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.
As you are aware, MS is an iceberg, with most of the MS disease activity and resultant damage being hidden. The study below expands the concept of the MS iceberg to the cerebral cortex or grey matter. Most lesions (~80%) found at post-mortem in the grey matter are not detected using specialised MR imaging. Please note that post-mortem MRI imaging in more standardised than that which happens in clinical practice and I suspect even more lesions will be missed in real-life.
Is this study important? You bet. We know that these grey matter lesions are associated with cognitive impairment, loss of brain volume and in particular progressive grey matter atrophy and are associated with poor longterm outcome and reduced quality of life.
Do you want to know what your true MS disease burden is? Based on this data and other studies it looks as if MRI is not the best way of doing this. I suspect a better marker will be ‘deep phenotyping’, i.e. interrogating the function of your nervous system using stress tests to see how you perform. Knowing you have cognitive impairments, for example, slow cognitive reaction times, difficulty with concentration and attention, poor memory or other specific deficits may be more meaningful to you. Or not? I say ‘or not’ as not all pwMS want to know that have cognitive impairment; they argue if nothing can be done about it is best to ignore it. This is called the ‘ostrich syndrome’.
Knowing you have cognitive deficits will allow you to take specific actions to address the problem and to potentially make important real-life decisions about your future. It also allows your HCP to take action to address some medical issues that are linked to cognitive impairment, i.e. poor adherence to treatments, physical accidents and comorbid depression and anxiety to name a few. One could argue that pwMS who have cognitive impairment should be put on a high-risk register for more proactive management and care.
It is clear that the burden of MS is not only physical but cognitive as well. This is another reason to diagnose, treat and manage MS effectively and as early as possible to prevent end-organ damage and preserve your grey matter. Can I please remind you that no all DMTs are made equal when it comes to preserving brain volume or grey matter.
This post reminds me of an infographic I put together about 5 years ago called ‘Grey Matter, Matters’, which I used to support a campaign I started to redefine MS as a ‘preventable dementia’.
Cortical demyelinating lesions are clinically important in multiple sclerosis, but notoriously difficult to visualize with MRI. At clinical field strengths, double inversion recovery MRI is most sensitive, but still only detects 18% of all histopathologically validated cortical lesions. More recently, phase-sensitive inversion recovery was suggested to have a higher sensitivity than double inversion recovery, although this claim was not histopathologically validated. Therefore, this retrospective study aimed to provide clarity on this matter by identifying which MRI sequence best detects histopathologically-validated cortical lesions at clinical field strength, by comparing sensitivity and specificity of the thus far most commonly used MRI sequences, which are T2, fluid-attenuated inversion recovery (FLAIR), double inversion recovery and phase-sensitive inversion recovery. Post-mortem MRI was performed on non-fixed coronal hemispheric brain slices of 23 patients with progressive multiple sclerosis directly after autopsy, at 3 T, using T1 and proton-density/T2-weighted, as well as FLAIR, double inversion recovery and phase-sensitive inversion recovery sequences. A total of 93 cortical tissue blocks were sampled from these slices. Blinded to histopathology, all MRI sequences were consensus scored for cortical lesions. Subsequently, tissue samples were stained for proteolipid protein (myelin) and scored for cortical lesion types I-IV (mixed grey matter/white matter, intracortical, subpial and cortex-spanning lesions, respectively). MRI scores were compared to histopathological scores to calculate sensitivity and specificity per sequence. Next, a retrospective (unblinded) scoring was performed to explore maximum scoring potential per sequence. Histopathologically, 224 cortical lesions were detected, of which the majority were subpial. In a mixed model, sensitivity of T1, proton-density/T2, FLAIR, double inversion recovery and phase-sensitive inversion recovery was 8.9%, 5.4%, 5.4%, 22.8% and 23.7%, respectively (20, 12, 12, 51 and 53 cortical lesions). Specificity of the prospective scoring was 80.0%, 75.0%, 80.0%, 91.1% and 88.3%. Sensitivity and specificity did not significantly differ between double inversion recovery and phase-sensitive inversion recovery, while phase-sensitive inversion recovery identified more lesions than double inversion recovery upon retrospective analysis (126 versus 95; P < 0.001). We conclude that, at 3 T, double inversion recovery and phase-sensitive inversion recovery sequences outperform conventional sequences T1, proton-density/T2 and FLAIR. While their overall sensitivity does not exceed 25%, double inversion recovery and phase-sensitive inversion recovery are highly pathologically specific when using existing scoring criteria and their use is recommended for optimal cortical lesion assessment in multiple sclerosis.
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?
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.
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).
