Happy New Year. I hope you are all safe and looking forward to 2022, which is going to be very different to 2020 and 2021 from a personal and MS perspective.
Case study: low-dose ocrelizumab due to adaptive dosing
Shortly after the beginning of the COVID-19 pandemic, my neurologist changed the frequency of my ocrelizumab infusions. It has been 14 months since my last infusion. He wants me to wait another few weeks to make sure I have an antibody response to a fourth dose of the Moderna COVID-19 vaccine before giving me my next infusion. I am very worried as I have noticed small things happening to me over the last 12 months that tell me my MS is getting worse. When I walk longer than about 20 minutes my left leg gets heavy. My bladder symptoms have also worsened. My neurologist is happy with my treatment as my EDSS has not changed. I am told it is 4.0. My last MRI done a few weeks ago is apparently stable with no new lesions. Is it okay to be on delayed ocrelizumab dosing or not?
Prof G’s Opinion:
Some of you may not know George Ebers. George is a celebrated Canadian neurologist who worked in the field of MS his whole life until his recent retirement. He is one of the deepest contemporary thinkers in the field of MS. He made many seminal contributions, including many observations about the natural history of the disease. As I get older, and hopefully wiser, I realise how deeply George has influenced my thinking.
It is now more than 20 years since I got to know George Ebers personally. The year was 1999 and we had just arrived in Venice to attend the European Charcot Meeting. We shared a water taxi to the conference hotel. It was during the taxi ride and at that meeting that George explained to me why the MS community had become blinkered by what the MRI was showing them about MS and by our fixation with relapses. He knew back then that both MRI activity and relapses were not MS; this was not some wild claim. George Ebers had acquired these insights from the London, Ontario, natural history study and from data from the original interferon-beta-1b study.
Over the next decade, George produced more data, published articles, spoke at conferences and helped set up the Sylvia Lawry Centre, a data-sharing alliance, to try and get the MS community to shift their attention away from relapses and focal MRI activity and focus on the ‘real MS’, i.e. disability progression and the progressive phase of the disease.
George later showed that the frequency of relapses in the first two years after disease onset were predictive of long-term outcomes, but outside of this narrow window they were not relevant to long-term prognosis. The latter observation was later backed by long-term MRI studies in patients with clinically isolated syndromes (CIS) in that only disease activity early on the disease course, i.e. within the first 5 years, predicted long-term outcomes albeit poorly. Once you get outside of these early windows MS runs its disease course from a neurodegenerative or smouldering disease perspective irrespective of focal inflammatory events. The important question is what is the focal immune response early in the disease course due to? I think if we can answer this question we will know what is causing MS.
I subsequently wrote a book chapter based on some of these insights in 2004 called ‘The yin and yang of inflammation in multiple sclerosis’. The arguments I made back in 2004 are very similar to the arguments I am making now. The only difference is that I now refer to the ‘real MS’ as smouldering MS. Smouldering MS is a term that goes beyond the clinico-radiological (relapse-MRI) worldview of MS and defines MS as a biological disease.
Abstract from the book chapter
The primary neurodegenerative hypothesis (1994): Although multiple sclerosis is a clinically heterogeneous disease it can be viewed as an inflammatory neurodegenerative disease with the clinical spectrum or phenotype determined by the presence or absence of focal inflammation, similar to that which occurs in infectious diseases, e.g. leprosy. The underlying neurodegenerative component of the disease may or may not be ongoing but it is modified by superimposed focal inflammatory events. The focal inflammation may be an appropriate host response directed at an unidentified aetiological agent or an inappropriate autoimmune response. These focal inflammatory events are responsible for clinical attacks and MRI disease activity. Although damaging in themselves the focal inflammation provides the biological substrate in the form of trophic and growth factors which promote repair and clinical recovery. Inhibiting the focal inflammatory events, e.g. with generalised immunosuppression, would reduce the relapse rate and MRI activity and remove the important trophic and growth factor support provided by the inflammatory infiltrates, but it may not affect the underlying primary neurodegenerative processes. This strategy would simply convert relapsing-remitting disease into non-relapsing progressive disease. There is evidence from infectious diseases that this phenotypic variability is linked to genetic susceptibility.
