Jetlag

J

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

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

61 comments

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  • It would be interesting to hear your thoughts on results from the the three NMOSD phase 3 trials that were presented at the meeting.

    • Yes, the data of all three monoclonals (satralizumab/anti-IL6R, inebilizumab/anti-CD19, eculizumab/anti-C5) for NMO were presented. The question is which monoclonal has the edge and will these prevent people with NMO being treated with off-label rituximab? It is nice that there will be competition and this can only benefit patients with NMO.

  • ”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.”

    If this is the case could the grade or absence of lymphopenia be a early indicator of treatment response in b-cell depleters?

  • “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.”

    If correct could grade of lymphopenia or lack thereof be an early indication of treatment response in b-cell depletes?

      • Thanks for the reply, so no on response rate and yes on better outcomes. That would be interesting as lymphopenia is regarded as a side-effect and not as the mode of action.

      • I think that this applies to all PIRTs, including cladribine and alemtuzumab….
        Has anyone analyzed subgroups based on grade of lymphopenia? And not just relative numbers (as patients do not start from the same levels!), but absolute numbers?

        • Very interesting to know if this has been done? If not it should be able to be done for cladribine right? as the data from Clarity has been release by Merck and is avalible for analysis?

  • Thanks prof G. Any news on Ocrelizumab brain atrophy? Or any news to settle b or T cell argument? Which drives inflammation first? Also is alem still available if you need a 3rd dose? Any reasoning why ibudalist only works in ppms and not in 2nd ppms? Any new ideas on pathogen of MS? Gut brain link? Any thing new to get excited about? Instead reworking old drugs in new settings?

    • The ocrelizumab brain atrophy data was presented at ECTRIMS; good but clearly not good enough. Ocrelizumab and anti-CD20 therapies, in general, are very effective but are not a cure for MS. This is why there is still plenty to do in MS.

      • Thanks prof G. Given phase 3 trial of Ofatumumab is about to finish this may. Do you think the 2 phase 3 trials will be more effective in reducing brain atrophy than Ocrelizumab? Although it targets b cells, but is many times more effective than Ocrelizumab. If not would this be the end of b therapies?

    • Yes, plenty. Dr Stefania had a lot of interest in her platform presentation on our off-label cladribine trial and several people asked me about both #ChariotMS and #OratorioHand.

      • What are the updates on these two trials and if both run simultaneously how would one be chosen over another?

  • Hi prof. Gavin,
    I have been a MS patient for 19 years and I totally agree with you on the issue that Lemtrada, should be available to be first-line treatment for more aggressive MS cases.
    I totally agree with your view regarding the recent episodes in the USA with Lemtrada.
    Personal note: If the goal is to improve the quality of life of pwMS you, and your colleges, should not consider the use of natalizumab as first line treatment, ie not for life, you have alternatives (Lemtrada and HSCT) that allow better quality of life.

    • The #MSAttack study is about the short-term use of natalizumab to protect the brain and spinal cord and give neurologists and patients time to diagnose and think about the long-term treatment of MS. It is the ultimate #TimeIsBrain strategy. It is not meant to replace Alemtuzumab and/or HSCT, but give you time to get to that position.

      We like to think of the #MSAttack strategy as being equivalent to thrombolysis in stroke.

      • How one would think for Alem. or HSCT when he/she is smouldering their MS so effectively with Tysabri? How often is to have a second attack during the period of waiting for results to come? Wouldn’t this strategy increase misdiagnosis?
        I know I wouldn’t like to be imposed with a serious drug before I get a diagnosis, that’s for sure. We need immunomodulating strategies for CIS (like metformin, minocycline, Vit D(?) -even IFNb has such properties) or at least immune reseting agents like Cladribine. Tysabri, Mayzent, what do they have to offer to a CIS patients?

        • We need immunomodulating strategies for CIS (like metformin, minocycline, Vit D(?) -even IFNb has such properties) …but they aren’t that immunomodulating.

        • “How one would think for Alem. or HSCT when he/she is smouldering their MS so effectively with Tysabri?”

          For sure this is major problem..

          Neuros say their patients are stable.

          Stable progression leading to secondary progressive ms in
          10..20..30…years or more. And they truly have no idea.
          As long as they’re walking…they think this patient is doing great.

      • Have there not been studies showing Natalizumab rebound relapse higher for those on short term treatment (as few as 2 doses) compared to patients on the drug long term (>2 years)? Also studies showing there’s not much in way of prevention for rebound (steroids, plasma exchange)?

