Tag: natalizumab

Japan epicentre of an Asian MS epidemic

I am about to return from a short MS meeting in Tokyo. This was my first exposure to Japan and Japanese culture. It is everything and more than I expected.

I am beginning to get a sense of what ikigai means. Ikigai translates ‘to a reason for being, encompassing joy, a sense of purpose and meaning and a feeling of well-being’. Ikigai derives from iki, meaning life and kai, meaning the realisation of hopes and expectations.

I first learnt about ikigai from the ‘Blue Zones’, a book by Dan Buettner, on the secrets of the world’s ‘happiest places’, where people are super-agers. One of the blue zones is Okinawa, a subtropical Japanese island to the South of Japan. Some of the philosophy underpinning happiness and super-ageing is cultural and is specific to the Japanese culture.

The lessons of the blue zones are applicable to our Brain Health initiative and I would urge you to read the book. Who knows it may change the way you want to live your life regardless of whether or not you have MS.

It is clear that MS is a problem in Japan and the incidence and prevalence is rising. Why? Japan is now one of the epicentres of the global MS epidemic; i.e. an area of the world where MS has gone from a low to a medium incidence area, similar to Iran, and will quite soon become a high incidence area. The clue to this is the rapidly increasing sex ratio of females to males that is now over 3:1.

As an MS community, we need to study these epicentres to see if we can pin down the cause of MS and put in place robust prevention trials. Japan has rapidly westernised and the Japanese neurologists I spoke to think this is the reason why the incidence of MS is increasing in Japan. Not sure I buy this at face value. What is it about the Western lifestyle that is causing MS? Could it be childhood obesity? Processed carbohydrate/sugar consumption? Smoking? Change in the epidemiology of EBV infection; a different strain, later infection, more infectious mononucleosis? Less sunshine and lower vitamin D levels?

It is interesting that Japanese neurologists think MS is more benign in Japan than elsewhere. I am not sure why they think this. All the evidence I saw this weekend points to Japanese MS being identical to Western European MS. Unfortunately for Japanese MSers, they have access to fewer DMTs and there are only two highly effective DMTs licensed in Japan, i.e. fingolimod and natalizumab. There is also a much higher JCV seroprevalence rate in Japan of close to 80% with a higher proportion of people with a high anti-JCV index. This makes the risk of PML potentially much higher in Japan. For example, there have been 4 cases of non-carryover PML on fingolimod, which equates to a PML rate of about 1 in 1,000 to 1,500 per fingolimod-treated MSer. This is an order of magnitude higher than the non-carryover PML rate on fingolimod outside of Japan and clearly needs further study.

Another factor is the reluctance of Japanese neurologists to use off-label treatments, for example, subcutaneous cladribine and rituximab. The reasons for this are multiple but mainly relate to lack of reimbursement and cultural factors. It was also clear that the Japanese neurologist, similar to British neurologists, are quite conservative and prefer a step-care approach. The Japanese are particularly concerned that because of their ancestry they may respond differently to DMTs, which have been tried and tested in other populations. In other words, they need data on the safety and efficacy of specific DMTs in their own Japanese MS population. To get a drug licensed in Japan Pharma has to trials in Japan.

As a result of the JCV problem extended interval dosing of natalizumab, also referred to as EID, and PML surveillance (3-monthly MRI monitoring) is very important for natalizumab-treated Japanese MSers. In fact, Japan is the one country that the derisking of PML for natalizumab is critical. Until other high-efficacy DMT arrive the Japanese are going to have to make do with fingolimod and natalizumab. In comparison, we are spoilt for choice in the UK and other high-income countries; we have forgotten what it was like to manage MS before the avalanche of new DMTs.

I have uploaded my slides from Japan on my slideshare site; you are welcome to download them and repurpose the slides for your own uses. I presented our #AttackMS study as a way to illustrate how important time matters in MS. I am not sure the Japanese neurologists agreed with such an active approach to treating MS. Do you?

Houzen et al.  Consistent increase in the prevalence and female ratio of multiple sclerosis over 15 years in northern Japan. Eur J Neurol. 2018 Feb;25(2):334-339.

BACKGROUND AND PURPOSE: The prevalence of multiple sclerosis (MS) is considered to be lower in East Asia than in Western countries. An increasing trend has been reported globally for the prevalence of MS. We investigated the changes in the prevalence and clinical characteristics of MS in the Tokachi province of Hokkaido, northern Japan from 2001 to 2016.