I continue to be amazed when I hear senior MS neurologists make the claim they have never prescribed alemtuzumab or referred any of their patients for HSCT and don’t intend to do so either. These same neurologists seem to be happy with natalizumab and ocrelizumab as their #1 high-efficacy go to DMTs. When I challenge them with the exceptional longterm outcomes for pwMS treated early with alemtuzumab or HSCT I get a glazed look, which I now learnt is cognitive dissonance.
“Cognitive dissonance refers to a situation involving conflicting attitudes, beliefs or behaviours. This produces a feeling of mental discomfort leading to an alteration in one of the attitudes, beliefs or behaviours to reduce the discomfort and restore balance. For example, when people smoke (behaviour) and they know that smoking causes cancer (cognition), they are in a state of cognitive dissonance.” Source: Simply Psychology
It is quite clear that both ocrelizumab and natalizumab are very effective DMTs at switching-off focal inflammatory disease activity in MS; a large number of pwMS on these therapies are NEDA-2 (relapse-free and no new T2 lesions on MRI). This is interpreted by these neurologists and the wider MS community that MS is all sorted. Go away, get on with your life and be happy.
What these neurologists don’t tell their patients on ocrelizumab and natalizumab that despite no relapses or new MRI lesions the accelerated brain volume loss due to MS is continuing unabated. These neurologists and their patients are being lulled into a sense of false security because they believe MS is focal inflammatory disease, when in fact the real MS is the smouldering disease, which drives end-organ damage.
I have addressed these topics many times on this blog. If you are interested in reading some of my back catalogue of posts on this particular topic you can start with the posts below or you could watch a recent lecture I have given on the topic.
It is clear that not all DMTs are made equal when it comes to preventing end-organ damage. At the top of the league table are alemtuzumab and HSCT (~0.2-0.25% loss per annum). Both these treatments are NIRTs (non-selective immune reconstitution therapies).
Natalizumab is probably next with an annual brain volume loss in the region of 0.25-0.30% per annum. Ocrelizumab (anti-CD20) comes next with a rate of brain volume loss of ~0.374% per annum (see latest data below).
Why do natalizumab and ocrelizumab, despite being very effective anti-inflammatory DMTs have only a moderate impact on end-organ damage? This and other observations have convinced me that MS is not focal inflammation, which represents the immune system’s response to what is causing MS. I suspect there is something going in the CNS of pwMS that is the real MS; I refer to this hypothesis as the ‘Field Hypothesis’.
What these observations are telling us that peripheral B-cells are an important part of the immune response to the cause of MS, but B-cells are not necessarily involved in driving the true MS pathology, which is causing the progressive brain volume loss.
What does this mean for the well-informed person with MS? Firstly, you and your neurologist may not want to dismiss alemtuzumab and HSCT as a first-line, or at least early, treatment option. These non-selective highly effective IRTs differ from anti-CD20 therapies in that they target both B and T cells. I suspect we need to target both these cells types early in the course of the disease to really get on top of the real MS.
I am aware of the appeal of anti-CD20 therapies and natalizumab in that they are safer and easier to use because of less monitoring, however, this may come at a cost in the long-term. Please remember that once you have lost brain you can’t get it back. With alemtuzumab and HSCT, the risk is frontloaded, and balanced against the potential long-term gains in efficacy, which are unprecedented. Choosing a DMT on a rung or two lower down on the therapeutic ladder gives you better short-term safety and makes the life of your MS neurologist less stressful, because of less monitoring and fewer risks, but at a potential long-term cost to your brain and spinal cord.
This is why making an informed decision about which DMT you choose is a very complicated process and subject to subtle and often hidden effects of cognitive biases; cognitive dissonance is just one of these biases. The one bias I am very aware of is the ‘Gambler’s Dilemma’, be careful not to be lulled into a false sense of security by your beliefs; most gamblers eventually end-up losing.
In reality, we need to move treatment target in MS way beyond NEDA-2 to target end-organ damage, i.e. brain volume loss, T1 black holes, the slowly expanding lesions (SELs), neurofilament levels, cognition, sickness behaviour, OCBs, etc. Our treatment aim should be to ‘Maximise Brain Health’ across your life and not just the next few years.
As yet we don’t know what the impact of alemtuzumab and HSCT are on the pathology of smouldering MS, but these agents must be doing something to these pathologies based on clinical and MRI outcomes (see below). Despite this data gap, I think we have enough empirical evidence that alemtuzumab and HSCT are doing some fundamental to the pathology of MS.
