Why was Tysabri taken off the market? Unpacking the PML risk and its pharmaceutical impact

October 10, 2025 •

4 min read

In 2005, just months after its accelerated approval, the manufacturers of the promising multiple sclerosis drug Tysabri (natalizumab) voluntarily withdrew it from the market following the discovery of a rare but fatal brain infection. This decision was in direct response to why was Tysabri taken off the market and fundamentally reshaped drug development and safety protocols for high-efficacy treatments.

Quick Summary

Tysabri's temporary market withdrawal stemmed from rare but fatal cases of Progressive Multifocal Leukoencephalopathy (PML) identified in clinical trials. It was later re-approved with a black box warning and a strict risk mitigation strategy.

Key Points

Initial Withdrawal: Tysabri was voluntarily pulled from the market in 2005, just three months after its approval, due to fatal cases of the brain infection Progressive Multifocal Leukoencephalopathy (PML) in clinical trial patients.
The Cause (PML): PML is a rare but often fatal viral brain infection triggered by the JC virus, which can reactivate in immunocompromised individuals. Tysabri's mechanism was found to increase this risk.
Re-approval: Following a safety review, the FDA re-approved Tysabri in 2006, but under a strict risk mitigation program to manage the risk of PML.
TOUCH® Prescribing Program: The mandatory risk program, overseen by the FDA, requires strict monitoring, patient education, and risk stratification based on factors like anti-JCV antibody status and treatment duration.
Current Status: Tysabri is not permanently off the market. It remains a high-efficacy treatment for MS and Crohn's disease but is reserved for patients where the benefits outweigh the carefully managed risks.
Black Box Warning: A 'black box' warning, the most serious FDA warning, is included on Tysabri's labeling to highlight the increased risk of PML.

The Initial Promise and Sudden Setback

First approved by the U.S. Food and Drug Administration (FDA) in November 2004, Tysabri (natalizumab) was a revolutionary treatment for relapsing forms of multiple sclerosis (MS) and Crohn's disease. As a monoclonal antibody, it worked by blocking immune cells from entering the brain and spinal cord, significantly reducing MS relapses and slowing disability progression. Its high efficacy led to accelerated approval, bringing much-needed hope to patients with severe autoimmune conditions.

However, this initial promise was quickly overshadowed by a devastating safety concern. On February 28, 2005, the drug's manufacturers, Biogen Idec and Elan Corporation, announced a voluntary suspension of its marketing and all clinical trials. This drastic action came after reports of two patients in a clinical trial developing Progressive Multifocal Leukoencephalopathy (PML), a rare and often fatal viral infection of the brain. One of the patients had died from the infection. A third fatal PML case was later identified in a patient from a different trial.

The Root Cause: Progressive Multifocal Leukoencephalopathy (PML)

PML is a serious and opportunistic viral infection caused by the John Cunningham virus (JCV), a common virus that most of the population carries asymptomatically. In individuals with compromised immune systems, the virus can reactivate and attack the brain's white matter, leading to severe neurological damage, disability, or death. Tysabri's mechanism of action, which involves inhibiting the migration of immune cells across the blood-brain barrier, inadvertently created conditions favorable for the reactivation of the latent JC virus. The initial cases occurred in patients receiving Tysabri in combination with another immunosuppressant, raising significant alarm within the medical community.

Symptoms of PML

Patients and healthcare providers are trained to recognize the symptoms of PML, which can progress rapidly. These include:

Progressive weakness on one side of the body or clumsiness of limbs
Disturbances of vision
Changes in thinking, memory, and orientation, leading to confusion and personality changes
Rarely, headaches and seizures

Because PML symptoms can mimic those of an MS relapse, a high degree of vigilance and diagnostic testing (including MRI and cerebrospinal fluid analysis for JCV DNA) is crucial.

Tysabri's Comeback: The Re-introduction and REMS

Despite the initial safety concerns, the drug's demonstrated efficacy was undeniable. Following a comprehensive review of the clinical and safety data, the FDA concluded that for certain patients, the benefits of Tysabri could outweigh the significant risks, provided robust safety measures were in place. In 2006, the FDA re-approved Tysabri, but only under a strict Risk Evaluation and Mitigation Strategy (REMS) known as the TOUCH® Prescribing Program.