METHODS: Prevalence was determined on 31 March 2016. Data-processing sheets were collected from all MS-related institutions in Tokachi province. We applied Poser’s diagnostic criteria for MS as used in our previous three studies. Cases of neuromyelitis optica spectrum disorders were excluded.

RESULTS: In 2016, the crude MS prevalence was 18.6/100 000 (95% confidence interval, 14.3-23.8) in northern Japan. Over the last 15 years, the prevalence of MS in the same area was 8.1, 12.6 and 16.2 in 2001, 2006 and 2011, respectively. The female:male ratio was 3.57, which increased from 2.63 in 2001. The ratios of primary progressive, relapsing-remitting and secondary progressive MS types were 2%, 84% and 14%, respectively.

CONCLUSION: Our results demonstrated a consistent increase in MS prevalence among the northern Japanese population, particularly in females, and relatively lower rates of progressive MS in northern Japan than in Western countries.

CoI: multiple

The Natalizumab #AttackMS Trial

We propose the very early use of natalizumab to maximise outcomes in people with very early relapsing MS.

In the European Union, natalizumab is licensed to treat adults with highly active relapsing-remitting multiple sclerosis for the following patient groups:

  1. Patients with highly active disease despite a full and adequate course of treatment with at least one disease-modifying therapy (DMT)

or

  1. Patients with rapidly evolving severe relapsing-remitting multiple sclerosis defined by 2 or more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.

The reason for this restrictive labelling is historical and relates to the undefined risk of developing PML prior to the implementation of JC virus serological testing to derisk PML. As a consequence of natalizumab’s restricted label, an increasingly small number of patients with MS are being treated with natalizumab.

Natalizumab’s attributes of being a very high efficacy agent, having a rapid onset of action, being relatively safe in the short-term (12 months) and having the ability to reverse its mode of action (washout or using plasma exchange) make it the ideal DMT to treat active MS acutely to prevent further damage.

There is emerging evidence that the earlier you treat MS the better the outcome. We have anecdotal evidence, from individual patients, that even short delays in starting DMTs may have consequences for individual patients with multiple sclerosis. In many parts of the world healthcare systems are not configured for the rapid diagnosis and treatment of multiple sclerosis, which results in many pwMS waiting months, and in some cases years, to be diagnosed and treated. We feel this laissez-faire approach to the management of MS is wrong and is counterintuitive to how we approach other neurological diseases in particular stroke where time matters.

We hypothesise that by treating people who are likely to have MS acutely with natalizumab we will improve outcomes, i.e. these patients will acquire less disability and may even have improved rates of disability improvement, compared to patients managed in a standard way.

We have therefore designed the #AttackMS Natalizumab trial to test these hypotheses and have approached Biogen to fund and/or sponsor this study.

The trial plans to recruit patients with clinically isolated syndromes, with an abnormal MRI (two or more lesions suggestive of demyelination), within 7 days of onset and to randomise them to being treated with natalizumab (300mg ivi 4 weekly) or placebo. Subjects will then be managed according to a protocol that will ensure they are diagnosed and considered for licensed treatments within an 8-week period. The latter has been chosen as it is within the timeframe set out by an international panel of MS experts as being an appropriate period of time for being diagnosed with MS and started on treatment (please note in most healthcare systems it takes longer than this). At 8 weeks, i.e. after their third infusion of natalizumab or placebo, subjects will be unblinded; those on natalizumab will then continue on natalizumab for another 10 infusions and those on placebo will be started on the DMT that their treating neurologist and themselves have chosen. Subjects will then be followed for a further 10 months.

The primary outcome will be an area-under-the-curve (AUC) analysis of serum neurofilament levels, a biomarker of neuroaxonal damage, performed on serial blood samples taken over the period of the study. Secondary outcome measures will include MRI, clinical and patient-related outcome measures (PROMS).

MRI metrics will include (1) new T2 lesions as a marker of focal inflammation, (2) single lesion MTR as a marker of remyelination, (3) T1 hypodensity as a marker of tissue damage. Clinical outcomes will focus on disease improvement using a composite of the EDSS, T25W, 9HPT, SDMT, and low-contrast visual acuity (LCVA). PROMS will include a fatigue scale and important symptom for pwMS that has been shown to be improved by natalizumab.

