ofatumumab – Prof G's MS Blog Archive

Clash of the Titans: the HILO study

Barts-MS rose-tinted-odometer: ★★★ (I am seeing blue and Spanish yellow today)
Roche blue (#0066CC) & Novartis Spanish Yellow (#F7B516)

Yes, I really do think that intrathecal (within the meninges that cover the brain and spinal cord) or CNS resident B-cells and plasma cells are pathogenic in MS. In other words, the cytokine or chemicals B-cells and plasma cells produce, in particular their antibodies, are what is driving some of the pathologies of smouldering MS. The evidence to support this hypothesis is well rehearsed on this blog and is the reason why we are testing high-dose ocrelizumab (more CNS penetrant) vs. standard-dose ocrelizumab (less CNS penetrant) against each other in two head-2-head studies. It is also the reason we are testing cladribine’s (CLADRIPLAS and CLAD-B) and ixazomib’s (SIZOMUS) effects in intrathecal B and plasma cell markers. Yes, I really do think we need to scrub the CNS clean of B-cells, plasma cells and their products, in particular the oligoclonal IgG bands.

I am therefore proposing a new study; the HIgh-dose versus LOw-dose anti-CD20 study or HILO Study.

In this study, I propose testing high-dose or double-dose ocrelizumab vs. standard or intermediate-dose ocrelizumab vs. low-dose ofatumumab against each other over two years and measure their impact on end-organ damage markers (slowly expanding lesions and brain volume loss) and on CSF markers of B-cell, plasma cell and microglial activity. The latter will include free kappa and lambda immunoglobulin light chains, OCBs, soluble CD14, etc. This will answer at least from a biomarker question whether or not we need CNS penetration of anti-CD20 monoclonal antibodies to target this component of smouldering MS. The following would also answer the question of whether or not you as a person with MS would want to be treated with high-dose or low-dose anti-CD20 therapy?

Would you want to be randomised into this study?

This study would be a clash of the titans; Roche vs. Novartis. Who would win? It really is not that important as Novartis is a major shareholder in Roche and hence when Roche makes a profit so does Novartis. The real winners will be people with MS, the data will allow them to make an informed decision about whether or not they want to go beyond NEIDA (no evident inflammatory disease activity) and be on a treatment that tackles the smouldering B-cell and plasma-cell driven processes within their brains and spinal cords.

SHOULD WE DO THE HILO STUDY?

Conflicts of Interest

MS-Selfie Newsletter / MS-Selfie Microsite

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.

How many ofatumumab doses should I miss?

Barts-MS rose-tinted-odometer: ★★★ (It feels like a sky blue rainy Friday = #87ceeb)

“Prof G how many of my monthly ofatumumab injections should I miss to guarantee that I will have an adequate antibody response to the COVID-19 vaccine?”

This was the gist of one of the direct messages I received on Twitter from a person with MS living in the US.

I really don’t know. However, I have tried extrapolating data from the repopulation kinetics of ofatumumab given 3-monthly and the modelling data below on ocrelizumab and rituximab. For ocrelizumab and rituximab to have 80% confidence it requires at least 9 months from the last infusion to the first vaccination to have a >50% chance of seroconversion in response to an RNA-based COVID-19 vaccine. This equates to missing close to one dose of ocrelizumab or rituximab as you have to wait 9 months then have two vaccine doses and wait 3-4 weeks after your second or booster dose of vaccine before recommencing your 6-monthly infusions. i.e. ~11 months after your last infusion. Although Mike Famulare has treated rituximab and ocrelizumab as being equipotent in his modelling I suspect he is wrong and the gap for ocrelizumab may in fact have to be substantially longer. I predict that the average person will need to wait about 11-12 months post their last infusion of ocrelizumab to be confident of an antibody response.

As ofatumumab, is a lower dose anti-CD20, with more rapid B-cell repopulation kinetics than ocrelizumab or rituximab (see figure below). I estimate that you will need to wait about 6 months from your last injection before being vaccinated and you would then have two vaccine doses and wait 3-4 weeks after your second or booster dose of vaccine before recommending your monthly injections. i.e. ~8 months later. As this is all based on modelling I suspect in real life you will simply need to wait for peripheral blood B-cell reconstitution to occur before being vaccinated. The problem with the latter is how high do your peripheral B-cells have to be before being vaccinated; more than 3, 5, 10, 20, 50 or 80 CD19+ B-cells per mm3? Clearly, this is something that needs further study and I would urge Pharma or one of the MS groups interested in answering this question to do the study. Let’s call it the ‘Peripheral B-cell Threshold Vaccine Study‘ or the ‘PerBeC Vax Study‘.

I want to reiterate that vaccine immunity is not only about B-cell and antibody immunity, T-cells also have an important role to play. Granted that if you don’t make antibodies it indicates that your follicular T-helper cells memory may not be that great, but this does not tell you about other CD4+ and CD8+ T-cell memory responses. Therefore, please be patient until these data emerge.

My message remains the same; #GetVaccinatedASAP. During this phase of the pandemic, some immunity is better than no immunity. The risk associated with getting COVID-19, particularly if you are on a B-cell depleting agent, far outweighs the risks associated with vaccination.

Seroconversion rate following complete COVID-19 vaccination vs. time since most recent b-cell depleting therapy (BCDT). Best fit, 80%, and 95% confidence interval shows logistic regresssion model of seroconversion probability over time.

Mike Famulare. Seroconversion after COVID-19 vaccination in patients using B-cell depleting therapies to manage multiple sclerosis increases with time between treatment and vaccination. Github v0.2 03 June 2021.

