Role of Natalizumab in Relapsing-Remitting Multiple Sclerosis Treatment
Natalizumab (Tysabri) is indicated as monotherapy for highly active relapsing forms of multiple sclerosis, including relapsing-remitting disease, but requires careful risk stratification due to the risk of progressive multifocal leukoencephalopathy (PML). 1
Mechanism of Action and Efficacy
- Natalizumab is an alpha(4)-integrin antagonist that prevents leukocyte trafficking into the central nervous system by binding to the alpha(4) subunit of alpha(4)beta(1)-integrin and preventing leukocyte adhesion to endothelial vascular cell adhesion molecule-1 2
- It has demonstrated high efficacy in clinical trials by reducing annualized relapse rates, preventing MS lesion accumulation on MRI, and decreasing the probability of sustained progression of disability 3
Indications and Patient Selection
- FDA-approved as monotherapy for relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease in adults 1
- Primarily recommended for patients who:
PML Risk Stratification
The primary safety concern with natalizumab is the risk of progressive multifocal leukoencephalopathy (PML), which requires careful risk assessment:
Risk factors for PML development include 5:
- Presence of anti-JCV antibodies (particularly with high index values)
- Duration of natalizumab therapy beyond 24 months
- Prior use of immunosuppressants
Risk stratification based on anti-JCV antibody index 5:
- JCV antibody-negative patients: PML risk approximately 1 in 10,000
- JCV antibody-positive with index ≤1.5: PML risk approximately 1 in 5,882
- JCV antibody-positive with index >1.5: PML risk approximately 1 in 855
- Risk increases substantially after 18-24 months of therapy, especially in JCV-positive patients
Monitoring Recommendations
MRI Monitoring
- For natalizumab-treated patients at high risk of PML (JCV seropositive, treatment duration ≥18 months), brain MRI screening should be performed every 3-4 months 5
- For patients at lower risk (JCV seronegative), annual brain MRI assessment is recommended 5
- MRI protocol should include FLAIR, T2-weighted, and diffusion-weighted imaging 5
- Any new lesions on subsequent scans that were not evident on the previous scan should trigger consideration of further investigation (e.g., CSF analysis) 5
JCV Antibody Monitoring
- Anti-JCV antibody testing should be performed every 6 months for patients who are JCV-negative or have a low antibody index (≤1.5) 5
- For patients with index >1.5, further anti-JCV antibody testing is not mandatory, but continued MRI monitoring is essential 5
Treatment Considerations for Switching Therapies
- Enhanced pharmacovigilance, including brain MRI every 3-4 months for up to 12 months, is required in patients who switch from natalizumab to other therapeutics (including fingolimod, alemtuzumab, and dimethyl fumarate) 5
- For patients at high risk of developing opportunistic infections who are switching disease-modifying drugs, brain MRI should be performed at the time the current treatment is discontinued and after the new treatment is started 5
Clinical Considerations and Caveats
- Natalizumab should not be used in combination with immunosuppressants or TNF-α inhibitors 1
- Physicians must consider whether the expected benefit of natalizumab is sufficient to offset the PML risk when initiating and continuing treatment 1
- Patients should be monitored for any new sign or symptom suggestive of PML, with immediate withholding of natalizumab if PML is suspected 1
- Due to the risk of PML, natalizumab is available only through a restricted distribution program called the TOUCH® Prescribing Program 1