Category: Lab Lessons

Black Swan

Most of you know by now that I am one of the main proponents supporting EBV as the primary cause of MS. I think EBV is actively driving MS disease activity. The corollary to this statement is that we may be able to treat MS with anti-EBV drugs. We have suggested that all MS DMTs work by affecting memory B-cell biology and that this is the cell that host the EB virus. At Barts-MS, we have an active research programme to test anti-EBV drugs in MS.

One way of targeting EBV is via immunotherapy and Michael Pender, from Brisbane, has been promoting this strategy for over a decade. His data on using autologous ant-EBV CTLs (cytotoxic T-lymphocytes) is impressive. Almost too good to be true! Most of the MS community has dismissed his data as being biased due to being unblinded and from one centre. However, if you drill down into his data you will see that most of the MSers he has treated have had quite advanced disease with high EDSS scores and the improvements in disability have been so profound that it would be difficult to ascribe this to biased EDSS-rating. I am convinced that Michael Pender is onto something big and something very important.

This is why the ATARA Bio early phase 1b data is my one of my #ECTRIMS2019 highlights. Instead, of autologous cells, ATARA Bio is using MHC-matched allogenic CTLs. The good news from their poster presentation is that these cells seem safe as a treatment and at the high doses they are reproducing Pender’s single-centre results.

I agree it is too early to be jumping up and down and that we need to wait for the results of a randomised double-blind controlled study, but imagine a world in which we treat MS with anti-EBV CTLs and our MSers notice profound improvements in disability? This would be a true paradigm shift, a black swan event! Overnight MS would be classified as an infectious disease. Could you imagine what would happen to the MS DMT market? I sincerely hope for the MS community that this remarkable story pans out to be true.

Prof G’s ECTRIMS Highlight #2

Pender et al. Preliminary safety and efficacy of ATA188, a pre-manufactured, unrelated donor (off-the-shelf, allogeneic) Epstein-Barr virus-targeted T-cell immunotherapy for patients with progressive forms of multiple sclerosis. ECTRIMS 2019 Abstract: P1657.

Introduction: Evidence suggests Epstein-Barr virus (EBV) infection is associated with multiple sclerosis pathogenesis. In patients (pt) with progressive forms of MS (pMS), autologous EBV-specific T cells may prevent progression and improve symptoms (Pender, et al. JCI Insight. 2018).

Objectives: To evaluate ATA188, an off-the-shelf, allogeneic, EBV-targeted T cell immunotherapy comprised of HLA-matched, in vitro-expanded, cytotoxic T lymphocytes in a first-in-human, multicenter, 2-part study in adults with pMS (NCT03283826). Preliminary data are reported.

Methods: Eligible pt (age 18‒< 66) are EBV-seropositive with pMS and an Expanded Disability Status Scale (EDSS) score of 3‒7. Cohorts (cht) 1‒4 (6‒9 pt/cht) receive escalating doses of ATA188. 1° endpoints: safety and identification of the recommended phase 2 dose (RP2D) of ATA188. Efficacy criteria: EDSS, MS Impact Scale-29, Fatigue Severity Scale, and 12-Item MS Walking Scale scores; timed 25-foot walk; 9-hole Peg Test; and visual acuity. A responder (R) has sustained ≥ minimal clinically significant (MCS) improvement from BL in 2 consecutive evaluations on ≥2 efficacy criteria; a partial responder (PR) has ≥ MCS improvement from baseline (BL) in any 1 evaluation on ≥2 efficacy criteria; and a non-responder (NR) has ≥ MCS decline from BL in any 1 evaluation on ≥2 efficacy criteria (if both criteria are met, pt is NR). Plasma inflammatory biomarkers (IL-2, IL-1β, TNF-α, IL-6) are monitored throughout treatment.

Results: As of 27 May 2019, 19 pt (53% male; median age, 56 years) have enrolled (6 in each of cht 1‒3; 1 in cht 4) and received ≥1 dose of ATA188. Treatment-emergent AEs (TEAE) occurred in 63% (12/19) pt and treatment-related AEs (TRAE) in 37% (7/19) pt; 1 pt (cht 2) had a grade ≥ 3 TEAE, and 1 (cht 4) had a serious TRAE. No dose-limiting toxicities or fatal TEAE have been reported. Efficacy data are available for cht 1 and 2: cht 1, 1 R, 1 PR, and 4 NR at 6 months and 1 R, 0 PR, and 1 NR at 12 months; cht 2, 2 R, 4 PR, and 0 NR at 6 months. On measures of disability, 3/6 showed improvement and 3/6 showed decline in cht 1; 4/6 showed improvement and 1/6 showed decline in cht 2. Inflammatory cytokines remained at or near baseline.

Conclusion: Preliminary data indicate ATA188 is well tolerated and improves efficacy measures in adults with pMS, even at lower doses. These results support continuing part 1 to identify RP2D for part 2, (randomized, double-blind, placebo-controlled portion).

