ADIOS

A

Yes, why can’t we use anti-CD20 therapies as an immune constitution therapy (IRT) or at least adapt the dose based on B-cell reconstitution kinetics? And if we can’t beat the Swedes why can’t we join them?

ADIOS = ADaptIve Ocrelizumab dosing Study

There is mounting evidence from NMO and rheumatology that anti-CD20 therapies can be used as either a maintenance therapy or an immune reconstitution therapy (IRT). Another way of using them is to adjust the dose based on memory B-cell reconstitution (MBR) kinetics.

Adapting the dose of anti-CD20 therapies using MBR or as IRT has appeal as it will almost certainly be safer in terms of infections, the emergence of hypogammaglobulinaemia and possibly the ability to respond to vaccines. It could also lead to better family planning by being able to expand the treatment-free period safely. Another plus would be cost-saving for the NHS and the other healthcare systems.

We are therefore in the process of designing a new trial to test standard interval dosing (SID) of ocrelizumab vs. adaptive dosing either using an MBR or an IRT protocol. What do you think? If you were on ocrelizumab would you sign up for this study? The advantage for you is that it may make your treatment safer in the long-term and it will potentially save the NHS millions.

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.

35 comments

    • This is just a proposal; we would have to get this funded etc. This will take a year or more to get off the ground. Science is a slow process.

      • Is there somewhere to register interest so when set-up, funding, ethics etc are complete Both sides can re-establish contact and shorten the recruitment phase?

        Thank you

  • If patients on Ocrelizumab are well-enough informed they will readily choose to participate in such a trial, IMO.

    Just 3 days ago, owing to our safety concerns, my spouse’s neurologist (in the US) agreed to dose based on MBR. My spouse will have blood values measured every 3 months.

    In addition to assuaging our safety concerns MBR treatment promises to provide substantial savings. Here are the real figures from my in-hand insurance bill. The amount billed for Ocrevus is $34,554. My insurance paid $31,004. My responsibility is $3,550. Obviously, annual costs would be reduced by 1/3 infusing every 9 months rather than every 6 months. And, possibly, infusions may be even less frequent.

    The drug company provides co-pay assistance to cover almost the entire $3,550 co-pay. HOWEVER, when you reach Medicare age (65 for my spouse) co-pay assistance goes away with virtually all insurance plans in the US. So, the elderly in the US get stuck with huge co-pays using MS DMTs.

    If the elderly in the US have the opportunity to join an extended dosing trial, they will do so in large numbers because of the potential financial saving, IMO. If the trial happens and there is a US arm, it may expedite participation if the upper age were 68 or 70. Just a thought.

    • I suspect that like the Swedes the concepts underpinning ADIOS are not new and exist for rituximab in other disease areas, therefore, neurologists will adopt this approach without a formal trial. Maybe real-life data that will emerge from Sweden and other data sources will be sufficient.

      • “I suspect that like the Swedes the concepts underpinning ADIOS are not new and exist for rituximab in other disease areas, therefore, neurologists will adopt this approach without a formal trial. Maybe real-life data that will emerge from Sweden and other data sources will be sufficient.”

        Sad to say the real-life data that will emerge will not be sufficient to alter clinical practice in a timely manner. Only rare and exceptional practitioners will be early adopters and only their few patients will benefit.

        Look at the time lag which undoubtedly played a role in the death of many MS patients and the devastating effects of PML in those who survived it which could have been avoided using dose extension on natalizumab.

        From the AAN meeting in March of 2013 we note this:
        Natalizumab Related PML: An Evolving Risk Stratification Paradigm
        Session Presenter: John Foley, Salt Lake City, UT
        “This researcher discussed correlations between demographic data and PML risk in MS patients on natalizumab (Tysabri).
        Natalizumab serum concentrations and receptor saturation are moderately correlated with PML cases. Interestingly, factoring in patient body mass dramatically increases this correlation.
        In patients, natalizumab serum concentrations and receptor saturation appear to increase with treatment frequency and duration, suggesting that lengthening intervals between treatments may lower concentrations and mitigate PML risk.”

        I pounded the table for more than a full year before my wife’s neurologist finally agreed to extend time between doses. I desperately argued because there was simply no other way available to possibly reduce PML risk. My wife’s high JCV titer was very concerning but she was also essentially free of MS whereas previously exacerbations were devastating. Those were times when I spoon fed her and cleaned her bathroom functions. Forgive me if that is too graphic.