B-cell depleting therapies (BCDT) such as ocrelizumab and rituximab used for the management of multiple sclerosis are associated with reduced seroconversion rates following COVID-19 vaccination. In this note, I reanalyze data from the literature to examine how the probability of seroconversion depends on the time interval between the last BCDT dose and the first vaccine dose. While uncertainty is high due to limited data, the results show that the seroconversion probability increases with time. Under a Bayesian interpretation of logistic regression, I estimate with 80% confidence that it requires at least 9 months from last BCDT to first vaccination to have a >50% chance of seroconversion following complete mRNA vaccination, with large uncertainty on when higher confidence of seroconversion can be expected. Among subjects who do seroconvert following vaccination, anti-Spike IgG levels correlate with time since last BCDT. Limited data indicate that levels comparable with immunocompetent response can be achieved with intervals of 12 or more months between BCDT and vaccination. With combined data from multiple sources, I argue that time development of the seroconversion probability and antibody response parallels that of CD19+ and naive B-cell repopulation following BCDT, suggesting that monitoring B-cell repopulation will be useful at the individual level for optimizing vaccine response while maintaining adequate MS control.

Pharmacodynamic response showing dose-response depletion of CD19 B cells and repletion kinetics (safety population). The median time to repletion based on Kaplan-Meier estimates was ≈11 months for the ofatumumab 3 and 30 mg every 12 weeks groups and ≈14 months for the ofatumumab 60 mg every 12 and 4 weeks groups.

Bar-Or et al.Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: The MIRROR study. Neurology. 2018 Sep 11;91(11):538.

Objective: To assess dose-response effects of the anti-CD20 monoclonal antibody ofatumumab on efficacy and safety outcomes in a phase 2b double-blind study of relapsing forms of multiple sclerosis (RMS).

Methods: Patients (n = 232) were randomized to ofatumumab 3, 30, or 60 mg every 12 weeks, ofatumumab 60 mg every 4 weeks, or placebo for a 24-week treatment period, with a primary endpoint of cumulative number of new gadolinium-enhancing lesions (per brain MRI) at week 12. Relapses and safety/tolerability were assessed, and CD19+ peripheral blood B-lymphocyte counts measured. Safety monitoring continued weeks 24 to 48 with subsequent individualized follow-up evaluating B-cell repletion.

Results: The cumulative number of new lesions was reduced by 65% for all ofatumumab dose groups vs placebo (p < 0.001). Post hoc analysis (excluding weeks 1-4) estimated a ≥90% lesion reduction vs placebo (week 12) for all cumulative ofatumumab doses ≥30 mg/12 wk. Dose-dependent CD19 B-cell depletion was observed. Notably, complete depletion was not necessary for a robust treatment effect. The most common adverse event was injection-related reactions (52% ofatumumab, 15% placebo), mild to moderate severity in 97%, most commonly associated with the first dose and diminishing on subsequent dosing.

Conclusion: Imaging showed that all subcutaneous ofatumumab doses demonstrated efficacy (most robust: cumulative doses ≥30 mg/12 wk), with a safety profile consistent with existing ofatumumab data. This treatment effect also occurred with dosage regimens that only partially depleted circulating B cells.

Classification of evidence: This study provides Class I evidence that for patients with RMS, ofatumumab decreases the number of new MRI gadolinium-enhancing lesions 12 weeks after treatment initiation.

Trial registration: ClinicalTrials.gov NCT01457924.

Conflicts of Interest

Preventive Neurology

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Medium

Anti-CD20 vs. Teriflunomide

Barts-MS rose-tinted-odometer: ★★ (seeing blue)

When I state that the real MS is smouldering MS and that relapses and focal MRI activity are not the disease I really mean it.

PwMS who are NEDA-2, without relapses and with no new MRI lesions, but getting worse must have something going on in their brains and spinal cords. This is why we need to go beyond NEIDA (no evidence of inflammatory disease activity) as a treatment target in MS and focus on protecting the end-organ so that pwMS can have enough reserve to cope with normal ageing when they get older.

One example or ugly fact to illustrate the disconnect between inflammation (relapses and focal MRI activity) and the end-organ (brain volume loss) is the recent ofatumumab vs. teriflunomide trials.

Gd-enhancing lesions (↓~95%): Ofatumumab >>>> teriflunomide

New T-2 lesions (↓~83%): Ofatumumab >>> teriflunomide

Relapses (↓~55%): Ofatumumab >> teriflunomide

Disability progression (↓~33%): Ofatumumab > teriflunomide

Brain volume loss (↓~0%): Ofatumumab = teriflunomide

If ofatumumab is so much more effective as an anti-inflammatory than teriflunomide why doesn’t it protect the end-organ more than teriflunomide? I don’t know but is clear, at least to me, that there is something else going on that is driving the end-organ damage in MS that is not linked to focal inflammation. Could something about teriflunomide’s mode of action that is downstream of focal inflammation be telling us something fundamental about the cause of MS?

Conflicts of Interest

Preventive Neurology

Twitter

Medium

Swiss Neurologists Challenge Lublin

Barts-MS rose-tinted-odometer: ★

I have just been chastised by someone from a Swiss Pharma company for suggesting that siponimod is a cul-de-sac DMT. Why can’t someone who is diagnosed and labelled as having SPMS who is started on siponimod be switched to any other DMT? I agree, but the absurdity of the situation arises because of the rigidity of the Lublin classification of MS (see below) and the salami-slicing of MS into multiple disease entities.

