#T4TD when it comes to Anti-CD20 therapy body size counts

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Did you know that if you are a large person standard dose ocrelizumab is not as effective as it is in a small person? 

When looking at the efficacy of anti-CD20 therapies such as ocrelizumab you shouldn’t bother looking at relapses and focal MRI activity (Gd-enhancing lesions or new T2 lesions) when comparing effectiveness between doses and competing products. Relapses and MRI lesions are ultrasensitive to the effects of anti-CD20 therapies and are suppressed, to almost zero, at relatively low doses. In scientific measurement-speak we refer to this as a floor effect; in other words, you can’t go lower than zero or near-zero. 

However, when you look at disability progression (the real MS) there is clearly a dose effect, i.e. the higher the dose of ocrelizumab relative to body size, the greater the B-cell depletion and the less likely you are to progress. Most commentators miss this insight and are lulled into a false sense of security by seeing the relapse and MRI data when the real MS may be smouldering away and shredding your brain unabated. 

For this reason, we really need to do studies with higher doses of ocrelizumab and almost certainly higher doses of rituximab and ofatumumab. The observation that rituximab, at relatively low doses, doesn’t prevent the majority of pwMS becoming secondary progress is not surprising when it seems we need more intensive and not less intensive B-cell depletion. 

There are two hypotheses that could explain the dose-effect of ocrelizumab: (1) CNS penetration and the need to scrub the brain free of B-cells, or (2) really deep tissue B-cell depletion. Higher doses of ocrelizumab may achieve both of these. The real question is what is it about B-cells that is driving MS?

Those of you who are up to speed with safety and vaccine readiness data will argue that higher dose ocrelizumab will come with a price. Yes and no. Until we do the studies we won’t know. In relation to vaccine responses, I suspect there will be little difference between low and high dose ocrelizumab as both will almost certainly ablate germinal centre function. 

In terms of long-term safety, I suspect we may not need to use high-dose or very high-dose anti-CD20 therapy long term; we may get away with using it as an induction therapy followed by a maintenance therapy. 

Does this have implications for you as an individual? Yes, don’t accept your neurologist saying your disease is under control simply because you are relapse and MRI activity free; remember smouldering MS is the real disease. There are now compelling reasons why we need to do the double-dose ocrelizumab trial or DODO study and other add-on studies to target smouldering MS. Do you agree?

#T4TD = Thought for the Day

CoI: multiple

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

69 comments

  • “Does this have implications for you as an individual? Yes, don’t accept your neurologist saying your disease is under control simply because you are relapse and MRI activity free; remember smouldering MS is the real disease.“

    REALITY CHECK. The annual neuro meeting is not a business meeting. There is a patient seeking the advice of a medical expert. My neuro is also a Professor. Are you prepared to join me at my next neuro appointment so that you can point out to my Professor that he knows jack shit about MS? I’ll bring some ice to put on your black eye.

    How is my Professor supposed to respond? “Yes patient you are quite right, I’ll write out a prescription for some drugs which you can take to address the real MS”. There aren’t any such drugs at the moment, so my Professor can only prescribe the ones that are available (anti-relapse drugs).

    My Professor is sick to death of hearing me say “Prof G says this, Prof G says that…”. His view is that Prof G is like a Meerkat – poking his head up from his hole and creating a lot of hot air and dust. As others challenge him, he’s back down the hole again. Come up with something to tackle smouldering MS and my Professor will be on board. Until then, I imagine the consulting rooms of most neuros have a dart board behind their door with the face of Prof G on.

    • 😉 I am not the only one who buys into the smouldering MS hypothesis. Most big Pharma do as well, which is why they are still investing in the development of different classes of DMTs and add-on DMTs. Maybe what I am really am saying is don’t accept low-dose rituximab over higher-dose ocrelizumab. Or interferon-beta over alemtuzumab. What you want are DMTs that normalise or near-normalise brain volume loss. Unfortunately, there are not many DMTs that do that 🙁

    • I think your professor would excommunicated for fighting. Off label prescription is possible

      Nice to know what your professor thinks, how should we respond to that. Sling some mud…..I think not

    • Sid you are a very unpleasant person. Why anyone would take offence to a medical professional advocating for people with MS is beyond me.

