News and events – Page 14 – Prof G's MS Blog Archive

Open letter to the EMA

Just back from ECTRIMS 2019 in Stockholm. My highlight was the alemtuzumab 8-year longterm extension data; the brain volume data is quite extraordinary (figure 5). In short, apart from HSCT, there is nothing that comes close to alemtuzumab in radically slowing-down or preventing end-organ damage.

Comi et al. Alemtuzumab improves clinical and MRI disease activity outcomes, including slowing of brain volume loss, in RRMS patients over 8 years: CARE-MS I follow-up (TOPAZ study). ECTRIMS 2019, P1235.

I was also disappointed to hear the rumour that the EMA’s article 20 procedure was not triggered by an EU member country, but by the EMA itself. A colleague told me that the adverse events reporting from Genzyme were so poor that the EMA could not establish whether or not the new adverse events were causally related to alemtuzumab. So to get some clarity on the new adverse events the EMA triggered their own article 20 procedure to simply get Genzyme to do the work they should have done in the first place.

If this is the case it saddens me that people with MS may not be able to access alemtuzumab early in the course of their disease due to poor internal procedures at Genzyme.

If I had MS I would want to have the option of being treated with alemtuzumab. This is why I wrote the following open letter to the European Medicine Agency. I sincerely hope they listened. I have yet to receive a response from them, but I hope someone at the EMA has MS or has a friend or family with MS and understands why treating MS early and effectively is so important.

Open letter the EMA sent on the 20th August 2019

European Medicines Agency
Amsterdam

Dear Sir/Madam

Alemtuzumab has transformed the MS treatment landscape. It not only provides superior short term efficacy, but a significant number of patients treated with alemtuzumab note improvement in disability. However, its main advantage over other DMTs is that a large proportion of patients go into longterm remission and normalise the rate of their brain volume loss. In regard to the latter, this is unprecedented in comparison to other licensed MS disease-modifying therapies, with the possible exception of haemopoietic stem cell transplantation (HSCT), which is not licensed and hence not widely available to treat patients with MS in Europe. Alemtuzumab, therefore, is the only realistic alternative to HSCT, which has become a very popular treatment choice amongst people with multiple sclerosis, in particular, ‘digital natives’ who get their information online. As with all DMTs the earlier you use them the more effective they are and the greater the benefit to the individual patient. Alemtuzumab is, therefore, an important treatment option for people with MS; being able to offer alemtuzumab early as a treatment option is an important factor in my clinical practice to dissuade many Britsih patients from travelling abroad for HSCT.

At our centre, Barts Health NHS Trust, we have now treated over 250 patients with alemtuzumab with over 40% being treated with alemtuzumab first-line. Patients receiving alemtuzumab first-line tend to have more active disease and less favourable baseline prognostic profile. Despite its side effect profile and the need for monthly monitoring, many patients are willing to take on the risks and the burden of monitoring to be treated with the most effective licensed DMT first-line. All our patients are extensively counselled about the risks and benefits of alemtuzumab treatment and sign an informed consent and a patient contract agreeing to the mandatory monitoring programme. We feel the use of alemtuzumab in the correct environment is relatively safe and the adverse events manageable. Not having alemtuzumab for use in early active disease would mean patients having to wait to fail several other, less effective, licensed DMTs prior to accessing alemtuzumab. I firmly believe in the concept that ‘time is brain and spinal cord’ in MS and delaying access to the most effective treatment would limit our ability to optimise the management of MS in patients with more active disease and in those with a poor prognostic profile. In addition, shifting the use of alemtuzumab to a population of patients with more advanced disease would unfavourably change the benefit-risk profile of alemtuzumab and make it less appealing as a treatment option.

The real-life data of alemtuzumab clearly supports it as being the most effective DMT on the market and its other attributes in relation to its posology make it a very appealing therapy; for example in women wanting to start or extend their families.

In summary, limiting alemtuzumab to a third-line, last resort DMT, will severely limit our treatment options for managing this devastating disease. Alemtuzumab offers many patients with MS a real hope of living as normal a life as possible, however, this option does depend on using alemtuzumab early in the course of the disease. I, therefore, appeal to the MS community and the European Medicine Agency to consider these factors when reviewing the benefits and risks of alemtuzumab as a treatment for MS.

