Ozanimod How does it work? Have we got a real clue?

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Last week I wrote a post about how pharma may report on the next Cladrimod (cladribine or ozanimod/posenimod) study in “Dr Dooley will be happy that their uncited work from 2016 has been repeated….MS drugs affect memory B cells!”. In that post I made a prediction on how the lymphocyte subset data would be reported from the next MS drug so that the potential for memory B cell depletion would be lost in a sea of T cell stuff. Little did I realise that this was to surface so quickly. So was I disappointed?

In my prediction…..No, in the result…..Yep absolutely

Effector memory cells are the ones accumulating in the CNS, so if CD8 T cells are important have to deplete this subset

The next study it turns out is with ozanimod. This is a sphingosine-1 phosphate modulator that is similar to siponimod and a bit like fingolimod where we know what happens to the the lymphocyte subsets. It reduces the numbers of central memory and naive T cells and has more of a limited effect on the effector memory T cell populations. This later population is usually the dominant cells in the CNS of MS. There is a marked inhibition of memory B cells…but this has not registed and so what happened with ozanimod?

There is a depletion of T cells and B cells notably with the higher dose

Then the subsets and central memory CD4 and CD8 T cells drop and effector memory T cells drop abit in the CD4 compartment and not in the CD8 compartment…But remember this is the major subset of T cells in the CNS during MS

Next T regulatory cells, which we are told control the autoimmune reactions and what happens yep you guessed it….they do down in number not up. However TH17s drop, so it this the key?

Then what’s next? The B cells subsets? Whats’ done….Nothing!!!!…It’s behind you!!!!, So do we have any idea how ozanimod may really work?…It’s a decrease in Th17 …should we say Yawn?. Now the study apparently was started in 2016 and maybe the authors hadn’t heard of memory B cells, but I will bet that they are depleted. This is an opportunity missed. We will just have to wait…so an easy explanation goes begging I suspect.

I can see the T cell marketing video already…..an orange juice moment

Effect of the sphingosine-1-phosphate receptor modulator ozanimod on leukocyte subtypes in relapsing MS.Harris S, Tran JQ, Southworth H, Spencer CM, Cree BAC, Zamvil SS.Neurol Neuroimmunol Neuroinflamm. 2020 Jul 31;7(5):e839. doi: 10.1212/NXI.0000000000000839. Print 2020 Sep.PMID: 32737072OBJECTIVE: To better understand ozanimod’s mechanism of action (MOA), we conducted exploratory analyses from a phase 1 study to characterize ozanimod’s effect on circulating leukocyte subsets in patients with relapsing multiplesclerosis. …

Objective: To better understand ozanimod’s mechanism of action (MOA), we conducted exploratory analyses from a phase 1 study to characterize ozanimod’s effect on circulating leukocyte subsets in patients with relapsing multiple sclerosis.

Methods: An open-label pharmacodynamic study randomized patients to oral ozanimod hydrochloride (HCl) 0.5 (n = 13) or 1 mg/d (n = 11) for ∼12 weeks (including 7-day dose escalation). Circulating leukocyte subsets were quantified using flow cytometry (days 28, 56, and 85) and epigenetic cell counting (days 2, 5, 28, 56, and 85) and compared with baseline (day 1) using descriptive statistics.

Results: Ozanimod caused dose-dependent reductions in absolute lymphocyte counts. Observed by both methodologies, circulating CD19+ B- and CD3+ T-cell counts were reduced by >50% with ozanimod HCl 0.5 mg and >75% with 1 mg at day 85. Based on flow cytometry, ozanimod HCl 1 mg showed greater decreases in CD4+ than CD8+ T cells, greater decreases in both CD4+ and CD8+ central memory vs effector memory T cells, and reductions in mean CD4+ and CD8+ naive T cells by ≥90% at day 85. In the flow cytometry analysis, changes in monocytes, natural killer, and natural killer T cells were minimal. Using epigenetic cell counting, greater reductions for Th17 than T regulatory cells were determined.

Conclusion: Ozanimod induced dose-dependent reductions in circulating B- and T-cell counts and differential effects on naive and memory CD4+ and CD8+ T cells and CD19+ B cells. Data characterized with both a novel epigenetic cell-counting method and flow cytometry support ozanimod’s MOA.