      Good to see Prof G has a thick skin with people like you around!

      Thank you for the blog info as usual Barts team.

  • Thank you a lot Prof. G for this important post, especially for me: I just started ocrelizumab last week after a long battle with my neurologist to start a high efficacy DMT very early and before any progression occurs (I have been diagnosed in 2019 with optic neuritis and they gave me DMF for one year before I managed to go for OCR).

    I am convinced we need high doses of anti-CD-20 at least at the front as an IRT but I guess it’s not possible right now? I am a small person (63kg, BMI 21) but what can I do more to optimize my outcome and try to control (a little, even marginal gains) the real MS? What would you do?

    Another question about OCR: if I look at the data, I agree that MRI activity is almost totally suppressed (around 0.06 T2 and 0.01 T1 in mean at each MRI scan) but it seems to me it’s not the same for relapses (still around 12% chance of having one every year). How do you explain this difference? Can we really say that OCR totaly suppresses relapses?

    • Unfortunately, it is almost impossible to get pwMS relapse-free due to pseudo-relapses. The problem is that pwMS are susceptible to transient or short-lived recrudescence of symptoms when they have an infection, are tired or exposed to extremes of temperatures. These are often misclassified as relapses. I am hoping that neurofilament monitoring will sort out the difference between true relapses with neuroaxonal damage and pseudo-relapses without evidence of neuroaxonal damage.

        • Yes, in advanced MS the deterioration that occurs with severe infection may not get back to baseline. The reason we think is that systemic inflammation activates and stimulates microglia to produce inflammatory mediators that damage axons and neurons.

    • Would be interested to hear how you won that battle. I left my appointment today in despair again as my neuro point blank refused to discuss any treatment more effective than DMF (am currently on GA). I had practised what I wanted to say for days and even printed out Prof G’s Time Matters report IN GERMAN to back up my argument about smouldering MS. Am considering going to see someone else but fear I’m fighting a losing battle.

        • Yes – was delighted to find the report exists auf Deutsch. I’m still a newbie with neuro English, let alone explaining stuff in a foreign language. Not sure how the German version would have gone down had I whipped it out in Doncaster!

          • If you whipped it out in Doncaster…Careful people get arrested for that:-).
            I seem to remember they had to create a South Yorksire Dictionary for the EU (Austrian) Neurologists, who couldnt understand the locals use of slang/Yorkshiire Dialect

          • Really? That’s brilliant. Would have loved to be a fly on the wall at one of those appointments. I bet my Yorkshire German is as equally intelligible – Guten Tag, me old cocker etc.

      • Sorry JO I just saw your question 2min ago. I won thanks to a ‘tiny new T2 lesion’ (doctor’s words not mine) on my 1 year IRM since diag. By the way this ‘tiny T2’ was missed both by the radiologist and my neuro. I knew about it only because I insisted to see the Pr. MS specialist (in order to discuss DMT strategy) who discovered it while looking at my IRMs. It was not a good news at first but at least it gave me an argument to finaly get OCR early (one year after diag, still EDSS 0).

        • Thanks, Bob! I’m glad that your instance paid off and that you got OCR early on.

          I had a day of feeling completely deflated and then decided that I’m not going to stop pushing either. Am not looking forward to my 1-year Post-diagnosis MRI, but am also thinking that new lesions might give me more leverage – awful that we have to think this way though. There’s also a new Danish study which suggests that induction therapy leads to better outcomes for patients, so I’m saving all the information I can find, ready for the next round!

          I hope that the OCR works out for you. All the best!

          • Jo, just continue to learn and discuss all of this with your medical team! My next goal is now to get into a trial for addon therapy (if it exists). I got my first OCR infusion (300mL) one week ago. No adverse event so far and feel great.

