Saturday, 1 July 2017

#ResearchSpeak & #ThinkSpeak: a new form of therapeutic nihilism

How can we prevent a new era of therapeutic nihilism in progressive MS? #ResearchSpeak #ThinkSpeak

A commentator asked about data to support the use of cladribine in PPMS. In reality there has not been a study particularly targeting PPMS, but several studies have investigated the impact of cladribine in chronic progressive MS, i.e. a population that includes both secondary and primary progressive MS. In general these trials have been under-powered and too short, based on recent insights, to give a definitive answer. The best study was the Rice or J&J (Johnson & Johnson) study that included 48 (30%) patients with PPMS. Importantly, in this study 71% of patients had a baseline EDSS score of >=5.5, which based on our therapeutic lag modelling would require a study duration of well over 3 years to give an answer using a lower limb outcome (EDSS). However, despite this study being too small and too short cladribine had a robust impact on T2 lesions, albeit more pronounced in the SPMS subgroup. It is clear from this study that cladribine is an effective anti-inflammatory in more advanced MS. 

Cladribine as a DMT has the added advantage of being CNS penetrant and targets both dividing and non-dividing lymphocytes and may even target plasma cells. Therefore we hypothesise that cladribine is the ideal DMT to be studied in more advanced MS and should form the base of the pyramid on top of which we can build a therapeutic pyramid to address neuroprotection, remyelination and neurorestoration. 


When I was at the EAN meeting last weekend, in Amsterdam, a MSology colleague expressed an opinion I had not heard since the interferon-beta-1b results were released in 1993. He stated that 'if ocrelizumab got licensed in Europe for PPMS and relapsing forms of MS it would become very difficult to do placebo-controlled progressive MS trials'. He implied that an ocrelizumab license would be disadvantageous to the progressive MS community, i.e. the academic community. He is one of the MSologists who are not impressed with the ocrelizumab trial results. The problem I have with this attitude is that it is a form or therapeutic nihilism, only this time it is being directed at people with progressive MS. If this person really understood the biology of MS he would realise that a 25% and 45% reduction in disability progression in the legs and arms, respectively, over a 24-36 month period is as good as it gets and that we need to use this as a platform to improve on. 

As a group we at Barts-MS have realised this and as a result are not wanting to target early progressive MS, but more advanced MS including people in wheelchairs. We estimate that our proposed subcutaneous cladribine trial (Chariot Trial) will cost in the region of £5M to complete. So if there any wealthy philanthropists out there who want to see people in wheelchairs in trials with the primary outcome the 9HPT, I am sure DrK would love to speak to you. 

If anything angers you in this post, please feel free to express yourself and to complete our survey. As suggested by someone on the blog, we will analyse the results and make them known to the MS community and the EMA. We need ocrelizumab licensed for PPMS and I personally don't give a toss about academics wanting to protect the status quo so that they continue to study untreated progressive MS. Can you imagine what it must be like to be a person with PPMS with walking difficulties and you start to notice subtle problems with your hands? You would be desperate to be treated with ocrelizumab. This is the human story of MS and academics should not forget that. 


Rice et al. Cladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial. Cladribine MRI Study Group. Neurology. 2000 Mar 14;54(5):1145-55.

OBJECTIVE: To evaluate the safety and efficacy of two doses of cladribine in patients with progressive MS.

BACKGROUND: Treatment of progressive MS patients with cladribine in a previous single-center, placebo-controlled clinical trial was associated with disease stabilization.

METHODS: In the current study, 159 patients with a median baseline Kurtzke's Expanded Disability Status Scale (EDSS) score of 6.0 were randomly assigned to receive placebo or cladribine 0.07 mg/kg/day for 5 consecutive days every 4 weeks for either two or six cycles (total dose, 0.7 mg/kg or 2.1 mg/kg, respectively), followed by placebo, for a total of eight cycles. Thirty percent had primary progressive MS (PPMS) and 70% had secondary progressive MS (SPMS). EDSS and Scripps Neurologic Rating Scale (SNRS) scores were assessed bi-monthly and MRI was performed every 6 months. The primary outcome measure was disability (mean change in EDSS).

