Saturday, 23 April 2016

ThinkSpeak & ResearchSpeak: my top highlight from the AAN 2016 meeting in Vancouver

The ASCEND SPMS trial demonstrates that SPMS is not an intractable problem #ThinkSpeak #ResearchSpeak #MSBlog #MSResearch #AAN2016

People with SPMS now have hope #ThinkSpeak #ResearchSpeak #MSBlog #MSResearch #AAN2016

My top highlight for the AAN 2016 are the ASCEND Trial results #AAN2016



"Most commentators have dismissed the natalizumab in SPMS trial, or ASCEND trial, as being negative and have simply moved on. 

One person said to me: 'SPMS is an intractable problem and it is best to prevent it by early effective treatment’. Another said: 'What did you expect, the ASCEND is just another negative SPMS trial, which could easily have been predicted from our experience with the interferon trials.' How cynical and sad? These attitudes entrench the concept of the therapeutic window in MS and perpetuate the concept that it is futile to try and develop treatments for SPMS. I disagree with both of these positions and prepared to go out on a limb and hypothesise that the therapeutic window remains open throughout the course of MS and it is not futile to try an develop treatments for SPMS. We have to give people with MS hope. In my opinion the ASCEND Trial was clearly positive; although the study did not hit the desired primary outcome natalizumab did show an effect in virtually flattening loss of upper limb function. Surely a treatment that protects upper limb function in people with SPMS is worth exploring further? To quote one SPMSer: 'Now that I am in a wheelchair my hands and arms have become my legs’.

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What is galling is the ORATORIO trial of ocrelizumab in PPMS was positive. Is ocrelizumab really superior to natalizumab? Is PPMS that different to SPMS? I would argue no on both accounts. The differences between the ASCEND and ORATORIO trials can be explained on differences in the study populations. The ASCEND SPMS population was older and more disabled; over 60% of study subjects had an EDSS of 6.0 or 6.5. In other words they had lost most meaningful reserve capacity in the motor system to their legs. We know from other studies that at a disability level of EDSS of 6.0 (unilateral support) or 6.5 (bilateral support) the EDSS is not a very good outcome measure over 2 years; most MSers with this level of disability spend many years at these levels before progressing to a higher level of disability. In measurement speak we refer to this as the ceiling effect of the EDSS. In comparison over 60% of PPMSers in the ORATORIO study had an EDSS of less than 6.0 and hence were at a level of disability on the EDSS scale that is more likely to move. In addition, with a disability below EDSS 6.0 there is more reserve capacity in the motor system to allow recovery of function and get a read-out in a two year period. In other words at lower levels of disability there is less therapeutic lag.

For the last 2-3 years I have been discussing two concepts, or hypotheses, on this blog, i.e. therapeutic lag and the length-dependency. The results of these two studies, with other evidence - new and old - strongly support both these related hypotheses. Therapeutic lag states that the more reserve that is lost in a specific pathway the longer it will take to see a treatment effect in relation to therapies that are targeting MS specific mechanisms. This is why the ORATORIO trial was positive on both the EDSS and timed-25-foot walk (T25FW), and the ASCEND trial was negative on both these outcome measures. I would predict that if the ASCEND trial had been longer in duration then it may have been positive on both of these outcomes, in particular the T25FW which is more sensitive to change than the EDSS. Unfortunately, the ASCEND trial did not allow for therapeutic lag. If these hypotheses are correct the treatment effect of ocrelizumab should be greatest in comparison to placebo in the ORATORIO trial in relation to upper limb function, which is assessed using the 9-hole peg test. We will have to wait for more detailed analyses from the ORATORIO trial to be published to see if this is the case.

So what have we learnt from the ASCEND trial?

  1. That non-relapsing SPMS is a tractable problem; if we focus on the relevant outcomes, i.e. neuronal systems that have sufficient reserve capacity to demonstrate a treatment effect using responsive outcome measures such as the 9HPT and the ABILHAND we have a chance of a positive trial. The ABILHAND is a validated patient-related outcome measure of hand and upper limb function. 
  2. If we are going to continue to have to use the EDSS as an outcome measure we are either going to have to study an earlier population, similar to the ORATORIO study population, or do longer studies to allow for therapeutic lag. 
  3. In my opinion we need to ditch the EDSS as a primary outcome measure in progressive MS trials. For those of us old enough to remember we have seen evidence for these arguments in relation to the interferon in SPMS trials. The European interferon-beta-1b SPMS trial was positive when the North American study was negative; the former was in a younger less disabled population, whereas the latter was older and more disabled. 
  4. If we are going to do studies in more advanced MS then we need to focus our attention on neuronal systems with functional reserve, for example upper limb and bulbar function (speech and swallowing). For this to occur we will need to bring the regulators (EMA and FDA) on board. I think this is possible and is now urgent. 
  5. I suspect that to have a realistic chance to modify the non-relapsing progressive phase of MS we will need to use highly-effective DMTs. I am not surprised that both ocrelizumab and natalizumab have produced positive trial results in these populations; please note my emphasis on positive.  Because of this I have been lobbing Pharma to do trials in advanced progressive MS (both PPMS and SPMS combined) with the highly effective DMTs, i.e. alemtuzumab, ocrelizumab, daclizumab, ofatumumab and cladribine. Let's see who is brave enough to take on the challenge. If Pharma won't do it we will. 