Pender et al. Epstein-Barr virus-specific T cell therapy for progressive multiple sclerosis. JCI Insight. 2018 Nov 15;3(22). pii: 124714. doi: 10.1172/jci.insight.124714.

BACKGROUND: Increasing evidence indicates a role for EBV in the pathogenesis of multiple sclerosis (MS). EBV-infected autoreactive B cells might accumulate in the CNS because of defective cytotoxic CD8+ T cell immunity. We sought to determine the feasibility and safety of treating progressive MS patients with autologous EBV-specific T cell therapy.

METHODS: An open-label phase I trial was designed to treat 5 patients with secondary progressive MS and 5 patients with primary progressive MS with 4 escalating doses of in vitro-expanded autologous EBV-specific T cells targeting EBV nuclear antigen 1, latent membrane protein 1 (LMP1), and LMP2A. Following adoptive immunotherapy, we monitored the patients for safety and clinical responses.

RESULTS: Of the 13 recruited participants, 10 received the full course of T cell therapy. There were no serious adverse events. Seven patients showed improvement, with 6 experiencing both symptomatic and objective neurological improvement, together with a reduction in fatigue, improved quality of life, and, in 3 patients, reduced intrathecal IgG production. All 6 patients receiving T cells with strong EBV reactivity showed clinical improvement, whereas only 1 of the 4 patients receiving T cells with weak EBV reactivity showed improvement (P = 0.033, Fisher’s exact test).

CONCLUSION: EBV-specific adoptive T cell therapy was well tolerated. Clinical improvement following treatment was associated with the potency of EBV-specific reactivity of the administered T cells. Further clinical trials are warranted to determine the efficacy of EBV-specific T cell therapy in MS.

TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12615000422527.

FUNDING: MS Queensland, MS Research Australia, Perpetual Trustee Company Ltd., and donations from private individuals who wish to remain anonymous.

CoI: multiple

What is MS?

The more I read,  think and assimilate information the more I realise that the real pathology behind MS is not the new acute lesion or relapse, but what is going on behind the scenes in the so-called slowly expanding chronic MS lesion or SEL. 

MS is a smouldering disease. 

In an analysis of the ocrelizumab-PPMS or ORATORIO trial, it is clear that SELs already existed in the brains of PPMSers when they started the trial and best predicted their clinical course during the trial. In contrast, brain atrophy or brain volume loss and new lesion activity did not predict disability progression. What is nice about this analysis is that it is in a PPMS population with a very low relapse rate, which excludes relapses as a confounder. 

I am not that concerned about brain volume loss not predicting outcome in this population, because it is out of sync with clinical outcomes; i.e. brain volume loss today is caused by pathology 2-3 years ago and hence needs to be correlated with clinical outcomes in the past. 

What is important in this study is that new MRI activity in the form of new T2 lesions did not predict disability worsening. In other words, focal inflammation is not associated with clinical outcome. In comparison, SELs or smouldering MS predicted clinical outcome. Based on basic medical philosophical principles around the definition of surrogate markers it is clear that new T2 lesions can’t be the disease we call MS, but SELs can. 

It is clear to me that MS is a biological disease and not an MRIscopic disease, i.e. what you see on MRI is the tip, of the tip, of the iceberg and that most of MS pathology is hidden from view when using conventional MRI. This is why you still deteriorate despite being NEDA (with no evident new disease activity). The NEDA in this context is referring to the absence of focal MS inflammatory activity, i.e. relapse(s) and new or enlarging lesions on MRI. The biology behind the worsening despite being NEDA is driven by the delayed neuroaxonal loss from previous damage, ongoing diffuse inflammation which has become independent of focal lesions (innate activation), ageing mechanisms or focal inflammatory lesions that are too small to be detected with our monitoring tools. Of all the processes listed here, the last one is the only one that is realistically modifiable by our current DMTs. 

The really important question this analysis raises is that when you treat someone with a DMT and they become NEDA how do you know they don’t have ongoing smouldering MS and hence would benefit from being escalated to a more effective DMT or should be included in add-on combination therapy trial? This is why we need to start using end-organ damage markers and more sensitive inflammatory markers to look for and define smouldering MS. Only then will we be able to start answering important questions. For example, does changing treatment in people with smouldering MS to more effective DMTs, for example, natalizumab, alemtuzumab or ocrelizumab result in them doing better? The ORATORIO analysis below would suggest the treatment effect in this situation is small. This is why we are going to need a new generation of add-on treatments that target CNS pathology, for example, hot microglia, antivirals (EBV and HERVs), CNS-penetrant anti-B-cell and plasma cell agents, neuroprotectives, etc. 

