The New Normal


Lab lessons: Read the documents and dont rely on the headlines

You were talking about getting a vaccine after waiting for B cells to repopulate and someone asked “What was the number for the B cells that met the fully reconstituted level for you?”

This asks the questions

  1. What is the normal Level of B cells?

2. Why may it be important to know?

To answer 2 first. It is increasingly clear to me that if you want to make an antibody response, then you are going to need the right type and sufficient number of certain B cell subsets to do that.

All drugs that work in MS can influence B cells and the ones that work well can influence them alot.

Therefore taking them may help your MS but it may mean that you do not respond well to the COVID-19 vaccine, such that you do not make an anti-SARS-CoV-2 antibody response.

Anti-SARS-CoV-2 antibodies help you not get symptomatic COVID-19

Therefore, avoidance of agents that stop you making a vaccine response, whilst allowing you to control your MS, seemingly would have advantages.

Drugs that deplete CD20 B cells inhibit MS but also inhibit your capacity to make a COVID-19 vaccine response, whether it is a RNA vaccine, a viral vector vaccine or an inactivated viral vaccine.

So the best way of making the COVID-19 vaccine response is to have B cells. But if you don’t have enough B cells the quicker they come back the faster you will be able to make a vaccine response.

If they come back quickly it is a good thing, vaccine wise. Disease wise, this may not be of concern because the B cells that come back quickly to make the vaccine responses are different from the B cells triggering MS. These cells come back very slowly.

So the question can arise are all the anti-CD20 antibodies the same?

I would say “No”.

To recap anti-CD20 attacks most B cells buut not the antibody secreting cells or the B cell precursors that make new B cells

As you can see above their are at least 8 antibodies and 4 of them are used in MS. The main one is ocrelizumab, rituximab is used alot off-label, ofatumumab has just arrived and ublituximab is coming soon as it has just finished its trials.

What is different between them?

Some are part-mouse, part human (chimeric and humanised with have rodent target binding elements called the CDR), some are all human. In the graph below the CDR are in yellow. The top line shows the amino acid building blocks for rituximab. Where the other antibodies differ the amino acid code is in red. Where they are the same it is in black

In addition they bind to different bits of the CD20 (see below)

Also Ofatumumab is given as a lower dose every month and it is injected under the skin at home. Rituximab and ocrelizumab are infused in hospital every 6 months.

Ocrelizumab and ublituximab are good at killing B cells and are more potent than rituximab. Obintuzumab is good at making the B cells commit suicide. So ocrelizumab is going to hang round a long time as it dose is 600mg and with a half life of about a month. There are reviews on the differences of the antibodies.

What happens when you stop. The B cells should return quicker with ofatumumab and ocrelizumab. Is this what you want if anything goes wrong like you get infected with COVID-19. Well that is easy both repopulate too slowly for this to be an important difference. Maybe it has value when changeing MS drugs

In the COVID era not having B cells can be an issue and may increase the risk of symptomatic COVID-19

Now back to question 1.

The number of basal B cells are different depending on the study and to some extent varies depending on age and where you live because some people are exposed to more infections than others.

Morbach et al. Clin Exp Immunol 2010 doi: 10.1111/j.1365-2249.2010.04206.x

Generally you have about 100-600 cells/µL; 10-15% of total lymphocytes B cells in your blood). Importantly the lower limit of normal was considered to be 80 cells per microlitre (a millionth of a litre).

No a big question we have in the lab at the moment and that is how quickly to B cells return when you stop MS drugs. We know what happens with ocrelizumab as we reported this data.

In the European label for ocrelizumab for ocrelizumab it says ” Treatment with Ocrevus leads to rapid depletion of CD19+ B cells in blood by 14 days post treatment (first time-point of assessment) as an expected pharmacologic effect. This was sustained throughout the treatment period………… In the Phase III studies…….up to 5% of patients showed B-cell repletion (> lower limit of normal (LLN) or baseline) at least at one time point (between doses)…….The longest follow up time after the last Ocrevus infusion (Phase II study WA21493, N=51) indicates that the median time to B-cell repletion (return to baseline/LLN whichever occurred first) was 72 weeks (range 27 – 175 weeks). 90% of all patients had their B-cells repleted to LLN or baseline by approximately two and a half years after the last infusion.

For those who can only read Amercian English here is the American Label for ocrelizumab

So this means if you want to stop, 50% of the people will have repopulated to the lower limit of Normal (LLN) in 72 weeks and 50% won’t by 2 and a half years there are still people that have not repopulated to the lower limit of normal. Boy this is a long time until your B cells come back. They don’t say what this limit is but based on graphs it is 80 cells per microlitre, as I have seen this marked on some manufacturer produced graphs

Now what about ofatumumab?

This is hard because the clinical dose is 20mg, but the published data only reports on 30mg and 60mg doses.