Yours faithfully

GAVIN GIOVANNONI

CoI: multiple

Early ECTRIM Blues

I arrived in Stockholm this morning on one of the first flights out of Heathrow. Terminal 2 was chaos. I assume everyone who was meant to be on one of the BA flights that was cancelled, transferred onto a competitor airline in Terminal 2. My flight was full and I am sure I was allocated the last seat on the plane. A small half-sized seat at the far left of the plane. The seat was up against the toilets and didn’t tilt. It was very uncomfortable. Fortunately my discomfort was short-lived and temporary, not like having MS.

I have given my first talk this afternoon around a case study of the ‘real MS’; smouldering MS in someone who is relapse and MRI activity free on fingolimod, but is getting markedly worse. Do you tell them they have SPMS and stop their fingolimod? Or do you escalate their treatment and hope for the best?

The problem with labelling someone as having SPMS is unhelpful without another treatment option or strategy in place for them. Telling someone with MS you now have SPMS is like telling them they have a terminal disease, i.e. it is now all downhill from here. At least having a potential new treatment for SPMS will allow us to offer some hope. The problem that I have is I have no evidence that switching someone who is NEDA2 with worsening MS onto another DMT will make any difference to them. This is an evidence vacuum that needs filling.

I am involved in another meeting tomorrow afternoon run by the MS in the 21st Century initiative to tackle this thorny issue about when and how to tell someone they have progressive MS. In reality, I think this is an academic exercise in that there is now ample evidence from a biological perspective that everyone has both relapsing and progressive MS together and the latter is there from the start. What we are trying to do with our treat early and effectively message is to protect brain reserve so that clinically apparent worsening stage of MS occurs much much later in life, Do you agree or not?

At the afternoon and evening meetings I attended, I was asked if there would be anything new being presented at the ECTRIMS. To be honest with you I don’t think so. Sure there will the positive ponisemod and ofatumumab studies, but these are really old news. Both these drugs are ‘Me Toos’; ponisemod being the 4th in-class S1P modulator and ofatumumab a 3rd generation anti-CD20 monoclonal antibody. There is really nothing new here. Me toos are very low hanging fruit for Pharma with much less risk associated with their development. Believe me, there is nothing transformational that is going to happen on Friday when we get new sets of data; only old news. What we will be arguing over is the percentage differences in relative efficacies between DMTs. We won’t be saying wow what an interesting finding; this is teaching us something new about MS.

What the MS field needs is some novelty, something new in terms of a mode of action, a new class of therapy, a new insight, a new paradigm, etc. That is what I will be looking out for and not the same old, same old.

Competition time

The MouseDoc and I want to have a little bit of fun in anticipation of the late-breakers at ECTRIMS and at the same time do a thought experiment.

We want to see how wise the crowd is when it comes to predicting trial results.

Aware crowds may be wiser than individuals. In the book ‘The Wisdom of Crowds: Why the Many Are Smarter Than the Few and How Collective Wisdom Shapes Business, Economies, Societies and Nations’ James Surowiecki argues that the aggregation of information in groups, results in decisions that are often better than could have been made by any single member of the group. He opens the book with an anecdote about Francis Galton’s surprise that the crowd at a county fair accurately guessed the weight of an ox when their individual guesses were averaged (the average was closer to the ox’s true butchered weight than the estimates of most crowd members).

We want to see how wise you are when it comes to guessing the outcome of the two phase 3 trials programmes being presented at ECTRIMS. We know they are positive, but how positive is the question? To make it a competition we will be giving away two prizes; a lego MRI scanner set or one of our #ThinkSocial Bart-MS T-shirts. You can choose your prize.

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

Please note the Janssen Pharmaceutical Company announced positive top-line results stating the study met its primary and most secondary endpoints. As you know ponesimod is a second-generationn S1P modulator. The question is how good will it be compared to Teriflunomide? It may help to remind you that fingolimod, the first licensed S1P modulator, reduced the annualised relapse rate by 52% compared to interferon-beta-1a (Avonex) in the TRANSFORMS study, but had no significant effect on disability progression.

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

Novartis has announced that both of their phase 3 trials of ofatumumab vs. teriflunomide met their primary outcome. 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) and that key secondary endpoints of delaying time to confirmed disability progression were also met.