RESULTS: Mean changes in disability did not differ among the groups at the end of the 12-month double-blind phase. Both cladribine treatments were superior to placebo for the proportion of patients having gadolinium-enhanced T1 lesions and for the mean volume and number of such lesions (p < or = 0.003). Differences were statistically significant at the 6-month evaluation time, with < or =90% reduction in volume and number of enhanced T1 lesions, which was maintained through final evaluation. This effect segregated largely with the SPMS group. The T2 burden of disease showed a modest improvement in cladribine-treated patients and worsened in placebo-treated patients. Most adverse events were mild or moderate in severity and not treatment limiting.

CONCLUSION: No significant treatment effects were found for cladribine in terms of changes in EDSS or SNRS scores. Both doses of cladribine produced and sustained significant reductions in the presence, number, and volume of gadolinium-enhanced T1 brain lesions on MRI, and cladribine 2.1 mg/kg reduced the accumulation of T2 lesion load. Cladribine at doses up to 2.1 mg/kg was generally safe and well tolerated.

Filippi et al. The effect of cladribine on T(1) 'black hole' changes in progressive MS.
J Neurol Sci. 2000 May 1;176(1):42-4.

We compared the changes of the volumes of T(1)-hypointense lesions seen on the magnetic resonance imaging scans of the brain from 159 progressive multiple sclerosis (MS) patients who were enrolled in a double-blind, placebo-controlled trial assessing the efficacy of two doses of cladribine. Although in patients treated with cladribine there was a tendency to have a lower increase of T(1)-hypointense lesion volumes than those treated with placebo, no statistically significant effect of cladribine on T(1)-hypointense lesion accumulation was found over the one-year double-blind phase. Furthermore, no significant treatment effect was also detected in a subset of 22 patients who received placebo during the double-blind phase of the study and cladribine during the subsequent one-year open-label phase. We conclude that cladribine does not have a major impact on the mechanisms leading to severe tissue destruction in progressive MS.

CoI: multiple

29 comments:

  1. The attitude of “it doesn’t work perfectly so have nothing instead is ridiculous”. It’s equivalent to saying “I can’t go afford to go on a three week holiday in Hawaii this year, so I will stay at home all year instead”. It’s not what you do, the reality is, if you cannot afford Hawaii you go to Butlins instead.

    It is sad to read that this attitude was provisioned by a clinical academic. If you cannot trust academic researchers to have their heart in the right place, then who can you trust? NIHR funded RCTs seem to be a rare commodity, and those that make the cut don’t seem to do well. If the MS community has to wait for academics alone to sort out this problem, I suspect we would be waiting for a very long time :(.

    Personally; I prefer the attitude that 15(?) years ago we had no treatments for RMS, but those who campaigned hard for the use of interferon (and it’s “Butlin’s efficacy profile”) in routine practice made industry perk up and go “maybe this disease is modifiable and funding more studies is a great idea”. 15 years later we have many options, and most people are optimistic that the outlook will continue to improve. I would hope(!) that an ocrelizumab licence/NICE tag would have the same impact. The commercial funders would recognise that PPMS is modifiable and that there is a significant socioeconomic value to treating PPMS; they would invest to get a better formula. If Ocrevus loses out, why would a pharma company burn it’s hand again.

    Sad thing is, this is someone’s life. I bet the person who made the comment would have a very different attitude if it was his daughter’s legs at stake and this was the only treatment available. I tend to find those who have never felt the fear of imminent and severe threat to their health, can be quite arrogant, but I would expect better from those charged with the task of caring for us.

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  2. Nice one profG...You are right,

    People sitting in their ivory towers saying we want to do placebo controlled trials if crazy, the biology says we need to deal with the inflammation and put something on top.

    We have a few trials that will read out soon e.g. MS-SMART, MS-Sprint will they look so smart if the effects are marginal.

    They sit there and say wouldn't if be fun to do this and their mates on the grant panels go Hooray excellent idea here's a wodge of cash

    Five minutes of real thought, a bit of reading and understanding.

    I hear you say This Doesn't happen.....This week I heard someone aiming to do a Treg trial...when asked how does daclizumab fit into the idea...Answer was what's daclizumab...Answer something that depletes Tregs by 50-75% and it improves MS......Response Oh I didn't know that.

