Saturday, 2 January 2016

ResearchSpeak: a New Year prediction

We need to focus on upper limb and bulbar function in progressive MS. #MSBlog #ResearchSpeak #MSResearch

Happy New Year! 


"The big challenge for 2016 is how we as a community, including the regulators, deal with the artificial separation between SPMS and PPMS. This is not a trivial issue and will affect how we manage MS and develop drugs for progressive MS going forward. As you are already aware ocrelizumab (anti-CD20) is effective in both relapsing-remitting (RRMS) and primary progressive (PPMS) MS. Will the regulators (EMA & FDA) give ocrelizumab a license for both RR & PPMS? If they do what will happen to people with SPMS? As you know I am a lumper, and not a splitter, and have rehearsed the arguments for making SP & PPMS the same disease many times on this blog.

What are the arguments for SP & PPMS being the same disease. MRI studies demonstrate that lesions on MRI in MSers with relapse-onset or PPMS are identical. The pathology and genetics of the two subtypes are the same. Similarly, when MS occurs in families and the first sibling develops RRMS the second and third siblings may develop either RRMS, or PPMS, in proportion to the incidence of these subtypes in the general population. The pathology of the two subtypes is similar. Once someone with relapse-onset disease develops SPMS it progresses, on average, at the same rate as PPMS. Importantly, a proportion of pwPPMS (~10-15%) will go onto to have relapses; although we classify these people as having progressive-relapsing disease they still have PPMS. I am not aware of any consistent biological differences between relapse-onset MS (RRMS & SPMS) and PPMS. In summary, relapse-onset MS (RRM & SPMS) and PPMS are the same disease.

If the regulators acquiesce and agree to lumping of SP & PPMS together they will have little choice but to give ocrelizumab a very wide indication. I suspect they may use other strategies to limit ocrelizumab's license, for example limiting its use to pwMS with active disease. The latter is usually defined as having had documented relaspes in the last 2 years or evidence of MRI activity in the last 12 months (increased lesion load or the presence of gadolinium-enhancing lesions).

My prediction is that ocrelizumab will be licensed for people with active MS regardless of initial presentation (relapse-onset or PPMS). The regulators will also limit its use to pwMS who are mobile. The latter criteria is based on the clinical trial entry criteria. So sadly MSers in wheelchairs will miss out yet again.

What about the people with inactive MS? If you are early in the course of the disease and you have inactive disease, careful monitoring is all that is required; if your disease becomes active you would then become eligible for DMTs. This wait-and-see strategy is how we practice already. If you have non-relapsing SPMS or PPMS (no relapses or MRI activity) but are still getting worse you will not be eligible for treatment. This does not necessarily mean that your disease is not modifiable. I suspect we have been unsuccessful in developing DMTs for this phase of the disease, because of poor trial design and our fixation with using the EDSS as a primary outcome measure. I remain hopeful that DMTs will help non-relapsing progressive MS for two reasons; firstly, I think there is a therapeutic lag and we simply need to do longer trials (please see previous post on this topic) and secondly, I think progressive MS affects different functional systems asynchronously; i.e. the asynchronous progressive MS hypothesis.

What is the asynchronous progressive hypothesis? I have made the argument in the past that the neurological systems to be affected first by progressive MS are those that have the most wiring and hence more likely to be hit by multiple lesions; this is why the motor system to the legs, bladder and the cerebellar or balance system are typically affected first when progressive disease starts. The other systems (vision, motor system to the upper arms, sensory system, cognition, etc.) tend to be affected later by 'overt' progressive disease. I say overt because there is evidence that the progressive component of MS is present from the start of the disease. The only reason we don't see it clinically is because the nervous system compensates. However, once the compensatory systems fail progressive MS ensues. This means that we may have different windows of opportunity to impact on these different functional systems. In other words there are multiple windows of therapeutic opportunity to act and we should therefore shift our focus in progressive MS on trying to delay the onset of progression in systems that are still not clinically affected by progressive MS. To do this we need to shift our focus away from the EDSS and use multi-dimensional outcome measures that focus on the importance of the other functional systems.

The natalizumab in SPMS trial (ASCEND Trial) supports this hypothesis; although it was considered to be a negative trial natalizumab did slow the rate of progression in loss of upper limb function. In my opinion this was a positive trial; once you lose the function of your legs your arms become your legs (see previous survey results). Despite the latter results and these new insights Biogen closed down their dimethyl fumarate (DMF) in SPMS trial. I have argued that this was a rather hasty decision as lessons learnt from the ASCEND study could have been applied to the DMF trial; adapting trials that are currently in progress is not a new concept. I am now convinced that our length-dependent axonopathy and asynchronous progressive MS hypotheses are correct. We should let these inform our current and future trial designs, i.e. adapt them and not stop them from happening.