At the end of the 12 months of the study treating neurologists and participating subjects in the natalizumab arm will be informed about their JCV serostatus and a decision will be made to continue on natalizumab or switch to another DMT. Subjects will then be rolled over into an extension study to be followed for a further 12 to 24 months to collect long-term clinical and MRI outcomes. The latter is important to assess brain atrophy or brain volume loss.

What we are interested in hearing from you the MS community is this trial ethical and do you think the scientific principles underpinning it are sound?

If you work for Biogen and are reading this blog post and are wearing your commercial hat you will see this trial may be the vehicle you need to resuscitate natalizumab as a mainstream DMT and to convince the EMA to reconsider natalizumab role in the management of MS and grant it a first-line license it deserves; particularly for people who are JCV seronegative.

At Barts-MS we are so convinced that the #AttackMS treatment paradigm will improve MS outcomes for individuals with MS that we have started using it already in a few isolated patients with highly active MS. We want to take this paradigm to all our of our patients. Yes, all of our patients, because we want to maximise their outcomes.

From a political perspective, this trial may nudge the MS community to be more proactive about treating MS and cement the message that we have been promoting for several years that ‘Time is Brain’. Why should we value the MS brain any less than the stroke brain?

CoI: multiple

Jetlag

Just arrived back from the AAN 2019 in Philadelphia. Jetlagged, which is why I am writing this at 2 am in the morning.

As always the AAN is more a meeting of meetings or networking in academic lingo. These meetings have allowed us to progress several of our ideas including (1) DrK’s #MSAttack study with natalizumab, (2) to think more deeply about our proposed ADIOS Trial (adaptive dosing ocrelizumab study), (3) support for our plasma cell and (4) social capital hypotheses and to (5) to gain a deeper understanding of the emerging new ’safety’ issues surrounding alemtuzumab.  

Alemtuzumab is getting an unnecessarily rough ride. I had an opportunity to review all of the vascular events and AEs that led to the EMA triggering article 20. These are all rare events. The intracranial haemorrhages appear to be related to transient hypertension and may relate to the amount of hydration the US infusion centres use when administering alemtuzumab. It is clear that MSers develop a transient rise in blood pressure when receiving alemtuzumab, which means this rare complication can be derisked with anti-hypertensives.

When it comes to the cases of arterial dissections and arterial thromboses on alemtuzumab I was not convinced alemtuzumab is to blame. The majority of the cases had comorbidities or had had procedures that are a more likely explanation for the ischaemic events. In many of the cases, the events were poorly characterised and it was not clear if they had occurred at all; this is particularly in relation to the so-called myocardial infarctions.

It is clear that most if not all of the ‘vascular cases’ have arisen in the USA. Why? I suspect it is because alemtuzumab is being used in a much riskier and older population compared to the other parts of the world. Herein lies the problem. The fact that the EMA has now copied the FDA and made alemtuzumab a 3rd-line DMT will shift the use of alemtuzumab into a riskier older population and thereby increase the likelihood of us seeing these vascular AEs in Europe.

To be honest I am not convinced that the risk-benefit profile of alemtuzumab has changed at all. I would, therefore, appeal to the EMA to include the new AEs in the SmPC, but not to change alemtuzumab’s label. We need to be able to offer alemtuzumab to MSer with early MS when they have the most to gain from the treatment. I am sure MSers are in the best position to weigh up the risks and benefits of alemtuzumab. My big fear is that restricting access to alemtuzumab will simply increase HSCT tourism abroad.

If I needed proof that our blog is read it was in abundance at the AAN. Several people were interested in our ADIOS trial and were thinking of doing versions of their own. The one caveat was new data that Stephen Hauser presented showing that the efficacy of ocrelizumab may be linked to the level of B-cell depletion, i.e. the greater the peripheral B-cell depletion the greater the treatment effect of ocrelizumab on disability progression. There was no dose-related signal on MRI or relapses because these have a floor effect, i.e. virtually all patients are NEDA 1&2 and hence it is impossible to use these outcomes to assess a dose-effect. The one caveat is the dose effect on disability was confounded by body weight; i.e. the larger the patients the less B-cell depletion. As you know MSers with an increased BMI (body mass index) are at increased risk of comorbidities, which may explain why they do less well on ocrelizumab and the observation has nothing to do with the level of peripheral blood B-cell depletion.

