The Committee of Medicinal Products for Human Use ( CHMP ) of the European Medicines Agency ( EMA ) has adopted a positive opinion recommending approval of a variation to the marketing authorization of Tysabri ( Natalizumab ).
The CHMP has recommended the approval of Tysabri for use as a disease modifying therapy ( DMT ) for relapsing-remitting multiple sclerosis ( RRMS ) patients with highly active disease activity despite a full and adequate course of treatment with at least one DMT.
The positive opinion is supported by long-term real-world experience from the Tysabri Observational Program ( TOP ), an ongoing observational, open-label, 10-year prospective study of RRMS patients.
According to the EMA, the updated risk estimates show that the risk of developing progressive multifocal leukoencephalopathy ( PML ) is small, and lower than previously estimated, at antibody index values of 0.9 or less, and increases substantially in patients with index values above 1.5 who have been treated with Tysabri for longer than two years.
In patients who tested negative for JC virus antibodies, the PML risk estimate remains unchanged at 0.1 per 1,000 patients.
Natalizumab is a monoclonal antibody that selectively binds to alpha4-integrin and is thought to interrupt the activity of inflammatory cells in patients with multiple sclerosis by blocking the interaction between alpha4beta1-integrin and vascular cell adhesion molecule-1. Disruption of these molecular interactions prevents transmigration of leukocytes across the endothelium into inflamed parenchymal tissue.
The specific mechanism(s) by which Natalizumab exerts its effects in multiple sclerosis have not been fully defined.
Tysabri has advanced the treatment of the MS patients with its proven ability to slow the progression of disability, reduce relapse rates, and impact the number of MRI brain lesions with a well-characterized safety profile.
Data from the phase 3 AFFIRM trial, which was published in the New England Journal of Medicine ( NEJM ), showed that at two years, Tysabri treatment led to a 68% relative reduction ( p less than 0.001 ) in the annualized relapse rate when compared with placebo and reduced the relative risk of disability progression by 42 to 54% ( 12-24-week sustained respectively, both p less than 0.001 ).
Tysabri increases the risk of progressive multifocal leukoencephalopathy, a rare opportunistic viral infection of the brain which has been associated with death or severe disability. Risk factors that increase the risk of PML are presence of anti-JCV antibodies, prior immunosuppressant use, and longer Tysabri treatment duration. Patients who have all three risk factors have the highest risk of developing PML.
Tysabri increases the risk of developing encephalitis and meningitis caused by herpes simplex and varicella zoster viruses and clinically significant liver injury has also been reported in the post-marketing setting.
Serious, life-threatening, and sometimes fatal cases have been reported in the postmarketing setting in MS patients receiving Tysabri.
Other serious adverse events that have occurred in Tysabri-treated patients include hypersensitivity reactions ( e.g., anaphylaxis ) and infections, including opportunistic and other atypical infections.
Clinically significant liver injury has also been reported in the post-marketing setting.
The overall benefit-risk profile of Tysabri remains positive. ( Xagena )
Source: Biogen, 2016