Coming back to cognitive dissonance. It could be argued that if an MS neurologist or MS centre does not offer alemtuzumab or HSCT to at least some of their patients then they are not providing their patients with sufficient choice. In addition, they will almost certainly not accept the concept of smouldering MS being the real MS.
Objective: To assess over 3 years of follow-up, the effects of maintaining or switching to ocrelizumab (OCR) therapy on clinical and MRI outcomes and safety measures in the open-label extension (OLE) phase of the pooled OPERA studies in relapsing multiple sclerosis.
Methods: After 2 years of double-blind, controlled treatment, patients continued OCR (600 mg infusions every 24 weeks) or switched from interferon (IFN) β-1a (44 μg 3 times weekly) to OCR when entering the OLE phase (3 years). Adjusted annualized relapse rate, time to onset of 24-week confirmed disability progression/improvement (CDP/CDI), brain MRI activity (gadolinium-enhanced and new/enlarging T2 lesions), and percentage brain volume change were analyzed.
Results: Of patients entering the OLE phase, 88.6% completed Year 5. The cumulative proportion with 24-week CDP was lower in patients who initiated OCR earlier, vs patients initially receiving IFN β-1a (16.1% vs 21.3% at Year 5; p=0.014). Patients continuing OCR maintained, and those switching from IFN β-1a to OCR attained near complete and sustained suppression of new brain MRI lesion activity from Year 3 to 5. Over the OLE phase, patients continuing OCR exhibited less whole brain volume loss from double-blind study baseline vs those switching from IFN β-1a (–1.87% vs –2.15% at Year 5; p<0.01). Adverse events were consistent with past reports and no new safety signals emerged with prolonged treatment.
Conclusion: Compared with patients switching from IFN β-1a, earlier and continuous OCR treatment up to 5 years provided sustained benefit on clinical and MRI measures of disease progression.
Classification of evidence: This study provides Class III evidence that earlier and continuous treatment with ocrelizumab provided sustained benefit on clinical and MRI outcomes of disease activity and progression compared with patients switching from IFN β-1a. The study is rated Class III because of the initial treatment randomization disclosure that occurred after inclusion in OLE.
BACKGROUND: A cohort of patients with poor-prognosis multiple sclerosis (MS) underwent chemotherapy-based immune ablation followed by immune reconstitution with an autologous hematopoietic stem cell transplant (IA/aHSCT). This eliminated new focal inflammatory activity, but resulted in early acceleration of brain atrophy.
OBJECTIVE: We modeled the time course of whole-brain volume in 19 patients to identify the baseline predictors of atrophy and to estimate the average rate of atrophy after IA/aHSCT.
METHODS: Percentage whole-brain volume changes were calculated between the baseline and follow-up magnetic resonance imaging (MRI; mean duration: 5 years). A mixed-effects model was applied using two predictors: total busulfan dose and baseline volume of T1-weighted white-matter lesions.
RESULTS: Treatment was followed by accelerated whole-brain volume loss averaging 3.3%. Both the busulfan dose and the baseline lesion volume were significant predictors. The atrophy slowed progressively over approximately 2.5 years. There was no evidence that resolution of edema contributed to volume loss. The mean rate of long-term atrophy was -0.23% per year, consistent with the rate expected from normal aging.
CONCLUSION: Following IA/aHSCT, MS patients showed accelerated whole-brain atrophy that was likely associated with treatment-related toxicity and degeneration of “committed” tissues. Atrophy eventually slowed to that expected from normal aging, suggesting that stopping inflammatory activity in MS can reduce secondary degeneration and atrophy.
OBJECTIVE: To describe detailed MRI results from 2 head-to-head phase III trials, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis Study I (CARE-MS I; NCT00530348) and Study II (CARE-MS II; NCT00548405), of alemtuzumab vs subcutaneous interferon β-1a (SC IFN-β-1a) in patients with active relapsing-remitting multiple sclerosis (RRMS).
METHODS: The impact of alemtuzumab 12 mg vs SC IFN-β-1a 44 μg on MRI measures was evaluated in patients with RRMS who were treatment-naive (CARE-MS I) or who had an inadequate response, defined as at least one relapse, to prior therapy (CARE-MS II).
RESULTS: Both treatments prevented T2-hyperintense lesion volume increases from baseline. Alemtuzumab was more effective than SC IFN-β-1a on most lesion-based endpoints in both studies (p < 0.05), including decreased risk of new/enlarging T2 lesions over 2 years and gadolinium-enhancing lesions at year 2. Reduced risk of new T1 lesions (p < 0.0001) and gadolinium-enhancing lesion conversion to T1-hypointense black holes (p = 0.0078) were observed with alemtuzumab vs SC IFN-β-1a in CARE-MS II. Alemtuzumab slowed brain volume loss over 2 years in CARE-MS I (p < 0.0001) and II (p = 0.012) vs SC IFN-β-1a.