I have made the point that primary progressive MS (PPMS) is simply smouldering RRMS and that all we are doing with our DMTs is converting people with RRMS to PPMS and delaying the inevitable progressive phase of the disease.  I don’t buy this because a proportion of pwMS who have been treated early on with an immune reconstitution therapy or IRT, in particular, alemtuzumab or HSCT, appear to be in very longterm remission and may even be cured of their MS (see the previous post on this topic). Some would argue, I included, that this group of patients has not been followed up for long enough to be sure they have been cured. I agree and this is why we need a deep phenotyping study to assess whether or not these patients have any evidence of ongoing MS disease activity. This study would help define smouldering MS, by looking for its absence. 

The MRI-centric view of MS has lulled many of us into a false sense of security and has resulted in us classifying MS as a focal inflammatory autoimmune disease of the CNS. In reality, MS is a diffuse disease of the CNS and the focal inflammatory events are simply the immune response to what causes MS. This is why the field hypothesis of MS is so relevant and fundamentally challenges our worldview of MS. 

If we don’t change our worldview of MS and explore what is happening in the trenches alongside the one we currently have our heads buried in we will be letting down the next generation of MSers. 

Image from ‘when is a paradigm shift required‘.

Elliott et al. Chronic white matter lesion activity predicts clinical progression in primary progressive multiple sclerosis. BRAIN 2019: 142; 2787–2799. 

Chronic active and slowly expanding lesions with smouldering inflammation are neuropathological correlates of progressive multiple sclerosis pathology. T1 hypointense volume and signal intensity on T1-weighted MRI reflect brain tissue damage that may develop within newly formed acute focal inflammatory lesions or in chronic pre-existing lesions without signs of acute inflammation. Using a recently developed method to identify slowly expanding/evolving lesions in vivo from longitudinal conventional T2- and T1-weighted brain MRI scans, we measured the relative amount of chronic lesion activity as measured by change in T1 volume and intensity within slowly expanding/evolving lesions and non-slowly expanding/evolving lesion areas of baseline pre-existing T2 lesions, and assessed the effect of ocrelizumab on this outcome in patients with primary progressive multiple sclerosis participating in the phase III, randomized, placebo-controlled, double-blind ORATORIO study (n = 732, NCT01194570). We also assessed the predictive value of T1-weighted measures of chronic lesion activity for clinical multiple sclerosis progression as reflected by a composite disability measure including the Expanded Disability Status Scale, Timed 25-Foot Walk and 9-Hole Peg Test. We observed in this clinical trial population that most of total brain non-enhancing T1 hypointense lesion volume accumulation was derived from chronic lesion activity within pre-existing T2 lesions rather than new T2 lesion formation. There was a larger decrease in mean normalized T1 signal intensity and greater relative accumulation of T1 hypointense volume in slowly expanding/evolving lesions compared with non-slowly expanding/evolving lesions. Chronic white matter lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in slowly expanding/ evolving lesions and in non-slowly expanding/evolving lesion areas of pre-existing lesions predicted subsequent composite disability progression with consistent trends on all components of the composite. In contrast, whole brain volume loss and acute lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in new focal T2 lesions did not predict subsequent composite disability progression in this trial at the population level. Ocrelizumab reduced longitudinal measures of chronic lesion activity such as T1 hypointense lesion volume accumulation and mean normalized T1 signal intensity decrease both within regions of pre-existing T2 lesions identified as slowly expanding/evolving and in non-slowly expanding/evolving lesions. Using conventional brain MRI, T1- weighted intensity-based measures of chronic white matter lesion activity predict clinical progression in primary progressive multiple sclerosis and may qualify as a longitudinal in vivo neuroimaging correlate of smouldering demyelination and axonal loss in chronic active lesions due to CNS-resident inflammation and/or secondary neurodegeneration across the multiple sclerosis disease continuum.

CoI: multiple

DODO study

When you are fighting a war, even if it is only a marketing war, small effects can be the difference between winning and losing.

The TENERE study below would indicate that teriflunomide has similar efficacy to interferon-beta-1a (Rebif). However, this study was underpowered to show a difference between these two DMTs. Based on this and other data I suspect teriflunomide is more effective than IFN-beta. Why?

(1) Teriflunomide is the only DMT to have a consistent effect on disability progression; i.e. both phase 3 placebo-controlled trials were positive on this outcome. (2) Teriflunomide also has a significant effect on brain volume loss compared to placebo; in comparison, subcutaneous IFN-beta-1a does not. (3) Teriflunomide is also 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 finding. (4) Finally, teriflunomide is a broad-spectrum antiviral agent, which may be part of its mode of action in MS. 

Putting all these factors together I think teriflunomide will perform better than expected in head-2-head studies than Rebif has done in the past. Why is this important? Two of our top guns alemtuzumab and ocrelizumab were compared to Rebif and had a relative reduction in relapses of ~45%.

A 45% relative reduction in relapse rate has to be the new target in phase 3 active comparator trials. This is if you want your DMT to bat in the same division as alemtuzumab and ocrelizumab.

