Roche is the first company to publish their data on how patients with MS are doing with COVID-19 who are being treated with ocrelizumab. Please note the data is on the first 100 cases that have been reported to Roche via their adverse event (AE) reporting mechanisms. Twenty-six of the cases have been reported as being severe with 5 being critical (see table below). These figures are pretty much in line with what happens in the general population in relation to COVID-19 outcomes with a similar proportion of severe and critical cases. The one caveat is that ocrelizumab-treated patients may be younger and have fewer comorbidities than the general population.
Some of my colleagues have accused Roche of hiding data and selective reporting. Why would they do that? Pharma’s pharmacovigilance systems are transparent and open to audit by the regulators. It is not in Roche’s interests to not be open and frank about their data. At the end of the day, the data is what it is and we need to use it to help us make decisions about treatment.
I agree the data is full of warts and open to interpretation. It is likely to be biased in that clinicians are more likely to report hospitalised and severe cases as AEs and miss the milder cases. For example, I have collected 9 patients who have likely had COVID-19 over the last 8-10 weeks. Only one of these nine patients was admitted to a hospital with moderate COVID-19. In this case, the COVID-19 syndrome was confirmed on chest x-ray and other clinical features and her nasopharyngeal swab was positive for SARS-CoV-2. She was fortunately discharged after 4 days well and didn’t need any ventilatory support. The other 8 patients with MS all self-isolated and recovered at home and had no swabs taken. Only the admitted patient is part of the UK’s official figures the other 8 cases are not. Patients with COVID-19 who have mild disease, who don’t come to the hospital to get swabbed don’t get counted in the official figures. The same phenomenon is almost certainly happening with ocrelizumab and our other DMTs. Mild cases are not getting swabbed, diagnosed and reported. I, therefore, suspect that the Roche data represents the worse end of the spectrum.
Overall the Roche data is in keeping with the Italian, French and other registry data that people with MS on ocrelizumab don’t appear to be at higher risk of getting severe COVID-19. This also needs to be interpreted in the context of the immunology of COVID-19 and SARS-CoV-2. It looks as if innate immunity (monocytes and macrophages) and T-cells, in particular CD8+ T-cells, are the most important lines of defence against SARS-CoV-2. The fact that two patients with X-linked agammaglobulinaemia recovered from COVID-19 and that anti-CD20 treated patients with no B-cells in the peripheral blood are recovering from COVID-19 tells you that B-cells are not essential for the antiviral response. The latter is also in keeping with the trial data that patients on B-cell depleting therapies don’t seem to have a problem dealing with viral infections.
Could there be an upside to B-cell depletion? Yes, I suspect there may be. As the humoral or antibody response emerges antibody-mediated damage to lung with complement activation may be responsible for some of the delayed tissue damage that occurs in COVID-19. This is why it will be important to get more data and better-defined comparator groups to see if anti-CD20 therapy treated patients may be doing better than expected. The recently presented Swedish data suggests not. However, the Swedish data is on rituximab, and not ocrelizumab, and the rituximab doses used in Sweden may not be high enough to block antibody responses to SARS-CoV-2 and hence the data can’t simply be extrapolated to ocrelizumab or vice versa. For those of you who don’t know ocrelizumab is a much more potent B-cell depleter than rituximab.
Now, what about vaccine readiness? Are people on ocrelizumab less likely to develop an antibody response after COVID-19 and if they do is the antibody response good quality, i.e. capable of neutralizing the virus and preventing reinfection? We are in the process of validating an ultrasensitive assay and doing an antibody study to answer this question. So watch this space.
Even if antibody responses to SARS-CoV-2 are blunted in ocrelizumabers, who have had COVID-19, this doesn’t mean they are not immune to reinfection. Cellular responses are likely to be sufficient to prevent reinfection. The latter has been shown to occur with the measles virus.
Vaccine readiness may become a real issue if a vaccine for SARS-CoV-2 emerges. However, I suggest crossing that bridge when we get there. With anti-CD20 therapies, all you will have to do is miss a dose or two, wait for naive B-cell reconstitution and then have the vaccine. We have very good data that after 3 or 4 courses of ocrelizumab missing infusions for the next 12-18 months is unlikely to affect MS disease activity. The latter observation is why we are still planning to do an adaptive-dosing study in the UK (ADIOS Study).