The cul-de-sac is based on the assumption that once you have progressive MS, either primary progressive or secondary progressive MS, you can’t become unprogressive and be subsequently re-diagnosed as having relapsing-remitting MS. This is explicit in the Lublin classification system that defines the clinical course of MS. According to Lublin progressive MS is a one-way street.

The reason we find ourselves in this ridiculous situation is that MS was salami-sliced up into three and four diseases in the 1990s to allow interferon-beta to get licensed under the US Orphan Drug Act. The Orphan Drug Act states that to be an orphan disease there have to be fewer than 200,000 US citizens with the disease. There are clearly more than 200,000 people with MS in the US, but there were less than 200,000 people with relapsing-remitting MS, secondary progressive MS or primary progressive MS in the 1990s. Subsequently, a fourth category was added to the classification system of clinically-isolated syndrome (CIS). Fortunately, CIS is gradually disappearing as the McDonald criteria are gradually nibbling away at this pseudo-category of MS.

Few people are aware of the history of MS becoming four diseases, but the consequences of this to the field have been enormous. For one it means that Pharma has had to do trials in all four ‘pseudo-MS disease states’ at great expense to the field. It has had major psychological effects on people with the disease. When you tell people they have SPMS it is like telling them they have a second disease that until recently was unmodifiable.

The other consequence of MS being three or four diseases is that once you have been diagnosed as having SPMS we are mandated under NHS England guidelines to stop DMTs. This is why most neurologists in the UK avoid labelling their patients as having SPMS.

The Lublin classification system is based on a clinico-radiological worldview of MS and is not underpinned by biology. If you take a biological worldview of MS, which is the correct philosophy based on our current thinking of what constitutes a disease, then MS is one disease and not three or four diseases.

Interestingly, I have been asked by the CONY Virtual Conference organisers to give a keynote plenary lecture on this exact topic, which I recorded yesterday.

The good news is that this Pharma Executive tells me that the Swiss Neurologists have decided that the Lublin classification system is incorrect and that according to the Swiss it will be fine to reverse out of the secondary-progressive cul de sac and to relabel their patients as having relapsing MS and to be able to switch their patients from siponimod to ofatumumab once it is licensed in Switzerland. I sincerely hope the Swiss neurologists publish their new classification system of MS, or MS roadmap, as the Lublin one is out-of-date. More importantly, will the Swiss neurologists be prepared to convince the NHS of their wisdom?

Lublin et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 2014 Jul 15;83(3):278-86.

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

Anti-CD20 Derisk Study

Barts-MS rose-tinted-odometer: ★★★★★

Did you watch the anti-CD20 debate on the triMS-online platform yesterday? The question that was asked was ‘Can we use anti-CD20 therapies as immune reconstitution therapies rather than maintenance therapies?’. I am not sure the debaters answered the question.

When I asked Anders Svenningsson, who is probably the world’s biggest adopter of anti-CD20 therapy as a treatment for MS, whether or not someone with MS could stay on anti-CD20 for life, he hesitated before saying ‘YES and NO’. His reason? SAFETY. He described things they were doing to try and reduce the risk of hypogammaglobulinaemia and infections in their patients on longterm anti-CD20 therapy. I am not sure it will work. Interestingly, he suggested stopping anti-CD20 therapy when pwMS get to 55-60 years of age when the risks of treatment outweigh the benefits. In other words, Anders Svenningsson is saying we can’t leave pwMS on anti-CD20 lifelong.

I have been making this exact point on this blog for several years and that is why I have proposed the ADIOS and iTeri studies as ways to derisk long-term anti-CD20 therapies. However, I have been thinking are there any other DMTs we could use after anti-CD20 that would potentially work to derisk the hypogammaglobulinaemia and tackle the cause of MS. I suspect yes. Fumarates, as monotherapy, or in combination with a neuroprotective therapy, also makes sense. The difficulty is what will be the primary outcome of such a trial and how would you do power calculations?

Maybe we could use a non-inferiority design and make safety the primary outcome. Would regulators buy that in addition to non-inferiority as a secondary outcome?

There are not many companies who have the resources, motivation and know-how to do such a study. Roche-Genentech and Novartis would not as this would eat into their franchise. In my opinion, the only company with big enough bollocks and know-how to take this on would be Biogen. Would they be interested?

This is potentially an opportunity for them to come up with a new combination pill of one of their fumarate formulations with an add-on neuroprotective. DMF will maintain MS in remission post-anti-CD20 and the neuroprotective will tackle smouldering MS, which is something anti-CD20 therapies don’t do. A fumarate-neuroprotection combination may actually not only show improved safety but superiority on end-organ damage markers (brain volume loss etc.).

The hypothesis is that if B-cells and in particular memory B-cells are driving MS then starting DMF for example before memory B-cell reconstitution occurs may actually make MS more responsive to fumarates. Add in a combination, to generate new intellectual property (Biogen need this as their fumarate patents are being challenged) and you have a new DMT.

If successful this new combination pill will probably become the most prescribed DMT in MS. Why? To quote Anders Svenningsson you can’t really remain on anti-CD20 lifelong so if you have to derisk an anti-CD20 at some stage. So why not do it before you develop hypogammaglobulinaemia? As more than 50% of MS patients will be treated with anti-CD20 therapy in the near future this combination therapy could potentially capture more than 50% of the market.

If you are on an anti-CD20 therapy (ocrelizumab, rituximab or ofatumumab) would you volunteer to participate in the DERISK study below?

