Adios to Adios….is DoDo going to be a Dodo?


Many years ago ProfG or should I say influenerG:-) as ProfG was introducted as the “Social Media influencer” at the At the Limits 2023 meeting yesterday, came up with the idea of the DoDo (Double dose) ocrelizumab trial as non-petite people did not deplete their B cells that well and showed more progression. He also came up with the Adios trial idea can’t remember what the adios was supposed to be but to me it was really a joke to say goodbye to standard 6 monthly dosing with ocrelizumab. This was based on the idea that some B cell subsets important to MS are depleted for more than 6 months and there could be similarities with cladribine and alemtuzumab. The manufacturers bit on the idea of DoDo and did the trial with a higher dose, but as Turkeys do not vote for Christmas they didn’t go for the idea of selling less product.

So the academics in the UK took up the challenge, but couldn’t get the funding and because of C0VID extended dosing was being used and had become practise in some centres. This would stop the studies having equipose as some places wouldn’t be able to recruit…so it is Adios to Adios:-(.

However COVID-19 meant the idea was sort of tested and cofirmed my hypothesis that strict 6 monthly dosing was over-dosing and that extended interval dosing (interval longer than 6 months between doses) could be done to allow for COVID-19 related vaccination whilst keeping MS in check. This supported the biology that we had suggested and it was a robust idea as others could see the same thing. The data below also supports the view that what comes back after B cell depletion is not the same as what was there before.

Rodriguez-Mogeda C, van Lierop ZYGJ, van der Pol SMA, Coenen L, Hogenboom L, Kamermans A, Rodriguez E, van Horssen J, van Kempen ZLE, Uitdehaag BMJ, Teunissen CE, Witte ME, Killestein J, de Vries HE. Extended interval dosing of ocrelizumab modifies the repopulation of B cells without altering the clinical efficacy in multiple sclerosis. J Neuroinflammation. 2023;20:215. doi: 10.1186/s12974-023-02900-z.

Background: Recent studies suggest that extended interval dosing of ocrelizumab, an anti-B cell therapy, does not affect its clinical effectiveness in most patients with multiple sclerosis (MS). However, it remains to be established whether certain B cell subsets are differentially repopulated after different dosing intervals and whether these subsets relate to clinical efficacy.

Methods: We performed high-dimensional single-cell characterization of the peripheral immune landscape of patients with MS after standard (SID; n = 43) or extended interval dosing (EID; n = 37) of ocrelizumab and in non-ocrelizumab-treated (control group, CG; n = 28) patients with MS, using mass cytometry by time of flight (CyTOF).

Results: The first B cells that repopulate after both ocrelizumab dosing schemes were immature, transitional and regulatory CD1d+ CD5+ B cells. In addition, we observed a higher percentage of transitional, naïve and regulatory B cells after EID in comparison with SID, but not of memory B cells or plasmablasts. The majority of repopulated B cell subsets showed an increased migratory phenotype, characterized by higher expression of CD49d, CD11a, CD54 and CD162. Interestingly, after EID, repopulated B cells expressed increased CD20 levels compared to B cells in CG and after SID, which was associated with a delayed repopulation of B cells after a subsequent ocrelizumab infusion. Finally, the number of changes in B cell subsets after both dosing schemes did not correlate with any relapses nor progression of the disease.

Conclusions: Taken together, our data highlight that extending the dosing interval of ocrelizumab does not lead to increased repopulation of effector B cells. We show that the increase of CD20 expression on B cell subsets in EID might lead to longer depletion or less repopulation of B cells after the next infusion of ocrelizumab. Lastly, even though extending the ocrelizumab interval dosing alters B cell repopulation, it does not affect the clinical efficacy of ocrelizumab in our cohort of patients with MS.

Anyway back to the story whilst researching my talk on “Beyond B cells” for At the limits 2023 in London, I mentioned the extended dosing, and after ingluencerGs talk I have to think would that mean an influence on progression. The same amount would get into the brain I would think so maybe no impact. However during my research for the talk ….it was evident that an Adios-like trial is being done with two doses and a watch and wait approach. (I would have done three doses to be like the phase II data and to be more like alemtzumab dose for a year…I would also monitor anti-drug antibody resposes because ocrelizumab hangs around for a long time and some may still be there when the B cells come back)Let’s see what happens. If DoDO succeeds and you get a new formulation of say 1200mg (double the current doses or may be 1800mg for big people) and extra dosing occurs this means the antibody will hang around even longer to extened dosing could be extended further.

Now influencerG was making the case that the double dose means more gets into brain (so is that 0.2% from 0.1%?) and so that is why it affects progression. Someone said intrathecal anti-CD20 delivered into the spinal cord gets it into the CNS and it didn’t do much more. The answer was the flow of the spinal fluid is down and out. However, I also remember that they drilled into peoples heads to put it in the brains and not much happened either.

Could it be there are less B cells in small people to get into the brain to do damage that is important and not what gets into the brain. However for ocrelizumab to work in the brain it needs complement and importantly natural killer cells to do the killing and there will be lower number of these cells in the MS brain than the blood.

