Tag: Ocrelizumab

#MSCOVID19 ocrelizumab

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.

#MSCOVID19: good news for anti-CD20ers

I am being asked why I have moved ocrelizumab and other anti-CD20 therapies into the low-risk categories of DMTs in my latest version of my DMT table.

The reasons I use to justify the change are several-fold.

Anti-CD20 therapies deplete B-cells and only have a small impact on T-cell counts and innate immune cell function. This is important because anti-viral responses don’t seem to be affected to a great extent on ocrelizumab and other anti-CD20 therapies. In the phase three ocrelizumab trial programme apart from seeing a small herpes zoster signal there was no clear viral infection signal. When viral infections occurred they tended to be mild or moderate. The severe infections were bacterial (pneumonia, UTIs and cellulitis).

We are seeing an increasing number of patients who have been treated with anti-CD20 therapies who have had COVID-19 doing well. We have just published a case report in MSARDs of a man with PPMS treated with ocrelizumab who did well (see below). This has to be good news for patients on anti-CD20 therapies.

Ocrelizumab also blunts antibody responses, which may be important in severe COVID-19. This may delay or prevent damage to the COVID-19 lung as some of the damage seems to be mediated by complement activation and microthrombi. The latter is indicative of damage consistent with IgG3 anti-viral responses and IgG antibody-dependent cellular cytotoxicity by macrophages and in some instance neutrophils. Antibody production against the SARS-CoV-2 spike protein may promote cytokine production that activates macrophage to become more destructive. Blunting these antibody responses with an anti-CD20 therapy may actually be beneficial, which is why we are predicting that anti-CD20 treated patients will have a lower risk of getting severe COVID-19.

What about hypogammaglobulinaemia then?

Yes, this does occur with anti-CD20 therapies but occurs at a relatively low level. As SARS-CoV-2 is a new human pathogen and hence we don’t have immunological memory against the virus this makes little difference to the risk of becoming infected with SARS-CoV-2. Hypogammaglobulinaemia may, however, put you at risk of getting secondary bacterial infections. Fortunately, these can be treated with antibiotics. 

What about vaccine responses?

Yes, anti-CD20 and other immunosuppressive therapies can blunt antibody responses to some vaccines. And yes, contrary to the dogma patients on anti-CD20 therapies do make antibodies to viruses and vaccines. I assume this happens because we still have B-cells in secondary lymphoid organs and/or there may be CD20 negative B-cells that can takeover antibody production. Please note that the latter is a hypothesis.

Antibody responses to glycoproteins (sugar antigens) are particularly affected by anti-CD20 therapies and this may be important in the context of coronavirus immunity as the spike protein is heavily modified with sugar molecules. However, all these arguments are theoretical; until a vaccine emerges I would focus on getting MS treated. We can cross the vaccine bridge if and when it gets built. I am still of the opinion that the government’s strategy is herd immunity and hence the majority of us will at some point become infected with SARS-CoV-2. Waiting for a vaccine that never arises is going to be difficult for individuals; how long can you realistically self-isolate and/or shield? 

We are very keen to do an anti-SARS-CoV-2 seroprevalence study in pwMS to see how many have been exposed to the virus and have not developed COVID-19 and to also look at antibody responses to SARS-CoV-2 in patients on different DMTs. We hypothesise that patients on anti-CD20 therapies will have as good an antibody response to  SARS-CoV-2 as patients not on anti-CD20 therapies. This hypothesis refers to qualitative antibody responses, i.e. neutralising or protective antibody responses.  

For the reasons above I have not stopped offering patients with active MS anti-CD20 therapies during the pandemic. This refers to both starting and retreatment. Some patients have chosen to delay their treatments until the pandemic is over and others have taken my advice and gone ahead with their treatments; this is their choice. But as I have said before the pandemic won’t be over anytime soon; the tail is likely to extend for 18-24 months and possibly longer. Therefore all the guidelines that have recommended delaying or postponing treatment with depletion therapies, i.e. the anti-CD20s, cladribine, alemtuzumab, mitoxantrone, cyclophosphamide and HSCT will have to be reviewed. We can’t stop treating MS or offering patients less effective options for the next 18-24 months. If we do what will be the consequences?

How many swallows does it take to make a summer? I am aware that one case report is not much, but there are an increasing number of patients being reported on social media who have been treated with an anti-CD20 and have had gotten through COVID-19 without a problem. 

I would urge all the national register studies to be please report your data on COVID-19 outcomes in pwMS as soon as possible. We need the data to formalise our treatment guidelines and to help allay the fears of our patients. Please use one of the archive repositories to get your data out to the MS community as soon as possible. Thank you.

Giovanni Novi et al. COVID-19 in a MS Patient Treated With Ocrelizumab: Does Immunosuppression Have a Protective Role? Mult Scler Relat Disord 2020 Apr 15;42:102120.

Background: Coronavirus disease 19 (COVID-19) is a novel disease entity that is spreading throughout the world. It has been speculated that patients with comorbidities and elderly patients could be at high risk for respiratory insufficiency and death. Immunosuppression could expose infected patients to even higher risks of disease complications due to dampened immune response. However, it has been speculated that overactive immune response could drive clinical deterioration and, based on this hypothesis, several immunosuppressants are currently being tested as potential treatment for COVID-19.

Methods: In this paper we report on a patient that has been treated with ocrelizumab (a B-cell depleting monoclonal antibody) for primary progressive multiple sclerosis who developed COVID-19.

Results: Despite complete B cell depletion, patient symptoms abated few days after hospitalization, and he was discharged to home-quarantine. Phone interview follow-up confirmed that, after 14 days, no new symptoms occurred.

Discussion: This report supports the putative role of immunosuppressive therapy in COVID-19 affected patients.

CoI: multiple

Participating in Oratorio-Hand?