    Depressing how some funders (not an MS Charity) want to throw their money away.

    Chariot can not fail but to do some good it needs support.

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    1. MouseDoctorSaturday, July 01, 2017 11:14:00 am
      ...
      People sitting in their ivory towers saying we want to do placebo controlled trials if crazy, the biology says we need to deal with the inflammation and put something on top.

      I sincerely hope these people in the ivory towers are not doctors, but I fear the answer. If a doctor, a clinician who sees patients with real life irreversible problems, thinks there should be a placebo trial for MS I ask that those people be named. People with MS have an absolute right to know which doctors are dangerous and they should stay away from.

      People with MS have been let down by neurology. Enough is enough - placebo trials for MS in 2017 is unforgivable, particularly for anti inflammatories. Rather than hiding behind the hippocritical oath, these "doctors" should be phased out.

      I'd put them in jail personally, but have still not become a judge and executioner :(

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  3. What happens to a person taking an anti-inflammatory and a neuroprotective? How well tolerated is that going to be? Two drugs with potentially very severe side effects? Plus all the drugs for symptoms people with progressive MS so commonly need to take? This is not sustainable, it's not an intelligent, refined solution. It offers me, as someone with PPMS, no hope at all. None.

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    1. What happens to a person taking anti-inflammatory and neuroprotective...better control of the disease processes occurring in MS.

      Somepeople may be doing this already.....sodium channel blockers are used for epilepsy, pain and other aspects, there are may anti-symptomatic drugs that will be neuroprotective, it is just that they have never been tested in that way and no one collects the data so you can tell this. So I suspect some people are already doing this. So it is happening already.

      You say but I still progress...maybe, but can you say that you still progress at the same rate and what would happen if you were getting an effective DMT too. This could be an interferon but it is not going to be sufficiently effective for everyone.

      You now have alemtuzumab and cladribine, alemtuzumab is gone in about 2-3 weeks, cladribine is gone in 24 hours so you have 40-50 weeks of being DMT free a year so neuroprotective drug is not going to interact. Do they have to have severe side effects, for the neuroprotectives maybe not.

      Some people are already taking loads of stuff, last week I heard of someone taking about 25 different pills a day. Look at the benefit of drug cocktails for people with HIV, many years ago do nothing and it was a death sentence. Biology tells us that there are differnet pathways affected in MS. It is unreasonable to think that one treatment can hit all pathways. However if you tested the symptomatic drugs for neuroprotective activity you maybe could be intelligent in the combinations to optimise the neuroprotective effect by targeting complementary pathways

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    2. Hello Cloud Cuckoo LandSaturday, July 01, 2017 5:15:00 pm

      It depends on the person though, doesn't it. I do not believe that any of the anti-inflammatories would benefit me enough to warrant their risks, given the nature of my MS. A low risk neuroprotective - now that really would be something... But there is currently nothing proven / available.

      It is similar to people smoking - not all develop cancer or even feel poorly on it, at least whilst still young, but some certainly do. I just need to smell a cigarette across the street to feel ill. I am intolerant to many things, am not physically robust, and I know that my quality of life would be markedly reduced on a DMT.

      You can't say that alemtuzumab or cladribine just leave the body - they have lasting effects, some of which may not be desireable at all.

      Current DMTs simply hammer the immune system.

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    3. I agree the current DMT are hammers to crack nuts and they have side effects..all drugs do.

      A low risk neuroprotective..come back on 13th for an idea.

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    4. Hello Cloud Cuckoo LandSaturday, July 01, 2017 6:52:00 pm

      I will - thanks! :o)

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  4. Crowd funding.

    Imagine yourself in my place - EDSS currently 6.5. Starting to notice subtle changes in my hands. Left leg seems to be following right leg in being unco-operative to say the least. Would I help to crowd fund something that may, just may, even just stop things as they are, even for a few years? You betcha.

    And all those other people with MS, and all their friends and relatives - a substantial number of them would too. After all, crowd funding raised over £1m to send one child to America for treatment recently, do you not think the MS community as a whole couldn't manage £5m?

    A lot of us are VERY DESPERATE.

    And I'll take the meds too. Side effects be damned, I'm watching my mobility drain away here while nothing is done to prevent it.

