Class Action…..Is CD20 depletion an IRT?

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Recently ProfG has been talking about immune reconsitution therapies and it has been asked if ocrelizumab is an IRT?

This is important to know because it says that you would not have to dose as frequently and whilst this may make a dint in the coffers of the manufacturer, it could mean an improvement in the risk:benefit profile for you…..if this is true.

No one wants an EMA or FDA investigation on side effects. Look at the problems with alemtuzumab if you don’t agree

ProfG seems to have been upsetting people by suggesting that if you deplete B cells for ever, it is not good news.

As a consequence he may have been knocked off the Roche Christmas card list, because of the suggestion that there could be infection risks from long-term B cell depletion risks. I am not on that list at the moment, but would not say no to a nice crimbo hamper:-). However, unless you buy into the “it is unknown” peddled by the Zombie science opinion leader brigade with the view that “if it hasn’t been shown it doesn’t exist”. This means that unless people all become “fungus mungus” then there is no problem. We know that serious infection risk is low, but it is not non-existant

I have to say “Come on people, think about it!” or simply just “think!”

Your immune system is there to protect you from infection, B cells are particularly good at getting rid of infections, get rid of B cells for ever and someone is going to suffer. It is not going to be the manufacturer. At the population level you will probably be OK, but if you are the unlucky individual, you will be unlucky.

I am sorry, but I don’t buy the alleged Ford Pinto approach to drug science. If you don’t get it. Watch “Class Action” . Maybe I will call it the “Astro Meridian” approach, in case Ford take the hump, about the way some companies appear to approach risk management. You are the car with the blinker problem, hopefully you won’t be hit when you are turning, but if you do, then you are literally in the hot seat. This makes me feel like Dr Pavel.

If ocreliziumab is an IRT you are being overdosed, but in reality even if it isn’t the case, the chances are you are still being overdosed. Why?

If we look at rituximab it is dosed every 6 months. It takes 8-12 months to replete CD19 B cells. Ocreliziumab is a more potent B cell depleter and it takes 15-18 months to replete, so why is it also given every 6 months?

Now if we look at the memory B cell depletion, this is maybe 15-24months (if you look at rituximab data) so with ocrelizumab would it be longer. We don’t know because there is no data. Shouldn’t we try and get it.

Now you can say the dosing schedule was selected when we didn’t know anything and I accept that. The Zombie opinion leaders will still say we don’t know anything. They go to ECTRIMS and teach the Status Quo.

You know me, I am not a fan of Status Quo. It all sounds the same:-).

If you accept that the memory B cell has any legs,then the six month dosing schedule is probably too frequent. The group from Genoa in Italy has data that support this. So you don’t have to be a Zombie. If you look at the time of memory B cell depletion with rituximab, it is more like 24.months. This suggests that following ocrelizumab they are gone for a long time. Maybe this gives a durable action for years. Is it IRT or long term immunosuppression.

My guess is it abit of both.

If you can extend the dosing schedule you perhaps do not keep you B cells out of existence and maybe, just maybe you can take a drug holiday, allow the drug to wash out, get pregnant, have a baby and still be protected. If this is true it is ADIOS to some of the competitors and the sales come rolling in.

Therefore, it makes sense to do these studies, just as it makes sense to do studies where you treat from onset and get the brain atrophy data that says alemtuzumab is not special, the important aspect is to ge on effective treatment early. maybe you show it is special, but the cladribine data from ORACLE suggests otherwise.

Any way what is this post all about?

It is about the study from Sweden. It reports on the effect of stopping rituximab and waiting …from 7 months to 8 years. There were 6 cases of disease activity from 92 people. To me this seems like rituximab is indeed an IRT, just as I said it was 2 years ago, as it seems to be alemtuzumab-like.

It’s not surprising if they work the same way. Unfortunately, there are some people who don’t buy this simplistic view as it makes it all too easy, especially when you sell the unknown, unkown idea. The companies and their opinion leaders want you to think each agent has a special mechanism of action. Do they really?

The study with ocrelizumab is happening as people run out of money and have to stop ocrelizumab. I say come on be brave, Do the trial and show this to be the case, as we need to know that this approach is safe. I’m sure profG and the Gang would love to do the trial.

Go on send a christmas card and give us that present of the ADIOS trial..you and I know it makes sense, let’s not wait to be hit whilst turning right, whilst flashing! After all no one wants to be caught with their pants round their ankles:-)

Interrupting rituximab treatment in relapsing-remitting multiple sclerosis; no evidence of rebound disease activity. Juto A, Fink K, Al Nimer F, Piehl F. Mult Scler Relat Disord. 2019 Oct 24;37:101468.