At the recent ORATORIO-HAND investigators’ meetings in Barcelona and Athens, several investigators’ made the point that it may be hard to retain people with PPMS in this trial because ocrelizumab has already been licensed to treat MS. I said YES and NO. 

For one a lot of neurologists, HCPs and payers don’t think the original ORATORIO trial was positive. They think the trial was driven by the 25% or so of the subjects with PPMS who had active disease, i.e. those with Gad-enhancing lesions at baseline. I have even heard some people claim that this trial was positive because it was contaminated by relapsing patients. This was not the case, all subjects had to have PPMS to get into this study. Any history of previous relapse excluded them from the trial. As a result of this doubt, many countries and insurance companies have not agreed to license or reimburse ocrelizumab for PPMS. To convince the naysayers, laggards and sceptics we need another PPMS trial to confirm the original results and extend the findings into pwPPSM with more advanced disease to show that ocrelizumab has a treatment effect in older and more disabled pwPPMS. This is why our age cutoff for the ORATORIO-HAND study is 65 and EDSS cut-off is 8.0 (wheelchair users). In the original ORATORIO study, these cutoffs were 55 years and EDSS of 6.5 (bilateral support, but still mobile). 

Statisticians will tell you that when you only do one trial, which is positive, there is about a 1 in 20 to 40 (2.5% to 5%) chance that result could be positive by chance. In statistical jargon, this is referred to as a false-positive result or type 1 error. This is why the regulators usually require two positive trials to license a product; the first trial to test the hypothesis and the second to confirm the results of the first trial. If one trial is positive and the second trial is negative, or vice versa, this usually results in a third trial being required. This is what happened with laquinimod in RRMS; you may recall the third trial (CONCERTO) turning out to be negative so the laquinimod MS development programme was halted. Herein lies a hidden danger. If ORATORIO-HAND is negative and does not confirm a significant treatment effect in PPMS it could be used by regulatory authorities to question the result of the ORATORIO trial and potentially withdraw the license. A negative result will justify payers refusal to reimburse the costs of ocrelizumab to treat PPMS. I am confident this is not going to happen, but we need your help to makes sure this does not happen. 

The ORATORIO-HAND is a very well-designed study and is adequately powered to give a positive result. The scientific principles underpinning this study are sound. However, if too many subjects drop-out to accept being treated with ocrelizumab when it is reimbursed in their countries or game the trial, i.e. find a way to unbind themselves, and drop-out this could potentially result in the study being underpowered, i.e. there are too few subjects to show a significant result when comparing placebo and active treatment groups. If this happens it could not only jeopardise treatment for themselves but the whole PPMS community. This is why I am appealing to all potential ORATORIO-HAND trial subjects if you are not sure about your longterm commitment to the trial you should not volunteer. 

We are very aware that half the trial subjects will be allocated to placebo. Someone investigators asked why didn’t we make the randomisation 2:1, i.e. for every one person on placebo two people would be allocated ocrelizumab. The logic is that by having a 2-out-of-3 chance of being on active treatment the more likely pwPPMS are likely to volunteer for the study and to stay the distance. There are two reasons for the one-to-one randomisation ratio; time and possibly cost. Increasing the time it takes to recruit study participants is important. We estimate to recruit another 500 subjects, to allow a 2:1 ratio, would take another 12-15 months, which means we would be exposing a third of the subjects to placebo for an additional 12-15 months and potentially denying many pwPPMS across the world earlier access to the ocrelizumab. A 12-15 month extension to the recruitment phase means 12-15 month delay for drug getting to wider PPMS population. These are the factors that convinced the steering committee to choose the 1:1 randomisation ratio. Although cost is an obvious potential consideration we didn’t even ask senior management at Roche the question. 

At the end of the day, we are asking pwPPMS to be altruistic. We are asking you to volunteer for a study and have a 50% chance of being randomised to a placebo knowing that ocrelizumab may be available to you as part of routine clinical practice or could become available to you during the trial. I know some people will ask does it have to be a randomised double-blind controlled trial? Could we generate the evidence in another way? The answer is no; the regulators will only change the label of ocrelizumab if the study is done to their standards. As you are aware it is virtually impossible to get a healthcare system-wide adoption of an MS treatment without a marketing authorisation from the appropriate regulatory body. 

There are also other advantages to being in a trial. We don’t know why but trial participants tend to do better than non-trial participants even if you are randomised to placebo. This may relate to better care offered in a trial or participating in a trial has psychological benefits that can’t be quantified. I favour the latter explanation. There is evidence that people who have a purpose, a sense of belonging and are valued have better health outcomes than people without. Being a trial participant gives you a sense of purpose and being valued in that they are contributing the greater good. I have also noticed over the years that trial participation expands social capital; trial participants get to know the trial staff and other trial participants. I even know of two study subjects from one of the early trials who ended up marrying each other. Others have become friends and see each other outside the trial unit; I have bumped into two of trials participants in a local east curry house together.  These intangibles can’t be quantified, but they definitely exist. 

In countries in which ocrelizumab is not licensed or reimbursed for treating PPMS the advantages of participating in the ORATORIO-HAND study are obvious. But even in countries where ocrelizumab is reimbursed receiving it as part of a trial may help as well. Although we can’t pay for you to participate in the trial all of your out-of-pocket expenses related to travel will be covered. 

I want to emphasise the positive of ORATORIO-HAND. For decades pwPPMS have felt neglected, ignored and left to smoulder away. Not anymore. The fact that the first ORATORIO trial was positive has shifted the goalposts and there will now be a flurry of PPMS trials. If ORATORIO-HAND fully recruits and is completed without too many dropouts the study will change the playing field for good. It will mean that PPMS is truly modifiable regardless of disease activity and potentially even people in wheelchairs will benefit. Getting a license for ocrelizumab in wheelchair users will affect the DMT stopping criteria, in other words even if you have to start using a wheelchair the treatment will have to be continued to preserve your arm and hand function. More importantly, it will get the whole MS community to say ‘Yes, we now agree that ocrelizumab works in PPMS’ and will allow pwPPMS across the world to access treatment. 