COI: No relevant

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MouseDoctor

19 comments

  • Another copy cat drug that doesn’t address the issue of ms but just lines the pocket of pharma and those that jump on the pharma bandwagon. How does it work? It doesn’t as the issue of smouldering ms continues with exception of HSTC and Alemtuzumab. Why not tell it like it is. If you had MS would you really care about these drugs? God prey no one gets MS but if someone in your family had ms would you paint such a rosey picture by giving false hope when a cure even if its found would be locked up in safe vault or the research killed by funding it to gain ownership so that it never sees the light of day. Is there any hope for those inflicted by such devastating diseases ? Yes there is. AI is on its way up to dominate all scientific endeavours, and pharma corrupted research is on its way out. Along with their champions. How do I know? I work in AI.

    • How does HSCT and alemtuzumab deal with soldering MS as neither get in the CNS to a large.extent….it sort of says the peripheral immune response sets off a neurodegenerative environment.

      • “neither get in the CNS to a large.extent…”

        Alemtuz. does not at all..and hence does not work on B cell follicles in spms…hsct seemingly does though.

        ” Agents that are currently approved for patients with MS have no or very limited bioavailability in the brain and spinal cord. In contrast, cyclophosphamide (CYC), an alkylating agent, penetrates the blood—brain barrier and CNS parenchyma well.”

        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3002608/

        • HSCT may depending on the protocol cyclophophamide can get in brain but it only targets dividing cells many of the cells in smoldering lesions will not be dividing so they wont be touched. Cladribine may be a better bet

      • Thanks MD. Not sure what you mean with conflict of interest, if promoting AI is COI. Every sconetific/technological revolution is preceded by a period of resistance. Just Google the number discoveries made by AI in the last year with no input from users on what to look for. My comments above were never directed at barts. My opinion of barts team is they are patient champions. Yes I promote ai because it is the most powerful tool out there that can make miracle discoveries in research.

        • Except let’s face it, it isn’t AI it’s machine learning using vast amounts of computer power and energy.
          AI does not exist………..yet and probably shouldn’t until robust safeguards are put in place.

    • Thanks…. so it says that inhibiting cytokines is a crap idea…I totally agree, they all exist in balances like ying and yang. One goes up it stimulates something to regulate it, one goes down it stimulates something else. So IL-17A production causes the Loss of IL-17A, IL-17A represses the Th17 cytokine program, primarily IL-17F and GM-CSF, by
      inducing autocrine production of IL-24. Thus, IL-17A has a dual role in Th17 cells:pathogenic as well as regulatory

      • 🙂

        Feedback Inhibition Definition

        Feedback inhibition is a cellular control mechanism in which an enzyme’s activity is inhibited by the enzyme’s end product. This mechanism allows cells to regulate how much of an enzyme’s end product is produced.

        Most biochemical processes are complex and multi-step, requiring multiple enzymes to get from the starting substrate to the desired end product.

        Typically, feedback inhibition acts on the first enzyme unique to a given pathway. For example, in the case of amino acid production, an amino acid may act as an inhibitor for the first enzyme in the pathway whose purpose is making more of that amino acid.

        One example of this that takes place in our own bodies is the production of cholesterol. Cholesterol in small amounts is useful to our cells’ membranes, but in large amounts, it can build up in our veins and arteries and become very harmful.

        Modern diets often result in dangerously high cholesterol as a result of eating too much of it – but in nature, it was sometimes necessary for our bodies to make their own cholesterol.

        The mechanism of cholesterol production in the liver is inhibited by presence of cholesterol in the blood. Large amounts of cholesterol in the blood actually prevents liver cells from transcribing the necessary mRNA to make the enzyme that makes cholesterol.

        So when we eat high-cholesterol diets, our livers produce less cholesterol than they would if we were not getting enough cholesterol from our food.

        In some people, dangerously high cholesterol can be a result of this feedback inhibition pathway getting turned off – resulting in the body continuing to produce its own cholesterol in addition to what is consumed.

        https://biologydictionary.net/feedback-inhibition/

  • It’s the equivalent of fighting with a blancmange, you can punch as hard as you like but it makes no discernable difference save to leave you exhausted.
    Thoroughly depressing and eloquently showing whyscientific blinkers means we are not progressing as fast as we should in the treatment of MS.

    • After this pandemic is over and life returns to normal. I’m going to move back to pharma and apply my ml skills in drug discovery usibg big data clusters and my biochemical background. Once I have reestablished my credentials as opposed to working in investment banking. I’m going to turn parasitic and eat pharma from the inside out. Assuming covid doesn’t get me first! Then start my own data research lab helping like minded pharma startups to take on the big guys. I have dream….

        • Maybe so, but the needs of many out weigh the needs of one. Err star trek search for spock. Anyways I still make a lot money out of it. Then I can put my feet up and make pretentious comments on this blog

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