  • I have RRMS since 2017 and am now 51 and an early retired NHS ward sister. I’m just asking the daft question- will there ever be a cure for this bloody awful disease?

    Regards Janet B

  • Thanks for another interesting post. Having worked in onc and haem, neurology is so behind when it comes to the use of these drugs and management of their side effects. This is highlighted by the unwillingness of some neurologists to even use treatments.
    MABs have been dosed in many settings as a per m2 dosage. When BSA can vary so much it makes perfect sense.

  • Hi,
    Does a C19 result of <1 UL (normal range 70-400) 0.1% mean that the B cells are being killed off enough to hopefully stop the slow burning disease? Or are you suggesting the levels need to be a lot lower than that?

    Thanks

  • Hi,
    Does a C19 result of <1 UL (normal range 70-400) 0.1% mean that the B cells are being killed off enough to hopefully stop the slow burning disease? Or are you suggesting the levels need to be a lot lower than that on Ocrevus?
    (On Lemtrada I did see 0.04 so is that flat bottom but on Ocrevus 0.1% <1.) What levels would you be looking at in order to know if the dosing is enough?

    Thanks

  • Great topic but OCR does NOT penetrate the BBB owing to size. Most drugs (99%, possibly) do NOT penetrate the BBB and hence studies that even looked at this from an intrathecal perspective to kill off B cell subpial follicles did not work, either let alone killing cells in the periphery. But MAbs do not penetrate the BBB so OCR dosing and increasing BBB penetration and scrubbing the brain of B cells does not fly although dosing interval at q 6 months for ALL patients is wrong and certainly BSA of a person does affect efficacy.

    Secondly, the brain atrophy studies almost to a fault NEVER talk about the effect of age and brain atrophy. Christina Azevedo’s study in NNN, 2019 elegantly pointed out that MS-specific atrophy DECREASES with age (-0.38 at age 30 vs. -0.12 at age 60) while the reverse is true for age vs. atrophy. The atrophy that one sees is mostly related to age, specifically in the thalamus and cortical thickness, I believe she said it was and it is NOT similar in various regions of the brain. So, clinical trials have to look at volumetric data in YOUNG RRMS patients not ANY patient population to be effective and relevant.

    Lastly, brain volume data, atrophy, cortical lesion descriptions, etc, are ALL better picked up on ultra-high strength MRIs, as we all know. The data culled from 1.5 T is not the same as that derived from 7 T. And we never talk about magnet strength since it now involves cost. And money and science do not mix.

  • Hi,
    What level of C19 would display a low enough level to show that the dosing is strong enough on Ocrevus?

    Thanks

    • It is not about peripheral blood counts, but deep tissue and CNS B-cells. We don’t as yet have biomarkers for these unless you are prepared to have serial LPs.

  • I know cladribine isn’t CD twenty, but do you think the current weight/dosing regime Is accurate enough? To me it seems like degree of depletion highly varies between individuals – what is driving this, if not the medicine, and how do one ensure sufficient depletion? (if not controlled by dosing)

    And I also notice that you are stating 1) “scrubbing” the brain is necessary for tackling smouldring MS, and 2) cladribine is very successful at this. Would you claim that cladribine is an as “purposeful” DMT as say alemtuzemab and ocrelizumab (+ the other CD20s), despite being seemingly less efficacious?

    • I have always taken the position that the current dose of cladribine, although effective, is probably too low. We chose the dose based on safety concerns, which remains the case.

      • Yes, I suspect that this was chosen to limit lymphopenia and AEs. But you guys (or pharma?) already have data about ppl that DID deplete more than average patient.
        Has anyone looked at those patients and if they fare better than those that did not deplete so much? This could be then used to either increase dosage or at least be aware of this and act accordingly.

  • I have to agree with Sid…

    “ Yes, don’t accept your neurologist saying your disease is under control simply because you are relapse and MRI activity free“

    My neuro isn’t a professor, but works in a hospital with a large ms focused department. He will agree a relapse free MRI won’t mean I don’t have any progression. He suggest I may became progressive….and than he concludes there is no class 3 evidence of a working medicine for progression without mri activity, so there is nothing he can prescribe… Bringing in all kinds of information from this forum does not change anything -> No class 3 evidence, no new prescriptions…..