We acknowledge that there are many legitimate reasons for why study subjects dropouts in clinical trials. We have factored this into the power calculations. What I am focusing on here is excess drop-outs over and above what we expect to occur from experience of other ocrelizumab trials. 

This post is simply rehearsing some of the reasons for pwPPMS who volunteer for the ORATORIO-HAND study to stay the distance and complete the study. Please let me know if you agree, or disagree, with these points. I am also keen to find other reasons to help the many participating centres retain their patients in this trial. 

CoI: multiple; importantly, I am the principal investigator on the ORATORIO-HAND study and I want to give this trial the maximum chance of being successful. Our #ThinkHand campaign will only be judged a success if and when we get a DMT licensed to protect upper limb and hand function in pwMS. 

De novo PML on ocrelizumab

In my career as a neurologist, I have seen three patients who developed PML (progressive multifocal leukoencephalopathy) without any apparent risk factors apart from being old. They were all over 70. Prior to the HIV epidemic, about 1 in 10 patients with PML did not have an obvious underlying risk factor except for age or immunosenescence of the elderly.  Immunosenescence is the term immunologists use to describe malfunctioning of the immune system with ageing.

Based on the fact that even ‘normal’ elderly people have a very small risk of getting PML, it comes as no surprise that age is an emerging PML risk factor in MS, and explains why relatively safe DMTs have been associated with rare cases of PML. The last case of DMF-associated PML, who had a total lymphocyte count above 500, was in her sixties and old-age partially explains the first de novo case of PML on ocrelizumab (see below). 

We received the notification from Roche today describing a case of PML in a patient treated with ocrelizumab as first-line therapy, who also had a mild lymphopaenia. The question you will be asking is why is a 76-year-old MSer being exposed to such a potent immunosuppressive agent?  I don’t know. Maybe he had very active MS and his neurologist wanted to offer him a highly effective DMT first-line (flipping the pyramid). 

As what has happened with alemtuzumab usage in the US we are likely to see a more severe and unexpected adverse event profile in MSers who are older on ocrelizumab. Being older means they are more likely to have comorbidities, immunosenescence and less biological reserve to deal with serious and life-threatening infections. 

Am I concerned about this case? Yes and no. Yes, in the sense that I would think twice about using such a potent immunosuppressive agent in an elderly person with MS. No, in that de novo PML is rare with anti-CD20 treatment and is highly unlikely to be a problem in younger people with MS. 

On reflection, cladribine would have been a better high-efficacy DMT for this patient. The fact that cladribine is a selective IRT (immune reconstitution therapy) and does not cause longterm immunosuppression makes it a safer agent in this population group. Unfortunately, when this patient was started on ocrelizumab oral cladribine was not licensed in the US and the current FDA label discourages first-line use of oral cladribine. So even if cladribine was available at the time it is unlikely that it would have been prescribed. An interesting topic that is emerging in the field is the management of MS in the elderly, including the management of highly-active MS in this population group. Maybe we should put this topic forward for one of our future triMS.online conferences?

ROCHE STATEMENT

In the interest of patient safety, and as part of our ongoing commitment to transparency, I am forwarding this information.

  • We are aware of a report of a confounded case of progressive multifocal leukoencephalopathy (PML) in a multiple sclerosis (MS) patient in the United States of America who was treated with Ocrevus®▼(ocrelizumab). The potential contribution of Ocrevus treatment to this PML case is difficult to quantify but cannot be ruled out.
  • The patient has a long-standing history of MS. They were previously untreated and hence Ocrevus was their first disease-modifying therapy (DMT). The patient was treated with Ocrevus for two years, with the initiation of treatment in July 2017 and the last dose was administered in February 2019.
  • The treating physician has reported this as a confounded case of PML. Contributing factors (confounders) reported by the physician are the patient’s age (78) with potential immunosenescence, low absolute lymphocyte count (ALC) prior to treatment with Ocrevus (max CTCAE grade 1, no subtypes available), as well as low ALC (max grade 2), low CD4+ (max grade 2) and low CD8+ counts during treatment, with Ocrevus as a probable contributor.
  • Roche follow the American Academy of Neurology (AAN) criteria to establish the diagnosis of PML, in addition to consultation with an external advisory panel of experts.
  • Patient safety is Roche’s highest priority, and, consistent with our safety reporting processes, we report to health authorities in accordance with standard pharmacovigilance processes.
  • Roche is in contact with the treating physician to help evaluate the case, providing support and expertise where appropriate. 
  • The overall benefit/risk for Ocrevus remains unchanged at this time. As of 30th September 2019, more than 130,000 people with MS have been treated with Ocrevus globally (1). To date, there have been no unconfounded cases of PML reported in patients treated with Ocrevus. All seven previous confirmed PML cases of patients treated with Ocrevus were confounded by and attributed to the previous DMT (carry-over cases). This is the first PML case in a patient treated with Ocrevus where the cause of the PML, although confounded, has not been attributed to a previous DMT.

The recommendations relating to PML in the approved product labelling for Ocrevus remain unchanged. Physicians should be vigilant for early signs and symptoms of PML, which can include any new-onset, or worsening of neurological signs or symptoms, as these can be similar to an MS relapse. If PML is suspected, withhold dosing with Ocrevus.

Please refer to the summary of product characteristics for full prescribing information here.

