Tuesday, 2 December 2014

Fallout from the INFORMS study

Where to next for PPMS? #ClinicSpeak #MSBlog #MSResearch

Is PPMS a different disease?

Unlikely; all the evidence from epidemiological, pathological, genetic and clinical studies imply that PPMS and non-relapsing SPMS are the same disease. You must also remember that apart from one interferon-beta trial in relapsing-SPMS there has yet to be a positive phase 3 SPMS study. So SPMSers and PPMSers are in the same situation.

Is PPMS and intractable problem?

Yes and No. Yes, in the sense that by the time someone presents with progressive weakness in the lower limbs a clinically apparent progressive disease course is primed and can’t be modified by anti-inflammatory medications alone. The same scenario exists for other neurodegenerative diseases, for example Parkinson’s and Alzheimer’s disease. By the time someone presents with clinical dementia and diagnosed with Alzheimer’s disease it is probably too late to modify the course of the disease as too many neurons have been lost. The same applies for the motor symptoms and signs of Parkinson’s disease. This is why we have a research project to try and screen the population to detect PD early so that we can try and modify it in the pre-clinical phase, i.e. before too many neurons are lost in the pathways we want to protect. The same is probably true for PPMS; therefore, we need to focus on the pathways yet to be clinically affected by clinically-apparent progressive MS, for example upper limb, brain stem, vision and cognitive function. The latter is what underpins the asynchronous progressive MS hypothesis

Do MSers with progressive disease have another pathology?

What I mean by this is that may be MS triggers a different pathological process that is not responsive to MS DMTs that have been shown to work in early MS. A good analogy is the rheumatoid joint; once rheumatoid arthritis damages the joint it triggers osteoarthritis that is driven by other processes that don't respond to anti-inflammatory medications. A similar thing may happen in MS. The strongest predictor for the onset of progressive MS is age. I suspect that inflammation in the brain triggers premature ageing and a large part of what we see with progressive MS is premature age-related changes. This may mean we require an additional therapeutic approach that targets ageing. Interestingly, simvastatin worked in SPMS in both year 1 and year 2 suggesting it is working on non-specific MS mechanisms. I suspect simvastatin is working as an anti-ageing drug, by impacting on age-related comorbidities (e.g. vascular disease). I suspect we may need to go this route in future trials, i.e. add simvastatin onto an anti-inflammatory drug.

Is fingolimod good enough?

Clearly it is not good enough. When you look at fingolimod’s impact on end-organ damage, i.e. it reduces brain volume loss to ~0.4% per year in year 2. 0.4% may not be good enough as this is as only at the upper limit of normal. In comparison, natalizumab and alemtuzumab reduce brain volume loss to ~0.20-0.25% in year 2, closer to the normal rate of brain volume loss, and they may reduce brain volume loss more than this in year 3 and beyond. Interestingly, with these two drugs you are more likely to get an improvement in disability another indication that they are more effective than fingolimod. However, in relapsing MSers fingolimod reduced and normalised CSF neurofilament levels at 12 months in the majority of treated subjects, similar to natalizumab treatment. On balance this data suggests fingolimod may not be up to the task of switching off smouldering inflammation in MS. This is why I am not giving up hope just yet, may be we need very high efficacy to have an effect in progressive MS; this is why we need to wait to see the results of the natalizumab in SPMS and ocrelizumab in PPMS trials.

Was the INFORMS trial long enough?

May be not. I have alluded to therapeutic lag on this blog many times. In the Barcelona PPMS trial it took 5 years follow-up to see an impact on IFNbeta on clinical outcomes. Maybe the INFORMS study needed to be longer.

Was the INFORMS treatment strategy correct?

I have been making the case for combination therapy strategy in progressive MS for a few years now. We need to build a treatment pyramid on top of anti-inflammatory pyramid. Novartis has been building a case for fingolimod being a dual-action drug, i.e. anti-inflammatory and neuroprotective. I think their claim may now be in tatters. If it was a dual-action drug it should have worked in PPMS. I think before shooting fingolimod down we need to wait for the second-half (all the results) and see what impact fingolimod had on upper limb function and other functional systems. Based on the asynchronous progressive MS hypothesis and therapeutic lag I suspect fingolimod will have a positive disease-modifying effect on neuronal systems with functional reserve, in particular upper limb function that was part of the composite outcome used in this study. If this is the case we as a community need to seriously rethink the way we are doing clinical trials in progressive MS. 

Where to from here?

I want to do a progressive MS trial with our most potent anti-inflammatory therapies, preferably an induction therapy, in combination with a neuroprotective drug. At the moment I would punt for alemtuzumab in combination with laquinimod or simvastatin or cladribine in place of alemtuzumab. Why and induction therapy? Induction therapies are easier to use and guarantee adherence.  Why laquinimod or simvastatin? Simple, we have proof-of-concept data that both these drugs are effective in targeting brain volume loss and disability progression.  

"Finally, I want to thank all our patients with PPMS who volunteered for the INFORMS study. Without your contribution this study would not have been possible. Hopefully, we will learn and move on and insights from this study will lead to a treatment that works in PPMS. We are not going to give up or surrender. The challenge is simply not one game of football; I predict that by the end of the INFORMS game it will MouseDoctor 1: ProfG 1 and by the end of the tournament we will have a drug licensed to slow down the rate of progression for both SP & PP MS."

CoI: multiple


  1. Prof G if progressive MS is there from the start do you think Gilenya is not good enough for MS regardless of the stage?