The peripheral B-cell depletion data, however, needs to be taken further and tissue and CNS B-cell depletion kinetics need to be studied further. I am convinced the ADIOS trial will be a good place to start with some of these studies. Clearly, it is time to get our grant writing hats on. We need to do this study in the UK.

DrK and I had several meetings with key stakeholders in Biogen about our #MSAttack study. There is little doubt about the efficacy of natalizumab in MS, its safety even in JCV-positive MSers when used for short periods, its rapid onset of action (weeks) and it reversibility (washout) that make it the only suitable DMT for this study. We have changed our trial design slightly, but hopefully, we will be able to get this study funded in the near future. If the #MSAttack study is successful it will change the way we treat and think about active MS and may help natalizumab obtain a first-line indication, which many MSers and CISers deserve; particularly if you want to save brain and spinal cord.

NeuroDoc Gnanapavan got very excited when she saw some posters supporting the use of proteasome inhibitors as a treatment for autoimmune disease. This supports our new SIZOMUS trial (Safety of IxaZOmib targeting plasma cells in Multiple Sclerosis) to try and scrub the brain clean of plasma cells. We will be letting you know much more about this trial in the next few weeks now that we have ethics and MHRA approvals. We will be needing volunteers for this study.

Saul, or Dr Reyes to some, is now one of the pioneers in studying social capital and MS outcomes. His poster on the topic was well received. It is clear that the social determinants of health outcome are very important and have not been systematically studied in MS. Dr Reyes will be changing all that and has many activities planned as part of his ECTRIMS fellowship The poster he presented at the AAN is self-explanatory, but if you have any queries please don’t hesitate to ask.

I have a new hero or heroine; Dr Riley Bove, from UCSF. Riley has developed a telemedicine service to help people with neurological problems in resource-poor areas.  The service is provided for free by the USCF residents and staff and is linked to an educational course to train the staff in these countries. The whole service is run using Zoom an online teleconferencing service. Well done Riley; if you lived in the UK I would be putting your name forward for an honours award from our Queen. And if I had more bandwidth I would join and contribute to your service; maybe something for my retirement? Could this platform be expanded to help diagnose and manage MS in resource-poor settings?

Dr Riley Bove, UCSF, AAN 2019

It is now 4:10 am and I am beginning to feel a bit groggy. So I will signoff now but will come back with some more AAN highlights in the week.

CoI: multiple

#AttackMS – a flipped pyramid

Why does Selma Blair’s speech sound slurred?

Whenever a celebrity gets MS and comes out of the ‘closet’ MS trends on social media. When Selma Blair attended the Oscar ceremony on Sunday night walking with a cane it caused quite a stir. You can now watch an interview with her on ABC News. You will notice that she has a slurred speech, which we call dysarthria and she is unsteady on her feet and needs the cane for balance. Her walking problem is called ataxia. It is clear from these signs that she has probably had a brainstem and/or cerebellar attack. This would be due to a so-called posterior fossa lesion, which is considered a poor prognostic sign.

In an interview in Vanity Fair, she talks about starting a monthly infusion therapy, which by inference must be natalizumab. As you are aware natalizumab is one of our most effective maintenance therapies and importantly is in the top league when it comes to disability improvement, i.e. no evident disease activity and disease improvement (NEDADI). As she appears to be quite early on in the course of her disease she has a good chance of some, or most, of her disabilities improving. However, against making a full recovery is the severity of her attack and the fact that she is now 46 an age when recovery mechanisms are known to be below par.

It is really a good sign that she is on a high-efficacy DMT (flipped pyramid) and has not being treated on a low efficacy therapy with the aim of escalating her therapy if and when necessary. Don’t forget time is brain so flipping the pyramid makes sense.

I am interested in knowing if natalizumab is being used as part of DrK’s #AttackMS paradigm (aka #BrainAttack), i.e. to get on top of the inflammation ASAP with natalizumab and to transition onto to another DMT later on if necessary, for example, if she was JCV-positive. I would also be very interested to know if an IRT (alemtuzumab or HSCT) was discussed as a potential treatment option with her?

Whatever you say it takes a brave person to come out and speak in public when you have such a potentially disabling disease and it when MS remains such a stigmatizing disease.

