#ECTRIMS2021: ocrelizumab the game-changer

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The next in the series of #ECTRIMS2021 long-term follow-up posts. This is the 7.5 year follow-up of the ocrelizumab OPERA 1&2 (relapsing MS) cohort. The efficacy data looks very impressive. 

  1. Annualised relapse rates well below one in 10 years or 0.1 p.a.

2. 82% of ocrelizumab treated subjects had no confirmed disability progression.

3. Less than 7% of ocrelizumab treated subjects needed a walking stick compared to 10% of subjects randomised to interferon for 2-years before switching to ocrelizumab. Sadly, the 2 years on interferon have come at a price; time really is brain and spinal cord. This data like most contemporary data sets make a strong case for flipping the pyramid. 

4. The safety of ocrelizumab looks similar to what it was 2-years ago. The risk of serious infections is 1.73 per 100 patient-years of follow-up; i.e. in 1,000 patients on ocrelizumab, 17 will have a serious infection per year. This needs to be balanced against the COVID-19 data showing a doubling of risk of severe COVID-19 in ocrelizumab-treated subjects and an ~80% chance of not seroconverting when being vaccinated with one of the COVID-19 vaccines.

Unfortunately, no end-organ damage data (brain volume loss) to present, but this will come in time.

It is clear that anti-CD20 therapies are a real game-changer when it comes to the management of MS; i.e. very high efficacy therapies, in terms of switching off MRI activity and relapses, with a relatively good short and long term safety profile. 

ECTRIMS-2021_OPERA-OLE-7.5-years-Poster_VA3-2

Giovannoni et al. Long-term  reduction  of  relapse  rate  and  confirmed  disability  progression  after  7.5  years  of ocrelizumab  treatment  in  patients  with  relapsing  multiple  sclerosis  in  the  OPERA  OLE. ECTRIMS 2021, P723. 

Introduction:  The  efficacy  and  safety  of  ocrelizumab  (OCR)  in  relapsing  multiple  sclerosis  (RMS)  were demonstrated  in  the  96-week  contro led  double-blind  period  (DBP)  of  the  Phase  I  OPERA  I  (NCT01247324) and  OPERA  I (NCT01412333)  trials.

Aims:  To  assess  the  efficacy  of  switching  from  interferon  (IFN)  β-1a  or  maintaining  OCR  therapy  on  disease activity  and  confirmed  disability  progression  (CDP)  after  5.5  years  of  fo low-up  in  the  open-label  extension (OLE)  of  OPERA  I  and  OPERA  I.

Methods:  In  the  DBP  of  OPERA  I  and OPERA  I, patients  were  randomised  to  receive  OCR  or  IFN  β-1a. Patients  completing  the  DBP  either  continued  OCR  (OCR-OCR)  or  switched  from  IFN  β-1a  to  OCR  (IFN-OCR) when  entering  the  OLE.  Adjusted  annualised  relapse  rate  (ARR),  time  to  onset  of  48-week  CDP  (CDP48)  and time  to  48-week  confirmed  Expanded  Disability  Status  Scale  score  ≥6.0  (time  to  require  a  walking  aid)  were analysed  up  to  Week  384.

Results:  Overa l,  76.3%  of  patients  who  entered  the  OLE  period  completed  OLE  Year  5.5.  Adjusted  ARR decreased  year-on-year  from  the  pre-switch  year  to  OLE  Year  5.5  in  IFN-OCR  switchers  (pre-switch,  0.20;  OLE Year  1,  0.10;  OLE  Year  5.5,  0.03)  and  was  maintained  at  low  levels  in  OCR-OCR  continuers  (pre-switch,  0.12; OLE  Year  1,  0.10;  OLE  Year  5.5,  0.03).  Rates  of  CDP48  were  lower  in  OCR-OCR  continuers  vs  IFN-OCR switchers  at  the  end  of  the  DBP  (4.1%  vs  8.5%  [Δ=4.4%;  p<0.001])  and  numerica ly  lower  at  OLE  Year  5.5 (17.9%  vs  21.5%  [Δ=3.5%;  p=0.118]).  Rates  of  patients  requiring  a  walking  aid  were  lower  in  OCR-OCR continuers  vs  IFN-OCR  switchers  at  the  end  of  the  DBP  (0.8%  vs  3.1%  [Δ=2.4%;  p=0.001])  and  numerica ly lower  at  OLE  Year  5.5  (6.6%  vs  9.5%  [Δ=2.9%;  p=0.060]).  Over  the  DBP  and  OLE  periods,  the  risk  of  CDP48 was  23%  lower  (overa l  percent  of  patients  with  CDP48  in  OCR-OCR  vs  IFN-OCR:  14.5%  vs  16.4%;  HR [95%CI]:  0.77  [0.60–0.98];  p=0.034)  and  the  risk  of  requiring  a  walking  aid  was  35%  lower  (overa l  percent  of patients  requiring  a  walking  aid  in  OCR-OCR  vs  IFN-OCR:  5.2%  vs  7.0%;  HR  [95%CI]:  0.65  [0.44–0.97]; p=0.034)  in  OCR-OCR  continuers  vs  IFN-OCR  switchers.