BACKGROUND: Rituximab (RTX) and other anti-CD20 therapies are increasingly used as disease modifying treatments (DMTs) in MS. However, data on reasons to interrupt treatment, alternative DMTs after anti-CD20 therapy and potential rebound disease activity are limited. The objective here was therefore to determine the rate and cause of RTX treatment interruptions and responses to subsequent DMTs in a large single centre cohort addressing also the hypothesis that there would not be rebound activity after discontinuation of RTX, regardless of reason for discontinuation and irrespective of subsequent treatments.

METHODS: A retrospective observational study of all relapsing-remitting MS (RRMS) patients having received at least one dose of RTX at the Karolinska University Hospital from 2009 to 2018 and having either stopped treatment or had more than one year since last RTX infusion, as identified in the Swedish MS registry with additional data derived from clinical charts.

RESULTS: As of February 2018, we identified 808 patients ever treated with RTX out of 1513 RRMS patients with current or previous DMT, 92 (11%) had terminated RTX; 27 (29%) stopped RTX due to pregnancy, 26 (28%) due to adverse events, 23 (25%) for other reasons, 9 (10%) due to stable disease and the remaining 7 (8%) due to lack of effect. The cohort of 92 patients was followed until April 2019, when 34 had restarted RTX, 27 switched DMT, 24 remained without DMT and 7 were lost to follow up. Of the 7 patients terminating RTX due to lack of effect, 4 started ofatumumab, 2 had autologous hematopoietic stem cell transplantation and 1 was lost to follow up. In all of the 92 patients, after initial RTX discontinuation, only 3 patients had relapses and 4 had new T2 lesions (one of which had both). Gadolinium was administered in 78% of follow up magnetic resonance imaging (MRI) with no enhancing lesions found (mean MRI follow up from RTX discontinuation 29 months, range 7-92 months, n = =77).

CONCLUSION:Findings are consistent with a low rate of RTX interruptions, with pregnancy and adverse events as most frequent reasons. A small proportion of patients switched due to breakthrough disease in context of incomplete B-lymphocyte depletion. Signs of ongoing disease activity in the remaining group was low regardless of whether a new DMT was started. These findings are consistent with a long acting effect of RTX in RRMS and absence of rebound disease activity phenomena upon stopping therapy.

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MouseDoctor

18 comments

  • Hi all, to the lay-person, does this mean that if you are given the first infusion with the follow-up in 2 wks that you should wait longer before you commit to the next? If this is the case, I’m guessing you can tell from blood tests whether the cells are still ok & enough to not to have wiped them out completely. From someone who is booked in for this drug – I’m nervous, my age, other comorbidities (arthritis, mild heart prob & bulging discs) along with I’m susceptible to cold sores (big time) are all factors to take into consideration if my immune system is going to be almost wiped out. Is there an alternative? Can you also press harder for the trials to be carried out more on side effects and consequences – DMDs or not DMDs, that is the question?

    • The first infusion and the second infusion two weeks later should be seen as one infusion. In PPMS trials they gave one 600mg dose verses the 2 x 300mg in RRMS. Depletion wis they are comparable. These are depleting the cells but it also catches new cells coming out of the bone marrow, which I think can be a good thing. A dose is a dose and these should not be self experimented.

      Yes you can look at blood cells to get ideas of whats going on but most hosptials only look at CD19 and this in my opinion is not enough.

      You should be aware that there is a slightly elevated signal from herpes infections as with most immunosuppressive agents.

      There are alternatives to every treatment but each comes with a risk:benefit. Ocrelizumab has a better risk profile than many other MS drugs.

      DMS on not DMD in my opinion is easy…DMD have had benefit over getting nothing

      CD20 is used for rheumatiod arthritis so you can get a double whammy

  • As a patient I will tell you why from personal experience I think IRT May be too good to be true. Many people, myself included actually start to feel a lot worse physically when approaching the time for next 6 month dose, then feel better after this next dose. There is clearly some pathology behind this science hasn’t yet fully explained but it’s real enough that many patients have advocated for 5 month dosing because they feel worse otherwise. Dose it as IarT you will have a lot of unhappy patients not feeling well – and who knows what that means. I’m still waiting for someone in the medical community to explain why this happens. What happens to those people who feel this very real worsening a few months later if you increase the dosing schedule? This may be theory to doctors but to those who feel better on this drug as you say you’re in the hot seat and the drawbacks of delayed dosing are real. Not sure how those patients should weigh the very real risk of feeling worse (and what that means for ms symptoms) with long term infection risk.