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

#MSCOVID19: good news

Barts-MS rose-tinted-odometer: ★★★★★

The late late-breaking session at the MSVirtual2020 meeting, which covered COVID-19 has already received a lot of air-time on social media. The big-data alliance confirmed the Italian data, i.e. that people with MS (pwMS) on anti-CD20 are at higher risk of getting COVID-19 and severe COVID-19 (hospitalisation, intensive care admission and/or ventilation) compared to pwMS on dimethyl fumarate. Importantly there was no mortality signal, i.e. pwMS on anti-CD20 don’t appear to be at higher risk of dying from COVID-19 and its complications. This is very good news!

1540 #MS patients with #COVID19. Treatment with B-cell depleting medications #rituximab & #ocrelizumab associated with higher rates of ICU admission, but not increased risk of death. @MSIntFederation #MSVirtual2020 @MustStopMS @MSViewsandNews @AaronBosterMD @shiftms #MSCOVID19 pic.twitter.com/sM0ukc2Hku
— Barry Singer, M.D. (@drbarrysinger) September 26, 2020

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However, the Big-Data alliance couldn’t confirm what the Italians have shown that treatment duration on an anti-CD20 is a risk factor. A clue to the latter is the observation that the COVID-19 risk was higher with rituximab compared to ocrelizumab in the Big-Data alliances graphs. As it is likely that rituximab-treated pwMS have been on treatment longer than ocrelizumab-treated patients would support this. Ocrelizumab has only recently been licensed and hence most people on ocrelizumab are likely to have been on it for a shorter period of time compared to rituximab-treated patients.

Is all this good news? Yes, very good news.

It clearly shows that people on anti-CD20 therapy have the ability to mount a robust immune response and recover from coronavirus infections, despite having a reduced B-cell and antibody response. This means that innate immunity and adaptive cellular immune responses are all that is required to recover from coronavirus and other viral infections. It will be important to study how robust the T-cell memory responses are post-COVID-19 in these patients as this will have implications for studying vaccine response when vaccines arise. What this means is that even if pwMS on an anti-CD20 don’t make an antibody response to a SARS-CoV-2 vaccine they may still have protective cellular immunity. This will also be good news. I sincerely hope Roche-Genentech and Novartis are planning to study vaccine responses in ocrelizumab- and ofatumumab-treated patients when the vaccines arrive.

The observation that the longer you have been on an anti-CD20 the greater your chances of getting COVID-19 and severe COVID-19 implies the risk may be related to hypogammaglobulinaemia and blunting of past cross-reactive immunity from being exposed to other circulating community-acquired coronaviruses. I illustrate this in the following slide. In short pwMS on anti-CD20 therapy are shifted to the right and are less likely to have asymptomatic infections and more likely to have severe infections.

This cross-reactive immunity to other coronaviruses may be the silver lining to the ominous grey clouds that have been hanging over us for months. It seems that between 40-60% of people in the general population have T-cell responses to SARS-CoV-2 without a history of having had COVID-19 and without an anti-SARS-CoV-2 antibody response. It now seems that these cellular memory responses protect these individuals from getting COVID-19. If this proves to be the case then herd immunity might be much higher than we realise and this could explain why the second surge in places like London and New York are much lower than other places that had smaller peaks during the initial wave of COVID0-19.

If this background cross-reactive coronavirus immunity hypothesis, backed by the observations we see in pwMS on anti-CD20 therapy, turns out to be true we may have already reached herd immunity in London and are not far off it in other areas of the country. New models by Gomes and colleagues, at the University of Strathclyde, and Lourenco and colleagues, at the University of Oxford, suggest herd immunity may occur at levels of exposure of 20% or lower. If this is the case then we will see it first in London. So please watch the London COVID-19 numbers if they stay low this will be very good news.

Gomes et al. Individual variation in susceptibility or exposure to SARS-CoV-2 lowers the herd immunity threshold. MedRxIV doi: https://doi.org/10.1101/2020.04.27.20081893

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads, the susceptible subpopulation is depleted causing the incidence of new cases to decline. Variation in individual susceptibility or exposure to infection exacerbates this effect. Individuals that are more susceptible or more exposed tend to be infected earlier, depleting the susceptible subpopulation of those who are at higher risk of infection. This selective depletion of susceptibles intensifies the deceleration in incidence. Eventually, susceptible numbers become low enough to prevent epidemic growth or, in other words, the herd immunity threshold (HIT) is reached. Although estimates vary, simple calculations suggest that herd immunity to SARS-CoV-2 requires 60-70% of the population to be immune. By fitting epidemiological models that allow for heterogeneity to SARS-CoV-2 outbreaks across the globe, we show that variation in susceptibility or exposure to infection reduces these estimates. Accurate measurements of heterogeneity are therefore of paramount importance in controlling the COVID-19 pandemic.

Lourenco et al. The impact of host resistance on cumulative mortality and the threshold of herd immunity for SARS-CoV-2. MedRxIV doi: https://doi.org/10.1101/2020.07.15.20154294

It is widely believed that the herd immunity threshold (HIT) required to prevent a resurgence of SARS-CoV-2 is in excess of 50% for any epidemiological setting. Here, we demonstrate that HIT may be greatly reduced if a fraction of the population is unable to transmit the virus due to innate resistance or cross-protection from exposure to seasonal coronaviruses. The drop in HIT is proportional to the fraction of the population resistant only when that fraction is effectively segregated from the general population; however, when mixing is random, the drop in HIT is more precipitous. Significant reductions in expected mortality can also be observed in settings where a fraction of the population is resistant to infection. These results help to explain the large degree of regional variation observed in seroprevalence and cumulative deaths and suggest that sufficient herd-immunity may already be in place to substantially mitigate a potential second wave.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

My position on anti-CD20 therapies has been criticised, why?