Ofatumumab is a 3rd-generation anti-CD20 monoclonal antibody. Ocrelizumab is already licensed and was compared to interferon-beta-1a (Rebif) in two parallel phase 3 trials (OPERA I & II); ocrelizumab reduced the annualised relapse rate by 47% and the rate of 3-month confirmed disability progression by 40% compared to interferon-beta in these trials.

I have recently argued that ofatumumab may be underdosed and that as a result, it won’t do as well against teriflunomide (which has similar efficacy to Rebif), compared to what ocrelizumab did against Rebif. Do you agree with me or not?

So please complete the survey below and leave your email address and name if you want to enter the draw for the prize.

CoI: multiple

MD Here….I asked a question in the comments

Happy Birthday

The Barts-MS blog turns 10 today. The first blog post on the 3rd September 2009, on the 2007 Association of British Neurologists’ DMT prescribing guidelines, is now obsolete. The link does not even work. What started as a small experiment has turned into an almost full-time job for us at Barts-MS. Please let us know what the blog means to you and whether or not you want any changes going forward. As always a publication needs to serve its readers.

Heat

My thoughts are for our readers with MS who are having to live through and cope with the latest heatwave. The BBC has just reported that this is the hottest late August bank holiday on record; “Temperatures had reached 33.2C (91.8F) at Heathrow by 14:16 BST, the Met Office said, beating the previous record of 28.2C set two years ago. On Sunday, the record for the hottest late August Bank Holiday weekend was broken, with a high of 33.3C”.

How are you tolerating the heat? I suspect many of you with heat sensitivity will be experiencing worsening fatigue, pseudo-relapses (heat-induced intermittent symptoms) and difficulty sleeping. Are you coping? Do you have any advice for your fellow MSers?

Please note that the main consequences of a raised body temperature in demyelinated, or remyelinated, pathways is slowed conduction. The commonest example is exercise-induced fatigue, but this summer’s heatwave will be causing symptoms without the need for exercise. Some of you will find difficulty walking difficult; your legs will begin to drag minutes into walking rather than after 20-30 minutes. Others will notice blurring of vision mid-morning when in the past this would only happen in the late afternoon. The reason for this is that the demyelinated segments in the nerve stop conducting due to conduction block induced by a slight rise in temperature affecting the functioning of the sodium channels. The latter are the molecules in the membranes of nerve cells that transmit the electrical signal down a nerve fibre, which require energy to work. These sodium channels are ion pumps, which are optimised to function at a certain temperature and explains why MSers are heat sensitive.

Most of you will have heard of Uhthoff’s phenomenon. Wilhelm Uhthoff (1853-1927) was a famous German Professor of ophthalmology who described temporary visual loss associated with optic neuritis linked to physical exercise. This was later found to be caused by a rise in body temperature. This phenomenon is now known to affect other neurological systems as well; for example, the motor system when walking, balance and sensory pathways and even the cognitive centres.

Apart from cooling, we do not had a treatment for Uhthoff’s phenomenon. The drug Fampridine has been licensed to improve walking speed in MSers. Interestingly, several MSers have said to me in the past that their heat sensitivity has improved since taking Fampridine.

CoI: Multiple

MSology Masterclass

We still have places left for this year’s MSology MasterClass from the 6th-8th November. The Multiple Sclerosis Academy aims to train healthcare professionals with a specialist interest in multiple sclerosis. If you are interested in joining the Academy and attending the MasterClass please register your interest via this LINK. This course is not only for HCPs from the UK we welcome international delegates on the programme as well.

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

#ThinkSocial

At Barts-MS we #ThinkSocial. We hypothesise that MS is like other chronic diseases and is affected by social capital and the social determinants of disease (SDOD). In short, if you have high social capital you will have a better outcome and if you have a favourable social profile you will also do better regardless of the type of MS you have. We are now actively researching these issues and have posted about them in the past and review them in this short video.

We hypothesise that you can increase your social capital by adopting practices to maintain and develop new relationships. These reciprocal relationships help you develop resilience to cope with chronic diseases such as MS. To this end, we are pleased to be involved with Oceans of Hope; a sailing charity that will ‘change the perceptions of multiple sclerosis by showing what is possible when people with a chronic disease are empowered to conquer their individual challenges, by engaging people whose lives are touched by MS and developing networks as a foundation for life-changing behaviours’.