For ease of reference, we have collated an overview of all confirmed PML cases to date (October 2019):

Confirmed case no.CountryReportedSettingConfounding factor(s)
1GermanyMay 2017Compassionate Use programmePrior DMT (Natalizumab)
2CanadaApril 2018Post-marketingPrior DMT (Fingolimod)
3USAMay 2018Post-marketingPrior DMT (Natalizumab)
4USAJune 2018Post-marketingPrior DMT (Natalizumab)
5USAJuly 2018Post-marketingPrior DMT (Natalizumab)
6LuxembourgSeptember 2018Post-marketingPrior DMT (Natalizumab)
7USAFebruary 2019Post-marketingPrior DMT (Natalizumab)
8USAOctober 2019Post-marketingAge (78) & low lymphocyte counts prior to, and during Tx

Mills and  Mao-Draayer. Aging and lymphocyte changes by immunomodulatory therapies impact PML risk in multiple sclerosis patients. Mult Scler. 2018 Jul;24(8):1014-1022. doi: 10.1177/1352458518775550. 

New potent immunomodulatory therapies for multiple sclerosis (MS) are associated with increased risk for progressive multifocal leukoencephalopathy (PML). It is unclear why a subset of treated patients develops PML, but patient age has emerged as an important risk factor. PML is caused by the JC virus and aging is associated with immune senescence, which increases susceptibility to infection. With the goal of improving PML risk stratification, we here describe the lymphocyte changes that occur with disease-modifying therapies (DMTs) associated with high or moderate risk toward PML in MS patients, how these changes compare to immune aging, and which measures best correlate with risk. We reviewed studies examining how these therapies alter patient immune profiles, which revealed the induction of changes to lymphocyte number and/or function that resemble immunosenescence. Therefore, the immunosuppressive activity of these MS DMTs may be enhanced in the context of an immune system that is already exhibiting features of senescence.

CoI: multiple

the HYPE study

It is clear that many MSers on continuous anti-CD20 therapy are concerned about the risk of developing hypogammaglobulinaemia and subsequent infections. Yesterday, I spoke to several neurologists at the O’HAND investigators meeting in Barcelona who informed me that they are considering giving their ocrelizumab-treated patients hyperimmune globulin replacement therapy (HYPE-Ig-RT) when they develop hypogammaglobulinaemia to prevent serious and potentially fatal infections. 

The problem I have with this is that HYPER-Ig-RT is expensive and for it to be covered by the NHS we will need to show that it is cost-effective. In response to these discussions Owen Pearson, an MSologist from Swansea, and I came up with the design of the HYPE study below.

The HYPE study

This is a randomised placebo-controlled trial to assess whether or not  HYPE-Ig-RT will work, i.e. reduce the risk of serious infection, infections and mortality in MSers on continuous anti-CD20 therapy. Please note we don’t think this study should be limited to ocrelizumab-treated MSers but should be open to any patient on anti-CD20 therapy, including those on rituximab and ofatumumab. 

What do you think of the HYPE study? Do we have clinical equipoise? 

Please remember for the payers, i.e. NHS England and insurance companies, to pay for HYPER-Ig-RT we need class 1 evidence to make the financial case to them. This study will test the hypothesis that HYPE-Ig-RT will derisk continuous anti-CD20 therapies and prevent some of the infectious complications related to hypogammaglobulinaemia. 

What is the risk of serious infections on anti-CD20 therapies? 

The following figures put the serious infection risk, i.e. infections requiring hospitalisation, on ocrelizumab in context. The overall figure is 2.24 serious infections per 100 patient-years. In other words for every 45 patients on ocrelizumab for 12 months one patient will be admitted to hospital with a serious infection. However, if you develop low IgG levels (hypogammaglobulinaemia) the risk rises to 5.48 serious infections per 100 patient-years or for every 18 patients on ocrelizumab for 12 months one patient will be admitted with a serious infection. This is why we are now monitoring peripheral blood immunoglobulin levels on an annual basis in all our patients on anti-CD20 therapy.

Derfuss et al. Serum Immunoglobulin Levels and Risk of Serious Infections in the Pivotal Phase III Trials of Ocrelizumab in Multiple Sclerosis and Their Open-Label Extensions. ECTRIMS 2019, 

CoI: multiple

O’HAND

I am very excited and proud to be attending and speaking at the first European Oratoria-HAND, or O’Hand, study investigator meeting in Barcelona. With Chariot-MS, the O’HAND study is the culmination of more than 4 years of work and campaigning for Barts-MS. 

However, our #ThinkHand campaign will only be considered a true success if we get a positive outcome from one of our studies and a DMT gets licensed to protect, or delay loss of, hand and arm function in people with more advanced MS. These trials have the potential to change the field and make more advanced MS modifiable. Many cynics think we are wasting our time. But if you have MS and you lose your lower limb function you become dependent on your hand and arms to maintain your independence. In other words, your arms become your legs. 

The following is my presentation from the meeting, which you can download from my bespoke SlideShare site. 

O’HAND Eligibility Criteria

Ages Eligible for Study:  18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:  All
Accepts Healthy Volunteers:  No

Inclusion Criteria:

  • EDSS score at screening and baseline >= 3.0 to 8.0, inclusive
  • Disease duration from the onset of MS symptoms:

Less than 15 years in patients with an EDSS at screening > 5.0 Less than 10 years in patients with an EDSS at screening <= 5.0

  • Documented history or presence at screening of at least one of the following laboratory findings in a cerebrospinal fluid specimen: Elevated IgG index or one or more IgG oligoclonal bands detected by isoelectric focusing
  • Screening and baseline 9-HPT completed in > 25 seconds (average of the two hands)
  • Ability to complete the 9-HPT within 240 seconds with each hand at screening and baseline
  • Patients previously treated with immunosuppressants, immunomodulators, or other immunomodulatory therapies must undergo an appropriate washout period according to the local label of the immunosuppressant/immunomodulatory drug used
  • For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use adequate contraceptive methods during the treatment period and for 6 months after the final dose of ocrelizumab. Adherence to local requirements, if more stringent, is required.
  • For female patients without reproductive potential: Women may be enrolled if post-menopausal unless the patient is receiving a hormonal therapy for her menopause or if surgically sterile

Exclusion Criteria:

  • History of relapsing-remitting or secondary progressive MS at screening
  • Confirmed serious opportunistic infection including: active bacterial, viral, fungal, mycobacterial infection or other infection, including tuberculosis or atypical mycobacterial disease
  • Patients who have or have had confirmed or a high degree of suspicion of progressive multifocal leukoencephalopathy (PML)
  • Known active malignancy or are being actively monitored for recurrence of malignancy
  • Immunocompromised state
  • Receipt of a live-attenuated vaccine within 6 weeks prior to randomization
  • Inability to complete an MRI or contraindication to Gd administration.
  • Patients requiring symptomatic treatment of MS and/or physiotherapy who are not on a stable regimen. Patients must not initiate symptomatic treatment of MS or physiotherapy within 4 weeks of randomization.
  • Contraindications to mandatory premedications for infusion-related reactions, including:

uncontrolled psychosis for corticosteroids and closed-angle glaucoma for antihistamines

  • Known presence of other neurologic disorders
  • Pregnant or breastfeeding, or intending to become pregnant during the study and 6 months after last infusion of the study drug
  • Lack of peripheral venous access
  • Significant, uncontrolled disease, such as cardiovascular, pulmonary, renal, hepatic, endocrine or gastrointestinal, or any other significant disease that may preclude patient from participating in the study
  • Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study
  • History of alcohol or other drug abuse
  • History of primary or secondary immunodeficiency
  • Treatment with any investigational agent within 24 weeks prior to screening (Visit 1) or 5 half-lives of the investigational drug (whichever is longer), or treatment with any experimental procedure for MS
  • Previous treatment with B-cell targeting therapies
  • Any previous treatment with bone marrow transplantation and hematopoietic stem cell transplantation
  • Any previous history of transplantation or anti-rejection therapy
  • Treatment with IV Ig or plasmapheresis within 12 weeks prior to randomization
  • Systemic corticosteroid therapy within 4 weeks prior to screening
  • Positive serum hCG measured at screening or positive urine β-hCG at baseline
  • Positive screening tests for hepatitis B
  • Any additional exclusionary criterion as per ocrelizumab (Ocrevus®) local label, if more stringent than the above
  • Lack of MRI activity at screening/baseline if more than 650 patients without MRI activity have already been enrolled, as defined by T1 Gd+ lesion(s) and/or new and/or enlarged T2 lesion(s) in the screening, to ensure that at least 350 patients with MRI activity will be randomized

Eligibility Criteria for Open-Label Extension Phase:

  • Completed the double-blind treatment phase of the trial or have received PDP OCR in the FU1 phase, and who, in the opinion of the investigator, may benefit from treatment with Ocrelizumab. Patients who withdrew from study treatment and received another disease-modifying therapy (DMT) or commercial ocrelizumab will not be allowed to enter in the OLE phase.
  • Meet the re-treatment criteria for ocrelizumab
  • For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use adequate contraceptive methods during the treatment period and for 6 months after the final dose of ocrelizumab. Adherence to local requirements, if more stringent, is required.
  • For female patients without reproductive potential: Women may be enrolled if post-menopausal unless the patient is receiving a hormonal therapy for her menopause or if surgically sterile

CoI: I am the principal investigator on the O’Hand study

For English PPMSers

“I love deadlines. I like the whooshing sound they make as they fly by” Douglas Adams, Hitchhikers Guide to the Galaxy.

There is one deadline that happened quitely earlier this month. NHS England turned on the blueteq form ocrelizumab treatment for PPMSers living in England; they did at the last possible timepoint dictated by the law. The good news is that the requirements for someone with PPMS to be treated are relatively simple. All that is required from us is the following:

1. Confirmation the patient has a diagnosis of early PPMS with active disease, defined by the appearance of new lesions confirmed by two MRI studies taken at least 6 months apart OR one or more gadolinium enhancing lesions on one MRI over the last three years.

2. EDSS score <= 6.5

3. A decision agreed at an MS multi-disciplinary team (MDT) meeting.

4. Recording of all the above in the patient’s records (for audit purposes).

This has been a long time coming and I want to thank all my colleagues who signed-up to the open letter we sent to the Chief Medical Officer (see below). I suspect the letter may have helped find a funding solution. It is clear that when there is a will there is a way.

I am also beginning to realise that NHSE is actually on the side of the patient and contrary to my previous perceptions NHSE want patients to access effective treatments. The problem is they have limited budgets and are beholden to the Department of Health and the political system of the day.

We may have won one battle, but the war continues. PPMSers in Scotland still have no access to ocrelizumab. How can we live in a country, with a socialist healthcare system, that allows your place of abode to dictate your access to treatment? If there is anything we can do to help PPMSers living in Scotland please let us know.

Open Letter

Professor Dame Sally Davies
Chief Medical Officer
Department of Health
Room 114, Richmond House
79 Whitehall
London SW1A 2NS
Email:CMOweb@dh.gsi.gov.uk

24 September 2018

Dear Dame Sally

Ocrelizumab for the Treatment of Primary Progressive Multiple Sclerosis

We are writing to you as concerned healthcare professionals for help. We are neurologists, nurse specialists and allied healthcare professionals who specialise in multiple sclerosis (MS). Although patients with the relapsing-remitting type of MS have access to many disease-modifying treatments no treatments until now have been licensed for those with the primary progressive type of MS (PPMS). In its final appraisal document [FAD ID938] NICE has not recommended the first available licensed treatment ocrelizumab, for treating early PPMS.

The problem with NICE’s appraisal determination (FAD) is that the price for ocrelizumab had already been set for treating relapsing-remitting MS (RRMS, FAD TA533), but this price was considered not cost-effective for the treatment of PPMS based on its efficacy in the PPMS trial. As there are currently no licensed treatments for PPMS ocrelizumab had to be compared with best supportive care or no treatment. In comparison, when NICE appraised ocrelizumab for RRMS it was compared to all the other licensed disease-modifying therapies (DMTs).