        So, it always comes down to balancing risk and reward.
        I have profound respect for our good doctor and over the years he was instrumental in achieving the best possible health for my wife. However, on dose extension we violently disagreed. His position was that there was simply not enough data to change dose schedule. My position was, by God, I want to do this and create the data validating, or disproving the validity of dose extension mitigating PML risk.

        For too long, my wife was at needless risk of PML. Then she went to 8 weeks between infusions with no change in MS appearing anywhere.

        Our present neurologist agreed to MBR in part because of a similar argument… how will we establish validity if PwMS on ocrelizumab do not participate in data collection. Some will have to volunteer and those who are convinced this MAY save their life, or this MAY help reduce the risk of serious infections are quite eager to participate.

        I must say, I am thankful to the point of tears to the brave and brilliant neurologist who agreed to proceed with treatment based on MBR. We are elated!

        Also, we are thankful or this blog. Please realize that this is the second time this blog has possibly saved my wife’s life or health… because of possibly de-risking natalizumab and ocrelizumab.

        Our gratitude to the Barts team is beyond expression. However, I must say, David Baker’s ballsy posts were instrumental in being able to make a coherent argument for MBR. So keep on speaking clearly spite of the hell you may occasionally catch from people slightly less impacted by human suffering.

        I urge the proposed study be done, if possible. Otherwise, data collection will be awfully slow, clinical practice will change even more slowly, and patients will suffer as a result, I believe. I believe the proposed study has a definite possibility of improving lives.

        Thank you an behalf of all PwMS.

        • Thanks.
          I totally agree the swedes have the data but the problem with real life is bias.
          The extended natalizumab dosing is ongoing and although not pml.risk free, it is looking better.

        • We dont have the data for MBR and people can relapse.with no peripheral blood B cells .
          The studies have to be done but i do think that for.most people reduced dosing could be beneficial. We need to do the studies and tjese should have been done at least 5 years ago.

          • Considering the problems which appeared in rheumatoid arthritis and lupus trials and considering ocrelizumab is a more effective B-cell depleter than rituximab, we thankfully were able to talk our neurologist into altering ocrelizumab’s 6-month dosing schedule… sort of like grabbing an umbrella when you are convinced rain is likely only the issue is much more serious to well-being.

            Unfortunately, we are among the select few who will ever get that option until reliable data establishes whether using ocrelizumab is going to be sunny weather or raining like hell. We do know that serious issues have arisen using B-cell depleters. Personally, this household sees threatening clouds; we are expecting rain and we see damn few MSers on ocrelizumab with umbrellas. Why? They, and their physicians have no sufficiently reliable forecast.

            I cannot imagine thousands of people using ocrelizumab not being interested in your proposed trial.

            It would be a tragedy if de-risking ocrelizumab requires the number of years de-risking natalizumab has taken.

          • I think it probably is abit better of a depleter and this may be of value. Whilst I was not going to aire these thoughts at present, in light of your comments you should be made aware of the ocrelizumab phase II extension study. Although not peer-reviewed published it is in public domain. To me it suggests that benefit is maintained for at least 18 months after the last dose (after 3-4 cycles), although the drug is probably active for some time after the last dose, given that only <5% of people start to repopulate their immature B cells and given its activity and half-life. This data also indicates to me that the infection risk is dropped by about 50% and serious infections do not occur in the treatment free period. Therefore the trial should be done. However will one's MS reactivate I don't known and is a risk too. This is the question and so needs to be properly monitored.

  • Finished the CHORDS trial and will be taking the MBR approach. Already know that my count is at zero at the 6 month mark. Would not want to wait for a relapse or new lesion for the next dose after going relapse and lesion free since Oct. 2016.

    • Have they let you finish the trial and that’s it? …Frankly I’m rather shocked by this.

      As I understand it, this is a Genentech sponsored trial and people have recieved 96 weeks worth of drug so I guess dose at 0, 24, 48, 72 (4 cycles). This trial involves 611 people.
      Perhaps you can tell me if there is a plan for follow up or treatment as it sound like ADIOS is being done by stealth if they finish you and you get nothing.

      Alternatively, is this a free start to the 6 monthly service?
      You have had a free test drive and now its time to buy the car?

      The phase II entension study gave results off 55 people. The CHORD study has 6 times the number. In one arm people got 4 cycles of ocrelizumab and then left them with nothing for 18 months, or longer and the majority of people remained relapse free without treatment up to week 144.

      Ocrelizumab depletes CD19+ B cells and about 5% of people start to show repoulation by 6 months and the it takes many more month to repopulate to the lower limit of normal. The time to repopulate is on average about 15 months but the range is 7 months to 42 months so if you are a slow repopulator your B cells could be down for some time.Apparently about 5% of people deplete for over 3 years.