Yesterday Novartis announced that both of their phase 3 trials of ofatumumab vs. teriflunomide met their primary outcome. The following is an excerpt of Novartis’ press release:

In ASCLEPIOS I and II, ofatumumab (OMB157) met primary endpoints to reduce the annualized relapse rate over Aubagio (teriflunomide) in patients with relapsing forms of MS (RMS).

  • Key secondary endpoints of delaying time to confirmed disability progression were also met;  additional secondary endpoints will be presented at ECTRIMS
  • Ofatumumab, a potent, fully-human antibody targeting CD20 positive B-cells, delivered sustained efficacy with a favourable safety profile
  • Novartis plans to initiate submissions to health authorities by the end of 2019. If approved, ofatumumab will potentially become a treatment for a broad RMS population and the first B-cell therapy that can be self-administered at home

If ofatumumab’s relative reduction in annualised relapse rate is not in the order of 45% the MS community is going to assume it is not as effective as alemtuzumab and ocrelizumab. Based on my comments above I suspect the relative reduction will be less than 40%. In other words, the effectiveness of teriflunomide may have been underestimated. Or the effectiveness of ofatumumab may have been over-interpreted and over-modelled.

An aspect that needs to be considered is that ofatumumab may be underdosed in these trials. 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. Is this important? I suspect yes. 

At the AAN this year Stephen Hauser presented early data suggesting that when it comes to disability progression, not relapse rate or MRI activity, the extent of exposure to ocrelizumab makes a difference. The greater the ocrelizumab exposure the more effective it was. This could be related to deep tissue and end-organ 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). 

Slide from Hauser et al. AAN 2019.

What I am trying to say is that if ofatumumab does not bat in the same league as ocrelizumab when it comes to relative relapse reduction to an active platform comparator then all these factors will come to the fore and make ocrelizumab 600mg 6-monthly a more effective anti-CD20 than ofatumumab 20mg sc monthly.

My response to the Stephen Hauser’s presentation at AAN was to immediately design a study of double-dose (1200 mg) vs standard-dose (600 mg) ocrelizumab 6-monthly (DODO study) to see if the higher dose of ocrelizumab has a bigger impact on the intrathecal B cell response than the standard dose. The study will include next-generation MRI and other biomarkers to test the hypothesis. If this study was positive 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 study to the portfolio.

So please watch this space. We will soon hear about the ofatumumab results; they are being presented at ECTRIMS in 2 weeks time.  And if you work at Roche please tell the powers that be that we are really, really, interested in doing the DODO study 😉

Vermersch et al. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial. Mult Scler. 2014 May;20(6):705-16. 

BACKGROUND: In previous studies, teriflunomide significantly reduced the annualised relapse rate (ARR) and disability progression.

OBJECTIVE: This phase 3, rater-blinded study (NCT00883337) compared teriflunomide with interferon-beta-1a (IFNβ-1a).

METHODS: Patients with relapsing multiple sclerosis were randomised (1:1:1) to oral teriflunomide 7-or 14 mg, or subcutaneous IFNβ-1a 44 µg. The primary composite endpoint was time to failure, defined as first occurrence of confirmed relapse or permanent treatment discontinuation for any cause. Secondary endpoints included ARR, Fatigue Impact Scale (FIS) and Treatment Satisfaction Questionnaire for Medication (TSQM). The study was completed 48 weeks after the last patient was randomised.

RESULTS: Some 324 patients were randomised (IFNβ-1a: 104; teriflunomide 7 mg: 109; teriflunomide 14 mg: 111). No difference in time to failure was observed. There was no difference in ARR between teriflunomide 14 mg and IFNβ-1a, but ARR was significantly higher with teriflunomide 7 mg. FIS scores indicated more frequent fatigue with IFNβ-1a, though differences were only significant with teriflunomide 7 mg. TSQM scores were significantly higher with teriflunomide. There were no unexpected safety findings.

CONCLUSION: Effects on time to failure were comparable between teriflunomide and IFNβ-1a. There was no difference between teriflunomide 14 mg and IFNβ-1a on ARR, though ARR was higher with teriflunomide 7 mg. The teriflunomide safety profile was consistent with previous studies.

CoI: multiple

Cladribine Retreatment

What do you do when you get recurrent disease activity on cladribine?

I am repeatedly being asked what to do about disease activity in patients treated with cladribine. The following is my suggestions on how to approach this thorny issue.

As you know disease activity on immune reconstitution therapies (IRTs) don’t necessarily mean you failed or are failing the therapy. Disease activity could be an indication to retreat with an additional course.  Interpreting when and what to do depends on when the disease activity emerges and how severe it is.

Post-course 1

If you have a relapse after the first course (cycles 1 & 2) of cladribine I would hold fast and have the second course. There is no reason why someone who has disease activity in year 1 post-cladribine won’t necessarily respond to the second course. There is, however, one proviso here. With alemtuzumab, another IRT, rare patients get rebound activity, over and above baseline activity, around months 7-9 post the first course of alemtuzumab infusions. Why this happens we don’t know. We have not observed this with cladribine yet, but it could theoretically happen. In this situation, the disease activity is so severe that most of these patients are offered alternative treatments, in particular, anti-CD20 therapies (rituximab or ocrelizumab), mitoxantrone, cyclophosphamide or HSCT. 