Move forward 20+ years
The question I am asking myself is why are we no further forward 20+ years later in tackling the real MS? Smouldering MS is the single biggest challenge facing the MS community today with the second biggest challenge being MS prevention. I now spend most of my time in my MS clinics explaining to my patients why they are getting worse despite having no obvious relapses and new lesions on MRI. If you have MS you may have a personal story to tell us. Please come forward, it is your stories rather than science that may move or at least nudge the field forward. The human brain seems wired to respond to a narrative rather than science.
In a previous MS Selfie Newsletter ‘Getting worse’ (2-July-2021), I explain why pwMS get worse. The problem we have at the moment is that we have no data on what to do with someone like you who almost certainly has smouldering disease and is NEIDA (no evident inflammatory disease activity). This is why we desperately need add-on treatment strategies or dual-action therapies to address smouldering MS.
Sadly, the pharmaceutical industry is nervous about doing add-on trials, because the regulatory environment is not conducive to the success of such trials. The FDA and EMA want each new agent to be tested separately or added onto an already licensed therapy. They also want the primary outcome to be based on the EDSS, which is not an appropriate outcome measure for smouldering MS in pwMS who are NEIDA. As a result of being forced to use the EDSS, smouldering MS trials need to be very large and extraordinarily long and hence are very expensive and too risky. All these factors act as a disincentive to doing add-on studies to target smouldering MS. This is why we need your help to lobby the regulators to change their stance and to make add-on trials more feasible. Until this happens I suspect I will be writing a similar Newsletter in 20 years time probably in my retirement. Do we really want MS history to repeat itself?
All this theoretical discussion doesn’t help you the person with MS. You have more advanced MS and realise you have smouldering MS or others may still be early in the course of your disease and wondering if your MS is smouldering away, i.e. is there evidence of smouldering disease and is it slowly depleting your reserve capacity, which will eventually result in you developing progressive MS. Please note smouldering MS is there from the very beginning and we have evidence for it in patients with radiologically isolated syndrome (RIS) or asymptomatic MS and in patients with CIS. So don’t think because you are well and fully functional that you have escaped smouldering disease.
I tend to give my patients with smouldering MS the benefit of the doubt and interrogate them as best I can to try and find ongoing focal inflammation. Yes, having ongoing inflammation on a DMT tells you the DMT is not working sufficiently well and predicts a poorer outcome.
In our centre, we would do a lumbar puncture to measure CSF neurofilament levels. Raised levels are an indicator of ongoing inflammation. Finding evidence of ongoing inflammation acts as a trigger to start a DMT or escalate and/or switch patients to another DMT. The latter comes with the caveat that the new treatment may or may not be effective at switching off the development of new lesions and hopefully prevent adding to the processes driving smouldering MS.
Please be aware that most of our anti-inflammatory therapies have only a modest impact on smouldering MS, except for possibly immune reconstitution therapies when started early (alemtuzumab, HSCT and possibly cladribine). Saying this there is evidence that in general the very high-efficacy DMTs (alemtuzumab, HSCT, natalizumab and high-dose anti-CD20 therapies) and some of the treatments that target specific processes (siponimod, cladribine and teriflunomide) do slow down the progression due to smouldering MS.
However, in the current treatment environment, which is dictated by regulators and payers, we can only justify switching if there is ongoing inflammatory activity. For example, switching of treatments in patients who have NEIDA is not allowed under the current NHS treatment algorithm unless it is done for reasons of safety and tolerability. Even then the options are limited. When we do make this switch we are doing it blindly without data that making the switch is going to do anything for the individual patient. I highlight this dilemma in a recent case study of someone on natalizumab who was NEIDA and clinically stable but had progressive brain volume loss and wanted to switch to alemtuzumab (MS Selfie case study, 23-Aug-2022). We eventually capitulated and did the switch on the condition the patient signed up to the monitoring requirements and the understanding that this switch may have no impact on the trajectory of their future brain volume loss. The patient was of the opinion that they wanted to have no regrets about the management of their MS in the future.