Some caveats. The cynic in me worries more about the payers than the regulators. The cost effectiveness calculations in relation to DMTs are based on the cost of the treatment versus the savings to the individual and society. Once a person with MS has lost their mobility they have already accrued a large amount of personal and societal costs. These include both direct medical cost and indirect costs for example loss of employment. The sad thing once a person becomes unemployment their worth to society drops. If this is the case then the payers, for example NICE, may judge the cost-effectiveness of DMTs in more advanced MS to be less favourable; in other words expensive high-cost drugs such as natalizumab and ocrelizumab may not be cost-effective in more advanced MS compared to early MS when preservation of function will save society more money. This is one reason why Pharma are reluctant to take on the risk and develop drugs for more advanced progressive MS. A potential way to counter this is to allow Pharma and payers to agree to a differential payment scale; the more disabled a person with MS is the less the company is able to charge for their drug. This may sound crazy but it makes a lot of sense to me; it would force pharma to move to an outcomes based remuneration system. Under this system payers will get better value for money and pwMS will get treatments that work. This will allow us to move away from a fixed-pricing system to a value-based pricing system. We seem to be getting used this in many other sectors, surge pricing systems are used by the airlines, software industry and Uber. If you have used Uber you will know all about surge pricing. I can see a world where the same agent is more expensive when used in early MS and as the patient becomes more disabled the price for the drug is less. The question is the NHS and the Pharmaceutical sector ready for valued-based pricing? I think so this is already being explored in oncology. Why should the NHS, or individual, pay for something that doesn’t work? On the other hand why should we deny people with progressive MS drug X because it is considered to be not cost-effective at their stage of the disease ?

You can see that I am all fired-up from the AAN with as many ideas whizzing around my head as minutes in the day! Attending conferences provides thinking, talking, networking and downtime. This AAN was no exception. I would like to conclude this post with a huge thank you to Biogen for having the balls to do the ASCEND study and for the SPMSers for volunteering to take part in the study. Without this study we wouldn't have these insights.

Finally, a appreciative thank you to a well-meaning and generous Pharma executive who gave up his first-class upgrade to try and help me get a good nights sleep. When I was sitting in the BA lounge waiting to board my return flight from Vancouver a senior Pharma Executive, who I know well, came over to chat to me. When he heard I was flying economy+ back to London he tried to get me a business class upgrade. He was called to the BA desk for a first-class upgrade and turned it down by asking BA if they could upgrade me instead. They said they would try. However, when we got to board we both had our originally allocated seats. I am grateful that someone would try give up the comfort of a first class upgrade to try help me get a good nights sleep. However, I would prefer him to lobby his company to do a SPMS trial based on the insights of the ASCEND study."

CoI: multiple

31 comments:

  1. Prof G you have stated that an aberrant immune response to EBV is responsible for MS. Since latent EBV is B-cell mediated why the optimism that Natalizumab, a T-cell therapy, would be beneficial in SPMS? Does Natalizumab have an effect on innate immunity in the CNS that may be driving SPMS? Also, as a patient, I was involved in the ASCEND trial, EDSS 6. Being on Tysabri for 4 plus years I can say my T25FW has deteriorated. Yes this is only one patient's perspective but I remain skeptical of the current highly effective immune modulators for progressive disease. I also realize Pharma is going to keep pushing for their drugs in all types of MS.

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  2. The cost of drugs issue is why many progressive MS are just going for HSCT. One time cost and you know it's
    stongest treatment possible so it's the most bang for your buck.
    Worldwide treatment waits are 1-2 years. So of course more damage is done while you wait.

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  3. Not the highlight I was waiting for. I was hoping for some hopeful news about repair (anti-lingo, stem cells...). Revisiting old (failed) trial data to squeeze out something positive sounds a bit desperate. The Promise 2010 initiative which many research teams were handed big chunks of money from promised neuro-protection and repair. Looks like they over-promised. At least the researchers attending AAN get to see a new city and contribute to global warming.