When we see recurrent disease activity in year 1 post-alemtuzumab we have often brought forward the second course of alemtuzumab. I see no reason why we wouldn’t consider this with cladribine as well, provided the total lymphocyte counts have recovered to above 800/mm3. 

Post-course 2 – year 2

If disease activity occurs in year 2 this is not good news. This would indicate that the patient has not responded to cladribine and would be an indication to switch therapeutic strategies. 

Post-course 2 – year 3 & 4

If you have disease activity in years 3 & 4 the timeframe covered by the current cladribine label you are not meant to retreat with cladribine. However, this makes no sense to me. IRT works by depletion and reconstitution. In some people, the two cycles of depletion with cladribine may not be sufficient to deplete the autoreactive pool and hence MS disease activity resurfaces. I personally think there is no reason why a further course of cladribine should not be offered alongside other DMTs in this situation. This is exactly how we use alemtuzumab in this situation; the difference being alemtuzumab is now licensed to be used in this way. Clearly there is an evidence gap around cladribine and hopefully, this will be filled as real-life data sets emerge in the future.

Post-course 2 – after 4 years

Similar to the above I see no reason why a further course of cladribine should not be offered alongside other DMTs in this situation. This is how we use alemtuzumab and other IRTs. I am aware of one patient in the US has had 7 courses of intravenous cladribine over a period of 21 years. 

The future

Cladribine has a variable treatment effect on the total lymphocyte counts. There are biochemical reasons why this may occur. I see in the future adapting the dose of cladribine we use to achieve an optimal level of lymphocyte depletion. This makes sense.

I also see cladribine being used as induction therapy, i.e. after an initial course of cladribine, we will be following it with maintenance therapy. Based on the memory B-cell hypothesis BTKi (Bruton’s Tyrosine Kinase inhibitor) or teriflunomide (antiproliferative/antiviral) makes the most sense at present. 

I would love to do a trial of an IRT followed by maintenance therapy. Any takers? Any funders? In terms of safety and cost, I would go off-label and test rituximab followed by leflunomide vs. rituximab as an IRT. 

The following is a visual summary of some of the information above.

CoI: multiple

Do you want a cure?

MSers want a cure. However, even if we have an MS cure in hand we may not prevent or reverse progressive disease. How can this be?

Focal inflammation damages nerves in two ways. It can shred and destroy nerve fibres as part of the initial inflammatory stage (acute neurodegeneration) or it can damage nerves and leave them functioning, but the resulting damage primes them to die off in the future; I call this delayed 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, etc.

Clearly, anti-inflammatory drugs that prevent new lesions 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 delayed die-off of neurons and axons.

What protects you from entering the clinically-apparent secondary progressive phase of the disease is reserve capacity, i.e. the surviving healthy nerve fibres in nerve pathways keep you functioning normally. I suspect that MSers, who have been treated with highly-effective DMTs and 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 the future. In other words, they were treated with DMTs too late to prevent SPMS. This is why we keep pushing the message ‘early effective treatment’ is the only way to prevent secondary progressive MS.

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 therapies to target the delayed neurodegenerative processes referred to above. The latter includes avoiding or reversing 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.).  

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 my drive progressive MS. The exception may be natalizumab. There are several reports of MSers 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.

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 to test a therapy for myeloma (malignant plasma cells) in MS. Can we scrub the MS brain free of plasma cells?

CoI: multiple

Envy – will we ever be in a position to prevent MS?

On the 5th August, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation (BTD) to teplizumab (anti-CD3) for the prevention or delay of clinical type 1 diabetes (T1D) in individuals at risk of developing the disease. This is quite amazing and has implications way beyond T1D. 

The question in relation to anti-CD3 treatment is this ‘true prevention’ or simply a disease-modifying effect, i.e. a treatment that prevents the end-organ damage that eventually leads to clinical T1D? These were all antibody-positive subjects at very high risk of developing T1DM; i.e. they had a ~85% chance of developing T1DM and arguably had subclinical inflammation or autoimmune attack ongoing in their pancreas when they were treated with anti-CD3. 

In the MS space, this study would analogous to treating radiologically-isolated syndrome and delaying RIS patients from having their first clinical attack. 

The question for MSers is that if we could identify who of your children or siblings are at very high risk of getting MS – for argument’s sake let’s say they had a  >50% risk of getting MS – would you volunteer them to participate in an anti-CD3 MS prevention trial? 

The difference between T1D and MS is that endocrinologists have insulin; i.e. when the end-organ fails you simply replace insulin. In MS when the end-organ fails you become disabled with all its socio-economic consequences.  Type 1 diabetics do so much better than MSers; in short, the stakes are so much higher for MSers.

