Saturday, 17 September 2016

Late Breaking News

250 - Efficacy and safety of siponimod in secondary progressive multiple sclerosis - results of the placebo controlled, double-blind, Phase III EXPAND studyL. Kappos, Basel, Switzerland
Background: There is high unmet need for treatments that delay disability progression in secondary progressive multiple sclerosis (SPMS). Siponimod (BAF312) is an orally active selective modulator of the sphingosine-1-phosphate receptor subtypes 1 and 5. EXPAND is the largest randomised controlled study in SPMS to date.
Objective: EXPAND is a phase 3, multicentre, randomised, double-blind, placebo-controlled study designed to evaluate the efficacy, safety and tolerability of siponimod in treatment of SPMS.
Design/methods: Patients with SPMS, defined by a progressive increase in disability (of ≥6 months duration) in the absence or independent of relapses, aged 18‒60 years and an Expanded Disability Status Scale (EDSS) score from 3.0‒6.5 were enrolled. Eligible patients were randomised (2:1) to receive either 2mg once daily siponimod (following initial dose titration starting at 0.25mg) or matching placebo. The event-driven study design allowed the blinded Core study stop after a pre-specified number of confirmed disability progression (CDP) events occurred. The primar
y efficacy outcome was time to 3-month CDP measured by EDSS. The key secondary outcomes were time to confirmed worsening of ≥20% from baseline in the timed 25-foot walk test and T2 lesion volume change from baseline. Safety assessments included reporting of adverse events (AEs), serious AEs (SAEs) and clinically notable laboratory abnormalities. Patients who completed the Core phase were offered to receive open-label siponimod in the Extension phase.
Results: Overall, 1651 patients were randomised in 31 countries. Baseline demographics and disease characteristics were previously reported, and they are representative of a patient population with SPMS. Overall, 1363 (83%) patients completed the Core study. Median time on study at core study completion was 21 months with majority of patients (87%) participating for ≥1 year. There were 449 CDP events (each patient could maximally contribute one event for the primary endpoint). AEs were reported in 85.3% and SAEs in 16.7% of patients.
Conclusions: Top line efficacy and safety results of the EXPAND study will be presented. The results of this large controlled study that recruited an active SPMS population with and without superimposed relapses will determine if siponimod delays disability progression in SPMS, and will contribute to a better understanding of the natural history of SPMS in a well-controlled trial setting.

COI None ProfG multiple
So  here we have it an drug with an effect on SPMS that slows progression in a phase III trial So this is good news.
The bad news I guess, is that the drug only slowed the rate of 3 month progression by 22% over so disease was not halted and an effect on 25 foot walking was not apparent and at the end of the study about 18% decided to withdraw which must mean that they were disatisfied with the outcome.
The question however is is this due an effect on disease activity rather than true progression and the answer is you can't truly answer this, however it was clear that there were people with relapses in the trial and about 35% had evidence of disease activity and relapses were reduced by about 55% compared to placebo, so just like you would expect for a sphingosine-1-phosphate modulator and indeed people who had MRI activity responded more than people who did not have gadolinium activity, but neverthe less there was still an effect in people without gadolinium at baseline but did they have lesions along the way we will never news.
So whilst this is a start, we have to do better.
Further disappointing news
Fluoxetine in progressive multiple sclerosis (FLUOX-PMS)

M. Cambron1, J. Mostert2, J. Parra3, M. D'hooghe4, G. Nagels4, B. Willekens5, D. Heersema6, J. Debruyne7, W. Van Hecke8, L. Algoed9, N. De Klippel10, E. Fosselle11, G. Laureys12, H. Merckx13, B. Van Wijmeersch14, L. Vanopdenbosch15, W. Verhaegen16, R. Hupperts17, G. Hengstman18, V. Michiels1, A. Van Merhaegen - Wieleman1, J. De Keyser

The trial failed P=0.07 is this a real trend or an indication for the effect of MS-SMART


30 comments:

  1. So despite all the hype, siponimod does really have any real impact for people with SPMS. Does it (or ocrelizumab) have any impact on progression? I think not. So 10000 neuros and researchers have a nice break in London town, and nothing positive for those with progressive disease! No breakthroughs on repair. No announcements on cause. Maybe better news at next year's ECTRIMS (don't bet on it).

    ReplyDelete
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    1. Yes it does have impact.
      Does it affect progression...start early enough and maybe progression does not occur.