My heart goes out to all the MSers with non-relapsing progressive MS. Don't get too despondent we will continue to work on getting progressive trials off the ground. We are currently in the process of designing a proof-of-concept study of testing a combination treatment in people with progressive MS who are EDSS 6.0 and above. Yes, we will include wheelchair users. We have also been lobbying Pharma to do the same. The primary outcome will deliberately ignore lower limb function and focus on the arms and bulbar function (swallowing and speech). From a Pharma perspective the problem with combination therapy strategies is that the regulators won't allow two novel agents to be tested simultaneously; in other words you have to take an already licensed treatment and add-on a second drug. The million, or billion, dollar question is which licensed DMT should be your platform treatment and what add-on drug will you use? We have some strong views on this and hopefully we will be able to generate good enough data in 2016, and beyond, to convince Pharma to do the necessary phase 3 trials to get a combination therapy licensed for non-relapsing (inactive) progressive MS in the future.

Our New Year message to you if you have progressive MS is that we won't give up on you, nor will we give up on your remaining arm and bulbar function."




CoI: multiple

13 comments:

  1. "What about the people with inactive MS? If you are early in the course of the disease and you have inactive disease, careful monitoring is all that is required"...

    I'm confused... so you advocate for pwMS to get on a 'highly efficacious' treatment EARLY? Simply having ms that is not being treated means subclinical damage is likely occurring. Outside of existing methods to measure this, there's no way of knowing for sure. Why wait for the disease to become 'active', which is virtually inevitable since ms is ultimately a progressive disease at some point?

    Why not treat these 'early inactive ms'ers' with a highly efficacious treatment like Lemtrada or Tysabri?

    ReplyDelete
  2. To read of such sense and sanity is balm to the soul in this crazy world of RRMS, SPMS, PPMS obsession. I have written to the UK MS Society to say I don't identify with their "Types of MS" website page, and never did. This classification becomes more and more absurd to me and it seems a real distraction in terms of understanding MS, and hence finding therapies that work for everyone and indeed, perhaps even a cure.

    "Our New Year message to you if you have progressive MS is that we won't give up on you, nor will we give up on your remaining arm and bulbar function."

    A thousand heartfelt thank yous.

    ReplyDelete
  3. But I'd like to add my opinion, for what it's worth, that surely the real therapy for MS will deal with the core of the disease, i.e. the progression, whatever is causing the progression to begin and to go on. It seems to me that that is the core of the disease, leading to abberrant, harmful immune system flares.

    When I had clinically evident flares which spiced up my "PPMS" recently, I was offered DMTs, but I rejected these given the potential side effects and the fact that they don't actually work very well. I don't like the idea of kidney damage, unknown long term NAB effects, hair loss, gastric upset, PML etc. No, I don't like losing neurones either, but surely, there is a better answer to be found. A stake for the heart of this disease. I live in hope.

    ReplyDelete
  4. Do you really want me to respond to this? Probably get me in a world of flack if I say my full piece.

    I agree, once the FDA approves Ocrelizumab they will do so for all forms of MS. Will they however merge terminology of SPMS and PPMS, no. Since SPMS appears to be a differing point of entry they wont take that step until clinically its shown SPMS/PPMS "entry" is same or quite similar via research. This makes sense from a safe ground aspect.

    In as far as Ocrelizumab, no they will not offer it as a first or second therapy option though insurer's need weigh in because costing is yet to be shown. Market economy might result in, "Its the best so lets charge like a Ferrari".

    Towards commitment's of not for profits towards PPMS/SPMS of course they will stay committed. Here's the thing. Its rather likely that soon more information in the puzzle of MS will be coming forth. Mere weeks back I spoke with two universities after a "tip" from people internal to those universities. Both are pretty confident that 2015 end of year research once their "tech" resources are brought to bare are going to show MS onset in "real time" as well as attacks in "real time". Deep scan MRI is also going to proof evidence was told (in RRMS).

    Time will tell.

    Whats clear is with Ocrelizumab and Lemtrada RRMS is on the run. Neuro's here at several events I have attended would like to see Lemtrada as a first line mechanism. From their experience this past year they say there is no reason for "most people" that Lemtrada should not be first line treatment.

    But of course, there is. Its called money. Not the expense per say of Lemtrada but other med's left out to monetarily wither.