CONCLUSIONS: Alemtuzumab demonstrated greater efficacy than SC IFN-β-1a on MRI endpoints in active RRMS. The superiority of alemtuzumab was more prominent during the second year of both studies. These findings complement the superior clinical efficacy of alemtuzumab over SC IFN-β-1a in RRMS.
CLASSIFICATION OF EVIDENCE: The results reported here provide Class I evidence that, for patients with active RRMS, alemtuzumab is superior to SC IFN-β-1a on multiple MRI endpoints.
BACKGROUND: Tissue damage in both multiple sclerosis (MS) lesions and normal-appearing white matter (NAWM) are important contributors to disability and progression. Specific aspects of MS pathology can be measured using advanced imaging. Alemtuzumab is a humanised monoclonal antibody targeting CD52 developed for MS treatment.
OBJECTIVE: To investigate changes over 2 years of advanced magnetic resonance (MR) metrics in lesions and NAWM of MS patients treated with alemtuzumab.
METHODS: A total of 42 relapsing-remitting alemtuzumab-treated MS subjects were scanned for 2 years at 3 T. T1 relaxation, T2relaxation, diffusion tensor, MR spectroscopy and volumetric sequences were performed. Mean T1 and myelin water fraction (MWF) were determined for stable lesions, new lesions and NAWM. Fractional anisotropy was calculated for the corpus callosum (CC) and N-acetylaspartate (NAA) concentration was determined from a large NAWM voxel. Brain parenchymal fraction (BPF), cortical thickness and CC area were also calculated.
RESULTS: No change in any MR measurement was found in lesions or NAWM over 24 months. BPF, cortical thickness and CC area all showed decreases in the first year followed by stability in the second year.
CONCLUSION: Advanced MR biomarkers of myelin (MWF) and neuron/axons (NAA) show no change in NAWM over 24 months in alemtuzumab-treated MS participants.
You may be interested in watching this online lecture I gave a week ago. It explains why relapses and focal MRI activity (Gd-enhancing lesions and new or enlarging T2 lesions) are not MS and why we need to focus on new therapeutic targets.
This week I am doing video consultations with all the volunteers who participated in the pivotal phase 3 and 10-year extension studies of the alemtuzumab clinical trials. My objectives are three-fold. Firstly, to make sure they are referred back into a routine NHS MS service and are not left floundering without follow-up. Secondly, to complete a few exit EDSS examinations of the last few subjects and thirdly, and most importantly, to thank them for their time and commitment to these trials.
During my video consultations, it dawned on me that I have never seen a cohort of patients doing so well 10+ years into their MS disease course. The majority are NEDA (no disease activity) fully functional and participating fully in life. Yes, fully in life; married, in civil and other partnerships, working, with families, playing sports, participating in creative activities, volunteering and with very few symptomatic MS problems. Yes, a few of them have thyroid problems, but these are all being managed without a major impact on these patients lives.
I am convinced that some of these trial subjects may actually be cured of having MS. I am witnessing something extraordinary and at the same time something very sad. Why have we, the MS community, not adopted early alemtuzumab treatment as the standard of care? Why wouldn’t you want to take a chance on a treatment that maximises your chances of staying fully functional and may even offer a cure?
The patients who are not doing so well, unfortunately, got onto alemtuzumab late and therein lies the epiphany; early highly-effective treatment is the only way to realistically slay this beast. Knowing what I know, if I had MS I would have no hesitation being treated with alemtuzumab or even HSCT.
The tragedy is that the MS community and the regulators have killed alemtuzumab relegating it to a second or in most countries a third or fourth line agent. This is an international tragedy and I am not sure if we will ever get alemtuzumab back to its rightful place as a first-line treatment option for early active MS.
Alastair Compston, his protege Alasdair Coles and the Cambridge team deserve all the plaudits for getting this innovation to the clinic. However, sometimes this is just not enough to get wide adoption of an extraordinary innovation.
I view the field of MS as being ‘Before Natalizumab or BN’ and ‘After Natalizumab or AN’ this vlog provides another important insight we have obtained from the reanalysis of the data from the original phase 3 or AFFIRM study.
Don’t mention the C-word as it raises unnecessarily high expectations is what many of my colleagues say. I don’t agree with them. Showing we have cured, or not cured, MS is how we will ultimately test the hypothesis that MS is an autoimmune disease.