I personally want to congratulate and thank Roche for putting their data into the public domain so rapidly. I have asked other Pharmaceutical companies to do the same. Having access to this data alongside other real-life data sets is what we and others are using to adjust treatment guidelines and is why we as an MS treatment centre are starting and redosing patients with MS with ocrelizumab. At last, we can say our practice is evidence-based rather than opinion-based.
Hughes et al. COVID-19 in persons with multiple sclerosis treated with ocrelizumab – a pharmacovigilance case series. MSARDs Available online 16 May 2020, 102192.
CoI: Multiple. Importantly I am a steering committee member on the ocrelizumab phase 3 development programme and I am PI on the ORATORIO-HAND study of ocrelizumab in PPMS.
Good news (as far as it goes these days!) – thanks for sharing 🙂
Thank you Prof G. So you would still advise ocrelizumabers (like that term!) that shielding is not necessary if otherwise fit and well, and that our children can go back to school?
It is helpful to understand the difference between Rituximab and ocrelizumab.
Will the effect last in people who have had two halves and one full dose?
Re: “Will the effect last in people who have had two halves and one full dose?”
Not sure. I would suggest going ahead with the next dose at least. The vaccine will not be here for some time.
Re: “So you would still advise ocrelizumabers (like that term!) that shielding is not necessary if otherwise fit and well, and that our children can go back to school?”
Yes, provided there are no other factors, for example, comorbidities, etc. Life has to get back to normal at some stage; you can’t with for the COVID-19 risk to disappear, which will take years.
Re: “It is helpful to understand the difference between Rituximab and ocrelizumab.”
Most people treat rituximab and ocrelizumab as being the same treatment, however, there are major differences between the two of them. I personally don’t think we know what the right dose of rituximab is for treating MS. We base all our decisions on relapses and focal MRI activity and that is not what MS is. MS is the end-organ damage that we measure with brain volume and grey matter atrophy, physical and cognitive disability progression, etc. When you look at these latter metrics you begin to realise that anti-CD20 therapies are not good enough. We, therefore, need additional add-on treatments to tackle the real MS.
Prof G,
“We, therefore, need additional add-on treatments to tackle the real MS”.
You and others have been saying this for the last 10-15 years. Why does nothing change ie why are there still no add on treatments? Is there anything in the current pipeline which looks promising and could become an add-on treatment or are we still in the realm of science fiction?
Complete inertia on behalf of pharma, still nursing their wounds after their stroke neuroprotectants went nowhere. Scientifically, it hasn’t been for the want of trying “Rex”.
“MS is the end-organ damage that we measure with brain volume and grey matter atrophy, physical and cognitive disability progression, etc. When you look at these latter metrics you begin to realise that anti-CD20 therapies are not good enough”
Why do you sit on the steering committee of the ocrelizumab phase 3 development programme When you know this expensive drug isn’t addressing the real MS? Are you involved in the development of any drugs that are seeking to address the real MS?
We desperately need a treatment for multiple personality disorder too 😉
I’m just a person with MS frustrated with the slow progress regarding treatments that really stop this wretched disease. Thanks for responding to my questions.
Believe me, as part of a group that has focussed on neuroprotection for many years, knowing that just tackling the immune arm of MS isn’t the sole answer, believe me I’m as frustrated as you are. To describe the pace as glacial, doesn’t come close and I suspect I may well be retied before this changes.
Very sad.
My questions are all relevant. I use different names as I don’t want to use my own name (privacy issue).
Prof G, do you mean that Ocreluzimab should be given to only those PPMS patients who have activity confirmed by either MRI or relapse? Can I find a writing from you which explains how Ocrelizumab works in PPMS, what the risks and benefits associated with taking Ocrelizumab in different PPMS subgroups, which patients with PPMS should consider taking Ocrelizumab, etc.? I am sure it would interest many patients as approvals, recommendations and limitations made by regulatory authorities vary country by country. I greatly respect your work and knowledge on the subject, therefore I would really value and appreciate your answer.