Barts-MS rose-tinted-odometer: ★★★★★

I have recently been criticised by a colleague for supporting the DODO (double-dose ocrelizumab study) and the ADIOS (adaptive dosing ocrelizumab study) studies. How you can I on the one hand support more ocrelizumab and on the other hand suggest reducing the dose in the longterm. I responded that it is all about timing and how you use anti–CD20 therapies.

You need higher doses of anti-CD20 therapy initially as an induction strategy to purge the various B-cell compartments of memory B-cells, which I hypothesise house latent EBV and the highly autoreactive population of B-cells that drive and maintain the MS-state. This population of cells may reside in the deep tissues and/or the central nervous system, which is why we are also testing CNS penetrant anti-B-cell strategies, simultaneously.

However, once you have purged these compartments say after 2 years of treatment you don’t need to maintain such high-doses of anti-CD20 therapies that are then suppressing normal B-cell biology and immune responses, which result in longterm complications. This is why we want to test using ocrelizumab as an immune reconstitution therapy, i.e. high-dose upfront followed by no treatment and wait to see if MS remains in remission or disease-activity returns requiring additional courses. The latter is one of the arms of our proposed ADIOS study.

In reality, if I could convince a national funding agency, a pharma company or wealthy philanthropist I would use anti-CD20 therapy as part of an induction-maintenance protocol. After two years of induction therapy with high-dose ocrelizumab, I would test different maintenance strategies in parallel. My agents of choice would be teriflunomide, leflunomide, IMU-838 or vidofludimus (selective second-generation DHODH inhibitor,) HAART (highly-active antiretrovirals), famciclovir or another anti-EBV viral agent. The hypothesis is to allow B-cell reconstitution after anti-CD20 therapy in the presence of ant-viral agent to prevent EBV reactivation and reinfection of new memory B cells. By doing this you will be derisking the long-term immunosuppression associated with anti-CD20 therapies and you should prevent the development of hypogammaglobulinaemia.

The problem with this trial proposal is the outcome measure; the power calculations are not trivial and the study would have to be very long. I also have reservations about whether or not the regulators will accept the induction maintenance strategy. Maybe we can sell it to them on safety, i.e. to prevent the development of hypogammaglobulinaemia and infections rather than on efficacy? If we go this route then there is only one agent we can use and that is teriflunomide, which is licensed to treat MS. As teriflunomide is coming off patent there is a chance the NHS may be interesting in funding such a trial; i.e. it would save them money. This is something I need to explore (another task for my expanding ToDo list).

The good news is that Roche has bought into, and run, with the principle of the DODO study and announced at MSVirtual2020 two high-dose ocrelizumab trials (see below). These trials up the stakes in the anti-CD20 wars and I am confident that we need higher doses upfront to purge deep tissue and possibly CNS pools of B-cells. Please note that you don’t need higher doses of anti-CD20 therapy to suppress relapses and focal MRI activity you can do that with current or lower doses. I am confident both these studies will show that higher-dose ocrelizumab is superior to standard dose ocrelizumab on disability progression or smouldering MS, but not on focal inflammatory events. In relation to the latter, we have hit the ceiling already.

You need higher doses up-front to target the drivers of smouldering MS; i.e. disease progression independent of relapses, accelerated brain volume loss, slowly expanding lesions (SELs) and the subpial cortical lesions. If these higher-dose studies are positive it will put clear daylight between ocrelizumab and the other anti-CD20 therapies and it would mean the ofatumumab and rituximab are currently being underdosed, at least initially in the first two years.

CoI: multiple

Twitter: @gavinGiovannoni

Medium: @gavin_24211

#MSCOVID19: getting ready for the vaccine

Informing patients about their potential coronavirus risks associated with anti-CD20 therapy is complicated and resulting in our patients being given different advice depending on who they see. The reason for this is that we don’t have the direct evidence to be able to dissect out why people on anti-CD20 therapy are at higher risk of COVID-19 and at higher risk of being admitted to hospital with severe COVID-19.

I doubt this increased risk relates to increased exposure to the coronavirus. Why should someone on ocrelizumab who attends their healthcare facility be at increased risk of acquiring SARS-CoV-2 infection compared to someone for example on natalizumab who attends for their infusion every 4-6 weeks?

The clue to the increased risk is in the detail of the data. It is apparent that the longer you have been on an anti-CD20 therapy the greater your risk; the risk of COVID-19 is particularly high if you have been on an anti-CD20 therapy for more than 3 years. This means that it must be due to prior exposures, i.e. exposures before the COVID-19 pandemic started.

In the general population, it is now clear that some people have T-cells and antibodies that cross-react with SARS-CoV-2 and that these protect these people from developing COVID-19 or severe COVID-19. These cross-reactive immune responses are likely to have developed in response to infection or exposure to other circulating coronaviruses; the viruses that cause the common cold.

My theory is that if you are on an anti-CD20 therapy with no B-cells and a poorly functioning antibody response and you get the common cold your immune system will not be able to make these protective cross-reactive anti-coronavirus antibodies. This would then reduce your chances of being protected from getting COVID-19 or getting only mild COVID-19 when you are infected with SARS-CoV-2.

I have tried to illustrate this in the following slide showing that people on long-term anti-CD20 therapies are more likely to get symptomatic SARS-CoV-2 infection, i.e. COVID-19, and when they do get COVID-19 it is likely to be more severe. Severity in this context is requiring hospitalisation and potential intensive care and ventilation.

What does this mean for you? It means that if you are about to start ocrelizumab, rituximab or ofatumumab then your chances of getting COVID-19 are unlikely to be different to another DMT, with the exception of interferon-beta that lowers your risk because of its antiviral effects.