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    1. I am sure they could, but would it happen,

      We have started the BartsMS charity and this is is one of the aims of the charity.

      £2 from everyone with MS and we are there, £50 from everyone in UK and we have £5,000,000, $20 for everyone on in the USA and we have $8,000,000 the pound is so crap at the moment £1 = $1.30 = £6,000,000 you get a lot more bang for your buck.

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  5. The Bart's MS-treatment pyramid is shocking in that we have ~20 treatments for inflammation and zero treatments for neuro-protection, remyelination and neuro-restoration. This is not Bart-MS fault but it makes a big statement as to where research is at in this greedy non-patient driven Pharma era. MS is a difficult disease obviously but treating 1/4 of the problem is not the answer.

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    1. I like a good pharma bash as anyone, but it is not fair to say they are not trying, GSK tested a remyelination drug, biogen as still in the process of testing their remyelination drug, we have Biotin there are nerve sprouting drugs..actualy anti-LIONGO1 is one of these. You have MS-STAT2 about to start what about MS sprint and you can be sure the new ALS drug will get tried in MS. There are loads of academic studies too. I agree this process is too slow.

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    2. However Pharma are getting burned...a positive result with ocrelizumab in PPMS and Siponimod in SPMS...no reward and they may ask why bother.

      I suspect they have and maybe that is why the MS pipeline of the big pharma companies looks rather barren.

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    3. Pharma speaks one language, which is money. They will always chase the money to appease their stockholders. If a governing body's approval of MS drugs were based on need and not based on pharma driven agendas, we would be much further ahead. Their "empty cupboards" would soon be full to meet unmet needs of the MS patient, as they will still make their billions.

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    4. "MouseDoctorSaturday, July 01, 2017 6:15:00 pm
      However Pharma are getting burned...a positive result with ocrelizumab in PPMS and Siponimod in SPMS...no reward and they may ask why bother."

      Or maybe pharma are getting burned because Ocrelizumab for PPMS is too little and too late for so many... maybe if they tried harder and had better results for PPMS earlier they would be onto a better gold mine :)

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  6. A few questions about cladribine:

    1. Why are the studies 17+ year old on progressive patients, i.e. isn't there one newer study on progressive patients?

    2. Does Dr. G base his current treatment of progressive MS on these studies which are MRI based and have little if any correlation with the actual clinical outcomes of the patient. Is he having any luck in treatment of his progressive MS patients with cladribine? Does he add "off-label" neuroprotective agents of label to his progressive MS patients like Simvastatin, Na channel blockers, Biotin, etc?

    3. Does cladribine have any effect on the EBV-induced memory cells in follicles in the brain? If so how does he measure it? Does he routinely measure LP-neurofilaments or Ab's in this progressive population?

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    1. Merck spent some time to turn an off-patent drug (s.c./i.v.) into an on-patent (oral) preparation and then went for the lower hanging fruit first, which is early relapsing disease where plenty of MRI activity and relapses facilitate positive outcome detection. At the time CLARITY and ORACLE MS were undertaken, this was entirely understandable. Who knows, had the EMA looked a little harder at the suspected cancer risk, and not misinterpreted lymphopenia as an adverse effect (it is "the effect"), Movectro may have obtained a license in 2011, patent life would have been longer, and trials in progressive MS an obvious follow-on project. Now it's a different story and I would be surprised if the company spends a few hundred million to develop Mavenclad for progressive disease, but may be there is a change of heart; we're working on it.

      We have a trial design for CHARIOT MS, which I'll post next week once our first collaborator meeting has taken place, however not (yet) the funding. We can do the trial for less than £5 million. Let me know if you know somebody able and willing to chip in big.

      Our current offer for people with progressive MS is entirely compassionate, with a plausible rationale, however limited data, and we're totally transparent about that. People have to sign consent that they have understood this.

      Do we have any luck? Well, you know that Ocrelizumab required 3 years and many hundred patients to show an effect, so fat chance to detect a difference with no control arm atm. What I can say is that the treatment is exceptionally well tolerated.

      The Biotin trial allows inclusion of people on DMT, so yes we are prepared to include people who are on cladribine.