    1. Re: "... do you think Gilenya is not good enough for MS regardless of the stage?"

      What do you think?

      No, I suspect that about 20% of RRMSers are responders using NEDA-4 (no clinical or MRI activity and normalised brain volume loss of less than 0.4% per year). This means that if you are treating to target to prevent end-organ damage 80% of MSers treated with fingolimod will need to be moved to a more effective DMT. Therefore it is not good enough for the majority of MSers. The problem is we are not treating-2-target of NEDA-4 yet; so many more MSers will be treated with fingolimod who really should be on a more effective DMT.
      You do realise that this statement is unrealistic at present as most of us are not measuring brain volume loss in routine clinical practice; unfortunately, there are a lot of methodological issues that need to be addressed before we can use brain volume loss in routine practice.
      In addition, we need evidence that moving someone who is NEDA-3 to a more potent DMT to achieve NEDA-4 is feasible and achieves a better outcome. If we don’t payers won’t pay and MSers won’t accept the risks associated with the more effective treatments.

  2. Such disappointing news for INFORMS- what do you think the chances are of the siponimod study in SPMS given the study endpoints are similar to INFORMS? There's not much evidence to suggest it is more efficacious in RRMS than gilenya, so do you think Novartis will bother to carry on with the study?

    1. Novartis will not halt their siponimod trial. We need it to be positive in SPMS. I am not sure if there is evidence that it is better than fingolimod. To make this claim you would need a head-2-head study.

    2. Fingers crossed for success in the siponimod study. Your posts about the asynchronous progressive MS hypothesis are really interesting and informative, and as you say, I guess we'll have to wait and see what the other outcomes from INFORMS are to get a better picture. But, if siponimod was to have any success, would it be more likely to be in patients with relapsing SPMS than non-relapsing forms - based on what is known about MS types? Trying to look for some light at the end of the tunnel for progressive MSers :-)

    3. Siponimod I think is a more selective not less selective drug than Gilenya so one wonders how it will be more efficacious, unless it has a better pharmacokinetic profile. But as Gilenya accumulates in the CNS in animals at least, if it were to be neuroprotective one would imagine that you would see it.

      Halt the study early...this is what Merck Serono did with Cladribine and I bet they are they kicking themselves now. They could have had a number of complete trials showing activity and be competing against Gilenya but they have incomplete data now, which I guess is worthless.

      I would bet that Siphonimod will be poisitive in relapsing SPMS, and suspect that when the data is analysed relapsing PPMS will respond too.

  3. Please excuse my ignorance, Prof G. I've just been told I need statins, but what effect is Simvastatin meant to have on my SPMS? Is it supposed to stop me getting worse or does it improve disability? Either way I'm not expecting a lot. I know it will reduce my chance of a stroke and heart attack.

    1. Re simvastatin


  4. When you talk about age-related changes and secondary pathology in progressive forms of MS that may differentiate them, I thought back again to the study I posted in the "unrelated blogger comments" section last month about impaired cerebrovasuclar reactivity in MS patients.

    This is likely due to a sustained proinflammatory conditions causing increase in nitric oxide synthase and the concommitant NO levels staying elevated causing desensitization and vascular haibituation, resulting in neurons that are performning demanding tasks to be left in a hypoxic state

  5. I saw a comment from Credit Suisse stating that probably the second endpoint was not a success either. If so , probably the other projects using the same target ( e.g. Receptos ) are "dead"

    Any thoughts on the Laquinimod mechanism? Probability of success in the ARPEGGIO PPMS study. Different target, effect on BA, but quite bad on relapses.

    MD, MD2, Prof G ?

    Regarding CONCERTO, I was told it might already be fully recruited and that data will be presented H1-2016. TEVA don't have to communicate if the study is fully completed. Have you any "insights" ?

    1. Re: "I saw a comment from Credit Suisse stating that probably the second endpoint was not a success either."

      The second outcome was the timed 25-ft walk, which is also a lower limb outcome measure. I am very interested in the 9-hole peg test.

    2. Re: "Probability of success in the ARPEGGIO PPMS study."

      High. The primary outcome is brain atrophy and not clinical.

      Concerto; no idea.

  6. Dear Prof G,

    I am PPMS , diagnosed 2 years and half ago and since the beginning I am on Rituximab + Amiloride (since 1 year).
    I am still worsening but I still hope that your theurapetic lag theory is right .
    You said "I want to do a progressive MS trial with our most potent anti-inflammatory therapies, preferably an induction therapy, in combination with a neuroprotective drug."

    HSCT is the most potent anti inflammatory therapy ( better than Alemtuzumab) so may be we need to start some PPMS and SPMS trials with HSCT in combination with a neuroprotective drug as Amiloride or Simvastatin?
    Do you agree?

    1. Re: "HSCT is the most potent anti inflammatory therapy ( better than Alemtuzumab) so may be we need to start some PPMS and SPMS trials with HSCT in combination with a neuroprotective drug as Amiloride or Simvastatin?"

      I think the risk:benefit of HSCT is difficult one to sell and it won't be accessible to all PPMSers. I think alemtuzumab is therefore a better option, or cladribine. The latter is cheap and this could be away back for it as part of a combination therapy strategy.

  7. Dear Prof G.

    Why do you think HSCT "won't be accessible to all PPMSers" ?
    Most of PPMSers do not show gadolinium enhancing lesion on MRI ; but do you
    think even Whit Out gadolinium enhancing lesions and With Out the presence of CSF IgM OCB , young PPMSers with low EDSS and short time from onset are still good candidates for HSCT or Alemtuzumab??


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