The TOUCH® program is a highly regulated system designed to minimize the risk of PML. Its key requirements include:

Only certified physicians can prescribe Tysabri.
Only certified pharmacies and infusion centers can dispense and administer the drug.
All patients must enroll and receive detailed education on the risks and benefits of the medication.
Patients must undergo regular monitoring, including testing for the presence of anti-JCV antibodies, which helps stratify their risk level.

Key Risk Factors for Tysabri-Associated PML

With the re-introduction of Tysabri and the subsequent long-term data collection, several key risk factors for developing PML have been identified and are central to the TOUCH® program:

Presence of anti-JCV antibodies: Patients who test positive for antibodies to the JC virus are at a significantly higher risk of developing PML.
Duration of therapy: The risk of PML increases with the number of infusions, particularly after two years of treatment.
Prior use of immunosuppressants: Patients who have been treated with other immunosuppressive drugs before starting Tysabri face a higher risk.

A Comparison of High-Efficacy Multiple Sclerosis Treatments

To understand Tysabri's place in the market and the enduring legacy of its safety scare, it's useful to compare it with other high-efficacy MS treatments. All have unique risk-benefit profiles and rigorous safety protocols.


Feature	Tysabri (Natalizumab)	Gilenya (Fingolimod)	Lemtrada (Alemtuzumab)
Mechanism of Action	Inhibits leukocyte migration across the blood-brain barrier.	Sequesters lymphocytes in lymph nodes, preventing CNS entry.	Targets CD52 on immune cells, leading to their depletion.
PML Risk	Black Box Warning. Highest risk for anti-JCV positive patients with prolonged therapy and prior immunosuppressant use.	Also carries a significant risk of PML.	Risk of PML is also present, requiring robust monitoring.
Administration	Intravenous (IV) infusion every four weeks.	Daily oral capsule.	IV infusion for two courses, 12 months apart.
Monitoring	TOUCH® Prescribing Program, including anti-JCV antibody testing and periodic MRI.	Regular lab work, ophthalmic exams, and monitoring for infections.	Extensive lab and thyroid monitoring, risk management program.
Other Serious Risks	Herpes infections, liver damage, hypersensitivity reactions.	Macular edema, bradycardia, severe infections.	Autoimmune conditions, thyroid disorders, serious infections.

Conclusion: A Precedent for Drug Safety

The story of why was Tysabri taken off the market is a landmark event in the history of pharmacology and drug regulation. It highlighted the unpredictable nature of post-market surveillance and the critical importance of balancing drug efficacy with potential catastrophic side effects. The subsequent re-approval, contingent on the strict REMS (TOUCH® program), established a new paradigm for managing risks associated with potent, high-efficacy drugs. For multiple sclerosis patients, it means access to a highly effective treatment option, but with the full, transparent understanding of its risks and the necessity of vigilant, continuous monitoring. The drug is not off the market permanently, but its availability is a testament to the evolution of modern drug safety standards. The FDA's detailed safety information on Tysabri serves as a critical resource for both healthcare providers and patients (https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/fda-drug-safety-communication-risk-progressive-multifocal-leukoencephalopathy-pml-use-tysabri).

Frequently Asked Questions

No, Tysabri was temporarily withdrawn in 2005. Following a thorough safety review, the FDA re-approved it for marketing in 2006, but with strict new safety measures in place.

PML is a rare and severe viral infection of the brain caused by the JC virus. It typically only affects people with weakened immune systems and can lead to death or severe disability.

Tysabri's mechanism, which prevents immune cells from crossing the blood-brain barrier to reduce inflammation in MS, can also hinder the immune system's ability to control the JC virus, leading to its reactivation in the brain.

The TOUCH® Prescribing Program is a mandatory Risk Evaluation and Mitigation Strategy (REMS) implemented by the FDA. It ensures that only certified doctors and facilities can prescribe and administer Tysabri and that patients are closely monitored for PML.

Doctors use several tools to manage PML risk, including regularly testing patients for anti-JCV antibodies, monitoring the duration of therapy, considering prior immunosuppressant use, and performing regular MRI scans to detect early signs of infection.

No, the risk of PML is not uniform. It is highest in patients who are positive for anti-JCV antibodies, have used Tysabri for more than two years, and have previously taken other immunosuppressant drugs.

Yes, other serious side effects include herpes infections (encephalitis, meningitis, retinal necrosis), liver damage, hypersensitivity reactions, and thrombocytopenia (low platelet counts).