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    Replies
    1. Re: "Revisiting old (failed) trial data..."

      This is brand new data; it was the first time it has been presented at a meeting.

      Delete
    2. Promise 2010 Promise Neuroprotection....That is what we did which was the phenytonin neuroprotection, likewise the SMART MS studies developed from the promise 2010 initative too, when doug Brown form the MS Society began the process of focusing the UK clinical trials network to specifically target progressive MS

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    3. But it's mid 2016. I'm seeing my neuro next week. What will he offer me for my SPMS? Absolutely nothing! All the conferences, research papers and Phase 1 trials (lamotrigine, phenytoin, cannaboids) have not made a jot of difference to me. Please correct me if I am wrong.

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    4. the ms smart has not finished recruiting and it depends on your neuro

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  4. You're grateful to a Pharma executive. We, the MS community are grateful that despite all the setbacks you are still fired up and trailblazing!

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    Replies
    1. We should all be grateful for Pharma, without them we would have no MS drugs.

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  5. As someone 'taken off' Tysabri in Aug. 2014 after relapse, which for first time didn't improve after oral steroids - because I was 'probably transitioning to SPMS (Why? Because I always attended hospital appointments in wheelchair ?)
    My personal experience: I need bilateral support, but before Aug. 2014 I could lift feet up step height and climb stairs (albeit with 2 handrails) and sit up and get dressed myself with a little help. After Aug.2014 & Tysabri stopped, I still climb stairs, but partner has to lift foot up step height (once I've taken weight off foot) and lifting my arms is much more difficult meaning I need help dressing, but I still have relatively strong arms (mostly). My confidence has been hit enormously, but as someone who used to be 'sporty' I know that it you do 'difficult' exercise regularly, it gradually gets easier, so I go to local therapy centre gym regularly and do arm exercises etc. every morning, but performance fluctuates.
    I'd love to just be able to climb stairs on my own again & dress myself. I'll (slowly) work at improving the other things, but I think just the first two items mentioned would really boost my confidence.

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  6. Re: "Finally, a appreciative thank you to a well-meaning and generous Pharma executive who gave up his first-class upgrade to try and help me get a good nights sleep."

    And we're now totally aware of the sweetners and back-scratching that comes with the MS business. There is so much money being played with and yet not one drug has materialised for progressive MS.

    The eco and carbon footprint from these conferences does not justify itself when we look at how poor the field of options are for advanced MSers.

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    Replies
    1. Hell is getting on to an aircraft and turning right. Can't remember who said that.

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    2. Re: "...not one drug has materialised for progressive MS..."

      This not quite correct. IFN-beta has a license for relapsing MS that extends into the SPMS phase. Similarly, in several countries mitoxantrone has a license for worsening MS that includes SPMS. More recently ocrelizumab has been shown to effective for slowing progression in PPMS.

      When you take a 20 year view of things, which I know is hard if you have MS, a lot of things have happened. I am therefore remaining positive.

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    3. Re: "The eco and carbon footprint from these conferences does not justify itself when we look at how poor the field of options are for advanced MSers."

      The AAN is a very large meeting and is not solely for MS, it covers stroke, dementia, epilepsy, headache, etc. The AAN and other meetings are not going to go away soon. What we need to do is make them more accessible to the outside world so that people with various neurological conditions understand why they are important.

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    4. The recently deceased pop star Prince had epilepsy. Many have even contributed to his early demise.

      Neurological diseases are indiscriminate.

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    5. The GravyTrain is now the GravyPlane!

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    6. Carbon footprint blah blah.

      As a clinican you have to accumulate continuing medical education CME credit each year to show that you are keeping up with current medical knowledge otherwise all they would be doing is giving steroids.

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    7. AnonymousSaturday, April 23, 2016 1:20:00 pm

      Re: "Finally, a appreciative thank you to a well-meaning and generous Pharma executive who gave up his first-class upgrade to try and help me get a good nights sleep."

      And we're now totally aware of the sweetners and back-scratching that comes with the MS business. There is so much money being played with and yet not one drug has materialised for progressive MS.

      The eco and carbon footprint from these conferences does not justify itself when we look at how poor the field of options are for advanced MSers.

      -----------------------

      How absolutely eDiculous.

      Anyone who keeps track of Prof G.'s work as well as MouseDoc's and Barts is quite well aware of the passion, hours and time they put into finding answers to MS.

      The fact that Prof. G was not flying first class to begin with is rather telling. Its not exactly a short flight either.

      ----

      In respect to PPMS and research. From what I see and read about MS (which is quite a bit) more research has occurred surrounding MS that actually makes a difference in the last 15 years than all years prior.

