When Fat is Useful: COVID-19 vaccine readiness and ocrelizumab

W

As you may know we have been publishing the trial results of ocrelizumab studies. The problem is that we write them in a style and manner that we chose and this may not be what pharma wants to say. This gives them an incentive to report the study before we say anything. If the information is out there in a readily searchable form (i.e a paper) then we have no incentive to report it. But if we say things they then may feel like they should respond to set the record straight and to give their view point. As such I am sure a few people will be cringing when they see this title and see how I have reported this information.

In this case their study says if the person weighs alot then there will be less effective depletion…So the good news is that they will be more likely to respond to the SARS-CoV-2 vaccines.

However, this paper was not written with COVID-19 in mind and yes, you can be large without being fat but, it paves the way for increasing the dose of the drug to see if it is more effective. There is a large range in the size of people but often your MS drugs are based on a one size fits all approach. Clearly if you give DrM&M the same amount of drug as ProfB then ProfB gets half the amount as DrM&M on an amount per kilogramme. So DrM&M gets overdosed, twice the effect or perhaps just twice the risk of side effects, as ProfB gets underdosed. Only one MS drug is dosed according to size and that is oral cladribine. As you pay per pill it is costly to be size Lard.

B cell depleting agents are clearly being used by many people and seems to be the number 1 choice these days. This is great as the manufacturer says Ker-Ching as the money rolls in. Then the problem comes……..the COVID-bloody 19 pandemic. It’s killing people and the solution we are told is vaccination. So people ask is this drug COVID-safe? and is it vaccine-ready?

If ones drug is often being used, people on ones drug are going to get infected more often and so people will find out what happens with COVID-19 on ones drug. Now the problem is when someone says ones drug increases the risk of infection and COVID-19…people and neuros are going to be more cautious about using it. So then fire-fighting and damge limitation is required, so you then may say but the infection risk is small look at this data.

Now put COVID-19 vaccination into the mix and it is more fire to fight. Not only does it get people thinking how to avoid the risks of COVID-19 it makes you think about vaccination readiness and COVID-19. This maybe more of an issue when the public are hearing vacccine, vaccine, vaccine every day in the news.

In the study below they dose every 6 months to maintain the B cells at low numbers and only 4% of people show a response. You say this is great for therapy. However, we know that you need B cells for an adequate vaccine response. Therefore, the data below suggests maybe many people taking this agent may struggle to make an adequate vaccine response. I am sure more than 4% can make a B cell response because the cell level will not need to be back to normal levels. But how good is it going to be and to what extent is it required to give protection from COVID-19. Only data will give us the answer.

Baker et al. 2020

The problem for the 6 monthly dosing schedule is if the therapy is not based on the right sciencitific approach. In this case get rid of CD20 B cells from the blood. With a different logic you dose every 6 months when you may be able to dose every 12-15 months. This means less spondoolies (derivation spondulix) for them and potentially more safety for you. The study below paves the way for the DoDo trial of a double dose of ocrelizumab. This may get a little bit more antibody into the brain and it may be that bit more effective in progressive MS. However it says the terminal half life is 26 days, saying that it takes a month for half of it to disappear. Simplistically 600mg dose drops to 300mg dose in a month, 150mg dose in 2 months, 75mg in 3 months, 37.5mg in 4 months, 18.75mg in 5 months and at this level it is still B cell depleting. So double the dose and you add an extra month of depletion. Fewer B cells means a reduced capacity to remove the drug. So after 3 ocrelizumab doses it takes about 62 weeks for your B cells to recover but 4 doses it takes about 72 weeks for your B cells to recover. When will you be vaccine ready?

Anti-SARS-CoV-2 antibodies are being manufactured by an MS drug company and are being given to people, so circulating antibody levels that can get rid of SARS-CoV2 virus can be estimated. Next you see what levels of neutralizing antibody are generated in people with MS treated with the different drugs.

Companies making MS treatments should actively be doing this to get the answer as quick as possible on how people respond to COVID-19 vaccination. Otherwise we will be drip fed the data from small academic studies. Vaccination failure after CD20 is news and will sell column inches.

