The tale of Two Civies. Aim for NEDA

McCarthy CL, Giovannoni G, Coles AJ. Timing is everything in the treatment of multiple sclerosis. BMJ Case Rep. 2015 Apr;2015. pii: bcr2014208960.

We present two similar cases of relapsing-remitting multiple sclerosis, both of whom received treatment with the monoclonal antibody alemtuzumab, but had significantly different long-term outcomes. 

  • Patient A is 12 years into their illness and was treated early in his disease course, they had no disability and continue to perform at a high level as a professional golfer. 
  • Patient B was initially started on interferon-β1a therapy and went on to have two disabling relapses on this treatment which resulted in a degree of fixed disability prior to the start of alemtuzumab. 10 years into their disease course they have moderate disability and daily symptoms of spasticity in his legs which impair their quality of life. 
  • These two contrasting cases highlight the difficult decision of when to start potent immune modulating therapies for multiple sclerosis in young adults who appear well early in their disease but have the potential to rapidly accrue irreversible disability from future relapses.

Alemtuzumab is an effective DMT, but there appears to be a constant flow of comments circulating about its therapeutic value. This view in my opinion is misguided. The question is not whether it works as it does,the question is the risk:benefit issues

This report of two civilians (civies) by ProfG & C highlight some stark consequences.  With active MS you may have the choice of Lemtrada, unless you have a risk-averse Neuro and worryingly an NHS trust that is rationing your access to drugs.

This study highlights the importance of aiming for and achieving NEDA, it may occur with a low efficacy DMT, but the chances are it may not. Some people on the blog have argued that relapses are not important in the prognosis of MS. This study highlights that this is not the case. Aim for NEDA it is risky not to.

CoI: Prof G was an author of the paper. Multiple 

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  • I have just had my first course of alemtuzumab – 3 months after diagnosis, 32 yr old female Edss 0. so I'm obviously in the treat it hard and early boat. What astounds me when talking to other mser's on injectables/orals is their opinion they are not "bad enough" for induction therapy and will wait and see if it gets worse. Why aren't neurologists highlighting that in most (but not all I agree) of mser's it will get worse. It's not if but when. There's a window of opportunity to get in there early before damage is done but it's being missed and people are being left with irreversible damage. When I was first diagnosed one neurologist told me my Ms was 'mild' and I wouldn't be eligible for treatment and see her in 20 years when I run into problems…… I don't want my neurologist to be kind to me to save my feelings they need to be telling us the reality of the disease so we can make informed choices about treatment options with the aim of safeguarding our futures. Thank god for sites like this!

  • If I got MS diagnosis today, I would want the strongest treatment from the start…
    But the paper cited is a case report. Let me report on a third case ( my own). I was on interferon for 3 years following MS diangosis, then no medication. (Looks like patient B so far, doesn't it? ) . But then I have patient A story: No disability.

    Can anybody predict the course of MS? Many have tried…

  • The reason we published these case reports in parallel is to simply show at an individual MSer level a delay in accessing high-efficacy therapy can come at a price. The second MSer wanted alemtuzumab 1st-line, but couldn't access it. When he did get it after 18 months he had acquired disability that was irreversible. There are potential consequences at an individual MSer level having delayed access to highly-effective DMTs. There is not right or wrong decision we simply have to live with their consequences. Interestingly, MSer 1 has had no autoimmune complications, whereas MSer 2 developed autoimmune thyroid disease.

  • Do you know what Patient A and B's EDSS was prior to alemtuzumab treatment? Is this going to be as relevant as how long you have had the disease in assessing your likely outcome? I think Neuro DocG said that epidemiologically people with EDSS of less that 2 is not associated with progression ('My take on AAN' last month)

  • If you want to hit hard, why not choose HSCT? It seems these days all MS therapies are aimed at immunosuppression which seems like a de-evoulution. The first line injectables may not have the stopping power, but I'm glad other researchers are interested in finding out what causes MS instead of just pushing ways to suppress your immune system.

    Those at the forefront of research are getting to the real problem in all forms of the disease, but it is too bad Pharma is going down the wrong path. As an example, look what can be achieved with a relatively safe drug such as Copaxone by adding a safe and generic drug that is in wide use:

    It's such a shame that this will never be pursued or that it is not on option to people. But I am grateful to those researchers who are uncovering the mysteries of MS.

    • "Why not choose HSCT?". I am afraid it is not currently licensed nor is Copaxone and Albuterol and so the question we have to ask is what mechanism is available to develop these different types of therapy because one can ask is it ethical to start testing a treatment option (as a Immune modulator DMT) that you cannot deliver as a real therapy as opposed to false hope

    • I was being sarcastic when I suggested HSCT as this is the ultimate in immune supressive therapy.

      But on a serious note, if someone in Britain was on Copaxone and relapsed and wanted to try Albuterol as an add on therapy, are you saying this is not possible? If there is evidence that it is effective at dramatically reducing the relapse rate it seems like this could be an option.

      I believe Professor G posted about off label prescriptions in the UK. Since this is an add on therapy to an approved treatment what is complication?

    • Sorry I cant sense the sarcasm unless you indicate it

      The primary clinical end point was the MSFC at 6, 12, 18, and 24 months. No significant treatment effect was observed at 24 months/ Therefore the trial may have been considered to fail as it was not followed up, The study was however probably based on a false logic as IL-12 inhibition d oes not inhibit EAE lrt alone MS.

      Maybe one of neros will answer

    • Yes, unfortunately they chose the primary endpoint as the MSFC. This measure is an unknown quantiny in MS trials. This measure was developed by the National MS Society who incidentally paid for the trial. I assume this was a requirement by the NMO.

