15th anniversary of high-potency treatments for MS
Fifteen years ago, the first of the high-potency medications was approved for the treatment of multiple sclerosis. At the time, some medications, such as the interferons (Betaseron, Avonex, Rebif) and Copaxone, were already on the market, but these were considered to have only modest efficacy in controlling MS.
That picture began to change with the arrival of Tysabri (natalizumab), and the new treatment marked a number of firsts. It was the first therapy specially designed for MS. And it was the first use of a monoclonal antibody in MS. This type of therapy (which now includes Lemtrada, Ocrevus and Kesimpta) uses antibodies to attack specific targets in the body. With Tysabri, that target is an adhesion molecule on the surface of immune cells. This sticky substance enables white blood cells to adhere to the lining of blood vessels as a prelude to invading the central nervous system. By blocking these adhesion molecules, Tysabri effectively blocks immune cells from entering the brain and causing inflammation and tissue damage.
An early study in people with relapsing-remitting or secondary-progressive MS found that Tysabri was highly effective in treating MS, reducing new lesions in the brain by over 90% and improving people’s overall sense of well-being (Miller and colleagues. N Engl J Med 2003;348:15-23). These results were confirmed in a two-year study called AFFIRM, which showed that Tysabri reduced new brain lesions by over 90%, relapses by about 67%, and lowered the risk of disability by just over 50% (Polman and colleagues. N Engl J Med 2006;354:899-910).
These results were a cause for celebration: here was a treatment that could quickly shut down disease activity in people with MS. Unfortunately, the celebration was short-lived. Four months after getting FDA approval, the manufacturer suspended sales of Tysabri in February 2005 due to safety concerns. A problem had arisen in a second trial called SENTINEL, which combined Tysabri with Avonex (Rudick and colleagues. N Engl J Med 2006;354:911-923). Two people in that study developed a brain infection called PML (for progressive multifocal leukoencephalopathy).
PML was a rare condition, and little was known about it at the time. It was later determined that the underlying cause was the John Cunningham (JC) virus. This virus infects most people but generally does not cause any symptoms and people remain unaware of it. However, in people with a suppressed immune system, the virus can get out of control and cause a potentially fatal brain infection. So it appeared that Tysabri, by blocking immune cells from entering the brain and causing damage in MS, also prevented the immune system from controlling the spread of the JC virus. (It is now known that PML can also occur with other MS drugs, such as Gilenya and Tysabri, because of their effects on the immune response.)
In the case of Tysabri, it appeared that the PML risk was higher if a person was immunosuppressed and/or if they stayed on treatment for a prolonged period. With those risk factors in mind, Tysabri was approved again. The FDA determined that Tysabri should be available because it offered substantial benefits in the treatment of MS – provided that the risks were properly managed. The development of a test (called Stratify) to detect antibodies against the JC virus helped to further determine a person’s risk of PML (Plavina and colleagues. Ann Neurol 2014;76:802-812).
People scheduled to start Tysabri typically get a Stratify test beforehand and during the course of treatment, and have periodic MRIs to ensure that no infection is developing. For most people, the risk of PML is less than 1 in 1,000 in the first two years of Tysabri treatment. That risk may be further reduced if Tysabri is dosed less frequently (such as every 5 or 6 weeks instead of every 4 weeks) (Ryerson and colleagues. Neurology 2019;93:e1452-e1462). That regimen of less frequent dosing is likely to be approved soon.
PML may have limited the use of Tysabri, but the treatment has maintained its place in MS care despite the availability of many competitors offering similar potency, such as Lemtrada and Ocrevus. One reason is the perception that Tysabri acts very rapidly – so it is very useful to treat people with severe or rapidly worsening MS. Another reason is its unique effects on the body. Unlike many other MS therapies, Tysabri does not kill off overactive immune cells or suppress the immune response. This unique mode of action has proved to be very useful during the COVID pandemic. Tysabri does not appear to impair a person’s ability to fight COVID and would not be expected to have a significant impact on a person’s response to COVID vaccination.
Those unique qualities have led to a resurgence of interest in Tysabri during the pandemic – just in time for the 15th anniversary.
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