We have been told that Roche had then agreed to lower the price for ocrelizumab so that it would be cost-effective for the PPMS indication. If this was accepted it would mean ocrelizumab having two NHS prices, a higher price for the treatment of RRMS and a lower price for the treatment of PPMS. Apparently, the Department of Health is not prepared to support differential pricing, despite having a mechanism with the blueteq system for tracking prescribing for the PPMS and RRMS indications.

NICE’s decision in association with the Department of Health’s Rules means an irrational decision has been made. It also creates inequity. People with PPMS who are prepared to pay for ocrelizumab privately will be able to receive the therapy, potentially in an NHS institution. Similarly, those who are fortunate may be able to move and be treated with ocrelizumab in another country where ocrelizumab is covered for the PPMS indication as other UK and EU countries have different decision-making processes.

We would appreciate it if you could review the Department of Health’s position on differential pricing as a solution for people with PPMS being treated with ocrelizumab? We are convinced that there must be a solution that will allow our patients with PPMS to be appropriately treated under the NHS.

Despite the pharmaceutical company conceding to the NICE target and the drug receiving a European license, it is now the government who is preventing patients receiving appropriate treatment for their MS simply due to a rule, arguably an irrational rule, created by the Department of Health.

We look forward to hearing from you.

Yours sincerely

Concerned NHS HCPs.

CoI: multiple


OVO Study

Finally, after a week or more of thinking and contemplation my opinion about the ofatumumab vs. teriflunomide trial data (ASCLEPIOS I and II); another of my ECTRIMS highlights. 

The result of the ASCLEPIOS I and II are not unexpected and in line with the treatment effects of anti-CD20 therapies with some caveats. 

Novartis summary:

  • Both ASCLEPIOS I and II studies met their primary endpoints in patients with relapsing forms of MS (RMS); overall ofatumumab (OMB157), a subcutaneous, potent, fully-human antibody targeting CD20 positive B-cells, delivered efficacy with a favorable safety profile
     
  • RMS patients on ofatumumab had a reduction in annualized relapse rate (ARR) by 50.5%  (0.11 vs. 0.22) and 58.5% (0.10 vs. 0.25) compared to Aubagio®* (teriflunomide) (both studies p<0.001) in ASCLEPIOS I and II studies respectively
     
  • Ofatumumab showed highly significant suppression of gadolinium (Gd) T1 lesions when compared to Aubagio®, demonstrating a profound suppression of new inflammatory activity
     
  • Ofatumumab showed a relative risk reduction of 34.4% in 3-month confirmed disability progression (CDP†) (p=0.002) and 32.5% in 6-month CDP (p=0.012) versus Aubagio® in pre-specified pooled analyses
     
  • Ofatumumab, if approved, will potentially become a treatment for a broad RMS population and the first B-cell therapy

My interpretation:

Inflammation: relapse rate, focal MRI activity (Gd-enhancing & new T2 lesions) and neurofilament data.

I have made the point that these three markers measure focal inflammation, driven by adaptive immunity, and there is little doubt that ofatumumab is superior in suppressing inflammation compared to teriflunomide. Does this make ofatumumab superior to other very high efficacy DMTs, such as natalizumab, rituximab, ocrelizumab, alemtuzumab and HSCT? I suspect not. To prove this we would need head-2-head studies. I also think there are floor effects on these outcomes, i.e. you can only reduce relapse rates to around 0.1 to 0.2 and no lower. Why? I suspect some relapses are pseudo-relapses and are due to intermittent symptoms in relation to infections, fatigue and possibly hidden symptoms. 

Please note that I don’t consider peripheral blood neurofilament levels (pbNFL) to be a neurodegenerative marker in the context of MS. All the data I have seen to date indicates that it is linked to focal inflammatory activity. Clearly more needs to be done in progressive MS with pbNFL to understand what it means in inactive or smouldering MS. 

End-organ damage: disability progression and brain volume data

I was disappointed with how ofatumumab did against teriflunomide in delaying disability progression and reducing the relative loss of brain volume. This will be ofatumumab’s Achille’s heel. Why? It is clear that MS the disease is not focal inflammation; I have made the point that based on the Prentice criteria, 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 very 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). 

Why did ofatumumab do so poorly on these metrics relative to teriflunomide? It could be that teriflunomide is the outlier and this opinion is based on several observations. 

  1. Teriflunomide is the only DMT to have a consistent effect on disability progression; i.e. both teriflunomide phase 3 placebo-controlled trials were positive on this outcome. In addition, the treatment effect or impact of teriflunomide on disability progression has always been greater than what you would expect from its impact on relapses. For the tuned-on readers, you would have noticed the same disconnect between relapses and disease progression was observed in the ponesimod vs. teriflunomide trial. 
  2. Teriflunomide also has a significant effect on brain volume loss compared to placebo, which again is out of proportion to its impact on relapses (see picture below). 
  3. 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. 
  4. 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? This needs more study, but teriflunomide is the outlier, or exception, that disproves the dogma. 

Is ofatumumab being underdosed? 

Ofatumumab is being given at a dose of 20mg subcutaneously monthly. This dose was chosen to keep B-cells depleted, but not severely depleted, so as to allow rapid repopulation of peripheral B-cells numbers if ofatumumab is stopped. In other words, B-cell depletion is relatively mild compared to ocrelizumab 600mg every 6 months. With ocrelizumab, it takes 6 months or longer to start to see B-cell reconstitution. 

I don’t buy this argument. The repopulation kinetics with ofatumumab are based on relatively short-term dosing studies in which deep tissue and in bone marrow B-cell depletion is likely to be relatively modest. I suspect with long-term dosing with ofatumumab deep tissue and bone marrow B-cell depletion is more likely and hence the B-cell repopulation kinetics will mimic that of rituximab and ocrelizumab. 