      Looking beyond the primary endpoint, the relapse rate is unprecedented:

      "Ten subjects experienced relapses during the study, 2 in the glatiramer acetate plus albuterol group and 8 in the glatiramer acetate plus placebo group. Subjects in the glatiramer acetate plus placebo group experienced a first relapse faster than subjects in the glatiramer acetate plus albuterol group (P=.03) (eFigure 2). The annualized relapse rate was 0.09 relapses per year for the glatiramer acetate plus albuterol group and 0.37 relapses per year for the glatiramer acetate plus placebo group."

      This is statistically significant even with the low sample rate. I find it amazing that trial designers have to decide before hand the primary end point, and the trial is considered a failure if the primary endpoint was not met.

      In this case it was an obscure measure of disability progression. How can anyone neglect the effect this has on relapse rate? Maybe in the realm of academics this can be justified but it is an ultimate shame to those suffering with the disease.

    • To further clarify the result of this study in terms of relapse rate over the 2 year trial.

      13 people were in the Copaxone + placebo group of which 10 had relapses.

      14 people were in the Copaxone + Albuterol group of which 2 had relapses.

      The odds ratio was 5.3 which means if you were on Copaxone + placebo you were 5.3 times as likely to relapse than if you were in the Copaxone + Albuterol group.

      The calculated annual relapse rate for Copaxone + placebo was 0.37. This equates to 2.7 years before the first relapse on this therapy (on average, extrapolated).

      The calculated annual relapse rate for the Copaxone + Albuterol was 0.09. This equates to 11.1 years before the first relapse on this therapy (on average, extrapolated).

      The p value for these results is 0.03. This means that thsee results would only happen by random chance 1 out of 33 times.

      The p value for something to be considered statistically significant is 0.05 or it happening by random chance of 1 out of 20 times.

      These results were obtained in a double blind randomized controlled trial which means neither the physicians or patients new which therapy arm they were on. This is the "gold standard" trial design.

      So yes the results were not that impressive when looking at the MSFC, but this is an unknown quantity to begin with. Clearly based on the relapse rate results there is an unquestionable response with the combination of Copaxone + Albuterol. It is amazing this result can be obtained with essentially docile drugs compared to the immunosuppressive alternatives. Hopefully further research can be conducted with this approach.

    • The relapse rate = 0.09 = 0.1 is the same as with Alemtuzumab NCT00050778 and other

      The trialist have to decide what is the primary endpoint to stop p-hacking or data dredging where after the event you do enough tests and you find one that is positive. You then say that is the primary endpoint and your trial then becomes positive..which could be fudging the result.

      I agree with you however that it appears frustrating that nothing then happens and maybe one could say that the triallists should be duty bound to sort it out one way or another before moving onto the next trial. We see time and time again with studies where a trend is claimed for it never to be repeated. However the problem is it is difficult to get the same study funded twice and especially when it is going to be difficult to get the compound licensed.

      I can appreciate how frustrating this is…not only do promising treatments get dumped but it also kills off chances of developing the basic science…e.g. who is going to support cannabinoid research when they are perceived as a failure even when planned data analysis show a positive result.

    • The trial was n=25 which is too small to make conclusions and this was done in 2010. Maybe someone knows if the Harvard Group were planning on doing more as the findings were interesting.

      Then what about mitoxantrone and copaxone

      A sustained 90% reduction in annualised relapse rate (p < 0.001) has been observed. Disability is stable or improved in all patients a mean of 36 (16-66) months from initiation of treatment. Early suppression of relapse activity with Mitoxantrone has been maintained at a mean of 22 months from last dose of this agent. Only two relapses have occurred in the cohort (n=27) since withdrawal of Mitoxantrone, occurring in the two patients who had previously been treated with Glatiramer Acetate.

    • Yes I saw that and was considering going down that route before I found the Albuterol trial. It sounds like drug development is a political game. It's too bad more can't be done with the Albuterol add on but I'm thankful a phase 2 trial was conducted.

    • I don't know whether the Harvard group is pursuing albuterol+copaxone trials – but I do know (a sample size of 1) that their new patients with active MS are being offered new orals or Tysabri (no word on copaxone/albuterol combo). Chemo was mentioned as a potential escalation option.

    • With reference to MD's post above concerning data dredging, I came across a new concept called data Fracking.
      "Data-fracking is the fracturing of a dataset by the application of a pressurized search through as many datapoints as is necessary to find one that has the appearance of being positive. Typically, data is combined with cortisol and caffeine, and the mixture is injected at high pressure into statistical analyses to illuminate illusory correlations along which the appearance of success may migrate to a press release. The products of data-fracking tend to be more gaseous than substantive."

      Pretty pertininent to many drug company trials 😉

    • On MouseDoctors comment that a sample size of 25 is too low, I would agree in most cases because the effect difference between the two arms is usually to low to detect with such a small sample.

      However, if the effect difference is large which is the case in the Albuterol trial it still was statistically significant. They also looked at brain atrophy, and although the %atrophy was lower in the Albuterol + Copaxone than placebo + Copaxone on average the sample size was not large enough to determine this to be statistically significant.

      But from what I have read there seems to be some real data behind the beta 2 adrenergic receptor agonist (which what Albuterol is) effect on immune homeostasis. Hopefully this will lead to new avenues in treatment.

  • So if a MSer with EDSS between 0-2 using Alemtuzumab as a treatment early in the disease, you may have a better prognosis (NEDA) than those who have chosen to moderate DMTs? But how to make sure of it in the absence of biomarkers indicating the course of the disease and the effectiveness of the treatment?

    • Biomarkers for effectiveness of treatment is MRI, but predictors of prognosis is more difficult, the more active disease are onset is worse prognosis as a rule of thumb



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