      Delete
    2. What about the patients that did not start early enough??? Here is hoping that there is a change in direction away from B and T cells, which have shown very little efficacy in stopping MS progression, despite what many top MS research neurologists preach. Also, hopefully, many researchers will now focus solely on increasing patient reserves through improved remyelination and neuro-restoration.

      Delete
    3. With PPMS like mine, you don't get the chance to start early enough.

      We need therapies that actually do something for _progression_.

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    4. "What about the patients that did not start early enough???"

      Who cares about those patients, apparently there are some people who believe those in wheelchairs shouldn't even be included in clinical trials.

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    5. Start too late when progression has taken hold and it is going to be much more difficult to stop.

      There are indeed people wanting to exclude wheeel chair users apparently for pivotal trials....if ECTRIMS allows us to post the video. Until then rather than constant sniping anything constructive to say?

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  2. Perhaps there should be a moment's pause in all of this for there to be a post that says: wow.

    What I mean by this is that, in this year's ECTRIMS, there seems to have been a number of papers that add light to what 3 years ago was a very dark place for people with progressive MS.

    Last year we had the very promising and hopeful news of high dose Biotin.

    And now we have, in this year's ECTRIMS, evidence that 1200 mg of A Lipoic Acid might reduce brain atrophy rates in people with progressive MS (and I am a little confused why this has not got greater play in the MS world). We have tentative good news from Siponimod. And we have good news from the Ocrelizumab trial in progressive MS.

    Hey. You can get high dose, pharmaceutical grade Biotin from compounding pharmacies. You can get ALA from credible health stores. And now you have either Siponimod or Ocrelizumab as possible future funded DMTs.

    Perhaps what we need to see now are trials that involve people taking combination therapies / interventions? I know... hard to have a double blind test etc, find funding, etc. etc... But given that many people with progressive MS will be downing Biotin and ALA now, it makes sense to see if there are at least no adverse effects of combination therapies and add ons.

    Because, let's face it, if you had progressive MS, wouldn't you be chugging down 300mg Biotin with breakfast, 1200mg ALA with lunch and then pestering your Neuro to give you Ocrelizumab for tea?


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    Replies
    1. I have PPMS. And I am not taking any biotin at all because it doesn't work for most people - I believe my very healthy diet provides all the biotin I need anyway. And I am not pestering my neuro for Ocrelizumab because it only works in a subset of people, would age my immune system and increase my breast cancer risk.

      I see no development for PPMS to write home about yet, and my neuro agrees with me. So does the doctor I see whom I would trust with my life.

      I would love some progress with progression. Not white elephants bathing in hogwash, which is all there has been so far. Not that I don't believe there are many earnestly trying, who are not just looking for the easiest route to profit.

      Delete
    2. which part of biotin news exactly is actually exciting?

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  3. Unfortunately the optimism of trying B&T-cell therapies in progressive MS is waning. The driver of neuronal loss and subsequent increase in the EDSS seems independent of lymphocyte modulation. A good burning debate would be : B&T-cell activation is driving the progressive phase of MS. It seems we are trying to fit a square peg in a round hole with regards to progression and the treatments for RRMS. In other words, the inflammatory component of SPMS is different than that of RRMS.

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    Replies
    1. These are very disappointing results no matter which way researchers/Pharma/statisticians try to spin this one. They are very similar results to the Ocrezulimab results.

      100% agree that B and T-cells have very little to do with progressive disease, in keeping with previous pathology results which show very little of their presence of in gray matter in progressive MS.

      Here is hoping Ibudilast, which works on decreasing the macrophages crossing the BBB, reducing inflammatory factors and reduced angry glial cell activation will provide much better results than this.

      Good luck getting this medication approved but hey the CRAB drugs got approval for RRMS with results on efficacy close to this (30% above placebo for reducing relapses and 0 effect on disability).

      Delete
    2. In my mind the Grey matter pathology suggests there is something bathing the CNS, and one candidate would be antibody or a soluble mediator and T cells or B cells could be a candidate.

      As you say results of this Nature are like the CRABs but from them bloomed others that were better

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    3. "from them bloomed others that were better"

      Or perhaps they actually send research on the wrong path, missing what progression is actually about. Perhaps this is a red herring, will lead to just more delay in finding therapies that really work for progression.