I wonder how the EMA will respond to teplizumab? Breakthrough Therapy Designation (BTD) is an FDA program designed to expedite the development and review of therapeutic candidates intended to treat serious or life-threatening diseases.  I predict that the European regulators arguing that in the modern era T1D is not a serious or life-threatening disease. We need to push back against such criticisms as they may use similar arguments if we ever get to this position in relation to MS. 

I am so envious of the T1 diabetologists. I have a dream of being in a position one day of either offering people at high risk of developing MS, or members of the general public, an intervention to either reduce their risk or prevent them from developing MS. The question I have is society, the MS community and the regulators ready for MS prevention studies? 

Herold et al. An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. N Engl J Med. 2019 Aug 15;381(7):603-613.

BACKGROUND: Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in patients with type 1 diabetes, but interventions that might affect clinical progression before diagnosis are needed.

METHODS: We conducted a phase 2, randomized, placebo-controlled, double-blind trial of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) involving relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease. Patients were randomly assigned to a single 14-day course of teplizumab or placebo, and follow-up for progression to clinical type 1 diabetes was performed with the use of oral glucose-tolerance tests at 6-month intervals.

RESULTS: A total of 76 participants (55 [72%] of whom were ≤18 years of age) underwent randomization – 44 to the teplizumab group and 32 to the placebo group. The median time to the diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group; the disease was diagnosed in 19 (43%) of the participants who received teplizumab and in 23 (72%) of those who received placebo. The hazard ratio for the diagnosis of type 1 diabetes (teplizumab vs. placebo) was 0.41 (95% confidence interval, 0.22 to 0.78; P = 0.006 by adjusted Cox proportional-hazards model). The annualized rates of diagnosis of diabetes were 14.9% per year in the teplizumab group and 35.9% per year in the placebo group. There were expected adverse events of rash and transient lymphopenia. KLRG1+TIGIT+CD8+ T cells were more common in the teplizumab group than in the placebo group. Among the participants who were HLA-DR3-negative, HLA-DR4-positive, or anti-zinc transporter 8 antibody-negative, fewer participants in the teplizumab group than in the placebo group had diabetes diagnosed.

CONCLUSIONS: Teplizumab delayed progression to clinical type 1 diabetes in high-risk participants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01030861.).

OXO Study

We want to build a sandwich to tackle the many facets of multiple sclerosis that result in neuroaxonal loss. At the base of treatment pyramid, we need an anti-inflammatory onto which we want to add a neuroprotectant, i.e. the combination therapy strategy.

You need to protect damaged and vulnerable axons so that you can then remyelinate them or restore their function. We assume this makes sense, but still, we get push back from many in the field who are determined to still do monotherapy neuroprotective trials. 

What is the point of protecting an axon, allowing it to be remyelinated and to recover function for it to be damaged again in the next round of inflammatory attack? 

Barts-MS Dictum: It makes no biological sense to do monotherapy MS neuroprotective trials in the modern era.

With this in mind, we had a ‘brainstorming’ session last week and came up with a new neuroprotective trial design in primary progressive MS; it is called the OXO PPMS trial or  ‘Add-on OXcarbazepine to Ocrelizumab in PPMS Study’. 

Why PPMS? We feel that PPMS has a massive unmet need and that as ocrelizumab is now licensed as the only DMT in PPMS it makes an ideal platform therapy. We have chosen oxcarbazepine, a sodium channel blocker, as our add-on agent because we have pilot data (animal and clinical) showing it may work and it seems to be better tolerated than other sodium channel blockers. In an ideal world, we would want this study to be done with a new agent that has a long patent life, which would allow Pharma to invest in the necessary studies to get the drug licensed. But alas we can’t find a Pharma company with a new sodium channel blockers who would be interested in MS.

Raj Kapoor, David Baker and I have spent an extraordinary amount of time trying to get Big Pharma to buy into the add-on sodium channel blocker neuroprotection paradigm. Sadly none of the decision-makers has bought into the paradigm, yet. Just maybe with new data and the fact that all the low-hanging fruit on the MS tree has been picked they may change their minds. 

Please note that neuroprotection is only a small part of the solution to worsening or progressive MS. To tackle this problem we need a lot more than neuroprotection, which is why we need to manage MS holistically. 

To reiterate the philosophy of marginal gains “if you break down everything we can think of that goes into improving MS outcomes, and then improving it by 1%, we will get a significant increase when we put them all together. This also means avoiding things that make MS worse”. This is why anti-ageing strategies, in particular, lifestyle factors, need to be included in the longterm treatment strategy to manage MS.  

What do you think of the OXO PPMS study? If you have PPMS would you volunteer for this study? 

CoI: multiple

#ThinkCognition

If you have MS-related cognitive impairment would you want a treatment to improve your cognitive function? 

