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Masitinib and multiple sclerosis

Posted on: March 02 2021

AAAAAAian.jpgIs a new drug on the horizon to treat non-active secondary progressive multiple sclerosis in 2021? Ian Cook reports

Although the cause of multiple sclerosis (MS) is still a mystery, there is general agreement that the disease and its progression involve a combination of two processes, neurodegeneration and autoimmunity.

Several types of immune cells, notably T and B cells, have traditionally been thought to play a central role in MS autoimmunity and neurodegeneration. However, there are many other types of immune cells in the body. Strangely, there has been until recently little interest in looking at the involvement of some of these other immune cells, in particular mast cells.



Mast cells

Mast cells are immune cells which cause sudden and severe inflammatory responses such as allergic reactions. When stimulated by a substance that causes an allergy, mast cells release a mixture of compounds into the surrounding tissues in a process called de-granulation. This causes sudden and sometimes potentially life-threatening reactions, something known as anaphylaxis or anaphylactic shock.

At the turn of the 20th century, it was found that mast cells accumulate at the edge of MS plaques. A century later, in 2001, researchers found the presence of mast cells and an increased concentration of mast cell constituents in MS plaques themselves. More recently, evidence has been found that mast cells play a crucial role in the inflammatory process and subsequent demyelination seen in MS. Evidence has also been found that several mast cell constituents are capable of causing demyelination and degradation of myelin proteins, with breakdown products stimulating further mast cell degranulation and contributing to activation of myelin basic protein (MBP)-reactive white blood cells.

Degranulation of mast cells next to myelin serves as a focus for inflammatory demyelination, leading to the damage of myelin sheaths by the action of enzymes as well as the discharge of vasoamines – substances which cause blood vessels to weaken or become leaky, and help circulating blood cells move across the blood brain barrier. It is also believed mast cells interact with other cells of the central nervous system, such as microglia, worsening neuroinflammation, which causes further neurodegeneration.

Treatment target

If all this is correct then it would mean that mast cells and microglia cells should be targets for MS drug treatments. For some time it has been known that inhibitors of mast cells, like anti-histamine drugs, can effectively slow the progression and severity of an animal model of MS called experimental allergic encephalomyelitis (EAE). These drugs limit the extent of mast cell degranulation, so mast cell research in MS is long overdue.

Now an MS drug which targets mast cells called masitinib is in trials. Masitinib is an experimental drug targeted at secondary (SPMS) and primary progressive MS (PPMS). It is taken as a tablet, twice daily, and it blocks biochemical processes involved in inflammation and immune responses, targeting both mast cells and microglia. In clinical trials it has produced some impressive results.

Last year, a phase 2b/3 clinical trial reported masitinib’s safety and effectiveness in 656 adults with primary or non-active secondary progressive MS. Participants were randomly assigned to receive either one of two doses of masitinib or a placebo (dummy drug), twice a day, for 96 weeks. The researchers also analysed the risk of disability progression and of reaching an expanded disability status scale (EDSS) score of 7.0 – reflecting a level of disability severe enough that you need to use a wheelchair.

The results showed the patients treated with the low-dose masitinib had significantly slower disability progression than those in the placebo group, irrespective of their type of progressive MS. Those receiving masitinib’s low dose were 39 per cent more likely to have either reduced disability or fewer disability-worsening events than those given a placebo. These masitinib-treated patients also showed a significantly lower risk of confirmed (three-month) disability progression by 37 per cent over 96 weeks. The patients who received masitinib also had a 98 per cent lower risk of reaching an EDSS of 7.0, compared with those in the placebo group.

When could it happen?

Given that masitinib has been extensively researched and found to be effective, one is bound to ask when will masitinib become available? Here the situation is slightly unclear. At some point, an application will be made to the licencing authorities such as the European Medicines Agency (EMA) in Europe, the Food and Drugs Administration (FDA) in the US and of course the National Institute for Health and Care Excellence (NICE) in the UK. Will these authorities be satisfied that the phase 2b/3 trial is enough proof? Here there is some suspicion that a further ‘confirmatory trial’ will be sought. As one neurologist put it, “For Europe, a second phase 3 would be helpful.’ Another neurologist added, ‘We need a money grant to do this study. I predict it will cost in the order of £4million to do.’ As someone who has SPMS without relapses I am tempted to say I hope that masitinib gets approval as soon as possible. Those of us, like me, with progressive MS, do not have time to wait.

Ian Cook reports regularly in our MS magazine, New Pathways. Why not subscribe to get these kind of articles directly to your door? Alternatively, you can receive your copy on an audio CD. Find out more