      We don't know whether memory cells in the brain are affected. Contrary to drugs that don't penetrate into the CNS cladribine certainly has the potential. At this time, however, we don't even know to what degree memory B cells in the peripheral are depleted; first anecdotal evidence suggests it works well that way, but data is preliminary.

      We encourage people with progressive MS to have 2 LP's over the course of 2 years in order to obtain their neurofilament levels, however this is not mandatory.

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    2. 1. Why so old...once oral clad arrived no-one would fund generic studies

      2. ProfG is the wrong person to ask, DrK is your man, but treatment is based on biology and takes insight from all published studies.

      It is probably too early to be making too many comments, but DrK says transparency is important so I am sure he will reveal info as it arrives. Once we have the data we will publish it.

      Two off label agents...I don't know, in terms of Cladribine there is class I evidence that it is anti-inflammatory as for the others there is in my opinion not such robust evidence in MS. Biotin is a pharma compound.

      3. As part of our use of cladribine off-label we are doing a lot of tests this can include neurofilament levels as this can inform on disease activity and whether the MS may respond to treatment.



      EBV and B cells in CNS, it is a good question and one we would like to address. We can measure OCB, immunoglobulin light chains, cells in CSF etc., but we need infrastructure and resource to maximise our opportunities.

      Does the desire to reduce grade 3/4 lymphopenia mean the dose is limited less gets into CNS.There are so many questions

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    3. Thanks so much for both your responses. Bart's Team should have a button at the top of your webpage for donations and choice of MS study that donors wish to support. Maybe that is available and I just cannot see it.

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    4. Here's the link:

      https://alumni.qmul.ac.uk/public/donate/donate.aspx

      @BartsMS_Charity

      We'll work a button into the Blog, thanks for your support.

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  7. At what point are the studies superfluous?

    At what point should doctors be using more common sense to prescribe inflammatory DMTs to patients who may stand to benefit from those drugs if the patient chooses to have it, regardless if the patient is not an ideal responder (ie. RRMS)?

    I ask the questions because it seems that chasing the efficacy of anti inflammatories for people in advanced stages of MS - when they would prolly benefit more from the other 3 levels of the pyramid - seems like an expensive exercise. All of this to convince the payers to pay and the neuros to prescribe?

    Who convinced the beurocrats that MS should be divided into 4 phenotypes, each of which must be specifically tested against a drug to be sure that the drug works for that particular phenotype?

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    1. we know inflammation is a problem in all stages of disease and we know we can do something about it from 350 dollars upwards. Should we not try.

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    2. Pharma and the regulators must take the blame.

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    3. Anonymous 3:37:00am

      'Who convinced the beurocrats that MS should be divided into 4 phenotypes, each of which must be specifically tested against a drug to be sure that the drug works for that particular phenotype?'

      Seperate labels reduces the number of cases. The rarer the condition, the more pharma and their puppets can get away with. Labels buy their freedom to increase profit at the expense of the patient. Moving goal posts, changing labels, it's all about money, sometimes we, the pwms benefit, but as we know that is not the ultimate goal of pharma.

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  8. Where is the chart of B and T cell counts after taking cladribine (x-axis being time, y-axis being cell counts)? Do the doses oral cladribine is given in drive B cells down to the absolute floor like ocrelizumab and alemtuzumab? This is my one worry with cladribine, that it may not be given in sufficiently high doses.

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    1. If you search baker and Schneider and find neurology neuroimmunology and neiroinflammation, you will see the graph of B cell depletion.

      We have made hypothesis it is a composite of B cells and the memory B cells are the critical population so you could have normal cD19 and floored By memory.We have to do the study then work out if we need to increase the Cladribine

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  9. Idea for raising the money for the trial. There are neuros who are practising medics and who are also academics (producing research papers etc.). So they receive compensation (salary) from the NHS and their academic employer (e.g. University). These neuros can make additional money from (i) private neuro practice; (ii) lecture tours to foreign countries; and (iii) advising pharma companies on trial design, running trials etc. Given that people with progressive MS in the UK have no real treatment options, perhaps neuros could donate 50% of the money they make from (i) - (iii). Its always annoyed me that neuros specialising in MS can make a load of money yet can offer nothing to their patients with progressive MS. I can't think of many other jobs where you get paid well but don't have to deliver anything!

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