If you happen to be on ocrelizumab, rituximab or ofatumumab already there is little you can do, because these agents are not rapidly reversible and even if you stop the treatment and allow your B-cell compartment to reconstitute you are unlikely to develop the cross-reactive immunity from common coronaviruses. However, by stopping your anti-CD20 and allowing your B-cells to reconstitute you will be allowing your immune system to prepare itself for a coronavirus vaccine in the future.

At the beginning of the pandemic, I was a bit cynical about the chances of a successful coronavirus vaccine emerging, but the preliminary phase 2 results of several vaccines and the immunological insights above have made me much more optimistic that we will have an effective coronavirus vaccine quite soon. When I say soon I suspect we will have one ready for general consumption early next year. In all likelihood, one of the first vaccines will be the Oxford-AstraZeneca vaccine that happens to involve a live virus, which itself will have implications for some of the MS DMTs.

If my predictions are correct the MS community may need to start getting vaccine ready or they can simply rely on herd immunity. With anti-CD20 therapy, this needs to be planned ahead and patients will need to miss one, two or possibly three infusions depending on their body size and individual B-cell reconstitution kinetics in order to prepare their immune systems for the vaccine.

Some critics of this strategy are saying that patients on an anti-CD20 therapy will still make T-cell responses to the vaccine that will in all likelihood protect them. Yes, this may be the case, but then how do you explain the above observations that people on anti-CD20 therapy are at increased risk of COVID-19 and severe COVID-19? I would interpret this as them having blunted T-cell responses to cross-reactive common coronaviruses. If this is the case pwMS on an anti-CD20 will have blunted T-cell response to the vaccine. In support of the latter is the observation that several pwMS on ocrelizumab who have had swab-positive COVID-19 have failed to make an antibody response to the virus. Please remember that good quality antibody responses are T-cell dependent. These observations are telling me that in all likelihood being on anti-CD20 therapy will prevent you from developing protective immunity to coronavirus from a vaccine.

Clearly getting more detailed population-level COVID-19 data in people with MS is very important. This is why we are trying to crowdfund our study to identify people who have antibodies to SARS-CoV-2. We will be able to use this resource to do nested immunological studies on pwMS on different DMTs to understand the cross-reactive immunology at both the T and B cell level to coronaviruses in general and test the hypotheses above. It will also allow us to study vaccine responses if and when the vaccines arrive.

If you are prepared to help with a small donation it would be much appreciated. Thank you.

CoI: multiple

A false sense of security?

Just catching up with my reading. Whilst I was away on holiday the ASCLEPIOS I and II trials was published in the New England Journal of Medicine.

There is little doubt that ofatumumab is superior to teriflunomide when it comes to suppressing focal inflammation, i.e. relapses, MRI activity and peripheral blood neurofilament levels. However, ofatumumab’s effectiveness against teriflunomide on the real MS (delaying disability progression and reducing the relative loss of brain volume) is less impressive. Is this just another example of a dissociation between the anti-inflammatory effects of an anti-CD20 therapy and its impact on the end-organ as measured using brain volume loss or is it telling us something about teriflunomide and the cause of MS?

Image from supplementary material N Engl J Med 2020; 383:546-557.

It is clear, at least to me, that MS the disease is not due to focal inflammation. Based on the Prentice criteria for disease surrogates, both relapse and focal MRI activity don’t predict disability outcomes in natural history studies and placebo arms of clinical trials. If focal inflammation was MS then relapses and focal MRI activity would predict outcome whether or not you are on a DMT. The point I making here may be a philosophical one, but it a critically important one. In comparison, sustained or confirmed disability progression has to be MS and is based on the pathological correlates that define MS (demyelination, neuroaxonal loss and gliosis).

So why does ofatumumab do so poorly on these metrics relative to teriflunomide, when you would expect it do better? I think teriflunomide is the outlier and this opinion is based on several observations.

Teriflunomide has effects on disability progression that are way and above what you expect from its impact on relapses and focal MRI activity; i.e. both teriflunomide phase 3 placebo-controlled trials were positive on disability progression, despite a moderate reduction in relapse rate (~33% vs. placebo).

Teriflunomide also has a significant and unexpected effect on brain volume loss compared to placebo, which again is out of proportion to its anti-inflammatory effects.

Teriflunomide is more effective when used 2nd and 3rd line. Teri is the only DMT to show the latter and this observation was seen in both phase 3 studies, which makes it likely to be a real, and a very important, finding.

Finally, teriflunomide is a broad-spectrum antiviral agent, which may be part of its mode of action in MS. Could teriflunomide be targeting the viral cause of MS independent of its effects on the immune system’s response to that virus? Could it be an anti-EBV agent? Although teriflunomide’s antiviral mode of action needs more study, I suspect this is the reason why teriflunomide is the outlier that disproves the dogma.

Despite these observations, I suspect the MS community is going to propel ofatumumab to blockbuster status within the first 12 months of its launch. However, I want to reiterate that I think anti-CD20 therapies are lulling us into a false sense of security, i.e. because anti-CD20 therapies are so good at suppressing relapses and focal MRI activity we think we have sorted out the treatment of MS. However, when you look carefully at the end-organ of pwMS on anti-CD20 it is clear that their brains are still being shredded by smouldering MS. It is clear to me that we need to go way and beyond ofatumumab and anti-CD20 therapies to target whatever is causing smouldering MS. This is why we need to think combination therapies and find an add-on therapy, possibly an antiviral, that normalises brain volume loss in people with MS who are rendered free of focal inflammatory activity.