Conclusions:  Switching  from  IFN  β-1a  to  ocrelizumab  at  the  start  of  the  OLE  period  was  associated  with  a rapid  and  robust  reduction  in  ARR  that  was  maintained  through  the  5.5-year  fo low-up  of  the  OLE  period.Compared  with  patients  switching  to  ocrelizumab  at  the  OLE,  patients  initiating  ocrelizumab  2  years  earlier had  a  significantly  reduced  risk  of  requiring  a  walking  aid  and  48-week  CDP.

Conflicts of Interest

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Preventive Neurology

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

50 thoughts on “#ECTRIMS2021: ocrelizumab the game-changer”

  1. Thank you Prof G & team for the amazing work.

    Would you be able to make a guesstimate based on available information how much better Alemtuzumab is at preventing BVL compared to Ocrelizumab – if both are administrated with all the same factors.

    Thank you!

    1. Anti-CD20 therapies reduce annualised BVL by 0.25-o.35% per annum and alemtuzumab by 0.05-0.20% per annum. The range depends on age and disease duration.

      Please note both therapies are associated with a higher rate of BVL in year one due to pseudo-atrophy.

      1. Are there long term data on NFL? I remember that OCZ clears OCB in some patients after some time like 1 or 2 years. If so also NFL coming from smouldering should decrease further with respect to relapses suppression only. If ocb are the driver of progression/smouldering of course.

  2. Looking at the data, it seems during year 4 ~ year 5 there is an increasing rate of #patients with progression – is it random?

  3. This post paints a rosy picture about Ocrelizumab, and by extension about Anti-CD20 too.

    But you recently posted something with a different tone
    https://gavingiovannoni.substack.com/p/anti-cd20-kool-aid-and-covid-19-vaccines

    And last year you had this one
    https://multiple-sclerosis-research.org/2019/03/why-is-everyone-drunk-on-anti-cd20-kool-aid/

    Wouldn’t it be better if posts were more balanced in their presentation of pros and cons?

    1. What is not balanced? I do mention the COVID-19 and vaccine issues in this post. I just can’t do everything with every post. The bottom line if you want a high-efficacy treatment, which is immunosuppressive, you have to take risks. You could always choose interferon beta, which is not immunosuppressive, but much less effective on average unless you happen to be one of the super-responders. Unfortunately, to treat MS or any other autoimmune disease for that matter, you have to choose your poison. If I had MS I would personally choose alemtuzumab or AHSCT, which come with risks that are probably an order of magnitude higher than that of an anti-CD20, but that is the risk I would take for a chance of being in long-term remission and for the slim chance of a possible cure.

      1. Thanks for sharing Prof. Pleasant reading as an ocrelizumab patient but doesn’t help with the hokey cokey of whether to stay on this therapy or double down on HSCT. I know that you’re in the HSCT / Alemtuzumab camp and can see that these are the best available therapies at the moment. The difficulty for patients is that they are taking the risks of these IRT now in order to preserve the long term but then there is always that doubt that in 5 years say, a whole range of new drugs are going to be on the table that would complement an anti-CD20 whereas the risk takers could be left with secondary autoimmune / malignancy risk for their reward. It would be interesting to have your perspective on this, based on the drugs that are in the pipeline

      2. I second this question as I am in the same situation and have the same concerns. thanks 🙂

      3. I have a feeling it’s quite a few of us…

        Stay on Ocrelizumab (more viable with hoping ATA188 to be a option medium term), switch to cladribine or fight for alemtuzumab…

      4. There are no right or wrong answers or decisions. All we can do is provide you with the information, hopefully in an easy to understand format, to help you make a decision.

        There is little doubt that ocrelizumab is very effective and rendering pwMS NEDA-2, i.e. no relapses or focal MRI activity, and in the short- to intermediate-term NEDA-3 (no disability progression). It is not however top of the pile in terms of normalizing brain volume loss. It is clearly safer than those therapies that have a greater impact on BVL. The decision between these different treatments is not easy.

      5. “whereas the risk takers could be left with secondary autoimmune / malignancy risk for their reward.”

        Your trying to hard to find a way to deny hsct…the worst thing about it..is that about 20% fail treatment right away.

