Thursday, 21 September 2017

The case for NEDA

I have been asked to look at the paper below, perhaps with a subtext to say how rubbish MS drugs are and how great HSCT is.

Rotstein DL, Healy BC, Malik MT, Chitnis T, Weiner HL. Evaluation of no evidence of disease activity in a 7-year longitudinal multiple sclerosis cohort. JAMA Neurol. 2015 Feb;72(2):152-8

IMPORTANCE: With multiple and increasingly effective therapies for relapsing forms of multiple sclerosis (MS), disease-free status or no evidence of disease activity (NEDA) has become a treatment goal and a new outcome measure. However, the persistence of NEDA over time and its predictive power for long-term prognosis are unknown.
OBJECTIVE: To investigate NEDA during 7 years as measured by relapses, disability progression, and yearly magnetic resonance imaging (MRI).
DESIGN, SETTING, AND PARTICIPANTS: Patients were selected from the 2200-patient Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital (CLIMB) cohort study. Patients were required to have an initial diagnosis of clinically isolated syndrome or relapsing-remitting MS and a minimum of 7 years of prospective follow-up that included yearly brain MRI and biannual clinical visits (n = 219). Patients were analyzed independent of disease-modifying therapy. Patients were classified as having early (recent-onset) MS if they were 5 years or less from their first MS symptom at enrollment or otherwise considered to have established MS (>5 years from onset).
MAIN OUTCOMES AND MEASURES: NEDA was defined as a composite that consisted of absence of relapses, no sustained Expanded Disability Status Scale score progression, and no new or enlarging T2 or T1 gadolinium-enhancing lesions on annual MRI. Relapses, progression, and MRI changes were also investigated as individual outcomes.
RESULTS: A total of 99 of 215 patients (46.0%) had NEDA for clinical and MRI measures at 1 year, but only 17 of 216 (7.9%) maintained NEDA status after 7 years. No differences were found in NEDA status between patients with early vs established MS. A dissociation was found between clinical and MRI disease activity. Each year, 30.6% (64 of 209) to 42.9% (93 of 217) of the cohort had evidence of either clinical or MRI disease activity but not both. NEDA at 2 years had a positive predictive value of 78.3% for no progression (Expanded Disability Status Scale score change ≤0.5) at 7 years. Only minor improvement was found in the positive predictive values with additional follow-up of 1 to 3 years.
CONCLUSIONS AND RELEVANCE:NEDA is difficult to sustain long term even with treatment. NEDA status at 2 years may be optimal in terms of prognostic value in the longer term. Our results provide a basis for investigating NEDA as an outcome measure and treatment goal and for evaluating the effect of new MS drugs on NEDA.


So  what does it say at 7 Years only about 8% have not had some form of disease activity, so MS is difficult to treat. If that disease activity in a clinically eloquent place, you may suffer the consequences of that activity for the rest of your life as in some cases damage done is not repaired. So do not do nothing , think of your brain health and do something and positively manage your condition.

"Most pwMS used first-line injectable agents because they were enrolled in 2000 through 2005 before oral disease-modifying therapies and natalizumab became available. Although comparing drug performance on NEDA is of great potential interest, such comparisons may be of limited value in an observational setting because of patient selection into specific treatment groups based on antecedent disease severity. Due to the small number of patients in each treatment group at each time point, we were underpowered to determine how specific therapies affect the predictive value of NEDA". 

This what we want to know. How good is each drug




Based on this natalizumab is best at 47%, followed by cladribine at 46% and the CRABS are 13-33%. 

As you know I am not a fan of CRABS, I never have been and never will be...so yes I am biased, but yes I accept that some people can do well on them...many don't. 


I think data generated from them simply muddy the water, because until the studies are done with the highly active agents we won't know the real answer

COI: I do not get support from any Pharma companies and mine is an opinion..others will disagree. 

Alemtuzumab is not very good, I was told once that it was our fault:-(.. as too many different people did the EDSS assessments and they did not tie up. Maybe, but I think you asked about this because of the NEDA data in the 5 year extension studies 

Havrdova E et al. Alemtuzumab CARE-MS I 5-year follow-up: Durable efficacy in the absence of continuous MS therapy.
Neurology. 2017;89(11):1107-1116. 