The American Label for ofatumumab from 2020 says “…resulted in a reduction of CD19+ B-cells to below the
LLN in 77.0% and 78.8% of patients, respectively, one week after treatment initiation, and in 95.0% and 95.8% of
patients, respectively, two weeks after treatment initiation”

B-cell Repletion
Data from RMS clinical studies indicate B-cell recoveries over the LLN in at least 50% of patients in 24 to 36 weeks post
treatment discontinuation. Modeling and simulation for B-cell repletion corroborates these data, predicting median time to B-cell recovery of 40 weeks post treatment discontinuation”

So ocrelizumab takes 72 weeks to repopulate and ofatumumab takes 40 weeks (a big difference) ,

Or does it? Because the European label says from 2021 it is 23 weeks

“B-cell repletion
Data from RMS phase III clinical studies indicate a median time to B-cell recovery to LLN or baseline
value of 24.6 weeks post treatment discontinuation. PK-B cell modelling and simulation for B-cell
repletion corroborate this data, predicting median time to B-cell recovery to LLN of 23 weeks post
treatment discontinuation”.

So ocrelizumab takes 72 weeks to repopulate and ofatumumab takes 23 weeks (a big, big difference) ,

So when the choice comes to taking an anti-CD20 which do you take one that hangs around for a long time or a short acting variant.

However, how is it 40 weeks American and 23 weeks European. Is it a typo?

No it is a New Normal.

Because in this case the Lower limit of normal is now defined as 40 cells/microlitre (pg 8). It is is obvious that it will be quicker to get to 40 cells per microlitre rather than 80 cells per microliter

So be wanred to look at the small print, because if you just hear the takehome message

How does this become the New Normal? On what basis?

It seems something invented by the Novasians and this is a new normal becuase in previous documents in the EMA we can see graphs in an assessment report. Importantly it says (page 56). “In Study G2102 the treatment period consisted of an initial loading phase (3 loading doses of 20 mg SC each on Days 1, 7 and 14) followed by a maintenance dose of 20 mg SC every 4 weeks, starting on Week 4. Depletion of B-cells was seen after the first injection and continued to decrease with subsequent injections. The proportion of patients that were below the lower limit of normal (LLN) of 80 cells /microliter after the three loading doses was 100%”

But on page 57. The new normal appears “Below LLN B-cell level (40 cells/µL) was observed for 96% of patients for as long as the treatment period continued”. Therefore, between study G22012 and Studies G2301 and G2302 (Phase III) trials a new normal was born.

Does/would the speed of repopulation influence your choice of anti-CD20 treatment?

Disclaimer: Please note that the opinions expressed here are those of the author and do not reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust or Queen Mary Univeristy of London.

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  • Thank you MD, very interesting

    I am lucky (am I ?) because I develop a strong anti body response according to my doctor bespite being on ocrevus. Does it means that ocrevus is not killing my B cells like it is suppose to do ? (I am NEDA3 since I have began ocrevus 15 months ago) Or did I get asymptomatic COVID before starting O ?


    • If your B cells are not being killed there is no point in contining your bloods will show a drop from their baseline, but if it was not killing them you may get disease activity .

      Did you get asymtomiatic disese before COVID maybe

  • Following the reasoning behind DoDo, if I am doing anti cd20 at all, I want the higher dose so ocrelizumab it would remain.

    Not so sure I want to stay on anti cd20 both for reasons of efficacy AND the vaccine issues – if frequent boosters are needed, ofatumumab is still inconvenient.

  • Is there any data or thoughts on patients on Ocrelizumab who have not developed anti-body response to both Covid-19 natural infection and the vaccine? Are they expected to be less at risk of Covid infection – due maybe to the role of T-cells, which may have been stimulated twice – and/or severe disease? Thanks much.

      • Thanks. Clearly, monitoring people who meet these two conditions (natural infection first, and then vaccination, without developing antibodies) is extremely important. I hope somebody is doing it. Data from Israel, UK and US could already show something.

  • Ocrevus 5 years here. If I were starting today, I would take Ofatumumab because the return of B cells is so much faster (though not as fast as I would like).

    Questions for MD – what do you think would be the repletion rate for a patient who switches from Ocrevus to Ofatumumab? Assuming a long term Ocrevus user takes 2.5 years to replete, if they did Ofatumumab for 1.5 years and then stopped, do you think they would be repleted bu the end of year 2.5?

    • repletion many be 27 weeks to 175 weeks the issue for ofatumumab is whether their are cumulative effects. I bet there are

  • Do you have depletion data on rituximab? Last dose was 18 months(72 weeks) ago and still no detectable B cell population, but did have small SARS-CoV2 anti spike RBD antibody response 7 months after second Moderna. (46 U/ml – Roche elecsys assay 0.8-250 u/ml) -just don’t know if that’s enough to stop freaking out about getting COVID serious disease. What do you think?

    • No unfortunately I don’t maybe we could ask Roche for this. However with regards rituximab it is much quicker than ocrelizumab but at 18 months the vast majority of people taking rituximab will make a good response I predict we have data for ocrelizumab and it is pretty good at 72 weeks. However you could be one of the small percentage that repopulated very slowly However above 0.8 on Roche is positive. This may increase further with a third dose if they are available

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