New MOD on the block. Is it too late?

Just as the Nibs are about to enter service here we see another MOD

Piali L, Birker-Robaczewska M, Lescop C, Froidevaux S, Schmitz N, Morrison K, Kohl C, Rey M, Studer R, Vezzali E, Hess P, Clozel M, Steiner B, Bolli MH, Nayler O. Cenerimod, a novel selective S1P1 receptor modulator with unique signaling properties. Pharmacol Res Perspect. 2017;5(6). doi: 10.1002/prp2.370.

Sphingosine-1-phosphate receptor 1 (S1P1 ) modulators sequester circulating lymphocytes within lymph nodes, thereby preventing potentially pathogenic autoimmune cells from exiting into the blood stream and reaching inflamed tissues.  S1P1 receptor modulation may thus offer potential to treat various autoimmune diseases. The first nonselective S1P1-5 receptor modulator FTY720/fingolimod/Gilenya® has successfully demonstrated clinical efficacy in relapsing forms of multiple sclerosis. However, cardiovascular, hepatic, and respiratory side-effects were reported and there is a need for novel S1P1 receptor modulators with better safety profiles. Here, we describe the discovery of cenerimod, a novel, potent and selective S1P1 receptor modulator with unique S1P1 receptor signaling properties and absence of broncho- and vasoconstrictor effects ex vivo and in vivo. Cenerimod dose-dependently lowered circulating lymphocyte counts in rats and mice after oral administration and effectively attenuated disease parameters in a mouse experimental autoimmune encephalitis (EAE) model. Cenerimod has potential as novel therapy with improved safety profile for autoimmune diseases with high unmet medical need.

Sphingosine-1-phosphate receptor 1 (S1P1 ) modulators sequester circulating lymphocytes within lymph nodes, thereby preventing potentially pathogenic autoimmune cells from exiting into the blood stream and reaching inflamed tissues. 

Is this really how it works?  
Fingolimod is said to work because it blocks entry of cells into the blood by blocking S1P1 receptor. If they can’t get in the blood they can’t get in the brain. So you don’t get MS.

S1P1 is used in conjunction with a chemokine called CCR7. 
Now, not all cells use CCR7 to escape, so the effector memory popluation CD45RO+, CD45RA-, CCR7-, escape leaving the central memory (CD45R)+, CD45RA-, CCR7+) and naive cells (CD45RA+, CCR7+), trapped in the lymph glands.

This is what happens in the blood after fingolimod

However, if you look in the brain of MS, the T cells that are getting there are CCR7- effector memory cells. 

So these are the cells you want to block getting into the brain, especially if MS is a problem of CD8 T cells.

Therefore, fingolimod would not be be blocking the cells you want to block!

So does fingolimod work by blocking T cells? or 

Is it because it depletes memory B cells from the blood?

Do cells get trapped so that the lymph nodes swell up? 
The answer is no!

I bet the action is else where, like the bone marrow or spleen. S1P1 is used in the bone marrow to exit.
Anyway..the new drug has a reduced cardiovascular effect profile. 

Yeah you may say. 

However by the time that cenerimod is developed, fingolimod will probably be out of patent. The cost will have plummeted and the advantage of lack of heart arrhythmia will probably be gone.

P.S. You should be asking what happens to the T cells based on absolute numbers, no percentages, as shown.

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  • Fingolimod ALSO suffers from another important, if not widely reported side-effect and that is disease-rebound and IRIS-like phenomena, making it a menace to patient safety. In this category is another drug as well, Natalizumab. Meanwhile, no single drug will work in MS and we will continue to flounder in the dark. MS as a disease needs to be attacked with drugs that do penetrate the BBB (Fingolimod, cyclophosphamide, etc) and drugs that act peripherally (Ocreluzimab, Alemtuzumab). My two cents.

    Meanwhile, the introduction of newer S1P modulators may or may not work, depending on their side-effect profile(s).

    Avasarala J, MD
    Greenville, SC

  • "They can't get into the blood and then into the brain, so you don't get MS". Yeah but a patient already has infiltrates into the CNS and a diagnosis of MS by the time they take a S1P modulator……too late, damage is done and neurodegeneration has started. We need compounds that act inside the CNS. Enough with this strategy to treat the periphery and not inside the CNS, the formulary is full of them.

  • "problem of CD8 T cells"

    Some Cd8+ t cell in the csf dont drive the disease

    The ex vivo distribution of CD8+
    and TEMRA
    cells in NAWM, WML and CSF of
    MS patients resembled data on WM and CSF under normal
    CNS conditions [16, 56]. However, compared to paired PB,
    T cells in WML of the MS patients analyzed showed
    significantly increased expression of markers indicative for
    antigen-induced cytotoxicity (CD59L and grB) and activation
    (CD69, grB and CD137). The increased expression
    of the co-inhibitory (TIM3 and PD1) and co-stimulatory
    receptors (ICOS), whilst not accompanied with increased
    CD57 expression, suggests that the CD8+
    T-cell underwent
    chronic activation in situ while retaining their proliferative

    In comparison, CSF-derived CD8+
    T cells had
    increased expression of both co-inhibitory markers, which
    refutes active involvement in CNS pathology [47].

    DOI 10.1007/s00401-017-1744-4

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