Dear all, I decided to take some time to review the mechanism of action of opaganib to better understand how this treatment might work against Covid-19. I believe I found some rather interesting pieces of information which should explain the dramatic impact of opaganib used in the in-vitro study of human lung and bronchial tissue which saw opaganib completely inhibiting covid-19 replication.
Before I go further I just want to remind that from the latest RDHL corporate presentation, opaganib works by selectively inhibiting the enzyme Sphingosine Kinase 2, which allows for the conversion of Sphingosine into Sphingosine-1-Phospate. Thus if opaganib works as it should, it should both inhibit SK2 activity and should stop the production and presence of Spingosine-1-phosphate in the human cells. As opaganib is working on the human-host cell factor, not the virus directly.
It is also important to note that there are 2 Sphingosine Kinases, SK1 and SK2. Opaganib is selective for inhibiting SK2.
This article looks at the replication of chikungunya virus in multiple human cell lines.
First they invstigated the importance of SK1 vs SK2 on viral inhibition, by inhibiting the gene expression of these kinases with selective small interfering RNA:(siRNA), selective for SK1 and SK2 inhibition.
It was shown in the first part of the Results section that when SK1 siRNA is used, there there is no impact on viral inhibition (Figure 1C), inhibition is equal to the control. But when SK2 siRNA is used there is very significant reduction of viral inhibition (Figure 1A), about 80+% viral inhibition. This is consistent with the adjacent figure which show that while both siRNAs against SK1 and SK2 succeeded in reducing SK1 and SK2 gene expression respectively, the viral inhibition was only seen in the inhibition of SK2. Hence suggesting that SK2 is important in the dramatic increase of viral inhibition/dramatic reduction in viral infection of cells.
This is already a good sign, however the article goes further into this investigation.
They then repeated the experiment using chemical, rather than genetic inhibitors of Sphingosine Kinase. This is where things get very interesting.
First they used a non-specific dual chemical inhibitor of SK1 & SK2, called 'SKI-II'.
The treatment of cells with SKI-II resulted in significant reduction in viral infection (Figure 2A), with 20-30 micrograms cause almost 100% inhibition of viral infection.
Then they treated the cells with a selective chemical inhibitor for SK2, thus allowing SK1 to operate normally but knocking out SK2 function. For this they used the SK2-specific inhibitor ABC294640 (ABC). Treatment with ABC and then exposed to the virus. ABC resulted in greater than SKI-II inhibition at lower doses than SKI-II, and at up to 80-90% viral inhibition, at a maximum tested dose of 30 micrograms, Figures 2A and 2B.
Hence again showing that it is indeed the inhibition of SK2 that has the major impact on inhibiting viral replication. Inhibition being brought on by the treatment of cells with the SK2-specific inhibitor ABC294640 (ABC). Now when we look at the opaganib Covid Trial, low and behold, opaganib/Yeliva's chemical name is ABC294640. https://clinicaltrials.gov/ct2/show/NCT04435106?term=opaganib&draw=2
The paper goes on to show the importance of SK2 compared to SK1 at the subcellular level. Unlike SK1 which is localized in general in the cytoplasm, SK2 contains both a nuclear localization signal (NLS) and a nuclear export signal (NES), this basically means that upon infection, while SK1 sees no important change in location, but SK2 is recruited by the virus and causes distinct re-localisation with the viral RNA and Viral Replication Complex soon after infection to specific areas and interaction with gene expression.
The above paper focuses on infection by chikungunya virus on an number of different cell lines, Live, Bine, Skeletal, Cervix...
Next I was curious to look more at Sphingolipids and Covid-19, where some papers have been written up. Including this one from just over 1 months ago. Wherein:
"Based on these features, we believe that sphingolipids might control SARS-CoV-2 infection in the host. SARS-CoV-2 utilizes the ACE-II receptor (Angiotensin-converting enzyme II receptor) on epithelial cells for its entry and replication. Activation of the ACE-II receptor is indirectly associated with the activation of S1P (Spingosine-1-phosphaote) Receptor 1 signaling which is associated with IL-6 driven fibrosis. This is expected to promote pathological responses during SARS-CoV-2 infection in COVID-19 cases." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605809/
If Covid is working through ACE-II, then we need to see on which cells ACE-II is expressed. ACE-II in commonly found in organs, according to wikipedia:
"Location within the body ACE2 is present in most organs: ACE2 is attached to the cell membrane of mainly lung type II alveolar cells, enterocytes of the small intestine, arterial and venous endothelial cells, and arterial smooth muscle cells in most organs."
Alveloar cells are those in the lung, which get damaged and scarred by covid causing the Respiratory issues.
Thus we seem to have a nice direct corroboration of Opaganib inhibiting Viral replications, via SK2 inhibition which is present in most cells in the body. Even if Covid activates ACE-II to start the production of Sphingolipid-1-phospahte (S1P), the inhibition of SK2 stops this production of S1P which stops the increase in IL-6 and tissue fibrosis, and also stops the recruitment of SK2 to the Viral Replication Complex, stopping viral replication in the lung cells.
And then we have the fact the the SK2 inhibitor we have data on is precisely Opaganib.
Together this would seem to show good logic for opaganib's dramatic in-vitro action on the human-lung cells, which thus should be alveolar cells.
It is also interesting to note that the initial research paper showed that SK2 inhibition was important at the beginning of viral infection, if SK2 inhibition treatment starts a few hours after viral infection, then the process can't be stopped.
This would lend to the idea that all cells that get exposed to opaganib before infection could be saved, so treatment with opaganib would be better to be done as soon as possible and prior to other treatments.
Given the DSMB recently unanimously recommended for the global phase 2/3 opaganib study to continue after a safety analysis of 70 patients, then we can at least assume safety isn't an issue and thus can be given to all patients as soon as possible.
Hopefully we have a great Covid treatment here. Another benefit, is that as Opaganib is working on a host-cell factor, it should keep being effective despite any mutations Covid might undergo including the new UK variant.
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