Natalizumab (Tysabri®) is a humanised monoclonal antibody against the α4 chain of α4β1 integrin. Monoclonal antibodies are antibodies that can be very specifically targeted to certain molecules; they thereby represent a way of inducing selective immunomodulation. “Humanised” means that a murine antibody clone has been grafted to a human framework in order to reduce its immunogenicity.

Integrins are a family of molecules that are part of the adhesion molecules, which are essential in virtually all cellular interactions of immune cells. The glycoprotein α4β1 integrin, also known as very late antigen 4, or VLA-4, is expressed on the surface of activated white blood cells and is an important mediator of cell adhesion and transendothelial migration. It plays a crucial role in determining whether inflammatory cells can enter the brain. Observations in animals with EAE have shown that preventing inflammatory cells from entering the brain can be an effective way to prevent new inflammatory demyelinating lesion formation.

Natalizumab is the newest drug added to the collection of disease-modifying therapies available for patients with multiple sclerosis. Its efficacy was most clearly demonstrated in two large phase III clinical trials.
The AFFIRM study was a placebo controlled study involving 942 participants worldwide. Participants were randomly assigned to receive either a 300 mg IV infusion of natalizumab or placebo every four weeks. After one year, those on active therapy showed a statistically significant, 66 percent reduction in relapse rate. After two years, natalizumab reduced the risk of sustained disability progression by 42 percent and the rate of clinical relapse by 68 percent. There were also favourable effects on the accumulation of new MS lesions on MRI and on measures of quality of life.
In the SENTINEL study, natalizumab was compared to placebo in patients who already used interferon beta-1a (Avonex®). The 1,171 participants worldwide who continued to experience disease activity during treatment with interferon beta-1a were randomly assigned to add natalizumab or placebo. Results after two years showed that natalizumab added to interferon beta-1a was significantly more effective than interferon beta-1a alone. There was a 24 percent reduction in the risk of disability progression and a more than 50 percent reduction in relapse rate.

Serious infections such as pneumonia and urinary tract infections were slightly more frequent in natalizumab-treated patients. Natalizumab has been associated with hypersensitivity reactions, including serious systemic reactions, which occurred at an incidence of less than one percent of patients. The long-term safety of natalizumab is unknown.

So far, three cases of progressive multifocal leucoencephalopathy (PML), a cerebral infection with JC-virus that often is lethal, have occurred during treatment with natalizumab. This infection is extremely infrequent in patients who are not immune suppressed; it occurred in two MS patients who were also on interferon beta-1a and in one patient with Crohn’s disease who previously had received other immunosuppressive treatments. Two of three patients died of their PML. A detailed review of possible cases of PML in as many other patients exposed to natalizumab found no new cases, which suggests a PML risk of roughly one in 1000 patients treated with natalizumab for a mean of about one and a half years. The risk associated with longer treatment is not known.
Future treatment with Natalizumab should include careful patient selection, as well as clinical vigilance and management strategies that allow early identification of any new cases of PML. Most likely, early suspension of natalizumab in potential cases of PML will improve prognosis if PML is confirmed.



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In the opinion of the Committee, natalizumab seems to be an important additional treatment option. The drug is very effective and well-tolerated, but long-term safety is unknown. Current practice indicates that natalizumab is mainly used in patients who have failed to respond to other disease modifying treatments (interferon beta, glatiramer acetate) or present with rapidly evolving active MS.