    • FYI many patients call this the “crap gap” and it’s existence goes against an IRG theory. Would love to understand why it happens

      • I’m not doubting the crap gap as I feel I may have experienced it (have only had two doses so far though, not much experience to go on yet). My question about it is, I did not think that DMDs were supposed to help with your current symptoms but just (hopefully) help to prevent NEW symptoms caused by new lesions/damage? I kind of felt like the easing up of my current relatively minor issues was an unexpected bonus.

    • Ditto
      At some stage after the last rituximab infusion – between 6 and 12 months later – my daughter starts to feel worse. It becomes harder to do the things she needs to do. Old symptoms start reappearing or worsening. Then we ask for the next infusion (the neurologist always needs some convincing)

      Everyone would like the rituximab to be an IRT, but unfortunately it does not seem to behave that way. This is the seventh year on rituximab ,and the tenth round of infusions

      • Thanks for your insight. I would point out that many people who recieve HSCT and alemtuzumab show disease activity and need extra courses, but you are saying that it can be longer than 6 months before another treatment is required.

  • Umm, actually there is data from Opera I and II srudies as it relates to CD27+ memory B cells. These B cell subsets were tested routinely during controlled clinical trial and open label extension. Roche has the data….will they analyze it and then publish it???

      • So go ahead and publish this yourself. I work in CompSci and we have something called Responsible Disclosure. It means that if you find a security bug in software, you notice the authors first and give them time to fix the flaw. You then still publish your findings, but users are already protected. If they don’t respond in time, you publish findings anyway.
        Yes, it’s not the same situation, but I see no reason to NOT use this principle here too.

        • Pharma, as a general rule prefers to keep data hidden at all costs and make requests for data as difficult as possible (they effectively control the data request portals) and can be stymied at every turn with the response that “this is about to be published”. The system as it is currently configured is simply not fit for purpose.
          MD could write a book on his experiences.

  • Just 11% (92) of 808 patients stopped ritux

    Reasons for stopping
    – 4% (33) lack of response or adverse events
    – 4.5% (37) pregnancy or stable disease
    – 2.5% (23) other reasons.
    The first group above would not resume ritux.
    It’s hard to say anything about whether the last group would resume.

    Later
    – 4.2% (34) restarted ritux
    – 3.3% (27) started another DMT
    – 3% (24) stayed without DMT
    – 0.8% (7) unknown

    The key point is that very few stopped at all. If the disease was so stable with ritux, then more would have stopped.
    Of those who stopped, a big chunk did restart. Again, if they had been so stable without ritux, they would not have restarted

    Rituximab is very effective, but the disease does not go away. Reminders of MS remain, and these reminders become more insistent as time from the last dose increases

    Nobody has suggested any maintenance treatment that can be taken instead of re-dosing. So I don’t really understand how rituximab can be considered an IRT

    • If disease was so stable people would have stopped. Not so sure. Tell this to a transplant recipient. Their kidnies work under immunosuppression and is stable stop your drug and your kidneys are gone in no time.

      However the data is the data and we will find that the 6 monthly dosing can be extended in some individuals. We know this from other conditions. I am saying we need a trial I am no saying stop taking drugs. It needs to be evidence based.

      How does it become an IRT you deplete pathogenic cells and if they return into a regulated environment then it can be an IRT. This is no different for alemtuzumab or cladribine. You don’t have to invent new mechanisms

    • ”The key point is that very few stopped at all. If the disease was so stable with ritux, then more would have stopped.
      Of those who stopped, a big chunk did restart. Again, if they had been so stable without ritux, they would not have restarted”.
      The conclusion is that if you extend the dosing interval to at least 1 year, you have very low rebound disease activity. Also, it is not stated that they restarted rituximab because they were not stable, the main reason for those that restarted was restarting after pregnancy, ie continuing the treatment.

      ”Rituximab is very effective, but the disease does not go away. Reminders of MS remain, and these reminders become more insistent as time from the last dose increases”. This is true for some patients. You have to weigh all these factors against the risk for side effects i.e individualized medicine.

    • Probably we know from the arthritis studies that lower doses cause depletion. It is a hammer alemtuzumab is a sledge hammer

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