How can a 33% NEDA over two years (see above) become 61.7% NEDA at year 3 60.2% NEDA at year 4 and 62.4% NEDA at year 5. It is a fudge of course and presenting the results this way hides the reality. 

It says in any given year only about 40% had evidence of activity but it does not say that 60% of people were disease free of 5 years which is what we want to know. 

Based on that presented previously as I don't have the paper result to hand but seem to remember it was only about 30% were disease free over this time, so if we look at the failures in the first two years the NEDA rate is much lower. In fact in the extension study the NEDA rate for the trial part was well over 60% how can that be? 

Well there are a significant number of people who did not go into the extension study, so I suspect a number of these were failures in the original study, remove them and efficacy goes up.  

It is simply bad refereeing that the authors get away with not reporting important aspects.
However, you say...HSCT is miles better

Sormani MP, Muraro PA, Schiavetti I, Signori A, Laroni A, Saccardi R, Mancardi GL. Autologous hematopoietic stem cell transplantation in multiple sclerosis: A meta-analysis. Neurology. 2017; 88:2115-2122.

The pooled proportion of NEDA patients at 2 years was 83% (range 70%-92%) and at 5 years was 67% (range 59%-70%).

Yes it is or yes it appears to be that way.  The pooled estimate of mortality due to the procedure was 2.1% (95% confidence interval [CI] 1.3%-3.4%).

If you have activity early on it is a poor prognostic sign of where you may end up.

The problem with NEDA. Which is no evidence of Disease control.


NEDA is only as good as you look for it.


(a) No MRI  Gadolium lesion


(b) No clinical Relapses


(c) No clinical progression....This is a problem as this is the outcome you desire, however if you have say PPMS and are progressing the NEDA rate for the treatment may be irrelevant because it depends on the course of the individual.


(d) Then we have NEDA-4..brain atrophy....If your brain is shrinking something is happening but is may not be nerve loss, because if you get rid of inflammation and oedema goes the brain shrinks, so the outcome is not fit for purpose.


Measure spinal cord atrophy and you can miss spinal cords that have lost 60% of their nerves but have not shrunk, so its not fit for purpose.


Maybe imaging grey matter volume is better.


(e) NEDA-5 and neurofilament. Having minimal neurofilament is an indicator of less nerve loss but you loose nerves due to inflammation of relapses and you loose nerves because of advancing disease. So there can be noise isn the system 


But the problem is if you use CSF the simple answer is if you don't live in Sweden, then no-one wants to have a lumbar puncture, so you have to rely on blood, the blood is not a direct correlate of the CSF.


(f) What about NEDA-6, 7, 8 could it be peripheral blood B memory cells  as a marker of disease activity. 


Do memory B cells have any correlate with disease activity in MS. In other conditions where anti CD20 antibodies work like arthritis, lupus, graft verses host disease, M.gravis, nephritis of the kidney, NMO etc etc..  


Why is HSCT so good compared to the DMT....well it is the ultimate DMT with the total immune clear out (Maybe missing the stuff in the CNS) and a complete reboot. 


People getting the HSCT tend to be more active people who have failed treatment, but when you look at the demographics they are different from other trials. 


People tend to have a higher EDSS and longer into their disease, which is a demographic you would associate with fewer relapses and a slow rate of deterioration.


So is there a fudge?


Is the efficacy artificially good?


Probably this is relevant and just as Prof G was taken to task for loading the ocrelizumab trials with people with active PPMS that respond to DMT, should we be saying that the HSCT trials are fudged too.


Of course I wouldn't say that before "BearMS" and the rest get on their high horse


A new review from Sweden looks at the same data and argues that whilst the data looks impressive, it is not without its faults.


It s open access so you can read it, if interested


Burman J et al.Autologous haematopoietic stem cell transplantation for neurological diseases JNNP http://dx.doi.org/10.1136/jnnp-2017-316271Neuroinflammatory diseases such as multiple sclerosis, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy and myasthenia gravis are leading causes of physical disability in people of working age. In the last decades significant therapeutic advances have been made that can ameliorate the disease course. Nevertheless, many affected will continue to deteriorate despite treatment, and the costs associated with disease-modifying drugs constitute a significant fiscal burden on healthcare in developed countries. Autologous haematopoietic stem cell transplantation is a treatment approach that aims to ameliorate and to terminate disease activity. The erroneous immune system is eradicated using cytotoxic drugs, and with the aid of haematopoietic stem cells a new immune system is rebuilt. As of today, more than 1000 patients with multiple sclerosis have been treated with this procedure. Available data suggest that autologous haematopoietic stem cell transplantation is superior to conventional treatment in terms of efficacy with an acceptable safety profile. A smaller number of patients with other neuroinflammatory conditions have been treated with promising results. Herein, current data on clinical effect and safety of autologous haematopoietic stem cell transplantation for neurological disease are reviewed.