The study below shows that dalfampridine, or fampridine, improves cognition in particular processing speed in MSers with cognitive impairment. Importantly the improvement on the SDMT (Symbol Digit Modalities Test) was greater than 4 points, which is considered clinically meaningful in that it is anchored to improved day-to-day functioning and quality of life. 

Dalfampridine has a complex mode of action and is thought to increase the so-called safety factor of conduction and synaptic function and improves the functioning of demyelinated or thinly remyelinated axons. 

Dalfampridine is currently licensed to improve walking speed in MSers. As it has not been green-lighted by NICE for use on the NHS most MSers can’t access this treatment. In London, some NHS hospitals have put in place a limited access scheme and therefore can prescribe fampridine for some of their patients. Despite this most MSers who take fampridine in the UK are having to pay for it privately, which I find totally unacceptable. Why should your ability to pay and access private healthcare dictate your access to a treatment that is being used extensively across the world? 

This cognitive study below suggests that similar mechanisms underlie both motor and cognitive performance in MS. What is important about this study is that it demonstrates the principle that MS-related cognitive impairment is a potentially treatable problem. It also raises the question of whether, or not, we should be doing routine cognitive testing in clinical practice and telling our patients they have cognitive impairment and hopefully in the future being able to offer them an effective therapy to improve their cognition or processing speed. 

De Giglio et al. Effect of dalfampridine on information processing speed impairment in multiple sclerosis. Neurology. 2019 Jul 22. pii: 10.1212/WNL.0000000000007970.

OBJECTIVE: To test a possible benefit of dalfampridine on information processing speed (IPS), a key function for cognitive impairment (CogIm) in multiple sclerosis (MS).

METHODS: In this randomized, double-blind, placebo-controlled trial, we included patients with a score on the Symbol Digit Modalities Test (SDMT) under the 10th percentile of the reference value. Patients were randomized in a 2:1 ratio to receive dalfampridine 10 mg or placebo twice daily for 12 weeks. They underwent a comprehensive neuropsychological evaluation at screening (T0), at the end of treatment (T1), and after a 4-week follow-up (T2). The primary endpoint was improvement in SDMT.

RESULTS: Out of 208 patients screened, 120 were randomized to receive either dalfampridine (n = 80) or placebo (n = 40). At T1, the dalfampridine group presented an increase of SDMT scores vs placebo group (mean change 9.9 [95% confidence interval (CI) 8.5-11.4] vs 5.2 [95% CI 2.8-7.6], p = 0.0018; d = 0.60 for raw score; and 0.8 [95% CI 0.6-1] vs 0.3 [95% CI 0.0-0.5], p = 0.0013; d = 0.61 for z scores; by linear mixed model with robust standard error). The improvement was not sustained at T2. A beneficial effect of dalfampridine was observed in the Paced Auditory Serial Addition Test and in cognitive fatigue.

CONCLUSION: Dalfampridine could be considered as an effective treatment option for IPS impairment in MS.

TRIAL REGISTRATION: 2013-002558-64 EU Clinical Trials Register.

CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with MS with low scores on the SDMT, dalfampridine improves IPS.

CoI: multiple

Inactive MS; does it exist?

I had an interesting discussion with some like-minded colleagues recently about active and inactive MS. We seemed to agree on what active MS is, be it in the relapsing or progressive phases of MS. However, we couldn’t really agree on what inactive MS is. Take this following case scenario; many said he was inactive, but others felt he had active MS and should have his treatment switched. Would you agree?

When you look at post-mortem studies of people dying with endstage MS they all have active inflammation within their brains. Active inflammation refers to both adaptive (memory responses) and innate (hard-wired) immune responses. MSers at death still have T-cells, B-cells and plasma cells in their brains in addition to astrocyte and microglial activation. 

If we extrapolate these pathological findings to life then all MSers have active MS. What is the solution in terms of forming a common nomenclature? Surely MS is a biological disease rather than a clinical disease? If this is the case we need to come up with a biological classification system to describe active and inactive MS.  

On reflection, I think we need to get rid of the terms active and inactive and describe what we mean pathologically using metrics. For example, 

  1. This patient has evidence of ongoing focal inflammation (relapses, new and/or enlarging T2 lesions and/or Gd-enhancing lesions and/or raised CSF NFL levels) in the last 12 or 24 months. 
  2. This patient has no evidence of ongoing focal inflammation in the last 24 months but has worsening disability (physical and/or cognitive) and evidence of smouldering MS with increased brain/spinal cord atrophy and/or an increasing T1 black volume. 
  3. This patient has no evidence of ongoing focal inflammation in the last 24 months, is stable clinically (physical and cognitive) and has no evidence of smouldering MS, i.e. no increased brain/spinal cord atrophy and a stable T1 black volume. 