CoI: multiple

NEDADI or ‘Nee Daddy’ another treatment target beyond NEDA

Prof G do you think disability improvement is a reasonable treatment goal?

NEDADI = no evident disease activity and disability improvement

Two weeks ago one of my patients with PPMS, who we treated with off-label subcutaneous cladribine, came for her annual follow-up appointment. Despite being treated with cladribine over 2 years ago she has unfortunately progressed from EDSS 5.5 to 6.5. Her latest MRI brain did not show any new T2 lesions. She asked why we hadn’t scanned her spinal cord. She is desperate for us to find some disease activity so that she can be retreated or preferably offered ocrelizumab. She has a well-off family member who is prepared to cover the costs of ocrelizumab treatment privately. What should I do?

As you know I don’t support private prescribing in the NHS as it undermines the NHS’ founding principles; free at the point of access and equity. However, it is difficult to say no to private prescribing if a patient insists, particularly as there is now a mechanism to do this under the NHS. I am also first a doctor looking after the individual patient and this takes priority over my duty as an NHS employee and guardian of its socialist healthcare ideals.

I didn’t agree to a private prescription for ocrelizumab. Instead, I batted the problem into the long grass and agreed to bring her via our planned investigation unit for an MRI of the spine and lumbar puncture to measure CSF neurofilament levels. If there are new spinal cord lesions and/or a raised CSF neurofilament level then we could potentially look at an additional course of cladribine, off-label rituximab under the NHS, private ocrelizumab or possible recruitment into a clinical trial. I suspect that the MRI will show no new lesions and the CSF NFL levels will be normal. If this is the case then she has NEDA with worsening disability. I did refer her to my blog post on this issue (EXPLAINING WHY YOU GET WORSE DESPITE BEING NEDA) so she could get some understanding of what was happening to her.

During the consultation, she asked me ‘why a friend’s daughter with very bad MS, who had been treated with alemtuzumab, had made such a remarkable recovery?’ Apparently, this young woman had been rendered partially paraplegic from a spinal relapse and after alemtuzumab had recovered function and was now walking almost ‘normally’ again. My patient wanted to know why there was such a difference between herself, someone with PPMS, and her friend’s daughter a young woman with highly-active RRMS.

You may remember the other day I asked you to guess why I was so impressed with the HSCT-MIST trial. Let me try and explain why.

Should we be changing our expectations of what DMTs can offer pwMS? Are we entering an era when the expectation of disability improvement becomes the norm? I certainly hope so.

The most impressive aspect of the recent HSCT-MIST trial was not the NEDA data or the improved safety of HSCT, which are obviously important, but the disability improvement data. During the first year post-HSCT the mean EDSS scores improved from 3.4 to 2.4 vs. a worsening from 3.3 to 4.0 in those on the basket of licensed DMTs. Is this unique to HSCT? How does this HSCT data compare to other treatment options?

The first DMT to show a convincing impact on disability improvement in a phase 3 controlled trial was with natalizumab in the AFFIRM study; at 2 years the probability of a sustained improvement in disability was 30% for natalizumab-treated patients and 19% for patients who received placebo.

Phillips  et al. Sustained improvement in Expanded Disability Status Scale as a new efficacy measure of neurological change in multiple sclerosis: treatment effects with natalizumab in patients with relapsing multiple sclerosis. Mult Scler. 2011 Aug;17(8):970-9.

The next convincing phase 3 result was with alemtuzumab-treated patients in the CARE-MS2 trial; alemtuzumab-treated patients were more than twice as likely as IFN-β-1a-treated patients to experience 3-month confirmed disability improvement (35% vs 19%).

Giovannoni et al. Alemtuzumab improves preexisting disability in active relapsing-remitting MS patients. Neurology. 2016 Nov 8;87(19):1985-1992.

Unfortunately, the latest HSCT trial did not report their disability improvement data as confirmed or sustained disability improvement at 3 months. The main reason for this was methodological in that patients patients on DMTs had a rescue option of being treated with HSCT. However, in the first 12 months, 12/55 (22%) of patients on DMTs compared to 38/55 (69%) who were treated with HSCT had an improvement in their EDSS. Based on the final data set I suspect that in a large proportion of the HSCT patients the improvements were sustained.

Burt et al.  Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial. JAMA. 2019 Jan 15;321(2):165-174.