If a randomised trial is done will it convince neuros to refer people to the procedure. 

Probably not, as they a a bunch of risk averse people, but it will stave off competition against current DMT for a while and by the time we get a definitive answer, drug patents will have run out:-). 

Isn't this what you wanted me to say?

8 comments:

  1. And what about Ocrelizumab? (especially NEDA3 and NEDA4)

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    1. ProfG has the knowledge on this I'ld have to read...but I am sure he has been stirring the pot by questioning NEDA-4, I question whether it is fit for purpose and I believe the answer is no, but its still been used.

      I was at a meeting many years ago when one of the MRI Gurus said just this and that Grey matter was much more sensitive

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  2. Conclusion :Neda and Neda related studies are complex and predisposed to interpretation ,anyway this is a real world study with real world people beeing treated with drugs that costs bilion( call it crabs) and people with MS been injected with those drugs should know what are their chances 2 5. 7 years down the line
    Thank for posting

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  3. Imagine Novartis or Merck or Biogen, introduces an innovative drug/therapy that offers disease remission, for some for few years and for some forever. It is magic! It has finally happened! No NEDA, NEPAD etc. Remission! BUT it has a 0.5% chance that you might die, and it will definitely affect your fertility, but not much other than that. I can see it alredy in the headlines! Oh, wait...


    Drugs fall behind patients needs and patients need at least to have a choice.

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  4. For many (if not majority) of pwms, DMDs offer false hope. False reporting of the numbers on this false hope, is adding insult to injury.

    On a heavily DMD biased blog. It's reassuring and refreshing to see an hsct post examining the numbers (if through gritted teeth).

    Why do DMD posts conflate NEDA data. But hsct don't feel that need?

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  5. To be fair it should be noted in the extension study that most people did not restart treatment so maybe the activity was minor.

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  6. Thanks for the informative, important & gutsy post MD, much appreciated and much respect.

    I guess we will have to depend on the neurology researchers to speak in a common language (NEDA-4, NEDA-5 etc) so that MS patients and their neurologists can weigh a drugs effectiveness in preventing disability vs side effect profile of that drug.

    I don't think a RCT (HSCT vs any patented DMD drug) will ever be done as this will not be in pharma's best interest, financially speaking.

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  7. The question to me that this post poses is this: if some people respond to some drugs, and some people respond to other drugs and some people don’t respond at all, then could it be the fact that MS is, in the end, a series of diseases that actually follow the same clinical path? Perhaps we should look at MS in this way: imagine a line of dominoes. Each domino is stacked very close to the other. If you took one domino away then it would not disrupt the cascade if the others were pushed. One domino might be Vitamin D deficiency. One might be Herpes Virus 6. One is EBV. One might be stress. One might be smoking. One is hormonal. One is genetic. One is lifestyle. One might be trauma. One is gut function. The list could go on. So someone with MS might have the issues of Vitamin D, EBV, genes and trauma. Another might have HPV6, smoking, gut and stress. In both cases the dominos fall uninterrupted. The impact on the body is the same, the drivers different.

    If this is the case, then one drug might impact the EBV, genetic, traumatised patient. Another drug might improve the life of the HPV6, smoker with IBS.

    Perhaps the world of neurology is too latched to the idea that there is a silver bullet that will cure all. Perhaps the efficiency of HSCT is that it is a sledgehammer to crack a nut, but that nut could – possibly – have been cracked with a less traumatic drug. Perhaps an anti-viral (PEP?), perhaps an anti-bacterial, perhaps a B-cell depleting drug, perhaps a T cell mediator.

    The inconsistency of responses to treatment, to me, should then be turned on its head. Not to say: the drugs don’t work. But to say: the drugs are working, just on those they are meant to work on. And the ones the drugs don’t work on might indicate that MS is not one disease, but a panoply of ailments, a domino chain of woe.

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