    Wither is the term of the day as is evolution. How vague a statement of me.

    As the pieces and solutions in the MS puzzle fall into place the fine folks at Barts MS have skills. They might decide lets now throw our research skills at why Ricks brain is seemingly always 2-3 years ahead of trends and curves and wonder about his crystal ball(s). But many an entities in the world of MS do not have a skill set that can move towards other chronic disorders. These might be deemed, "disodors".

    Aka: Wither and/or evolution.

    I would estimate that y'all at Barts know exactly what I am saying even as far as the tweet, retweet and "to tweet or not to tweet that is the question" Shakespeare 2015. Our decision to sit in global scope is because its the right thing to do, not the easy thing to do.

    I guess I will leave it there.



    ReplyDelete
    Replies
    1. Lemtrada is first line.....in Europe

      Delete
    2. And in Australia. Many neurologists here enforce their own criteria though unfortunately, requiring patients to fail several other therapies. But the criteria allows it to be utilised first line.

      Delete
    3. Some parts of Europe... perhaps. In my (European) country lemtrada is not used first line, second line or any line whatsoever.

      Delete
    4. In the USA from what Neuro's have told us, granted, thats a limited population of them we are in contact with is that Lemtrada is the Last line of defense. At least two other DMT's need fail before it is tried except with the more severe progressing RRMS cases. Thats protocol.

      This is where costing makes one go, "Hmm". Told Lemtrada in the US, about $120K costing. Thats the full two year series.

      With other meds in the same area in cost over a two year span. Thus, "Things that make one go Hmmm?"

      Delete
  5. Prof G,

    Can you please provide your opinion on the first comment above?

    "What about the people with inactive MS? If you are early in the course of the disease and you have inactive disease, careful monitoring is all that is required"...

    Why not treat these 'early inactive ms'ers' with a highly efficacious treatment like Lemtrada or Tysabri? Why let the disease march on & continue to shred reserve capacity?

    I fail to understand why you would suggest risking allowing subclinical damage to potentially wreck havoc when there are options to slow it or even stop it. Of course there are risks associated with any DMT, but there's a certain risk of ms progression if left untreated.

    ReplyDelete
    Replies
    1. Re: "
      I fail to understand why you would suggest risking allowing subclinical damage to potentially wreck havoc when there are options to slow it or even stop it. Of course there are risks associated with any DMT, but there's a certain risk of ms progression if left untreated."

      In the UK we can only prescribe DMTs to pwMS with active disease; i.e. some form of focal inflammation within the last 12-24 months. If we can't demonstrate inflammatory activity then the pwMS would not be eligible for treatment under the NHS in England. If we are audited and found to be prescribing outside of the guidelines then our hospital is fined the cost of the drug treatment.

      Yes, I agree with you that despite being NEDA-3 for 2 years or longer MS may still be active. However, NEDA-4 (brain volume loss) and NEDA-5 (spinal fluid neurofilament levels) are not accepted as activity markers of MS by the wider community nor NHS England at present.

      I will be talking about this further when we have our first case study webinar.

      Delete
    2. Thanks Prof G,

      I'm in Australia where fortunately there aren't such strict prescribing criteria - anyone with definite RRMS is eligible.

      So, assuming there are no restrictions on prescribing criteria, would you still propose leaving anyone with 'inactive disease' untreated, if the are in fact RRMS & early in their disease?

      Delete
    3. Re: " In the UK we can only prescribe DMTs to pwMS with active disease; i.e. some form of focal inflammation within the last 12-24 months":

      What is the definition of active?

      Suppose the patient has had no clinical change or symptom in the last 12 months, but the latest MRI shows two new non-enhancing lesions (small ones) when compared to the MRI of a year ago

      Would this be considered be considered active or inactive?

      Delete
    4. Anon 10:16am:

      I would say absolutely - that is simply new MRI activity.

      The harder question is the presence of new symptoms in the ABSENCE of MRI changes. Some neurologists in Australia won't consider a patient to be progressing or active until they see MRI changes.

      Since we know that MRIs do not tell the whole story, this seems absurd. Treat the patient not the scan! And the MacDonald criteria requires only one OR the other (MRI changes OR clinical signs).

      But then there's the problem of patients correctly reporting symptoms & ascertaining whether these are a reliable & accurate marker when they present in the absence of MRI changes. I would be interested to know how Prof G & his team deal with this dilemma? Would you escalate treatment when an RRMS patient was showing new clinical signs in the absence of MRI changes?

      Delete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.