A corollary of the above is the complacency of many HCPs when managing patients who are apparently stable clinically with NEIDA as highlighted in this case study. Their position is that it is better to ignore what may be happening beneath the surface because there is little that can be done in the current environment. I understand this position but knowing that the patient in front of you has smouldering MS may make you more proactive in managing the patient, i.e. looking harder for subtle ongoing inflammatory activity, having a discussion about the holistic management of MS and optimising brain health in general or referring them for potential add-on studies to tackle smouldering MS such as our SIZOMUS trial, which is targeting CNS resident B-cells and plasma cells.
Safety of Ixazomib Targeting Plasma Cells in Multiple Sclerosis, NCT03783416.
The more pwMS who realise they have smouldering MS the more questions will get asked about add-on treatments. Hopefully, this will compel the wider MS community to tackle this problem. A proactive approach to identifying smouldering MS may slow down the adoption of clinical practices that may exacerbate the problem, for example, such as above of switching this patient from high-dose anti-CD20 therapy to low-dose anti-CD20 therapy.
I have been arguing that until we have evidence that switching from higher dose anti-CD20 to low dose anti-CD20 doesn’t exacerbate smouldering MS, i.e. what is the impact of the switch on disability progression and the rate of accelerated brain volume loss and other end-organ biomarkers, we shouldn’t be doing it routinely. Relying on relapses and MRI activity to say that high-dose and low-dose anti-CD20 therapy are equally effective is ignoring the real MS and the insights we have acquired about MS over the last 20-30 years. One of the reasons why we are doing two high-dose vs. standard-dose ocrelizumab studies in relapsing-MS and primary progressive MS is to see if the observation that higher doses of ocrelizumab are having a greater impact on disability progression than lower doses is real.
A Study to Evaluate the Efficacy, Safety and Pharmacokinetics of a Higher Dose of Ocrelizumab in Adults With Relapsing Multiple Sclerosis (RMS) - NCT04544436
High-dose vs. low-dose anti-CD20 therapy
To move our treatment target beyond NEIDA (no evident inflammatory disease activity) the new focus has to be on preventing end-organ damage and he processes driving smouldering MS, i.e. stopping disability progression, normalising brain volume loss, flattening neurofilament levels, stopping slowly expanding lesions from getting bigger, clearing the CSF of oligoclonal IgG bands and if possible promoting repair and recovery of the nervous system.
What good is to be free of relapses and focal MRI activity if you are getting worse? This is why the concept of using low dose anti-CD20 therapy is so flawed. It is clear that study subjects exposed to lower doses of ocrelizumab in the phase 3 trials, due to body size, do as well as those exposed to higher doses in relation to relapses and MRI activity, but not in relation to worsening disability or smouldering disease.
In the phase 3 ocrelizumab trials, we selected to use a fixed dose of 600mg of ocrelizumab intravenously every 6 months. By doing this we realised smaller pwMS would be getting a bigger dose of ocrelizumab compared to larger people. For example, someone weighing 60 kg will get 10mg/kg of ocrelizumab 6-monthly compared to 5mg/kg for someone with MS weighing 120 kg. By measuring drug concentrations we could divide trial subjects into four groups or quartiles; representing four dosing levels. Despite there being no difference between these four groups in relation to the treatment effect of ocrelizumab on relapses and MRI activity those subjects who received higher doses and had greater B-cell depletion, were less likely to progress (to see data). This higher-dose treatment effect on smouldering MS, i.e. beyond NEIDA, was seen in both the relapsing and primary progressive populations.