People with MS (pwMS) want a cure. However, even if we have an MS cure in hand we may not prevent or reverse progressive disease. Focal inflammation damages nerves in two ways. It can shred and destroy nerve fibres as part of the initial inflammatory stage (acute neurodegeneration) or inflammation sets up processes that result in delayed worsening. The acute inflammatory MS lesion also damages axons and neurons but they manage to remain functioning albeit in a vulnerable state. However, this damage primes these axons and nerves to die off in the future. I like to call this delayed post-inflammatory neurodegeneration.
The mechanisms that result in delayed neurodegeneration of nerves or smouldering MS are many and include innate immunity (hot microglia), energy deficits (mitochondrial dysfunction), excitotoxicity (calcium overload), free radicals (oxygen and nitrogen radicals), premature ageing, intrathecal plasma cell production of pathogenic autoantibodies, persistent viral infection, etc.
Clearly, anti-inflammatory drugs that prevent new lesion formation, such as natalizumab, alemtuzumab and ocrelizumab, will not be able to prevent the delayed neurodegeneration from previous inflammatory lesions. What has happened in the past has happened; i.e. the water under the bridge analogy. So if you have relapsing MS and have had a lot of inflammatory activity in the past that have damaged many nerve fibres, even if you go onto a highly effective DMT that renders you NEDA, it is not going to prevent the ongoing loss of nerve fibres that are primed to die off from previous inflammation in the future. This is why did the PROXIMUS trial and are promoting the OXO trial; add-on neuroprotective drug to try and modify the primed but delayed die-off of neurons and axons in the future.
What protects you from entering the “clinically-apparent” secondary progressive phase of the disease is your reserve capacity, i.e. the surviving healthy nerve fibres in nerve pathways keep you functioning normally. I suspect that pwMS, who have been treated with highly-effective DMTs and who have now become secondary progressive, had a low reserve capacity and a large number of damaged nerve fibres that had been primed to die off. In other words, they were treated with DMTs too late to prevent SPMS in the vanguard pathway (the neuronal pathway with the most damage). This is why I keep pushing the message ‘early effective treatment’ is the only way to prevent secondary progressive MS.
The same processes happen in PPMS the only difference is pwPPMS don’t have the earlier relapses that bring them to the attention of the medical profession in the initial stages of the disease.
There are two conclusions to be drawn from these observations; (1) it is best to have your MS treated effectively early in the disease course to maximise your reserve capacity, and (2) we need additional add-on neuroprotective, remyelinating and neurorestorative therapies to target the delayed neurodegenerative processes referred to above.
In addition to this, we need to avoid and/or reverse any other factors that prematurely age the nervous system. The ageing hypothesis of progressive MS is a major factor that underpins our Brain Health campaign, which targets non-specific factors that have been associated with more rapid progression in MS (smoking, co-morbidities, lack of exercise, infections, etc.). Common to all these factors is that they reduce your reserve and hence bring forward and speed up progressive MS.
So unless you are rendered NEDA early in the course of your disease it may not prevent you from entering the progressive phase of the disease, i.e. it will not be the panacea you want. In addition, our licensed DMTs don’t kill long-lived plasma cells that continue to make intrathecal (within the CNS) antibodies that may drive progressive MS. The exceptions may be natalizumab and cladribine.
There are several reports of pwMS on natalizumab losing their OCBs (oligoclonal bands or antibody bands). It now emerges that plasma cells live in a ‘niche’ or home and that to keep them in the niche they use the VCAM-1-VLA-4 adhesion molecule interaction. Natalizumab disrupts this interaction and hence it is plausible that natalizumab may reduce the life expectancy of intrathecal (inside the CNS) plasma cells. If this proves to be the case natalizumab may still have the edge on the other DMTs in this regard.
A recent report from Poland showed that about 50% of pwMS treated with intravenous cladribine more than 10-years ago had lost their oligoclonal IgG bands and were more likely to be stable than the those who have not lost their OCBs. There is old and new data emerging suggesting that the immunoglobulin is present in the cerebrospinal fluid of pwMS is toxic to oligodendrocytes (cells that make myelin) and can stimulate microglia. Just maybe the immunoglobulins are responsible for the slowly expanding lesions (SELs) or the subpial grey matter lesions that are such an important part of progressive MS
To target plasma cells, which are long-lived, we will need add-on therapies. This is high on our list of priorities and we are starting the SIZOMUS trial, COVID-19 permitting, to test a therapy for myeloma (malignant plasma cells) in MS. We are also looking at the effects of cladribine in a similar way (CLADRI–PLUS and CLAD-B studies) and we also want to look at the impact of very early treatment of MS with natalizumab as well (ATTACK-MS study). We also have a longish list of other potential therapies we would like to try as well, but we need help with this, i.e. funding, colleagues to share the workload and potential Pharma interest to give us access to some of the compounds we have identified as potentially promising.