What about the new kids on the block, i.e. ocrelizumab and cladribine? Unfortunately, we don’t have published data on cladribine, but I will try and rectify this and will ask for the analysis to be done. However, the phase 3 pooled OPERA data of ocrelizumab has been published; 21% of ocrelizumab-treated patients had disability improvement confirmed after at least 12 weeks compared to only 16% of  IFN-β-1a-treated patients.

Hauser et al. Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med. 2017 Jan 19;376(3):221-234.

So the league table for disability improvement of HSCT over alemtuzumab, over natalizumab, followed by ocrelizumab seems to mirror the brain atrophy or end-organ damage data. Are you surprised? I am not. A large driver of disability improvement is reserve capacity, i.e. brain reserve or put simply the size of your brain, which predicts and provides the substrate for recovery. This is another reason why you would want your MS treated early and just maybe you would want to flip the pyramid and go for the DMTs that offer you the best chance of disability improvement.

Hidden in this data may be a clue about the pathogenesis of MS. What differentiates HSCT and alemtuzumab from natalizumab and then from ocrelizumab? Could it be the transient depletion and reconstitution of the T-cell compartment?

Joanne Jones and her colleagues from Cambridge showed that among trial participants with no clinical disease activity immediately before treatment, or any clinical or radiological disease activity on-trial, disability improved after alemtuzumab but not following interferon β-1a. They suggested that this disability improvement after alemtuzumab could not be attributable to its anti-inflammatory effects and suggested that T lymphocytes, reconstituting after alemtuzumab, permit or promote brain repair via the production of growth factors in particular brain-derived neurotrophic factor (BDNF),  platelet-derived growth factor (PDGF) and ciliary neurotrophic factor (CNTF). If their hypothesis holds out then this may be another reason why NIRTs (non-selective immune reconstitution therapies) outperform SIRTs (selective immune reconstitution therapies) in going beyond NEDA, i.e NEDADI. And just maybe you need these cells to traffic to the central nervous system to deliver these growth factors.

Jones et al. Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity. Brain. 2010 Aug;133(Pt 8):2232-47.

Another piece of the puzzle is the positive effect alemtuzumab has on the MRI metric called magnetization transfer ratio or MTR, which is a measure of tissue integrity. In a small study, the mean MTR fell in 18 untreated MSers in normal-appearing grey and white matter. Conversely, mean MTR was stable in 20 alemtuzumab-treated MSers, which suggests alemtuzumab protects against tissue damage. This MTR data mirrors the clinical observations and is congruent with some of the basic science. Wouldn’t it be nice to do an experiment of using natalizumab post-alemtuzumab to see if by blocking T-cell trafficking we blunt the alemtuzumab-associated improvement in disability, i.e. to test whether T-cell trafficking is required to drive repair mechanisms?

Button et al. Magnetization transfer imaging in multiple sclerosis treated with alemtuzumab.  Mult Scler. 2013 Feb;19(2):241-4.

So what do I tell my patient? Do I tell her that the reason why she has not improved is that she is older, has more advanced MS and hence less reserve capacity to allow disability improvement? Or that we may not have tackled the root cause of her MS with subcutaneous cladribine? I stuck to the former explanation as the latter is simply a hypothesis that needs more thinking, more debate and some new experiments to establish if the treatment hierarchy in relation to end-organ damage and disability improvement is based on the different modes of action of our DMTs.

Despite the reasons behind these observations we are now entering an era were disability improvement is not an unreasonable expectation for pwMS, provided they are treated early and with high-efficacy DMTs.

How many you have been told about disability improvement on DMTs?

CoI: multiple, please note that I am a co-author on the natalizumab, alemtuzumab and ocrelizumab disability improvement papers.

Beyond NEDA

Prof G are we being lulled into a false sense of security by being told that we have no evident disease activity (NEDA)?

A patient of mine, who I have been looking after now for over 11 years, asked me in clinic a few weeks ago why despite being NEDA for 6 years, on a highly effective maintenance DMT (fingolimod), has she gone from being able to run 5-10 km to needing a stick and barely managing to walk from the Whitechapel Underground Station to my clinic (~200m), without having to stop and rest?