        • Not aware of this, but it is not relevant here. We are proposing 12 months of natalizumab treatment and then it is up to the patient and their HCP to decide on what to do after 12 months.

      • “The #MSAttack study is about the short-term use of natalizumab to protect the brain and spinal cord and give neurologists and patients time to diagnose and think about the long-term treatment of MS. ”

        How many have permanent damage from first or second attack..?
        You guys can handle Natalizumab but most u.s. centers no confidence.

        • Not aware of this, but it is not relevant here. We are proposing 12 months of natalizumab treatment and then it is up to the patient and their HCP to decide on what to do after 12 months.

          • We have many examples of patients with active MS having severe and in some circumstances, devastating relapses waiting to be diagnosed with MS and being started on a DMT. This is the main reason for us proposing the #AttackMS trial.

          • “We have many examples of patients with active MS having severe and in some circumstances, devastating relapses waiting to be diagnosed with MS ”

            Are these cases more frequent than the cases of devastating rebound relapses after stoping Tysabri (or then going on Gilenya to postpone a little this rebound effect)?

            Speed up the diagnosis process instead of making Biogen even richer by getting ALL MS patients in one drug. Patients have wash out periods from drug to drug and thus there is inevitable risk of getting relapses during their disease course, so you can’t pretend that this is not the way it is with MS today.

      • ABSOLUTELY TIME IS BRAIN NOT ONLY IN STROKE, I LIKE THE IDEA OF MS ATACK STRAGETY THAT WILL GIVE TIME WITHOUT HARM TO NEURONS.

  • I don’t know where you find all of this energy, you truly where chosen to use your extraordinary brain, in the way that you so passionately do, to try and help figure out how you may possibly, find a drug to counteract the the body’s ability to self-destruct. XX❤️

    • “I don’t know where you find all of this energy…”

      Commotion hides the motion..says the sleight of hand magician…
      But here commotion hides the lack of motion(progress) says the Dr. of disease.

      Why in the western world does everone adopt a busy..jet set..exhausted persona..?
      “Thus, by telling others that we are busy and working all the time, we are implicitly suggesting that we are sought after, which enhances our perceived status.”
      https://www.thecut.com/2016/12/pretending-to-be-busy-is-a-status-symbol.html
      https://www.google.com/search?client=firefox-b-1-d&q=pretend+to+be+busy

      All theses therapies and yet none stop or even seemingly delay progressive disease.
      So now what..back to square one.. ?..
      Any doubts on B cell therapy…we listen to S. Hauser.

      https://www.ncbi.nlm.nih.gov/pubmed/30851128

      “Longitudinally persistent cerebrospinal fluid B cells can resist treatment in multiple sclerosis.”

      We demonstrate complex patterns of clonal B cell persistence in CSF and blood, even in patients on immune-modulating therapy. Our findings support the concept that peripheral B cell activation and CNS-compartmentalized immune mechanisms can in part be therapy resistant.
      https://www.ncbi.nlm.nih.gov/pubmed/30747723

      Clearly biologic agents or small molecule drugs are only way forward.

      • RE: “All theses therapies and yet none stop or even seemingly delay progressive disease.”

        You should spend some time reading the blog more. Patients with MS treated early, very early, with highly effective DMTs do very, very well. Some are going 15+ years in long-term remission. The question we are asking ourselves is have we cured these patients of their MS?

        It is the watchful waiting / slow escalation treatment paradigm that needs to be questioned; it allows the CNS to be primed for degeneration which drives progressive or worsening MS.

        Interestingly, the people with MS pushing for 1st-line HSCT understand this very well.

    • Yes, but nothing to report except we are in the process of designing the phase 3 trial whilst we wait for the phase 2b trial to report out. In addition, Biogen will be progressing their oral small molecule remyelination strategy. Exciting times and glad to see Pharma is still moving forward with remyelinating therapies.

  • What is there for those of us with progressive disease that started a long time ago? Any progress on EBV? Any neuroprotectives, repair agents? Or is it still all about immune system destruction, incapacitation?

    • There were a lot of post-hoc analyses presented on siponimod including more detailed data on its effects on cognition. All very exciting. I will do an additional post on this when I get the time.

  • With the Tisch experiments on mice and Ibudilast results, was AAN the point where we can say that PPMS is a similar but different disease from RRMS/SPMS?

  • Why, why, why is so little being written about Ibudilast on this blog – and elsewhere??? Or am I mistaken? I mean for goodness sake, this is a relatively safe drug with a history of use in the Far East which suppresses cytokines – the things that cause so much damage following infections. And it slows brain shrinkage!!! In PPMS!