From these post-hoc analyses of the phase 3 ocrelizumab trials, it is clear that you need higher, and not lower, doses of anti-CD20 therapy to tackle smouldering MS. At the moment these observations only apply to the initial two years of treatment and hence it is possible you may only need higher doses as an induction strategy to purge the various B-cell compartments of pathogenic (disease-causing) cells. I hypothesise that the deep tissue compartments house memory B-cells, which may be an important sanctuary for latent EBV and/or the highly autoreactive population of B-cells that drive and maintain the MS disease state. This population of cells may reside in the deep tissues and/or the central nervous system, which can only be reached with higher doses of anti-CD20 therapy or other CNS penetrant anti-B-cell strategies, for example, ixazomib, cladribine, BTK inhibitors, etc. This is why we potentially need higher doses of anti-CD20 therapies, and not lower doses, to go beyond the peripheral B-cell target.
Once you have purged these compartments, say after 2 years of anti-CD20 treatment, you may not need to maintain pwMS on such high doses of anti-CD20 therapy, which will then continue to suppress normal B-cell biology and immune responses with potentially long term complications. This is why I have proposed potentially using high-dose 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 what we are proposing to do in the ocrelizumab adaptive dosing or ADIOS study.
Another strategy would be two years of induction therapy with high-dose ocrelizumab followed by a maintenance therapy such as teriflunomide, leflunomide, IMU-838 (vidofludimus) or ASLAN003 (selective second-generation DHODH inhibitors), HAART (highly active antiretrovirals), famciclovir or another anti-EBV viral agent. This induction-maintenance (IM) strategy is one arm of the ADIOS-IM trial we hope to do in the UK in the near future.
The hypothesis that we are testing above is to allow B-cell reconstitution after anti-CD20 therapy in the presence of an antiviral agent to prevent EBV reactivation and reinfection of new memory B cells. By doing this you will also be derisking the long-term immunosuppression associated with anti-CD20 therapies and preventing the development of hypogammaglobulinemia. This strategy will also allow patients to respond to vaccines and deal with infections as the follow-on maintenance anti-viral therapies are not immunosuppressive treatments.
What are low dose anti-CD20 therapies?
Lower dose anti-CD20 therapy is a moving target and in my opinion should not be equated with peripheral B-cell counts, which are a poor surrogate for what is happening in the deep tissues and CNS. We need better and more accessible biomarkers to study these compartments, but we are working on this as a research project. At present receiving ocrelizumab less than 6 monthly and being on rituximab or ofatumumab could be classed as low-dose anti-CD20 therapy. Please remember in the Swedish cohort rituximab had less impact on brain volume loss compared to interferon beta and despite ofatumumab being vastly superior to teriflunomide in suppressing relapses and MRI activity, it was not superior to teriflunomide at slowing down brain volume loss in year two of the ASCLEPIOS I and II clinical trials (NCT02792218 and NCT02792231). Please pause here and ask yourself why?
A fundamental question you should ask yourself
So what would you choose your MS to be treated with; low-dose anti-CD20 or high-dose anti-CD20?
I am aware that many neurologists are choosing the low-dose route based on the assumption that it is safer than high-dose anti-CD20 therapy. However, I think with both strategies the B-cells remain very low particularly memory B-cells. I am therefore not sure the adaptive dosing strategy is safer. I think using ocrleizumab as an IRT or induction therapy is safer, but not using intermittent or adaptive dosing when you don’t allow sufficient peripheral B-cell reconstitution and for a long enough period of time to allow normal B-cell immunity to resume. I am researching the latter at present and will do a separate post on this specific issue in the next few weeks.
I am sure you have a lot of questions about the issues raised in this Newsletter. Many of the points I cover in this Newsletter should not be new to you.
Potential conflict of interest
Please note that I am a member of the steering committee of the high-dose ocrelizumab studies, which are being sponsored by Roche.
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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 Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.
Case study: are we ready for adaptive ocrelizumab dosing?