We know what vaccination responses are like when started one month after ocrelizumab(Baker et al. 2020). They are present but poor, what are they like if we wait to 5 months after ocrelizumab. I predict they will still be poor but a bit better than at 1 month. Why say this?. Because we know what happens with rituximab. This repopulates at a quicker rate than ocrelizumab and most people with autoimmunity repopulate within 12 months (Thiel et al 2017). However vaccinations between 6-12 months can still be blunted (Baker et al. 2020).

Come on companies lets get the data. Likewise MS Societies mobilize your global registries to collect the vaccination data

Gibiansky E, Petry C, Mercier F, Günther A, Herman A, Kappos L, Hauser S, Yamamoto Y, Wang Q, Model F, Kletzl H. Ocrelizumab in relapsing and primary progressive multiple sclerosis: pharmacokinetic and pharmacodynamic analyses of OPERA I, OPERA II and ORATORIO. Br J Clin Pharmacol. 2020 Nov 17. doi: 10.1111/bcp.14658. 

Aims: Ocrelizumab is a humanized monoclonal antibody that selectively targets CD20-positive B cells and is indicated for treatment of patients with relapsing forms of multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS). The pharmacokinetics and pharmacodynamics of ocrelizumab in patients with RMS or PPMS patients were assessed.

Methods: A population pharmacokinetic model was developed based on data from the Phase II study and the Phase III studies OPERA I and OPERA II in patients with RMS. Data from the ORATORIO Phase III study in patients with PPMS became available after model finalization and was used for external model evaluation.

Results: The ocrelizumab serum concentration vs. time course was accurately described by a two-compartment model with time-dependent clearance. Body weight was found to be the main covariate. The area under the concentration-time curve over the dosing interval was estimated to be 26% higher for patients with RMS weighing <60 kg and 21% lower for patients weighing >90 kg when compared with the 60-90 kg group. The terminal half-life of ocrelizumab was estimated as 26 days. The extent of B-cell depletion in blood, as the pharmacodynamic marker, was greater with increasing ocrelizumab exposure.

Conclusions: The pharmacokinetics of ocrelizumab was described with pharmacokinetic parameters typical for an immunoglobulin G1 monoclonal antibody, with body weight as the main covariate. The pharmacokinetics and B-cell depletion in blood were comparable across the RMS and PPMS trials, and the extent of blood B-cell depletion was greater with higher exposure.

About the author

MouseDoctor

7 comments

  • Sorry but this post has lost me.
    I take ocrelizumab, to be honest I just want to know whether the potential vaccines are OK for me.

  • Hi MD

    Having just read your last post – I thought I’d better read this one too!

    Just one question and please answer honestly, I won’t hold it against you!

    Is Ocrelizumab a ‘High DMT’ or would you consider it a lower or medium one in comparison to all the other available therapies?

    Also, COVID-19 -have you come across patients that are Asymptomatic (pwMS) and on a treatment? Do you have any thoughts that the depletion of the B cells & immune suppressed that they don’t actually develop COVID-19 & all its symptoms, as severe as previously thought?

    Just a thought too – I was on a treatment called Tecfidera for 2 years and whilst on treatment I did not develop an severe colds or viruses (just mild and only lasted a day or so). I mentioned this to my Neuro at the time – as I asked him that the treatment had made me invincible to all the normal viruses that circulated throughout the year (I worked in a large comprehensive school with viruses on the go every-day!) My Neuro answered – ‘it could help!’

    Best of luck with everything and for everyone to keep well – and ‘carry on regardless :)’

    • In my mind it is a high DMT…If you have been following me you will see I have been suggesting that they MS DMT may all work in the same way and the difference between the trial results of ocrelizumab and alemtuzumab is time of treatment from disease onset….I could be wrong but they need to do the ocrelizumab staight from diagnosis.

      Come across patients as asymptomatics…yes I have believe there was a an ocrelizumab treated person, but asymptomatic people may be 50-80% so I suspect there are alot about.

      Thoughts B cell depletion and COVID-19 lots of them….there is more to data to appear.

By MouseDoctor

Translate

Categories

Recent Posts

Recent Comments

Archives