Hauser et al. Ofatumumab versus Teriflunomide in Multiple Sclerosis. N Engl J Med 2020; 383:546-557.

BACKGROUND: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known.

METHODS: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.

RESULTS: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, −0.11; 95% confidence interval [CI], −0.16 to −0.06; P<0.001) and 0.10 and 0.25 in trial 2 (difference, −0.15; 95% CI, −0.20 to −0.09; P<0.001). In the pooled trials, the percentage of patients with disability worsening confirmed at 3 months was 10.9% with ofatumumab and 15.0% with teriflunomide (hazard ratio, 0.66; P=0.002); the percentage with disability worsening confirmed at 6 months was 8.1% and 12.0%, respectively (hazard ratio, 0.68; P=0.01); and the percentage with disability improvement confirmed at 6 months was 11.0% and 8.1% (hazard ratio, 1.35; P=0.09). The number of gadolinium-enhancing lesions per T1-weighted MRI scan, the annualized rate of lesions on T2-weighted MRI, and serum neurofilament light chain levels, but not the change in brain volume, were in the same direction as the primary end point. Injection-related reactions occurred in 20.2% in the ofatumumab group and in 15.0% in the teriflunomide group (placebo injections). Serious infections occurred in 2.5% and 1.8% of the patients in the respective groups.

CONCLUSIONS: Among patients with multiple sclerosis, ofatumumab was associated with lower annualized relapse rates than teriflunomide. (Funded by Novartis; ASCLEPIOS I and II ClinicalTrials.gov numbers, NCT02792218 and NCT02792231).

CoI: multiple

#MSCOVID19: summertime

To me three swallows make a summer; one from Sweden, a second from Iran and now a third from Italy. I have little doubt more will emerge soon.

A few weeks’ ago I explained that having asymmetrical information is never a good thing. Tragically I have known about the data published yesterday on the Lancet’s pre-publication archive for several weeks.

The new data shows that ocrelizumab-treated Italian pwMS were more likely to get COVID-19 and severe COVID-19 compared to other DMTs. This now supports the Swedish rituximab data presented by Jan Hillert on the iWiMS COVID-19 webinar in May and the Iranian survey data on rituximab (see Safavi et al. below). The message across these three data sets is now quite consistent; anti-CD20 therapies affect the biology of COVID-19 differently to other DMTs.

How anti-CD20 therapy increases your chances of getting COVID-19 suggests it either (1) increases your exposure to the SARS-CoV-2 virus, which to me is not plausible unless it is due to increased exposure to the virus as a result of attending hospitals for infusions, or (2) it reduces your chances of having an asymptomatic infection. To me, the latter seems most likely and is meanable to study.

The immune responses to other human coronaviruses, the ones that cause the common cold, may cross-react with SARS-CoV-2 and help keep the virus in check and explains why some people get asymptomatic or mild infections. Having had a common cold in the recent past has given you some built-in protection against getting COVID-19 and severe COVID-19.

I hypothesise that if you were B-cell depleted from being on an anti-CD20 when you had that common cold your immune system doesn’t make the necessary high-quality or high-affinity cross-reactive antibodies that you now need to protect yourself from getting symptomatic COVID-19 and potentially severe COVID-19.

Should this data on anti-CD20 therapy change clinical practice? If you are already on an anti-CD20 therapy there is little you can do about your preexisting immunity to community-acquired coronaviruses; you either have immunity or you don’t. Similarly, you can’t simply revere the action of anti-CD20 therapies as it takes months to years to reconstitute your peripheral B-cell pool. Therefore I would simply recommend that if you are on an anti-CD20 therapy being extra-vigilant when it comes to trying to avoid being exposed to SARS-CoV-2 (social isolation, personal hygiene and avoiding high-risk environments).

What about starting an anti-CD20 therapy? The decision to do this must be individualised and weighed against the risk of getting COVID-19. In countries where this risk is very low anti-CD20 therapies will be safe.

The issue of vaccine readiness may affect your decision to be treated with anti-CD20 therapy. People who are B-cell depleted, as a result of anti-CD20 therapies, make blunted vaccine responses. This is not surprising because anti-CD20 treated patients lack germinal centres in their lymph nodes and spleen. Germinal centres are the immunological equivalent of a university. It is in the germinal centres that T-cells help B-cell mature, class switch their antibodies, i.e. go from IgM to IgG for example, and to then undergo affinity maturation of the antibody genes to produce high-quality antibodies. Without germinal centres, your immune system can’t educate your B-cells to make high-quality antibodies and hence vaccine response are poor.

For people on anti-CD20 therapies, if they want to maximise your chances of responding to a vaccine you are going to have to pause your treatment to allow your immune systems to recover before receiving a coronavirus vaccine. When should you do this? Not now. I would not recommend this until an effective vaccine emerges. Only cross bridges when they are built and only if you need to cross them.

There is still a relatively high chance that all of the 150+ SARS-CoV-2 vaccine candidates will fail; vaccine development for respiratory viruses is notoriously difficult.

These data is likely to be relevant to ofatumumab and other anti-CD20 therapies.

Not surprisingly interferon-beta which is an antiviral protects you from COVID-19 and exposure to high-dose methylprednisolone in the last 4 weeks increased your chances of severe COVID-19. The latter supports our current policy of asking patients to shield for 2 weeks after steroids and to be extra-vigilant.

Interestingly, there is a strong trend in the Italian data suggesting that natalizumab-treated patients may be at increased risk of COVID-19. Whether this is a real signal or not waits further data, but again the Swedish data supports this. This observation would not be surprising as we know natalizumab reduces trafficking of lymphocytes to mucosal membranes, which may be relevant in early anti-coronavirus immunity.