MS amidst the CoVID19 pandemic is probably a low key event and perhaps the pandemic does not increase or worsen outcomes, as compared to the general population. Use of DMTs in MS amidst the pandemic is the larger issue and even that probably causes a minimal effect, if that. All the published literature (at breakneck speed) attests to that.
On the question of pharmacovigilance, as far as I know in the US of A, companies need NOT give out their datasets (or we would have no worries) and they absolutely do NOT. Perhaps the Barts London Medical School has a different approach or vice-versa, may be the companies furnish the data. In the USA, only a select few ‘researchers’ or folks with connections (old boys’ network) do get these results but for the rest of ordinary blokes (talking about myself now), no data bases are out there that I can dig into. I would love to, and there are nuggets of information hidden in those data bases, but I know of none that is out there in the public domain. Companies ought to be regulated enough to have laws on the books asking them to furnish data available to the public so that even a computational biologist or a math-driven data scientist unconnected to the subject can look at the data sets. After all, once de-identified, what is the problem ? Therein lies the secret. They will NOT divulge information.
Thanks Prof G. Good news for COVID 19 patients. Too bad CD20 therapies are not as effective in treating MS leading to disease breakthrough from smouldering ms. Shouldn’t lemtrada be studied given its the most effective in treating ms and closest thing we have to cure for MS? Also why does diabetes make COVID 19 severe? Or is that a red herring? Given BAME are more susceptible to COVID 19 and most BAME happen to have diabetes as pre existing condition. Also if you notice all patients shown in tv footage dying not only happen to be obese but also lack muscle mass. Why aren’t body builders dying from COVID 19?
I’m highly cynical when it comes to the word pharma and transparency
Ya, you are right when profit comes into play, nevertheless Big Pharma helps more than they hurt, without the drugs many would die quick. More fun/life thru pharmaceuticals I say. Cannabis is about to big Pharma/big Corporate, Lord help us all. The whole country will be Singing “Shot by the Sheriff”. LOL.
Thanks Prof G, I’m really no medical expert so apologies if the questions are answered above. I’m 18 months since diagnosed and had 2x half doses and 2x full doses of Ocrelizumab, last dose in January.
From reading your blog am I correct in saying you’d recommend missing the next couple of treatments in order to then have the COVID vaccine and in fact, if I was to have it in September say, it wouldn’t work?
Also, if we’ve had COVID would we test negative for antibodies if we’re not able to make them for COVID because of the Meds?
Apologies for my lack of medical knowledge! #facepalm
No point missing any thing because at the moment there is not vaccine. It is a theorectical possibility that you will not make an adequate anti viral response therefore in the future you could halt the treatment to allow your B cells to recover to make the anti-vaccine response. However, we will find out soon enough. We have no heard of over 150 people taking anit-CD20 and we will be able to see what happens, lets seen if this is stopped I have seen a report from spain where a person made an anticovid response
You shouldn’t plan something that doesn’t exist, a vaccine may be found, but will the vaccine work as planned. The Flu shot can’t match up, ever. Many questions with no answers, live your life, don’t worry about variables you can’t control.
Prof G I discovered your blog today, I need to brush up on immunology. But Damm, you are so transparent, it is refreshing. Why isn’t HSCT available in the USA? My Dr said not til 2024, maybe.
First positive vaccine data from China already
Very interesting! When do you think we will see ABN DMT guidance updated to reflect what we are increasingly finding out? April 2nd was quite a while ago…. an understandably conservative stance at the time but surely time to rethink and stop denying patients effective treatment?
Thank you Prof G and Roche this information is incredibly helpful. May I ask if you are a Reception teacher taking Ocreluzumab would you consider the risks to be low enough to return to teaching? I have been given a shielding letter from my neurologist (I am otherwise healthy, last full dose 5th March, letter sent to all patients on Ocrelizumab) but I am desperate to get back work if it is considered the risks make me no more likely to get severe COVID than the general population.
The important risk factors for the population are age and co-morbitities and for MS more disabilitiy which probably equates to more co-morbiditities