Anyway there is a brain shuttle anti-CD20 in development which should make more get into the brain. This is based on another antibody that can cause cell suicide rather than needing complement so will it be adios to adios and dodo too? Time will tell. Anti-CD20 will probably not traget the plasma cells in the brain and maybe you need something else.

Any what was beyond B cells in my talk…Yep you guessed it “More B cell inhibitors are coming”

UPDATE I asked question of differences of atrophy of big verses little people and ofatumumab and have removed the thoughts as the data on atrophy differences accoding to BMI isnt good enough to say there is anything in the view. I am not sure there is anything to suggest that the lower dose used in ofatumumab leads to worse atrophy than ocrelizumab…suggesting to me effects may be peripherally driven and not have alot to do with CNS entry…Happy to be proved wrong

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  • MD,

    Not sure why this 2 day at the limits event is taking place c.2.5 weeks before ECTRIMS / ACTRIMS. As an outsider, it seems to be the same old people presenting the same stuff eg Prof Acherio and EBV (I’m not picking on him, just an example).

    The issue to be resolved is progression / smouldering MS. Therapies are needed (now) to tackle compartmentalised inflammation in the CNS and slowly expanding lesions. However, we seem to be going round in circles with double dosing of an approved therapy or extended dosing of an approved therapy. In breast cancer (as an example) the researchers / pharma companies come up with new drugs with new mechanisms in response to new understanding of the disease. Why does this not happen in MS? We now have a better understanding of what’s driving progression, but try and tackle it with the existing treatments!

    Is there any hope to tackle smouldering MS in the near future ie next 5 years? I know there are lots of BTK inhibitors in trial + Sizomus + MSstat. What would you bet your pension lump sum on for best tackling smouldering MS? Or will they all fail and you can do your usual “told you so, wrong drug, wrong dose, wrong trial design”.

    • Maybe…Not sure why ECTRIMS is 2.5 weeks from this meeting?

      I am not involved in the programme so I don’t know why people were selected but there were new faces to me and as for our new student it will have all been new. There were certainly subjects that I have never heard before. I am certain that there would be no interest in discussions of the multidisciplinary team function within the UK at ECTRIMS or the differences in treatment practises across the UK.

      Now to my role I was asked to talk about “Beyond B cells” and the B cell subsets. Therefore I examined the pharma pipleines of MS companies and their phase II, III programes that is what is coming MS’s way. They have the DoDO phase III trial ongoing ..I looked at trials in clinical and picked out some academic studies but they are in phase III and so at least 5 years away fromMS even iif they work. ProfG threw down the challenge for shouldering MS etc. I reported on pharma pipeline in saving nerves,,,there were sessions of microglia and astrocytes and approaches in progressive MS,

      You know of MS stat , sizomus but there are others

      At the limits is about talking and discussion at the time for questions is nearly as long as the talks. It is very differnt at ectrims .

      • What would you bet your pension lump sum on for best tackling smouldering MS?….I’ve bet so many lump sums and believe we have some hits but they haven’t made the trial journey in a way thats needed.

        • MD,

          Thanks for your detailed response. There appears to be a lot going on. Fingers crossed that something emerges soonish to address smouldering MS.

  • does Rituximab need other cells to kill? is that all why intrathecal failed? is there much consideration required switching between rituximab/ocre/ofa/future acd20’s?

    • Rituxi will use cells to kill but it is is good at what we call complement fixation ocrelizumab and ublituzimab are designed to have better antibody dependent cellular cyctotoxicity meaning that natural killer cells neutrophils are doing the killing. But some are good and better than the current antibodies at directly killing the target. This is the basis of the brain shuttle antibodies being tested.

      The reduced killing mechanisms in brain wont have helped but the idea that they kill longlived plasma cells in the brain is bad biology as the plasma cells do not have CD20. The hope as tobe you get rid of them by CD20 destroying the niche that supports the plasma cells. It hasnt happen yet.

      There are gene variants that help anti CD20s work better also some antibodies cause anti-drug antibodies that stop them working and so you have to switch

      • so safe to say as long as you wait for current dose expire switching to other aCD20s from a aCD20 is straight forward.

        • I’m not a doctor but I would think switching from one to another is easy. You cant deplete a cell thats not there and if it is not there you arent going to get the infuion reactions so may be very easy.

          ProfGs comments

          I think there will be data from ocrelizumab to ofatumumumab switch in the trial with what I thought was the worst name ever for a trial.

          At a meeting I thought I heard it as OLIKOS which sounds like something that should not have happened in the 1940s. when many people died. Maybe it was my Dyslexia and I read it wrong but I remember talking to the Novartis rep about it.

          Anyway having looked it up it is OLKIOS on some sites but look another website it is is described indeed described by Dr Robert Naismith, MD: OLIKOS is a 1-year open-label study maybe because O is pronouned Oh rather than in OL
          so the American internation doesn’t sound so bad as with my Northern Accent

          Yep just looked on clinical trials. gov it is OLIKOS (OMG) ts meaning shifts even within Faux pas or what

          Whats is OLIKOS the greek god of ?…….dyslexia there is OLIOS The ancient Greek word oikos refers to three related but distinct concepts: the family, the family’s property, and the house. I

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