      Perhaps sadly RRMS has had the most focus but in the same sentence RRMS has the most patients and also moves to SPMS in a scant 8-12 years historically before the new DMT's.

      Now that effective DMT's truly exist for RRMS the research community is placing quite a bit of focus on PPMS and this will surely ramp up.

      Towards effective SPMS/PPMS treatments there are some in the pipelines, MedDay MD1003, Innate Immunotherapeutics MIS416 to name two.

      ----

      In as far as Eco footprints, I'd personally rather see these conferences which are trying to accomplish something (note the AAN is about more than MS) .vs. the Eco footprint of BMW plants producing cars costing $50,000 and up .vs. one's that make sense.

      If the globe truly wants put a dent in environmental matters then the first step is changing the presumptuous petrol pigs power platforms into reasonable transportation.

      More Eco footprint agony is released in 20 minutes of daily London (or other city) automobiles than all these conferences combined.

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    8. Brilliant blog post.

      A question that comes to mind in respect to Pharma trials is the money equation. Do/would they see that in respects to market as profitable venturing?

      We simply dont know how long range efficacy of the DMT's will pan in the sized populations now using them. There are clues of course.

      If the meds stave off SPMS in considerable fashion would it make economical sense to Pharma to invest?

      Its said that 80% of people who have MS or get MS is about 80%.

      Is train of thought the other 20% are PPMS, Fulminant MS, Benign MS?

      Or does that 20% include SPMS?

      Delete
    9. Well said, Ms Unites, for both your answers above. I find it very hard (impossible, actually) to understand the posters who are so negative and cynical about the team who run this blog.They are negtive whilst at the same time taking advantage of using the blog?!?

      Delete
  7. Of the list of highly effective DMTs, only one of them gets past the blood-brain barrier in appreciable concentrations. Would you speculate that cladribine has a better chance at efficacy for progressing disability patients than the antibodies?

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    Replies
    1. let us test it and put it to the sword or not, but as you say it is the only on that acts in the CNS and kills plasma cells

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  8. This is so "MS speak", the neuros can't even decide if the trial failed or succeeded. "Tomato ...tomato , potato.....potato.....let's call the whole thing off.":-)

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  9. Mr Gavin

    Did the Conference shade some ligt on the rather high incidence of malignacies with with ocrelizumab in PPMS, namely 11 patients (incidence 2.3%) ?

    P

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    Replies
    1. I suspect you counter this with the data in the relapsing remitting trials which did not show this but shows what can happen in trials.

      From that based on stuff presented or discussed on internet so it was 9 malignancies (or the 11 cancers reported) verses 0 in placebo and I think 6 breast cancer verses 0 in only one trial. If we think it was only 3 malignacies v 0 in the cladribine (European originated drug) trial and this got rejected by the FDA what will they do to this American oriniated drug?

      Therefore licencing may not be a slam dump

      Delete
  10. I'd really like to see a trial of Cladribine and Ocrelizumab in SPMS...


    I know a guy who has SPMS and is fingolimod, brain atrophy stabilized in the motor disability continues to progress ...

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  11. 2 Questions to Prof G!


    I don´t now what happend, but I think it was some kind of technical error when I 1 hour ago tried to publish a question at the comment area, connected to the above blog post. I Think my comment never manage to be posted. So I try again.

    So, since the subject of this blog post is PPMS, I have a two questiona with régard to the ongoing study with Laquinimod phase II in PPMS. You Prof G brought the study up in a blog post published in late februari this year. And you Prof G, are also the principal investigator of this study. So my first question is: how many patients are now involved/reccruited into this ongoing PPMS study with laquinimod, given that the high dose was terminated. My second and last question would be: when could one expect that we approximately will have results ?


    Marc

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    Replies
    1. Both posts were in spam maybe because it says "you profG"
      However to address your post I think DrK is leading our laquinimod PPMS study, but I could be wrong.
      However we have no idea about how many people are recruited teva collates this data. According to clinical trial .gov end date Q3 2017

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    2. Thanks MD,

      BUT referring to the blog post 26 febr, " ResearchSpeak: reply to an email from an expert PPMSer" Prof G states that he is the Principal Investigator of this study. Check it out for yourself.


      http://multiple-sclerosis-research.blogspot.com/2016/02/researchspeak-reply-to-email-from.html

      Reg
      Marc

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    3. All will be revealed when all is revealed as MD has said. We get a few queries from market analysts trying to get advance notice of trial results so please don't be offended if we approach questions like yours with due caution.

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    4. A principal investigator does not mean that you get a sneaky preview. Data is blinded and will be until it is finished and ready to view. The guy or gal doing the statistics will get first view.

      As with all trials you have to wait until the data is cracked.

      Delete

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