      6. Trying too hard to deny HSCT….Not sure I am denying HSCT, Are you trying too hard to promote it..it cuts both ways

      7. I included in my presentation on why I think anti-CD20 is not good enough to treat MS in the long term and why we need to think beyond NEDA. I presented data, mainly from ocrelizumab, that shows MS continues to smoulder away on ocrelizumab despite patients being NEDA

        Why you change your mind?

        Is that because you are the tbe first author off the paper?

      8. I haven’t changed my mind, read the comments. It depends on your treatment target. Most MSologists are happy with NEDA-2 or NEDA-3. In addition, my position on smouldering MS is a hypothesis; I don’t really know if IRTs really impact smouldering MS. The follow-up times for AHSCT and alemtuzumab cohorts are too short; they could still come back with SPMS at 15, 20 or 25 years. This is why I always prefix ‘cure’ with ‘a potential cure’.

      9. “they could still come back with SPMS at 15, 20 or 25 years. ”

        How..?

        If you are at a normal brain volume loss you will not turn spms. The first treated in 1999-2001 in San Diego and by Dr. Burt did not.
        Most failures were apparent in the first 5 years post treatment…They still got lesions and still had ms.

  4. Can I draw your attention to this information.
    In the first two years people are given beta interferon or ocrelizumab and then all are switched to ocrelizumab. As you can see there is space between the two lines at the end of the trial..meaning ocrelizumab is better than beta interferon. But importantly that space is largely maintained and so what is lost in those two years of beta interferon essentially stays lost.

    I hope the regulators take note when they approve controlled trials

    1. What is early? Ocrelizumab isn’t available on the NHS until a confirmed diagnosis of RRMS. Even then it’s not often prescribed as a 1st line. On the basis that MS is causing damage well before the first clinical symptoms that would suggest most people who receive any high efficacy treatment receive it very late.

      1. Things are, on the whole, improving, but it still takes far too long to confirm the diagnosis, and that time is potentially precious. As part of our strategy to overcome a lacklustre approach to DMT we will recruit from Jan/Feb 2022 to AttackMS, a trial of starting Natalizumab within 14 days of first symptoms (https://multiple-sclerosis-research.org/2019/05/the-natalizumab-attackms-trial/). Reason we are using natalizumab is it’s short half-life (in and out the system within a short time frame), with a beneficial risk profile in the short term, irrespective of your JCV status. This could then be followed by a B-cell depleting DMT once the diagnosis of MS is settled (AttackMS will include people with CIS as well as very early MS).

      2. It’s good to see trials looking at treatment from the earliest symptoms. But, it seems there is a lot that could be done for current pwMS using already available treatments if the escalation paradigm wasn’t so widely accepted.

        To ProfG’s comment below, the progression on Ocrelizumab was likely due to smouldering MS because they started Ocrelizumab too late. Currently most people are surely staring too late, setting in motion a progression to disability that can’t be treated. It seems pretty shocking that pwMS are not given the effective treatments despite them being available, particularly as this would surely be more cost-effective in the long-run

    1. Indeed they will fade, but will some of us be alive to see the fading?

      This 3rd primary dose for covid is like a fabled unicorn. Heard nothing from GP/neuro/NHS. Stories abound of medical staff telling patients the 3rd dose IS the booster/they’ve never heard of it/ the Green book—what’s that?/don’t believe everything you read on the internet/try 119/ring 111/contact GP/contact neuro/ try booking it on the website (which is for normal doses so won’t let you)

      as if life wasn’t hard enough as it is……………………………

  5. Very impressive, 82% of people with no disability progression and less than 10% ARR.

    What’s the main cause of require a walking aid or wheelchair? Relapse of the spinal cord, fatigue or brain volume loss?

    1. More likely too late onto ocrelizumab and hence smouldering MS is the culprit. It is unlikely not to be due to ocrelizumab not doing its job (suppressing relapses and focal MRI activity).

      1. From the charts, it looks like disability progression was faster in the interferon group but then slowed to match the Ocrelizumab group after they switched, with the gap remaining throughout the trial.

        Does that mean that ‘early’ treatment is treatment before sustained disability rather than time from diagnosis? Or do those who received Ocrelizumab later progress faster regardless?

      2. Yes the slopes changed because the treatment did that but the extra disability sustained during the interferon was never recovered

      3. to MD, I get the gist you and Prof G wants to pass on and I fully agree. But the graphs on Ocr and Alem are both % patients, so the people progressed would always be excluded, the fact the gap is maintained/narrowing is actually telling no difference after moving onto a higher efficacy (same additonal number progressed). I know on the average EDSS graph the additional points would never recover. Also it bothers me that researchers always communicate at DMTs at a group’s level, where the results can be sub-divided by known factors to tell a more detailed story?