      Delete
  4. Lipoic acid I missed it as I went for breakfast:-(

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  5. This was posted on this website at the end of August:


    "For those of you with SPMS who thought you had been forgotten some great news yesterday. Siponimod, a S1P receptor modulator, has hit its primary outcome in the EXPAND SPMS trial. This is great news for the field and for the first time progressive MSers have treatment options. This also means that it is going to become very difficult doing new studies without comparing them to existing DMTs, in this case Siponimod, in the progressive MS space."

    The results don't look that great to me. Don't the researchers and neuros get it? People with progressive MS want treatments to stop progression, so they can plan for the future. Simvastin to me looked the most promising treatment but has died a death. Ocrelizumab and siponimod are just having an impact on the inflammatory mechanism and not providing any neuroprotective benefits. Despite the hype, ECTRIMS 2016 was a damp squib. At least we found out how to make a peg test contraption. I might try building my own wheelchair from a supermarket trolley and some duct tape.

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  6. Just seen the MS Question Time at ECTRIMS 2016.

    MouseDoc, you are the secret weapon in Team G. You really communicate clearly and cogently in the videos you do. You need to do more short videos or podcasts on MS. You're a great communicator.

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    Replies
    1. I agree with you. Doc Baker, should consider doing vid's towards explaining aspects of MS & research.

      Delete
  7. Dear MD,

    I think that it is a bit strange that you judge the EDSS results from this Siponimod study in SPMS rather hard, even if result was not super with 22% risk reduction in EDSS 3 months.

    To be noted, Ozrelizumab accomplished a risk reduction in the same range, i.e. 25% risk reduction for Ocrelizumab in PPMS.

    Both Ocrelizumab and Siponimod are pioneers in their segment of MS.

    So, how can you elevate Ocrelizumab rather high in your blog and at the same time be more distant to the edss result with this Siponimod drug ? Both drugs produce the results within the same range on EDSS. A little bit confusing for me.

    For me this is a bit strange, without me personally taking a detail stand as to if the efficacy on EDSS is good or not. But if I would say something, it would be, that both Ocrelizumab and Siponimod produce an effect in EDSS that is about the same and it is rather modest efficacy.

    Please advice on this
    Regards
    Camilla B.

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    Replies
    1. Dear Camilla
      You will note that this post was posted minutes after the presentation and concerned the results of Siponimod and Prozac and not ocrelizumab.

      There was little time to digest or review the results.

      If ProfG had posted then it may have been a glass half full, but he may have been aware of the result and had time to digest it. Furthermore he did not give me his rose-tinted glasses. He can do this when the papers are published

      I do not believe that I have put ocrelizumab on a pedestal above Siponimod they are both pioneers in there respective progressions but likewise I believe that we have to be able to do better.

      We will see what the regulators think...carte blanche or a restricted approval...

      Furthermore I am not sure that I have ever commented on the ability of ocrelizumab outside its effect on the annualised relapse rate.

      Progression is not typically associated with relapses but it is clear that activity is still part of MS in these stages and we know that both Siponimod and anti-CD20 inhibit this type of disease activity.

      In my mind questions need to be answered of both of these agents and one can do this when the data is presented. I have not had access to it.

      Delete
    2. The only time I have commented on progression is to highlight the difference between progression of hand and lower limb function


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  8. I agree with the comment about Mouse Doc. I met him today at MS Life and told him how clear and engaging he was on Question Time.

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  9. The siponimod data has to be exciting! When we started with interferons we had a 30% reduction in relapse rate and we are now talking about treating-2-target and NEDA. Something small over 2-years may grow into something big over 3, 4, 5 and 10 years. Incremental gains is the name of the game and to achieve this we have to start somewhere.

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  10. What was the maximum transient drop in HR with the titration scheme?

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  11. Just curious what is the reason for only targeting S1P1/5 receptors, rather all S1P receptors 1-5? Any information on what these receptors do and if this may help the side effect profile when compared to Fingolimod which targets all 5. Thanks.

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    Replies
    1. The immune effect is mediated by S1P1 receptor and the S1P5 is thought to affect the glial response. Each receptor you target comes with a potential side effect. Fingolimod doesn't target S1P2

      Delete
    2. The immune effect is mediated by S1P1 receptor and the S1P5 is thought to affect the glial response. Each receptor you target comes with a potential side effect. Fingolimod doesn't target S1P2

      Delete

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