What this patient doesn’t know, despite no new visible T2 lesions, is that she has developed obvious, to the naked eye, progressive brain atrophy.  This particular patient prompted me to write a few blog posts to try and explain what is happening to her brain. Before reading the remainder of this post you may want to read the following posts:

An important question in relation to this patient is why do some DMTs have such a profound impact on end-organ damage markers, in particular, brain volume loss and others do not? Not all DMTs are made equal when it comes to preventing, or slowing down, brain volume loss.

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 next with an annual brain volume loss in region of 0.25-0.30% per annum. Ocrelizumab (anti-CD20) comes fourth with a rate of brain volume loss of ~0.30-0.35% per annum. Fingolimod 5th at ~0.4% per annum. Cladribine has a rate of loss of brain volume of ~0.55% per annum with the other runs after that.

For me, the disappointment are the anti-B cell therapies, ocrelizumab and cladribine. Despite these DMTs being very effective at switching off new focal inflammatory lesions (relapses and new T2 and Gd-enhancing lesions) their impact on end-organ damage is only moderate. These observations have convinced me more than ever that focal inflammation is not MS, but simply the immune system’s response to what is causing MS. The latter hypothesis is what I have been presenting as part of my ‘Field Hypothesis’ for several years on this blog.

What these observations are telling me is that peripheral B-cells are a very important part of the immune response to the cause of MS, but they are not necessarily involved in driving the true pathology, which is causing the progressive brain volume loss. The caveat to this is that anti-CD20 therapies and cladribine may not be eliminating the B-cells and plasma cells within the CNS, which is why we need add-on treatments to try and scrub the brain free of these cells to see if the brain atrophy rate ‘normalises’. This is why we are starting a safety study this year of an add-on myeloma drug to target the CNS B-cell and plasma cell response to test this hypothesis.

What does this mean for the average person with MS? Firstly, you may not want to dismiss alemtuzumab and HSCT as a treatment option. These NIRTS differ from anti-CD20 therapies and cladribine in that they target both B and T cells. We may need to target both these cells types to really get on top of MS. I am aware of the appeal of anti-CD20 therapies and cladribine; they are safer and easier to use because of less monitoring, however, this may come at a cost in the long-term. The SIRTs (selective IRTs) may not be as good as the NEDA data suggests. Please remember that once you have lost brain you can’t get it back.

The tradeoff with alemtuzumab and HSCT is the frontloading of risk to get the greatest efficacy over time. Choosing a DMT on a rung or two down on the therapeutic ladder gives you better short-term safety and makes the lives of your MS team easier, because of less monitoring, but at a potential long-term cost to your brain and spinal cord.  This is why to make an informed decision about which DMT you choose is a very complicated process and subject to subtle and often hidden effects of cognitive 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 lose.

Over the last few years you may have seen a theme developing in my thinking as we move the goalposts in terms of our treatment target beyond NEDA-3 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 decade. Please stop and think!

When I was preparing this post I dropped Prof. Doug Arnold an email about the impact of alemtuzumab and HSCT on the slowly expanding lesion or SEL. Unfortunately, these analyses have not been done despite good trial data sets being available for analysis. He said it was a resource issue; i.e. a euphemism for money and permission to do the analyses. For me, these questions are the most important ones to answer in 2019. Wouldn’t you want to know if alemtuzumab and HSCT were able to switch off those destructive SELs in your brain? Knowing this may impact your decision to go for the most effective DMTs; frontloading risk to maximise outcomes in the long term.

What should I advise my patient; to stay on fingolimod or to escalate to a more effective DMT?

The following articles are the important ones for you to read or at least be aware of:

Article 1

Lee et al. Brain atrophy after bone marrow transplantation for treatment of multiple sclerosis. Mult Scler. 2017 Mar;23(3):420-431.

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.

Article 2

Arnold et al. Superior MRI outcomes with alemtuzumab compared with subcutaneous interferon β-1a in MS. Neurology. 2016 Oct 4;87(14):1464-1472.Neurology. 2016 Oct 4;87(14):1464-1472.

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.

CLINICALTRIALSGOV IDENTIFIER: NCT00530348 and NCT00548405.

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.

Article 3

Vavasour et al. A 24-month advanced magnetic resonance imaging study of multiple sclerosis patients treated with alemtuzumab. Mult Scler. 2018 Apr 1:1352458518770085. doi: 10.1177/1352458518770085.

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.

CoI: multiple