Saúl Reyes, our Social Capital ECTRIMS fellow, Sue Radford (MS Brain Health) and I are in Edinburgh today to support Oceans of Hope and to celebrate what they are doing for people with MS. Sailing in the open ocean may seem quite extreme, but you could launch and run your own initiatives locally.

A lot of you were quite upset by my post of a patient of mine who is socially isolated and living on a diet of tea & toast. As a medical practitioner working in the NHS as it is currently configured I am relatively powerless to change this lady’s trajectory. This is why we need social prescribing and initiatives like Oceans of Hope, which promise to change things.

I envisage a future when social prescribing will be part and parcel of the holistic MS service we provide and we will have much less social isolation and more importantly better MS outcomes and happier MSers. Or am I wrong?

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.).

Measles a known unknown

I was called to casualty to assess one of my patients with MS who was on natalizumab. She had been admitted with a temperature, confusion, seizures and a generalised skin rash. Within thirty minutes of seeing her, she went into status epilepticus and had to be sedated, intubated and admitted to ITU. Within 72 hours she was dead. At post-mortem, she had a measles pan-encephalitis. Four days before presentation she had unknowingly come into contact with a friend’s child who had measles. The friend was a staunch anti-vaxxer who believed that the measles vaccine caused autism and would corrupt her child’s immune system.

The above scenario is fictitious, but could happen, or more likely will happen sometime in the near future. This is a ‘known unknown’.

Things have a tendency to happen in threes; I experienced two today let’s hope the third remains science fiction.

(1) As I left home this morning on my daily commute to Whitechapel I finished listening to an Audm podcast “FEAR, MISINFORMATION, AND MEASLES SPREAD IN BROOKLYN” by Amanda Schaffer (Wired, 24-06-2019); scary stuff about the real impact of the anti-VAXX campaign on residents in Brooklyn, New York.

(2) I followed this by reading a review about measles in the latest NEJM (Strebel & Orenstein. Measles. N Engl J Med. 2019 Jul 25;381(4):349-357), which reminded me of medical school and my time on the medical wards in South Africa.

I then had flashbacks to my days as a neurology registrar in South Africa seeing and managing many patients with SSPE (subacute sclerosing panencephalitis) a relatively rare, but fatal, complication of measles infection.

More recently there was a fatal case of measles inclusion body encephalitis presented at our Association of British Neurologists meeting; tragically this young woman had not been vaccinated against measles.

Why is this important? We are living through a measles epidemic. The anti-VAXX campaigners have convinced enough parents over the last two decades to not vaccinate their children against measles, mumps and rubella (MMR). Once a certain proportion of the population is not immune to measles, so-called herd immunity becomes ineffective; i.e. the shield offered by a population of people immune to measles is too porous to isolate susceptible people from wild-type infection in the community. In fact, vaccination works because of herd immunity.

Another factor to consider is that unvaccinated people also get MS. If you are unvaccinated and have not been exposed to the wild virus you are now at relatively high-risk of acquiring measles as an adult. If you then decide to go onto longterm immunosuppression to treat your MS you are putting yourself at risk of serious complications from these infections, in particular measles. In addition, once you are on a longterm immunosuppressive therapy you can’t be vaccinated with the MMR vaccine as it is a live attenuated vaccine.

Measles is also a neurotropic virus and hence seeds to the brain. If you are on natalizumab and contract measles you will be in serious trouble. Natalizumab works by blocking trafficking of lymphocytes to the CNS and hence will stop your lymphocytes detecting, attacking and clearing the virus from the brain. The consequences of an unimpeded measles virus infection of the brain will be in all likelihood be lethal. This is a similar scenario to what happens with PML. Although natalizumab is being fingered here there is a risk will all of our immunosuppressive DMTs.

Because of this known unknown, I am proposing that all MSers are screened at baseline, i.e. before initiating a maintenance immunosuppressive therapy, to make sure they have immunity to MMR. If they are antibody negative they should be offered the option of receiving the MMR vaccine, or at least the individual components of the vaccine if they are still available in your country, to make sure they are immune to these viruses before they start treatment with the DMT concerned.

I sincerely hope my case scenario remains fiction and things don’t have to happen in threes.