I suspect that we will have very few MSers in category 3, simply because with an MS-centric view of the world we are forgetting that MSers are human and will age and will get comorbidities. Therefore, how do we include ageing and comorbidities, which affect these biomarkers, into this classification system? In addition, none of our metrics is black-and-white so there is scope for miss-classification. What is clear that if you take this approach then MS is one, and not two or three, diseases. A person with PPMS with new lesions will be treated in the same way as someone in the relapsing-remitting phase of the disease. Do you have a problem with this?

Thoughts, please?  

CoI: multiple

Goalposts

We need to keep pushing the envelope and moving the goalposts in terms of our treatment targets in MS. 

As MS advances innate immune activation with microglial and astrocyte activation occurs. However, the latter may be adaptive in response to damage and hence a good thing, which is why I am sceptical about treatments aimed at targeting these cells in advanced MS. 

In comparison, B-cells and plasma cells are a different story. These cells are part of the adaptive immune system and are likely producing pathogenic, or damaging, antibodies. B cells and plasma cells set-up shop in the brain and spinal cords of MSers and churn out these heat-seeking missiles that are likely to be responsible for smouldering MS; i.e. the cortical lesions and the slowly expanding lesions or (SELs), which cause disease worsening even in those MSers who are NEDA (no relapses or no new or enhancing MRI lesions). The problem we have is that our current DMTs don’t appear to target these cells with the possible exception of cladribine that is a small molecule and gets into the brain and spinal cords of MSers.  Konrad Rejdak and colleagues in Poland have shown that about 50% of cladribine treated MSers lose their oligoclonal IgG bands (OCBs) from their CSF and that the patients who lose their OCBs tend to be stable compared to those who don’t lose their OCBs. We need to replicate these findings and supports our hypothesis to target CNS-resident plasma cells in MS.

Please note spinal fluid OCBs and immunoglobulin free light chains are at the bottom of our treat-2-target pyramid. This is our new goalposts.

This is why we are starting two studies in parallel, and want to start more studies with additional agents, to see if we can get rid of OCBs in MSers.

Our first study will look at oral cladribine’s effect on B-cell and plasma cell activity within the brain and spinal cords of MSers. Does cladribine reduce OCBs and immunoglobulin production? This study is called the “Oral Cladribine B-cell study” or CLAD B.

The following are the inclusions criteria for CLAD B:

  1. Patients with RRMS who are being treated with oral cladribine at Barts Health NHS Trust
  2. Patients must be willing and able to undergo lumbar punctures
  3. Patients who are OCB positive in their CSF (from previous diagnostic lumbar puncture) 

In our second study, we are testing a myeloma drug called Ixazomib in MS. Ixazomib is a second-generation proteasome inhibitor that works against malignant plasma cells. This study is called “Safety of targeting plasma cells in Multiple Sclerosis: A phase 1b randomised, double-blind, placebo-controlled trial” or SIZOMUS.

The following are the SIZOMUS inclusion criteria:

Each participant must meet all of the following inclusion criteria to be enrolled in the SIZOMUS study:

  1. Male and female patients 18 to 65 years old at screening.
  2. Must have a diagnosis of MS, and:
    1. Patients with RRMS must be on DMT
    2. Patients with progressive MS must not be on DMT
  3. Participants with RRMS must be on stable DMT (i.e. must not have had a relapse within 1 month prior to the screening visit)
  4. OCB positive CSF either from a previous CSF analysis or from the screening CSF analysis
  5. Patients must be willing and able to undergo lumbar punctures
  6. Agree to use of effective contraception

For those interested in proteasome inhibitors there is an emerging evidence base of them working in autoimmune diseases in general, in particular with the 1st-generation drug called Bortezomib. 

Do you think we are crazy? We have been working on getting these trials off the ground for over 3 years and the ideas, and hypotheses, underpinning these trials goes back more than 15 years. I originally wanted to do a thalidomide trial, targeting plasma cells, way back in 1997. However, I was advised against it by Professor W. Ian McDonald who thought it would be too risky. 

If you live in London, or the home counties, and are interested in participating in these trials, and you think you are eligible, let your HCP know and they can contact us.

Baker et al. Plasma cell and B cell-targeted treatments for use in advanced multiple sclerosis. Mult Scler Relat Disord. 2019 Jun 26;35:19-25

There is increasing evidence that agents that target peripheral B cells and in some instances plasma cells can exhibit marked effects on relapsing multiple sclerosis. In addition, B cells, including plasma cells, within the central nervous system compartment are likely to play an important role in disease progression in both relapsing and progressive MS. However, current B cell-targeting antibodies may not inhibit these, because of poor penetration into the central nervous system and often oligoclonal bands of immunoglobulin persist within the cerebrospinal fluid despite immunotherapy. Through targeting B cells and plasma cells in the CNS, it may be possible to obtain additional benefit above simple peripheral depletion of B cells. As such there are a number of inhibitors of B cell function and B cell depleting agents that have been developed for myeloma and B cell leukaemia and lymphoma, which could potentially be used off-label or as an experimental treatment for advanced (progressive) MS.

CoI: multiple