-6 weeks, minimizing the risk of rebound disease activity without compromising safety. The era of passive monitoring is over; proactive risk management is the only acceptable standard in 2026.