Our challenge and objective are to scrub the MS brain free of B-cells and plasma cells!
Some people don’t buy into this hypothesis, but it is also supported by the observation that pwMS who receive higher doses of ocrelizumab do better than those receiving lower doses. I think that this may be related to more CNS penetration of ocrelizumab and is why I have proposed that Roche do a double-dose or DODO study. In relation to the DODO study, it is not necessarily about giving double-dose ocrelizumab indefinitely, but only early on as induction therapy and then to explore post-induction safer maintenance therapies (BTKi or teriflunomide). Please see the iTeri and iBruT studies in the slide show below. I can’t stress how important these observations are and they have made me question whether or not we have optimised the dose of both ocrelizumab and rituximab and other emerging anti-CD20 therapies.
So yes, we may be able to cure you of MS with IRTs but you may not realise it depending on when in your course you are treated. So as you can see we as an MS community have a lot still to do when it comes to improving disease outcomes of people with MS and yes we need to mention the C-word. We need to define what a cure means and how to look for it so that we can declare victory or not.
CoI: multiple
PS there is quite a lot chatter going on Twitter in relation to this post.
This post explains why I have started to refer to cladribine as a small molecule anti-CD20/CD19 therapy and why oral cladribine should be part of the exit strategy to treat MS during the tail of the COVID-19 pandemic.
Although we use cladribine as an immune reconstitution therapy and often compare it to alemtuzumab it is, in fact, closer to anti-CD20 therapies in terms of its immunodepletion profile. This distinction is particularly important during the COVID-19 pandemic because it has allowed us to classify cladribine in an intermediate risk DMT, which allows us to treat MS with an IRT when we can’t use alemtuzumab.
Cladribine’s pros:
Cladribine is an oral therapy; hence no visits to COVID-HOT hospitals or institutions.
It kills cells gradually by a process called apoptosis. Cells dying from apoptosis are phagocytosed or swallowed by macrophages and as a result, there is no cell lysis or bursting open of the cells and the release of their contents that causes a cytokine release syndrome. This means there is no need to pre-treat patients with steroids, which we are trying to avoid at present.
Cladribine does not deplete monocytes and neutrophils and has a moderate impact on so-called NK cells. As the innate immune system is left intact there is a low risk of bacterial and other infections during the depletion phase and the innate cells can help fight viral infections, such as SARS-CoV-2.
T lymphocytes are in general depleted by about 40%-50% and most patients don’t drop their counts below 500/mm3. In the phase 3 programme about a quarter of patients had a grade 3 or 4 lymphopaenia, but this tended to occur after the second course in year 2 in subjects who were redosed when their lymphocyte counts had not recovered to above 800/mm3. We have used the trial data to model grade 3 and 4 lymphopaenia. I.e. less than 500/mm3, and estimate that less 5% of cladribine treated subjects will develop lymphocyte counts less than 500/mm3 if we stick to the redosing guidelines. This is very important as lymphopaenia is probably the most important risk factor for viral and severe viral infections.
In the T-cell compartment, the CD8+ T-cells were less effected than CD4+ T-cells. This is important because CD8+ T-cells are the cells responsible for fighting viral infections. This probably explains, apart from a small risk of herpes zoster reactivation, why we didn’t see an increase in viral infections compared to placebo in cladribine treated subjects in the phase 3 trial programme. The viral infections that did occur tended to be non-specific upper respiratory tract infections and were mild to moderate. In fact, the infection profile on cladribine, including the zoster signal, was much more similar to that which we see with ocrelizumab compared to alemtuzumab.
Cladribine is a remarkably good depleter of B-cells. B-cells number drop quicker than T-cells numbers; i.e. within days to weeks. In addition, B-cells are depleted by about 90% and importantly memory B-cells are severely depleted and to a similar level that we see with alemtuzumab. Importantly, when the B-cell numbers return these are so-called naive B-cells, which come from the bone marrow and are not memory B-cells. Interestingly, when you stop an anti-CD20 therapy such as ocrelizumab or rituximab and allow B-cell reconstitution they are also naive and are not memory B-cells that return in the short-term. In other words cladribine, alemtuzumab and ocrelizumab have similar effects on B-cells.
Please note that because ocrelizumab and rituximab are given as maintenance or continuous therapy there is a small increase in the incidence of serious infections over with time and the development of hypogammaglobulinaemia. This is not seen with cladribine. Once the immune system reconstitutes post-cladribine it can fight infections, immune survey the body for cancers and mount immune responses to new viral infections, such as SARS-CoV-2, and vaccines. In relation to vaccines both live and inactivated component vaccines can be given after cladribine.