      Next is the question of what hapens to the memory B cells? I dont know, but they are long gone with rituximab for many more months that the CD19+ repopulating cells, which tend to be naive cells. I found the protocol (WA21493) of the phase II extension study and it indicated that memory B cell levels were tested in the trial completed over 6 years ago.

      What happens long term with no ocrelizumab
      (a) Long term treatment benefit like alemtuzumab, rmembering that it is not infallible and many people saw break through disease activity
      (b) Disease reactivates after memory Cells repopulate
      (c) Disease reactivates before memory B cells repopulate

      Studies suggest that it takes 1-3 years for meory B cells to replete.
      Rituximab (with Glatiramer) suggests efficacy for about 23 months post treatment. This was off only one cyle which may not be enough.

      Anyone on no treatment I would recomend you think about (a) Switching (b) Ensure you are being monitored and if there is evidence of disease reaccurerence (MRI) switch to something else.

      If we look to alemtuzumab about 50% of people will see some disease break through.

  • Given there is over 2 years of real. Life data for Ocrelizumab and over 20 years of real life data for Rituximab. You maybe able to extract this information from machine learning api on spark and not just from expensive clinical trials. In addition it will show patterns that you weren’t even looking for. Just ask your IT department.

    • Agree there is looks of rituximab data to learn from. I guesss our Swedish Colleagues are best placed to interogate rituximab data

  • Given your recent posts on b therapies undertreating given the role of T cells. Why would you want to do this trial other than keeping researchers employed?

    • Ocrelizumab is already the fastest selling DMT to be launched in MS; there are well over 70,000 people on the drug. I would not be surprised if it takes 70% of the MS market. So yes, we need to answer these questions and we can’t treat all pwMS with alemtuzumab or HSCT. PwMS and HCPs won’t buy into this. Nor do my colleagues necessarily agree with me on the T-cell hypothesis.

      • Thanks Prof G. Isn’t it more imperative to do a trail to prove your hypothesis to stop this DNT before countless convert 2nd progressive MS? Not say the devastation it will cause their families. When someone forms a hypothesis its based on their knowledge, experience and intuiition. Given you are the most prominent MS scientist in UK at least. Do you think its morally right to shrug your shoulders and say its just hypothesis an not proven to justify inaction?

        • Steady profG wont be able to fit through doors with this complement with a swollen head. Many people do not change until the regulators say so.there are early.adopters and dinosaurs. They best people to answer quickly are the Swedes because of their rituximab use.

    • Also, hypotheses are just that and should not affect your clinical decision making until they have been tested and shown to be false or true 😉

    • Agree there is looks of rituximab data to learn from. I guesss our Swedish Colleagues are best placed to interogate rituximab data

      As to “Why would you want to do this trial other than keeping researchers employed?”.

      Because I keep an open mind and you have to accept the B cell idea is wrong, not quite right, I want to know the answer as this is progress.

      Reply

  • I have asked the same to MD: How can anti-CD20 be considered reconstitution when the drug just progressively eliminates CD20 B cells (and with this elimination comes an apparent remission of disease symptoms).
    His reply was that if you leave B cell reconstitution to happen the disease will not reemerge for a while.
    Rituxan is an old drug being used in certain MS patients for over 12 years, apart from RA and NMO. So we cannot pretent we will invent the wheel with O.
    From personal experience, patients who have been treated with RTX for over a decade and even those who have developed hypogammaglobulinaemia, have never been left to have CD20 B cells (or else they need to change treatment). Even if the dosage and the treatment intervals are adjusted to the patients B cell reconstitution, it is considered DANGEROUS to leave the patient with those B cells.
    Even after adjustment, hypogammaglobulinaemia is still possible to happen especially after the 7th year on the drug.
    So how can you suggest that anti CD20 is a “reconstitution” therapy? It is a therapy that can long term eliminate CD20 B cells and this effect demands adjustment to treatment application. Nothing new here.
    Cladribine could have a more complex mechanism than antiCD20 therapies that allows this reconstitution to happen.
    If I am wrong please provide the data.

    • CD20 depletes and then the B cell repertoire is reconstituted. Just like alemtuzumab reconstitutes the T and B cell repertoires. Therefore it can be depletion, reconstituion and resetting the tolerogenic balance. Therefore calling CD20 depletion an immune reconstituion therapy is not an issue.