  6. Interesting! As I wrote in another post, I am in full decision to switch: alemtuzumab or ocrelizumab?
    I try to explain myself, but I’m Italian so forgive my English.
    I’m a woman and I had my diagnosis of RRMS in 2018 with norb (light and largely solved vision problem). Negative rachicentesis and some small lesions, no spinal cord but “only” at the level of the brain. My EDSS was, and still is, equal to 1.

    I started with Tecfidera, but after a year and a half my 3 MRIs showed new lesions, some active. So I switch with Fingolimod.
    After a year of Fingolimod and 2 still not clean resonances, with 3 new lesions, one of which is active. (My lesions are localized on the left periventricular region, the new active lesion is in the right periventricular area and dull lesions are at the level of the corpus callosum in the right frontal site.)

    So here I am now, at 34, with a new therapy change.
    My neurologist first proposed Lemtrada to me as the most effective therapy in my case and considering the change from Fingolimod. Then, given my fear of serious side effects and my doubts (will they be right?), She proposed me as a safer alternative (but will it be just as effective?).
    From this article I read that switching from Fingolimod can have problems for both Alemtuzumab and Ocrelizumab. Is it right?

    Beyond the problems related to switching, I struggle to choose … I wouldn’t want to miss the opportunity to make a super effective drug like Lemtrada now that I’m fine, but I don’t know if the risks are actually there.

    I am reading your articles to get an idea but it is not easy…
    I don’t know if you can give me information that will help me clarify my ideas.

    1. Switching from fingo to siponimod first for a month for shorter half life and no need to wait in between, then wait 2 weeks to start Alem could be an option?

      Switching from fingo to OCR would be less of a problem, stay off the drug for 1-2 weeks and start the first half dose of OCR, and by the second half dose the trafficking effect should warn off.

      I’m just a patient so please someone from the blog could comment….

  7. Prof G,

    I’m grateful to you and Team G for all the work you undertake. Thanks to Team G and other MSologists we now have a range of drugs to address focal inflammation / relapses: Alemtuzumab, Cladribine, Natalizumab and the anti-CD20 therapies.

    However, I suspect that many MSers who receive these therapies will not end up progression free ie they will still accumulate disability because either:

    – the therapies were started too late (allowing smouldering MS to kick off) or

    – smouldering MS was there at the outset and focal inflammation/ relapses are just a response.

    Should all MS research teams now be shifting away from the success of therapies which address focal inflammation ie we have highly effective therapies.

    Where are we with add-on therapies to tackle smouldering MS / progression?

    When you have time, could you do a quick post on BTK inhibitors. Professor Hauser thinks they could be the answer to the “other half” of MS = progression.

  8. Patient 20 years post diagnosis here. Many years on copaxone as interferons elevated my LFTs. Switched to Ocrevus a few years back related to progression and MRI activity. No new MRI signal since starting Ocrevus. This said, I of course have smoldering MS. You mention add on therapies to damp down the smouldering MS.

    I have read on your blog that there have been no add on therapies studied in conjunction with Ocrevus. DO I have that correct? I am in the US and I cannot imagine our private insurance system/ employer sponsored care allowing/approving two incredibly expensive treatments to be used concurrently. Is Ocrevus with add on treatments being used anywhere?

    1. “This said, I of course have smoldering MS. You mention add on therapies to damp down the smouldering MS.”

      The only add on therapy is hsct.
      It really does stop many people’s spms progression..

      1. HSCT is a sledge hammer, not an addon therapy in any sense.

        Now mind you there are uses for sledge hammers…

  9. I am looking for the comparison data on the efficacy between alemtuzumab and ocrelizumab. Are there any articles where I can find them?
    Thanks

  10. If ocrelizumab is the game-changer it needs to demonstrate that it is impacting on the various aspects of MS – focal inflammation / relapses which are driven by the peripheral immune system and progression which is driven by the immune system in the CNS / B cells resident in the CNS. It has demonstrated high efficacy in the former (as have many highly effective DMTs) but I’ve seen no evidence of efficacy against the latter. A game-changer needs to do more than just address relapses.

    1. It is a game-changer because it has resulted in the MS community flipping the pyramid, i.e. using high-efficacy therapies first-line. Before ocrelizumab, most people were put on a low efficacy platform therapy and only escalated to a high efficacy therapy later.

      1. A game-changer for a patient is a treatment which stops progression / accumulating disability (for good). For too long MS researchers / pharma have defined what MSers want / need ie reduction in relapses rather than what MSers want ie no walking aid, no wheelchair, normal expectancy (not an 8-10 year reduction compared to the average). These are metrics which should be used to test the efficacy of treatments rather than the number of relapses / lesions. The tail has been wagging the dog for too long!

      2. While I agree, that’s closer to the holy grail than a game changer 🙂

        While I do not really like the relapse focus either, the issue is what are good end points? Confirmed disability worsening could be but are even harder to objectively measure than relapses… (lesions are convenient in that regard)

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