    I have slow PPMS, and I will swear upon my life that what stirs the slumbering beast of the disease within me is infection, i.e. cytokines. I am in a fairly unique position in that I am able to isolate myself to a high degree and avoid infections. So I know that this is what makes me worsen.

    Ibudilast could be a wonder drug for people like me.

    • We posted the main report from AAN2019 on the ibudilast trial about 3-4 weeks ago.
      So please search and you will find.There was no effect on neurofilament levels suggesting that nerve damage is stilll odccurin

      “This is a relatively safe drug”…You could say the same for anti-TNF…but in MS it made worse., Ibudilast it is a PDE4 inhibitor and TNF and macrophagee inhibitory factor locker, Rolipram is a PDE4 inhitor, its trials were terminated due to worsening
      Ibduilast was developed to inhibit asthma nNot autoimmunity

      Yes it may be useful it with need another trial sorry to say

  • Can I please ask what if at all is discussed for those already in wheelchairs and in the progressive phase.
    What do neurologists usually prescribe?
    there is all the talk of what to do as early as possible but what about those who have missed the boat what is the general plan for those people please?

    • No trials have been done in wheelchair users. We are trying to change that with ORATORIO-HAND and CHARIOT-MS studies.

      • I know there are no drugs currently but what treatment do neurologists manage to offer; mitoxantrone, cladribine? Which is the favoured treatment currently for the supposedly untreatable?

    • I think is is 3 out of 20 (15% of total) not 1 out of 4. In each year it is 60% but the next year it may not be the same 60% and so one. They are fudgung the data to make it seem better than it is. If we remember the 5 year data it was said that 40% were NEDA between year 2 and 5 and so between year 5-8 there are more drop outs. Now if we rememebr only 40% were NEDA in year 0-2 so is this now 15% of 40% who are NEDA , so now does this mean that alemtuzumab only induces NEDA in 6% of the starting population from year 0-8.

      I wish the manufacturers were more open. How can you make an informed choice when you are being given half-facts.

      That they seem to be hiding data makes me very concerned. How many people who started on Alemtuzumab 8 years before were still NEDA?

      However, I think this is problematic because NEDA is made up of a metric that is driven by relapses and progression (which may not respond well to alemtuzumab).

      • Oh wow – your understanding is even gloomier than mine. Any chance you could ask the authors on our behalf?

        They can push all the amazing BVL figures out, but how many are actually benefiting from it. I am not sure about your 6% but if this stands, it merely captures the wrongly diagnosed or benign MS,

        I am still feeling that we are not getting the full picture here. How does NICE approach this with their QALY modelling?

  • I started from the beginning with PPMS. So even if I could turn the clock back, current therapies are no use. I’ve lost hope in there being any treatment in time for me. I’m fighting to do all I can for myself, diet, exercise etc.

  • Me gustaria saber ya que ha comentado el tema, del Alemtuzumab si se han encontrado algún caso, de Neumonitis pos Lemetrada.
    Le cuento mi primer ciclo fue en Agosto del 2016 y el segundo en Agosto del 2017, En Septiembre del 2018 empece ha fatigarme mucho y tener la saturación, de Oxígeno en sangre muy baja, despues de hacerme RX de tórax y Tac con contraste y sin, Me han diagnosticado Neumonitis.

    • I would like to know since you have discussed the issue, Alemtuzumab if they have found any case of Neumonitis pos Lemetrada.
      I tell you my first cycle was in August of 2016 and the second one in August of 2017. In September of 2018 I started to fatigue myself a lot and have the saturation, of oxygen in blood very low, after doing RX of thorax and Tac with contrast and without , I have been diagnosed with Pneumonitis.

  • I was diagnosed at 54. Prior to that I was in perfect health. I had minor symptoms for many years. I fell down a flight of stairs 6 years ago, my legs and feet went numb and 6 months later I was diagnosed with RRMS. By the end of that year, my disability increased to the point of being approved for permanent disability. I tried a couple of DMT’s which didn’t work. I have no new lesions but my disability has progressed even more. I did round 1 in 2016 and ended up with double pneumonia or what my neuro said was chemically induced pneumonitis. I did round 2 in 2017 and was diagnosed with Graves’ disease 9 months later which is worse than the MS. I’ve read a couple of articles stating that there were studies done showing that hyperthyroidism as a side effect of Lemtrada is much higher than the manufacturer reported. Those studies were done in the UK and not included when it was submitted for US FDA approval. Have they changed the protocol to try and avoid that particular side effect? The treatment has had no effect on my MS.

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