Bob
Yes, there are a range of sphingosine-1-phosphate (S1P) inhibitors, both on the market as well as under development, but comparing different S1P inhibitors is not an apples-with-apples comparison:
the first point relates to safety. S1P is a regulator of a wide range of crucial pro-survival signaling pathways. Not surprisingly, indiscriminate blocking of S1P function leads to a wide range of side-effects, some life-threatening, which is why S1P inhibitors have made little clinical progress to date. To the best of our understanding, Veyonda is the first and only highly selective inhibitor of S1P activity, meaning that its action is highly targeted, resulting in very few toxicities
the second point relates to efficacy. Like pretty much every other bodily function, S1P function is complex, and calling any drug an S1P inhibitor is like saying that all cancer chemotherapeutics are the same. There is a fairly wide range of S1P inhibitors, all working in slightly different ways and therefore producing different clinical effects.
S1P is produced inside the cell membrane by the action of the enzyme, sphingosine kinase (SK)
S1P then leaves the cell where it interacts with five S1P receptors (known as S1P1 – S1P5) located on the outer surface of the cell
Each of these 5 receptors activates signaling pathways that drive a wide range of functions that essentially keep the cell alive and functioning.
There are two main ways drugs block S1P activity. The first is to stop it being produced in the first place by blocking SK activity; the second is to let it be made and then block it from working by preventing it from connecting to the five S1P receptors.
Veyonda and opaganib appear to be the only two drugs in the first group and obviously have yet to reach market, whereas the second group has quite a few drugs approved and on the market including the drug, fingolimid (Gilenya, Novartis). Most of these second grouping drugs are used in the treatment of multiple sclerosis.
In terms of Veyonda and opaganib:
there are two types of sphingosine kinase - SK1 and SK2 – both capable of producing S1P
It is our view that if you want to block S1P production effectively, then you need to block both enzymes
Idronoxil inhibits both SK1 and SK2 because it is a broad inhibitor of kinase activity; Redhill Pharma states that opaganib selectively inhibits only SK2.
In terms of other inhibitors:
The link above shows the different drugs designed to block S1P from connecting to the five S1P receptors
To limit the toxicity of these drugs, they have been designed to only hit one, two or three of those receptors, not the whole five
Looking overall, the important distinguishing features of Veyonda are:
That it comprehensively blocks the production of S1P because it blocks the action of both SK1 and SK2
That it comprehensively blocks the action of S1P because it is depriving all five S1P receptors of their fuel
That this comprehensive inhibition of S1P function is highly limited to cells with high turnover (eg. cancer cells, cells involved in the cytokine storm), sparing healthy cells and resulting in a very well-tolerated mechanism of action
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