    • This is why I promote my marginal gains philosophy of treatment for MS. There is a lot you can do outside of DMTs and the pharmaceutical management of MS.

  • Forgive me if I’m just not putting the info together correctly, but I’m wondering, what’s the relationship between this idea that a higher dose of Ocrevus is more effective, and the idea that the dosing interval for anti CD-20 therapies should be extended? Or perhaps I’m off base and they aren’t related. Is the extended dosing interval only relevant in the current vaccine readiness/pandemic situation or would it always be preferable? I’m a 52kg woman receiving Ocrevus every 24 weeks, so I feel fortunate that my body size perhaps gives me a leg up on effectiveness but am trying to wrap my head around how dosing interval is related. Thank you!

  • “the greater the B-cell depletion and the less likely you are to progress”

    “really deep tissue B-cell depletion”

    So “MORE IS MORE”

    Makes sense to me 🙂

    (Thats why myeloablative hsct in Canada as a great track record)

    Mark Freedman
    June 14, 2020 at 1:35 pm

    https://multiple-sclerosis-research.org/2020/06/hsct-a-cure/

    Why is this a new thought? We have done this in >50 patients with some stable/improved for >20 years!

    https://multiple-sclerosis-research.org/2020/06/hsct-a-cure/

    Now

    Question Doc Mouse as saying time and time and time again that any drug proein based wont get in the brain

    with significant doses

    So how come more is more aproach work in anti cd20 progression free survival

    I remember a study some moons ago were they inject rituximab directly in the cns compartement and still

    people progress

    Obrigado

  • OK. Why be bothered about the effects of Ocrelizumab when its not a cure? Alemtuzumab and HSCT are potential cures and need to be derisked through addon therapy or medication. There is no logic in the on going debate in MS of T vs B cells. In my opinion, both camps are blinded by their own prejudices.

    • The longer I research and think about this, the more I follow that line of thought.
      I will give ocrelizumab credit for one thing though: it cleared my cog fog up and thus made me able to do the research.

      • If it behaves like Alemtuzumab than why not just use Alem? Is it because of secondary autoimmunity problems with alem?

  • Yes yes yes please. Can I be on the trIal even though I live in Norwich? I had a internet Appointment with my Neurologist which worked well and it can with you too. I have an EDDS of 7 and diagnosed in 1994. To say I feel desperate is an understatement. Failing that Can you give me advice on how to persuade the Neurologist to treat me. Thank you.

  • Good research work Professor G and compadres – knowledge is Power after all! so can everyone stop having a go; or come up with some independent evidence-based solutions?!
    My wise, intelligent Aunt ( imagine a posh , educated lily Savage) read this and the comments and declared
    “so basically you are all lab rats and they haven’t got a clue, dont you need to find the cause you find the right treatment. At least that Prof G is curious and trying; and he hasn’t even got it …I am so glad you’re skinny self did not agree to an icarus infusion?” (Out of the mouths of 88 year olds eh…)
    However, She and I particularly liked
    “There is a lot you can do outside of DMTs and the pharmaceutical management of MS”
    It takes a brave, selfless moral man (and he is only human) to say those words in this current climate.
    Respect to The Don G from Aunt Dorothy and I

  • Thanks a lot for the T4TD. Few other points that also definitely need to be highlighted. Clearly fixed-dose regimen for any DMT may not be suitable. In the recent article from your colleagues, Baker et al. in MSARD, they highlighted the issue of neutralising antibodies with the low-dose regimen vs. standard- or high-dose regimens. On the contrary, can we define an endpoint for B-cell depleting therapies (maybe any biomarker other than circulating population of B-cell) to circumvent the issue of unnecessary and risky profound and prolonged immunesuppression. Even the traditional IVIg dose is moving from per kg body weight dosing to response-guarded dosing for chronic neurological disorders like CIDP/AIDP given that some will be under- and others overtreated. How to strike a balance?