The other important thing about cladribine is the monitoring requirements are low. Once you have had a course you only need a full blood count to be done 3 and 7 months after starting treatment. The rationale for this is that the 3-month time-point is where the nadir occurs and the 7-month time point is to check for recovery of lymphocyte counts. What this means during the COVID-19 pandemic is that if you are treated with oral cladribine and at 3 months your lymphocyte counts is above 500/mm3, which will be the vast majority of treated patients, you don’t need to self-isolate. In the 3-4% who have a lymphocyte count below 500/mm3 at month three, you will need to continue to self-isolate until your counts go above 500/mm3. To find out the latter you could wait another three months for the next blood test our you could ask your GP or MS team for an earlier test.
When you look at how cladribine works, i.e. it needs to be activated by an enzyme call DCK (deoxycytidine kinase) and broken down by an enzyme called ADA (adenosine deaminase), the profile of cells expressing the correct ratio of these enzymes matches the B-cell population that expresses CD19 and CD20 and explains why B-cells are more susceptible to the effects of cladribine than T-cells.
Another advantage of cladribine is that as a small molecule it penetrates the CNS. Cerebrospinal fluid (CSF) levels are about 25% of what is found the peripheral blood and at a level that would target B- and T-cells within the brain and spinal cord. I think this property of cladribine is very important and is one of the reasons why we are exploring cladribine as a treatment for progressive MS in the CHARIOT-MS trial.
In a similar way to ocrelizumab, I think cladribine has been hard done by COVID-19 guidelines that have stated not starting or not redosing cladribine during the COVID-19 pandemic. Why? Where is the science to support this position?
Now that we can see the pandemic is not going to end anytime soon and with a vaccine 18 or 24 months away I think we should reconsider using oral cladribine as it addresses many of the issues of treating highly active MS in these troubling times and it has the added advantage of leaving people with MS with a reconstituted vaccine-ready immune system if and when a SARS-CoV-2 vaccine arrives.
Please note that I am not saying cladribine and/or anti-CD20 therapies are safe. They have well-defined risk-benefit profiles that are less risky than what has been proposed by many people in terms of developing severe COVID-19. These risk-benefit profiles simply allow you to counsel patients with active MS about their treatment options during the COVID-19 pandemic.
I personally think both anti-CD20 therapies and cladribine are two highly effective therapies that allow a treatment exit strategy during the long tail of the SARS-CoV-2 pandemic.
I am on call at the Royal London Hospital and sitting in my office digesting some of my daily COVID-19 reading. However, something has just hit me between the eyes and I have to say wow aloud!
WOW!!
The paper and editorial below show you just how infective SARS-CoV-2 really is and why we are not going to win this battle for our vulnerable people without an effective anti-viral and/or vaccine. It also tells me that if we don’t get a vaccine things will not normalise for a very long time.
Who said the R0 (R-zero) for this virus was less than 3 and therefore we would get herd immunity at about a 60% seroprevalence rate? Not me!
R-zero or the basic reproduction number for SARS-CoV-2 is the expected number of cases infected by one case in a population where all individuals are susceptible to infection. The original calculations were based on symptomatic index cases and symptomatic contacts with positive swabs. The fact that a large number of people (possibly up to 50%) have now been shown to get asymptomatic infections and that the test for the virus is not 100% specific. This means that approximately 25% of cases with COVID-19 defined by clinical definition have negative nasopharyngeal (nose & throat) swabs; i.e. 25% of infected people who may be shedding are not detected with the swab test. Based on these assumptions I have estimated that in normal life (no social distancing) that the R-zero is likely to be somewhere between 6 and 7. This means that to get herd immunity, a point when natural transmission in the population stops, you need somewhere between 80% and 86% of the population to have immunity.
However, the study below just published in the New England Journal of Medicine makes me think this may even be an underestimate. In a well done ‘classic’ epidemiology study in a nursing home in Seatle, 23 days after the first positive test result in a resident, 64% tested positive for SARS-CoV-2; more than half (56%) of the residents were asymptomatic at the time of testing. Only half of these residents then went on to develop symptoms a few days later. A quarter of shedders never became symptomatic and most of these ‘asymptomatic shedders’ were shown to shedding viable virus. Tragically of the 57 residents who were shown to be infected with SARS-CoV-2 infection 15 died; a mortality rate of 26%.
Why is this so important? In short, a high or very high R-zero means that the government policy of relying on herd immunity to protect the vulnerable is not going to work.