I suspect these observations will have implications for other infectious diseases. I would not be surprised when we study the immune responses and outcomes to other viral infections, for example, seasonal influenza the same patterns will emerge. Now that we have set-up COVID-19 registries I would urge the MS community to keep them open so that we can study what happens with the next influenza epidemic emerges, which is only months away.

Sormani et al. Disease-Modifying Therapies and COVID-19 Severity in Multiple Sclerosis. The Lancet Preprint 8-Jul-2020.

Background: Immunosuppressive and immunomodulatory therapies are a major issue during the current coronavirus disease 2019 (Covid-19) pandemic, and in anticipation of possible next waves.

Methods: In a nationwide study we retrospectively collected data of persons with Multiple Sclerosis (PwMS) with suspected or confirmed Covid-19. We assessed the association of therapies for MS with Covid-19 by comparing their observed frequency with the one expected in non-pandemic conditions (expressing the association by Odds Ratios [OR]). We evaluated baseline characteristics and MS therapies associated to a severe Covid-19 course by multivariate logistic models.

Findings: Of 784 PwMS with suspected (n=593) or confirmed (n=191) Covid-19 and a median follow-up of 84 days (range=30-135), 13 (1·66%) died: 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-three (4·2%) were admitted to an Intensive Care Unit; 90 (11·5%) had a radiologically documented pneumonia; 88 (11·2%) were hospitalized. We found an excess of patients treated with Ocrelizumab (OR=1·84,95%CI=1·31-2·56, p<0·001) and a reduction of patients treated with Interferon (OR=0·47,95%CI=0·33-0·67, p<0·001) as compared to the frequency of use of these DMTs in the Italian MS population. After adjusting for region, age, sex, progressive MS course and recent methylprednisolone use, the therapy with an anti-CD20 agent (Ocrelizumab or Rituximab) was significantly associated (OR=2·59,95%CI=1·43-4·67, p=0·002) with an increased risk of severe Covid-19 course. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR=6·0,95%CI=2·2-16·5, p=0·007).

Interpretation: This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, the study detected elements of risk and protection with respect to Covid-19 in MS. These will need to be considered in countries where the pandemic is persisting and in preparation for post-pandemic scenarios.

Funding: Roche donated the web-Platform and funded a fellowship to the University of Genoa.

Safavi et al B-cell depleting therapies may affect susceptibility to acute respiratory illness among patients with multiple sclerosis during the early COVID-19 epidemic in Iran. MSARDS Published:May 12, 2020.

Objective: To determine whether the course of COVID-19 is more severe in patients with MS and if MS disease-modifying treatments (DMTs) affect the risk of contracting the disease.

Methods: In a cross-sectional survey, data were collected by sending a questionnaire to 2000 patients with a demyelinating disease through an online portal system. Collected data included the current MS DMT and patient-reported disability level, history of recent sick contact, recent fever, respiratory symptoms, diagnosis with COVID-19, and the disposition after the diagnosis. We defined a COVID-19-suspect group as patients having fever and cough or fever and shortness of breath, or a presumptive diagnosis based on suggestive chest computed tomography. We calculated the proportion of COVID-19-suspect patients and compared their demographics, clinical characteristics, and DMT categories with the rest of survey-responders, using univariable and multivariable models.

Results: Out of 712 patients, 34 (4.8%) fulfilled our criteria for being in the COVID-19-suspect group. Only two patients required hospitalization. No patient required intensive care. In a multivariable model, disease duration (p-value=0.017), DMT category (p-value=0.030), and history of sick contact (p-values<0.001) were associated with the risk of being in the COVID-19-suspect group. Being on B-cell depleting antibodies (as compared to non-cell depleting, non-cell trafficking inhibitor DMTs) was associated with a 2.6-fold increase in the risk of being in the COVID-19-suspect group. (RR: 3.55, 95%CI: 1.45, 8.68, p-value=0.005).

Conclusions: The course of infection in patients with MS suspected of having COVID-19 was mild to moderate, and all patients had a full recovery. B-cell depleting antibodies may increase the susceptibility to contracting COVID-19.

Shen et al. Delayed Specific IgM Antibody Responses Observed Among COVID-19 Patients With Severe Progression. Emerg Microbes Infect. 2020 Dec;9(1):1096-1101.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly worldwide since it was confirmed as the causative agent of COVID-19. Molecular diagnosis of the disease is typically performed via nucleic acid-based detection of the virus from swabs, sputum or bronchoalveolar lavage fluid (BALF). However, the positive rate from the commonly used specimens (swabs or sputum) was less than 75%. Immunological assays for SARS-CoV-2 are needed to accurately diagnose COVID-19. Sera were collected from patients or healthy people in a local hospital in Xiangyang, Hubei Province, China. The SARS-CoV-2 specific IgM antibodies were then detected using a SARS-CoV-2 IgM colloidal gold immunochromatographic assay (GICA). Results were analysed in combination with sera collection date and clinical information. The GICA was found to be positive with the detected 82.2% (37/45) of RT-qPCR confirmed COVID-19 cases, as well as 32.0% (8/25) of clinically confirmed, RT-qPCR negative patients (4-14 days after symptom onset). Investigation of IgM-negative, RT-qPCR-positive COVID-19 patients showed that half of them developed severe disease. The GICA was found to be a useful test to complement existing PCR-based assays for confirmation of COVID-19, and a delayed specific IgM antibody response was observed among COVID-19 patients with severe progression.

CoI: multiple