      The question would be is B cell depletion enough to stop disease. This action would not tolerizse the T cell, So do you need to get both T and B cell depletion for long term benefit.
      It could be that you deplete B cells and it takes month to years to repopulate and this is not really a reset. Disease will reactive in all inividuals. Does this happen I don’t know. Show me the data that it does or it doesn’t

      I totally agree there is gold dust in the rituximab archive. If I had access to the swedish registry I would be in their hunting for information.

      Leaving people with those B cells is dangerous…..You have to think that maybe the B cells that come back are not those B cells, but differnet B cells that may be your friend and not foes. Repertoire analysis has been done with ocrelizumab (published at ECTRIMS in 2017, and still not surfaced. Maybe therefore killing your friends every 6 months is overkill and more likely to influence infection.

      However I think there will be a literature on people reciving continous treatment and those not getting treatment

      • Assumptions but no data.
        In RA in order to achieve low activity disease (or remission) they administer RTX with metotrexate. This combinatoin can possibly bring a modest “reconstitution”.
        Does this ring a bell about your b cell theory?

  • Just found out that two American groups are doing their own version of AVIOS. I am not surprised as it is an obvious question that needs answering.

  • My wife has just been diagnosed with MS and has a heavy burden of disease in both brain and spinal chord. It seems she has been progressing over the last 17 years after being hospitalised with ADEM (MS in retrospect) in 2002 and no follow-up. No symptoms indicative of ongoing MS until recently. MRI then whamo, you have MS. After reading Prof G’s posts, I want to start her on ocrelizumab which is allowed in Australia (she is British but now lives with me in Australia). The problem is finding a neurologist who will treat hard as she is showing no signs of disability other than some slight double vision which is resolving (with no active lesions on MRI). I also want to derisk this approach by dosing based on MBR. Again, it’s hard to convince neurologists to do this. I work in clinical research and have managed a couple of rituximab studies where this approach was utilised with good outcomes. The studies were in rheumatology but I think the premise is solid. So, our search for a neurologist who will entertain this idea continues.

    • If you live in Australia, I think it will should not be hard to find a neurologist who dosn’t treat effectively as soon as possible. They are top of the pile when it comes to treatment availability compared to the UK being second from Bottom. They are thinkers and I am sure they will consider what they deem as best option. If they are heavy CRAB prescripbers then they are probably not the neurologist for you as they go the softly softly route. The neuros and nurses in Oz have experience and opinions of ocrelizumab and so I am sure they can give you good advice if it is approriate for your wide.. Im not a neuro
      COI multiple

      • Sorry I’m a bit late to the party….. but I’ve only recently discovered Barts; as I’ve been distracted by shitms and the wonderful wheelchair kamikaze…..anyway; As the esteemed Professor says:

        ‘I think we need to do the ADIOS study sooner than later. Don’t you?’

        Erm yes and no. But I’ll get to that later.

        And, the American chap who banged his fists and demanded a different treatment protocol (bloody well done to you) – I think the Ocrevus patients in the U.K. should do the same thing…(and consider using the word litigation in the same sentence…)carpe diem- they can’t wait for ADIOS to conclude and need this intel now; and it should have been provided to them in the beginning. And Is available without more research, time and money being used investigating what we already know, well Prof G does.

        The neurologists should do everything they can now; to help prevent any future adverse outcomes; and listen to Sig G when he explains the optimum treatment protocol.Now.

        So that’s the no argument and the yes argument requires a lot of money. And time, which is by definition money.

        Hmmm …I’ve always hero worshipped jk Rowling; and I think it’s about time We/I dropped her a line to tell her of the need for her to throw large amounts of money at Sig Giovanni, so he and his merry band of fellow geniuses can morally independently, and ethically facilitate the very best outcomes for all of us.

        Actually no; the Wheelchair Kamikaze is one of the most intelligent, verbose, literate wordsmiths I know – I think a collaborative letter, after consultation with us all here and Sig Giovanni; written by Mr Kamikaze would be outstanding ? What do u think …

        • Luv it

          Dear Feathers.
          Welcome to the blog

          I hope a spellin mistake with ShiftMS:-), but if you have just arrived to the blog. I’m to funny one:-(I 4. The G’s do the serious stuff.

          Whilst trawling through the back catalogue, check out some past posts, as I hate to say that you write awfully like our homey rapper pal from Bradford-DrDre right down to the Don Giovani spellin. It’s uncanny.

          Maybe he will make a show and you can do a duet. I know our readers would love this:-)

          Good luck contacting JK, ProfG I mean DonG SigG etc has tried for years. Please let him know your secret if you get through.

          You are right they have had the indication for this for years (at least six) and after a few trips round the block, taking about a year they have agreed to release the data under lock and key. The legals are now done so let’s have a look…more on this in the future.

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