Let me explain. Whilst we are socially distancing we reduce the R-zero of SARS-CoV-2 to less than 1 and hence the number of new cases falls and we flatten the curve. This is what is happening in the UK and many other countries at present. However, as soon as we stop the lockdown and allow social interaction the R-zero will rise above one and we will get more cases. But because this virus is so infectious we may need herd immunity to be well above 80% (possibly 90%) for the epidemic to peter out. At which time point the government is hoping to let vulnerable people remerge from self-isolation and feel confident that they will not be susceptible to being infected and dying from severe COVID-19.
The bad news is that 15.2% of the UK population is over 70 years of age (data from Age Concern) the government definition of the vulnerable population based on age. This is not taking into account all the other vulnerable groups who are less than 70 years of age, i.e. those who are obese and/or have diabetes, cardiovascular, respiratory diseases. This means that by the time we get herd immunity many more people will die from COVID-19. This is why the scientific community needs to push for anti-virals and an effective vaccine. But herein lies a problem.
To develop and test an effective vaccine we really need an epidemic to be in full swing, i.e. on the upside of the curve and not on the tail. A vaccine trial is like a drug trial; subjects are randomised to an active or SARS-CoV-2 vaccine arm or a comparator arm (placebo or another vaccine) and then you see whether or not there are fewer cases of COVID-19 on the active arm compared to the comparator arm. However, if there are too few cases developing COVID-19 because of social distancing, using face masks, hygiene measures, etc. it will take too long to get enough events or trial subjects getting COVID-19, to show the vaccine is working. This is why we the rich-world may need to go to parts of the world where social distancing etc. is not feasible and the R-zero remains high, i.e. the squatter camps, shantytowns, favelas or slums of the low and middle-income countries of the world.
We, the rich world, may have no choice but to take this low/middle-income route for the sake of the world. But if ‘we’ do take this route to develop an effective vaccine we have to make it ethical. We will have to offer these countries priority access to the vaccine. If we don’t it will be a travesty. I can imagine the headlines in the press if we don’t. ‘Vaccine Imperialism: How the Rich World Exploited The Poor!’
What are the implications for you if you have multiple sclerosis. If you are vulnerable you need to be prepared to self-isolate/shield for a very long time. If you are not vulnerable then you really need to prepare yourself for becoming infected with SARS-CoV-2 and getting COVID-19. I have a section on MS-Selfie that addresses this issue. I will be updating this section over the weekend as there are additional things you can do as an individual and as a family to help derisk your chances further.
I am sorry for bringing you bad news at the beginning of the weekend, but as always I feel it is important, to be honest, and frank.
The information in this post is quite complex so if you have any questions please feel free to ask.
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can spread rapidly within skilled nursing facilities. After identification of a case of Covid-19 in a skilled nursing facility, we assessed transmission and evaluated the adequacy of symptom-based screening to identify infections in residents.
METHODS: We conducted two serial point-prevalence surveys, 1 week apart, in which assenting residents of the facility underwent nasopharyngeal and oropharyngeal testing for SARS-CoV-2, including real-time reverse-transcriptase polymerase chain reaction (rRT-PCR), viral culture, and sequencing. Symptoms that had been present during the preceding 14 days were recorded. Asymptomatic residents who tested positive were reassessed 7 days later. Residents with SARS-CoV-2 infection were categorized as symptomatic with typical symptoms (fever, cough, or shortness of breath), symptomatic with only atypical symptoms, presymptomatic, or asymptomatic.
RESULTS: Twenty-three days after the first positive test result in a resident at this skilled nursing facility, 57 of 89 residents (64%) tested positive for SARS-CoV-2. Among 76 residents who participated in point-prevalence surveys, 48 (63%) tested positive. Of these 48 residents, 27 (56%) were asymptomatic at the time of testing; 24 subsequently developed symptoms (median time to onset, 4 days). Samples from these 24 presymptomatic residents had a median rRT-PCR cycle threshold value of 23.1, and viable virus was recovered from 17 residents. As of April 3, of the 57 residents with SARS-CoV-2 infection, 11 had been hospitalized (3 in the intensive care unit) and 15 had died (mortality, 26%). Of the 34 residents whose specimens were sequenced, 27 (79%) had sequences that fit into two clusters with a difference of one nucleotide.
CONCLUSIONS: Rapid and widespread transmission of SARS-CoV-2 was demonstrated in this skilled nursing facility. More than half of residents with positive test results were asymptomatic at the time of testing and most likely contributed to transmission. Infection-control strategies focused solely on symptomatic residents were not sufficient to prevent transmission after SARS-CoV-2 introduction into this facility.