I also think rapid B-cell repopulation is likely not to be relevant as the new B-cells will almost certainly be bone marrow-derived naive B-cells and not memory B-cells. 

The question I have is the 20mg per month of ofatumumab sufficient to penetrate the CNS and clear the intrathecal of CNS resident B-cell follicles? 

At the AAN this year Stephen Hauser presented data indicating that when it comes to disability progression, not relapse rate or MRI activity, the extent of exposure to ocrelizumab is very important.

The greater the ocrelizumab exposure the more effective it was at delaying disability progression. This could be related to deep tissue (peripheral) and end-organ (central) B-cell depletion. There is mounting evidence that the B-cells and plasma cells within the brain and spinal cord of MSers are driving some of the slow-burn we see clinically and on MRI (smouldering MS). What I am saying is that ocrelizumab could be superior to ofatumumab when it comes to scrubbing the brain clean of pathogenic B-cell follicles. Therefore it more important than ever to test this hypothesis in a head-2-head study of ocrelizumab vs. ofatumumab (OVO study) or  the DODO study comparing double-dose (1200 mg) vs standard-dose (600 mg) ocrelizumab (DODO study) to see if the higher dose of ocrelizumab has a bigger impact on the intrathecal B cell response than the standard dose. 

I would suggest these studies include next-generation MRI and other biomarkers to test the CNS penetration hypothesis. If these studies are positive, i.e. ocrelizumab is superior to ofatumumab and double-dose ocrelizumab is superior to single-dose ocrelizumab, it will not only tell us a lot about how anti-CD20 therapies work in MS, but it may answer the question of whether or not we need to target the intrathecal or CNS B-cell response in MS. The latter hypothesis is being tested by our group in two studies at present. We would love to add a third and fourth study to the portfolio. If you work for Novartis or Roche please tell the powers that we are really, really, interested in doing both the OVO and the DODO studies.

What about teriflunomide?

Don’t forget that the implications from the ponesimod vs. teriflunomide and ofatumumab vs. teriflunomide trials are quite profound. Teriflunomide is quite a remarkable DMT and we need to explore its antiviral effects in MS in more detail and understand what it is doing in MS independent of its rather weak anti-inflammatory effects. This is why I have proposed using teriflunomide as a maintenance therapy post-induction. In my ECTRIMS hot topic presentation, I called the trial the iTeri study (see slide show above). 

If you work for Genzyme-Sanofi please tell the powers that be that we are really, really, interested in an induction-maintenance trial with both teriflunomide (iTeri study) and a second with your BTK inhibitor (iBruT study).

CoI: multiple

Derisking anti-CD20 therapy

An important highlight of ECTRIMS this year was the data on the safety of the anti-CD20 therapies as a class. It is clear that prolonged, and sustained, B-cell depletion is not safe. Hypogammaglobulinaemia will become a problem with the risk of both common and opportunistic infections. 

Stephen Hauser presented the 7-year ocrelizumab safety data and there is a clear uptick in infections in year 7. His poster also included a probable opportunistic infection signal.  As of January 2019, there were six potential serious opportunistic infections that had been reported from the ocrelizumab clinical trials.

  1. Systemic Pasteurella infection in a patient with RMS following a cat bite (resolved)
  2. Multisegmental herpes zoster infection in a patient with RMS, treated with intravenous (IV) acyclovir (resolved)
  3. Enterovirus-induced fulminant hepatitis in a diabetic patient with RMS, resulting in liver transplant
  4. Candida sepsis in a patient with PPMS who had stopped OCR treatment 11 months previously and was receiving cancer chemotherapy (resolved)
  5. Viral meningitis in a patient with RMS, cerebrospinal fluid positive for varicella-zoster, treated with IV acyclovir (resolved)
  6. Herpes zoster (monodermatomal) in a patient with RMS treated for a neutropenic fever (not assessed as an opportunistic infection) (resolved)

Continuous anti-CD20 therapy prevents you from forming germinal centres (where B-cells get educated and selected to make antibodies) in lymph nodes and the spleen. In other words, the anti-CD20 therapies result in what I refer to as a functional splenectomy. This causes a scotoma, or blind spot, in your immune system which means you can’t mount a vigorous immune response to new infectious agents or vaccines. In reality, your immune responses are muted. 

Image from Family Doctor

I highlighted in my hot topics talk on ‘DMTs in RRMS 2019: what remains to be achieved’ about the problems of having a functional splenectomy on anti-CD20 therapies. I recommended that all MSers be vaccinated with the polyvalent pneumococcal vaccine (Pneumovax) and possibly the vaccines for Haemophilus influenzae type B and Meningococcus. In addition, all MSers should have the annual flu vaccine, but with the inactivated component flu vaccine and not the live flu vaccine. In fact, MSers on anti-CD20 therapy should avoid coming into contact with recipients of the live flu vaccine in case it becomes more virulent and infects them. Please note the live flu vaccine is used in the UK in young children and it is recommended that children who have parents or family members at home on immunosuppressive therapies should not have this vaccine. 

Another option open to people on longterm anti-CD20 therapy is antibiotic prophylaxis against infections with these encapsulated bacteria. I suspect this may be necessary when MSers develop hypogammaglobulinaemia and recurrent infections, similar to the NMO cases described below. It is clear that anti-CD20 therapies will need annual immunoglobulin levels measured so that if hypogammaglobulinaemia develops MSers can we warned. I suspect immunoglobulin replacement therapy will only be required in the case of recurrent infections, for example, sinus or chest infections; for example, the NMO patient on longterm rituximab who developed bronchiectasis.  

I would also recommend that MSers on immunosuppressive therapies wear a medic-alert bracelet that states they are on an anti-CD20 therapy. This would help HCP in an emergency if you are too sick to provide a history. An American colleague told me about one of his ocrelizumab-treated patients, who was fit and well, who died suddenly in the emergency department after presenting with a high temperature and not feeling well. I suspect the cause of death was probably septic shock from one of the encapsulated bacteria discussed above. 