  • Have to say agree with Jo above. Some uk hospitals don’t even have Ocrelizumab as a treatment option. Notwithstanding that I was under the impression that you have to meet guidelines to even start any kind of DMT , I.e 2 relapses in two years or relapse and enhancing lesion in two years as a minimum so some people with RRMS aren’t offered anything.. Took over two years for me to be offered any DMT, DMF and all injection based DMT. I was under the impression they put your initial presenting symptoms and if you have had any enhancing lesions in some computer program and it spurts out the drug options . Or have I been duped?

  • Your question: “What is it about B-cells that is driving MS? ” is a thinking-outside-the-box one.

    B cells are never wrong. They are doing exactly what they are supposed to do. What’s driving MS is something like a bad fit in affinity maturation and probably oxygen-related at some point. Oxygen levels seem to play an important role on the metabolism and in general the function of adipose-derived structures. They are so basic.

    The origin of MS is a brain injury of some type and severity. MS is more of a condition than a disease since it becomes the person who has it. Many of these injuries occur at birth, a time when insulating processes are prolific. Stuff can go very wrong in a setting of hypoxia and lipids can look like virus in the humoral immunity environment. God forbid a bad memory. It’s this which must be erased, not the B cell.

  • I have had 3 full doses of OCR. I am 6′ 230lbs. Before each full dose i experienced what i would consider progression or a milder relapse at about 8 weeks prior to the next dose. It was labeled as “crap gap” because no new lesions on current MRI and blood test still showed CD19 at 0. These test results do not reflect how I really feel. This theory makes sense to me. I’m a larger male and so far 8 weeks before each dose i feel like i’m going downhill.
    I have requested my infusions moved up to 20 week intervals but my Neurologists thinks the insurance company will fight it (Im in the USA)

    Do you think 20 week dosing is more appropriate for some one of a larger size since obviously we cannot get a higher dosage?

  • INTERESTING TOPIC! When I had the “my smoldering MS needs a stong DMD” conversation with my top neuro, I attempted to present as evidence my disproportionate to age, asymmetrical atrophy of certain parts of my brain. I was surprised to learn that the exact import of atrophy measurements, rate, and atrophy alogorithems were not universally accepted. However, a post infection insidious and unresolved weakness, increased cognitive difficulties, an initial aggressive course, duration of my illness, and a family history of aggressive MS, were factors which helped determine it was time for me to go on a stronger DMD. But it is still unclear to me why the rate of dispropotionate atrophy around older brain lesions can not be tracked or why other scanning tools (spect ?) Can’t determine atrophy. For my own fun, I write note to MRI staff on personal health questionaire at sign in that atrophy of certain structures has been observed on my brain and to comment on it. They oblige, simply it is observed. So yes, more studies are needed to quantify smoldering MS and brain atrophy.

  • Hi Prof G. All other things being equal (BMI), do you think ocrelizumab is better than rituximab in preventing end-organ-damages ? Is there a big difference between the sizes’ dose ?

  • Hi prof G, hi Mouse Doctor,

    Just to see the glass half full for a moment.

    I know and agree that the real ms is smouldering ms and progression but shouldn’t we realise also all the progress of modern treatments ? I mean, OCR for example, is in my mind just incredible about new T1 and T2 when I look at the OPERA studies. I am alone ? We are speaking about 90% reduction compare to an actual real treatment, rebif, isn’t it? Something like a near total suppression of relapse and new T1/T2, isn’t something great ? Of course it’s not suffisent but it was in my mind a necessery first step and we achieved it, arent’t we ? (It was not trivial I think). Ok it’s not good at PIRA but suppressing almost totally the RAW composite is not that bad in my view. It’s maybe because I am newly diagnosted (2019) but if I can now avoid strong and bad relapses and very bad new T2 in an horrible spot, it is something that make me feal great, I shouldn’t ?

    By the way, in your mind, does OCR – if begin early before any progression – could avoid smouldering ms ?

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