Keeping immune cells out of the brain
Natalizumab: blocking the way in
To leave a blood vessel, an immune cell first has to stick to the vessel wall. Natalizumab is an antibody against alpha-4 integrin, one of the molecules that immune cells use to grip, so the cells can no longer hold on and pass into the brain. In the AFFIRM trial it reduced relapses by 68 per cent compared with placebo.
The price is that the brain's normal immune surveillance is reduced too. A small number of people taking natalizumab develop PML, a brain infection caused by the JC virus. The risk is higher in people who carry antibodies to the virus, who have taken natalizumab for longer or who were treated with immunosuppressants before.
Where medicines act
S1P modulators: keeping cells in the lymph nodes
Fingolimod works further upstream. It grew out of research on myriocin, a compound made by a fungus, and acts on the receptors for a signalling molecule called sphingosine-1-phosphate (S1P), which immune cells follow to leave the lymph nodes. Without that signal, many of them stay where they are and fewer reach the brain. In 2010 fingolimod became the first tablet approved for MS in the United States, after the FREEDOMS trial showed less than half as many relapses as with placebo. Siponimod, ozanimod and ponesimod act on the same receptors more selectively.
What they taught researchers
For relapses and new lesions, the idea holds up well. For progression without relapses, it largely does not. Natalizumab did not meet the primary disability endpoint in the ASCEND trial in secondary progressive MS, although a secondary measure of hand function showed benefit, and fingolimod did not slow it in the INFORMS trial in primary progressive MS. Siponimod, tested in a broader group of people with secondary progressive MS, many of whom still had some inflammatory activity, slowed disability modestly.
These results suggest that blocking immune-cell entry alone may be insufficient to prevent progression. They helped motivate research into mechanisms inside the brain, including smouldering inflammation and the medicines described in article 9.
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Key terms
- Integrin
- A grip molecule on immune cells that lets them stick to vessel walls. Natalizumab blocks α4 integrin.
- PML
- Progressive multifocal leukoencephalopathy: a rare, serious brain infection by the JC virus, linked to some MS medicines.
- Lesion (plaque)
- An area of damage where myelin has been lost and the tissue scarred.
- Relapse (attack)
- New or worsening symptoms lasting at least 24 hours, without fever or infection to explain them.
- Placebo
- A dummy treatment that looks like the real one, used so that trial results reflect the medicine itself.
References
- 1. Yednock et al. (1992)
- 2. Polman et al. · A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis (AFFIRM). NEJM (2006)
- 3. Bloomgren et al. (2012)
- 4. Brinkmann et al. (2010)
- 5. Kappos et al. · A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis (FREEDOMS). NEJM (2010)
- 6. Kapoor et al. · Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND). Lancet Neurology (2018)
- 7. Lublin et al. · Oral fingolimod in primary progressive multiple sclerosis (INFORMS). Lancet (2016)
- 8. Kappos et al. · Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND). Lancet (2018)
Next · Lesson 6 of 11
Removing B cells
How anti-CD20 antibodies changed the understanding of MS.
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