The facts that (1) the clinical development programme of ocrelizumab was stopped in rheumatoid arthritis and lupus because of infections and excessive number of deaths, (2) that there is a herpes zoster signal on ocrelizumab, (3) there is blunted vaccine response, in particular to pneumococcus, and (4) ocrelizumab reduces immunoglobulin levels explains why there are infectious complications on ocrelizumab.

So if you are on rituximab, ocrelizumab, ofatumumab or any othe anti-CD20 please be vigilant and take care. On the other side of the coin are the benefits of these treatments and their ease of use and low monitoring burden. As with all DMTs the risks need to be balanced against the benefits. 

Tallantyre et al. Secondary Antibody Deficiency and infection following B-cell depletion for CNS neuroinflammation. ECTRIMS Online Library. Oct 25, 2017; 199742; EP1722

B-cell depleting anti-CD20 monoclonal antibody therapies have demonstrated promising clinical efficacy in suppressing relapses in individuals with neuromyelitis optica (NMO) and multiple sclerosis (MS). However, uncertainties remain about the optimum treatment schedule. In rheumatological disease, anti-CD20 agents are most often employed for short-term induction therapy and are subsequently replaced by longer-term maintenance therapy. In contrast, repeated cycles of anti-CD20 monoclonal antibody therapy are proposed as maintenance therapy for CNS neuro-inflammatory disorders. Post-marketing surveillance will be essential to fully uncover the long-term safety profile of repeated B-cell depletion. Hypogammaglobulinaemia is a recognised consequence in a proportion of patients treated with medium- to long-term B-cell therapy and may play a role in the increased incidence of infection observed in the anti-CD20 arms of treatment trials. We report 5 cases of serious infection associated with hypogammaglobulinaemia occurring in patients receiving rituximab for NMO. The cases were all female, all had low IgG with variable reductions in IgM and IgA. The cases had a mean treatment duration of 3.1 years, but not all cases had had extensive exposure (treatment duration range 0.5 – 6.2y). We review the evidence relating to hypogammaglobulinaemia following anti-CD20 treatment for neuroinflammatory disorders and propose an algorithm for monitoring and treatment of this recognised complication.

CoI: multiple

Results time

It is time to set in stone our #CrowdThink competition results. We had over 110 responses; thank you. If you want to know more about the rationale behind this competition you need to read my post on the DODO trial and the post explaining the rationale behind the COMPETITION.

Study 1: Oral Ponesimod Versus Teriflunomide In Relapsing MUltiple Sclerosis (OPTIMUM).

The Crowd has predicted that ponesimod will reduce the ARR (relative annualised relapse rate) and CDP (confirmed disability progression) compared to teriflunomide by 33.8% (interquartile range=24.5-44.3%) and 21.2% (interquartile range=10.0-25.0%), respectively.

This would suggest that ponesimod is probably batting in the same league as fingolimod. I wouldn’t put too much weight on the TRANSFORMS study that compared fingolimod to interferon-beta-1a. The majority of subjects were failing interferon who went into that study and were then randomised to fingolimod or back onto interferon-beta-1a. This study inflated fingolimod’s relative efficacy as it was being compared to interferon-beta failures on interferon-beta.

Study 2: Efficacy and Safety of Ofatumumab Compared to Teriflunomide in Patients With Relapsing Multiple Sclerosis (ASCLEPIOS I & II)

The Crowd has predicted that ofatumumab will reduce the ARR (relative annualised relapse rate) and CDP (confirmed disability progression) compared to teriflunomide by 41.2% (interquartile range=34.0-49.0%) and 29.3% (interquartile range=20.0-37.3%), respectively.

These results are interesting and broadly put ofatumumab in the same ballpark as ocrelizumab as well; 41% is close enough in my book to 47% for it not to register as being meaningfully different to ocrelizumab. In comparison, 29.3% for CDP is too far away from 40% to be dismissed. The question is this because of ofatumumab being inferior to ocrelizumab? Or teriflunomide is superior to interferon-beta-1a (Rebif)? I would favour the latter interpretation. The former interpretation would support the hypothesis for the need to target intrathecal B-cells and that the higher dose of ocrelizumab is superior at doing this compared to the smaller but more frequent ofatumumab dosing. These results would support us pushing for the DODO study to be done.

However, would it not be a more interesting story if ofatumumab out-performed ocrelizumab? This would be against my predictions, but it opens a new vista on how anti-CD20 therapies work. If ofatumumab outperforms ocrelizumab it would argue for a peripheral mode of action, i.e. keeping peripheral B-cells depleted continuously, rather than using intermittent depletion paradigm of rituximab and ocrelizumab. It would also challenge the hypothesis that we need to have CNS penetration for targeting of the intrathecal B-cell compartment.

The peripheral B-cell hypothesis would raise very interesting questions about whether or not anti-CD20 therapy is working as an anti-EBV agent and keeping the memory B cell compartment, which hosts EBV, suppressed.

I have already been criticised by a few people at this conference for my musings on the potential results of these trial. Don’t we live in a world where free and open thought is allowed? I speculate and write these sorts of posts deliberately to be controversial. But I would hope that they stimulate you to think more deeply about MS and what these results could mean for us and in particular people with MS.

Let’s hope it is not the same-old, same-old; i.e. another me too study of an anti-CD20. Let’s hope the results support either the central B-cell depletion hypothesis or the peripheral-continuous B-cell depletion hypothesis. The former supports our programme of activities to scrub the brain clean of B-cells and plasma cells and the latter to treat MS with anti-virals, in particular, anti-EBV drugs.

To conclude, I was very disappointed that two-thirds of you chose the MRI lego set over my #ThinkSocial T-shirt as a prize. I am clearly not a very good T-shirt designer ;-(

Lego MRI scan set
Barts-MS #ThinkSocial T-shirt

CoI: multiple