Research: Beta Interferon and Progression

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BACKGROUND: Few studies have analysed long-term effects of immunomodulatory disease modifying drugs (DMDs).

OBJECTIVE: Assessment of the efficacy of DMDs on long-term evolution of multiple sclerosis, using a Bayesian approach to overcome methodological problems related to open-label studies.Methods: MS patients from three different Italian multiple sclerosis centres were divided into subgroups according to the presence of treatment in their disease history before the endpoint, which was represented by secondary progression. Patients were stratified on the basis of the risk score BREMS (Bayesian risk estimate for multiple sclerosis), which is able to predict the unfavourable long-term evolution of MS at an early stage.

RESULTS: We analysed data from 1178 patients with a relapsing form of multiple sclerosis at onset and at least 10 years of disease duration, treated (59%) or untreated with DMDs. The risk of secondary progression was significantly lower in patients treated with DMDs, regardless of the initial prognosis predicted by BREMS.Conclusions: DMDs significantly reduce the risk of multiple sclerosis progression both in patients with initial high-risk and patients with initial low-risk. These findings reinforce the role of DMDs in modifying the natural course of the disease, suggesting that they have a positive effect not only on the inflammatory but also on the neurodegenerative process. The study also confirms the capability of the BREMS score to predict MS evolution.





However we also have a conflicting report

Shirani et al. Association between use of interferon Beta and progression of disability in patients with relapsing-remitting multiple sclerosis. JAMA. 2012 Jul;308(3):247-56


OBJECTIVE: To investigate the association between interferon beta exposure and disability progression in patients with relapsing-remitting MS. 

DESIGN, SETTING, AND PATIENTS: Retrospective cohort study based on prospectively collected data (1985-2008) from British Columbia, Canada. Patients with relapsing-remitting MS treated with interferon beta (n = 868) were compared with untreated contemporary (n = 829) and historical (n = 959) cohorts. 

MAIN OUTCOME MEASURES: The main outcome measure was time from interferon beta treatment eligibility (baseline) to a confirmed and sustained score of 6 (requiring a cane to walk 100 m; confirmed at 150 days with no measurable improvement) on the Expanded Disability Status Scale (EDSS) (range, 0-10, with higher scores indicating higher disability).

RESULTS: The median active follow-up times (first to last EDSS measurement) were as follows: for the interferon beta-treated cohort, 5.1 years (interquartile range [IQR], 3.0-7.0 years); for the contemporary control cohort, 4.0 years (IQR, 2.1-6.4 years); and for the historical control cohort, 10.8 years (IQR, 6.3-14.7 years). The observed outcome rates for reaching a sustained EDSS score of 6 were 10.8%, 5.3%, and 23.1% in the 3 cohorts, respectively. After adjustment for potential baseline confounders (sex, age, disease duration, and EDSS score), exposure to interferon beta was not associated with a statistically significant difference in the hazard of reaching an EDSS score of 6 when either the contemporary control cohort (hazard ratio, 1.30; 95% CI, 0.92-1.83; P = .14) or the historical control cohort (hazard ratio, 0.77; 95% CI, 0.58-1.02; P = .07) were considered. Further adjustment for comorbidities and socioeconomic status, where possible, did not change interpretations, and propensity score adjustment did not substantially change the results. 

CONCLUSION: Among patients with relapsing-remitting MS, administration of interferon beta was not associated with a reduction in progression of disability

We kind of have heard about this study before because George Ebers has spoken about the effect of interferon on progression and has suggested that relapse rate does not influence progression except early in disease course. However tell that to someone who has had a disabling relapse they they are not relevant. 

The two studies have different outcomes and so are not easy to directly compare, but differences in science are commonplace and this is why things are repeated. Eventually one gets consensus. You would  have though pharma would collect this type of information, but it may not be the info it wants to hear, so they do not do it.


Prof G says “The problem with the data from the Canadian study is that it is not controlled and hence their will a lot of bias that cannot be taken into account. For example, the untreated contemporary and historical cohorts had a longer disease duration for the same level of disability at baseline; this would imply that they had more benign disease. They would therefore expect to do better than a cohort with more active disease (shorter disease duration for same level of disability). The fact that they did as well as each other to EDSS 6.0 implies that IFNbeta must have been doing something”. 


Furthermore Prof G says “The bottom line is IFNbeta is not a very effective treatment; this study confirms this. That doesn’t mean we shouldn’t use it as some MSers respond better than others and in the UK, at least, you have to fail first-line treatments to access the more effect second-line treatments. For this reason alone IFNbeta has many years left in its legs and hence the rush to develop long-acting preparations and cheaper biosimilars. My main worry with them is the legacy NABs to INFbeta will leave behind.”

Let us hope that as we move into the age of more effective treatments that an effect on progression will be clear. I am hopeful that it will.

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MouseDoctor

27 comments

  • The publication of the Canadian research really sheds a bad light on MS research. It may be correct in that beta-interferon has no impact on progression. But how come so many studies led us to believe that they did have an impact – a recent study suggested beta-interferon users had greater survival levels after 21 years. What are we as patients expected to believe – we are the ones who have to make choices about which drug to use and slowing progression is a big pull. I'm sure the author of the study enjoyed their 15 minutes of fame – i wonder if they gave thought to all those on beta-interferon who now go to bed each evening without any idea if the injections they have to give themselves will do anything in the long-term. I'm not suggestign such research should be covered up, but how come it is so opposite to other research about beta-interferon?

    I want to get on Alemtuzumab when it becomes available. Can I trust the results of the various trial which suggests that it reduces disability (SAD) compared with Rebif? Who can I trust anymore – clearly not the pharma companies with their marketing budgets etc. Clearly not the researchers who come out with contrary results.

  • Re: "sheds a bad light on MS research."

    Not at all; not all studies go in the same way. What we need is to interpret the results correctly! If you set your significance level at 0.05; 5% of trials will be positive by chance. Similarly, if trials are not powered correctly, a negative result may mean the study was not large enough to detect a positive effect.

  • "But how come so many studies led us to believe that they did have an impact"

    This is one way of doing it. It involves the so called "immortal bias"

    http://www.ncbi.nlm.nih.gov/pubmed/18668635
    "Immortal time bias in the study of effectiveness of interferon-beta in multiple sclerosis."

    Unfortunately, the comment is not free for download. In short, the writers recalculated the rate ratios of an INF-b study for secondary progression, EDSS 4 and 6 compared to untreated patients, by incorporating the "immortal time", that is the time period between first admission and first administration of IFN.

    The result was that the corresponding rate ratios of 0.38, 0.70 and 0.60 (secondary progression, EDSS 4, EDSS 6) of the original study where adjusted to 1.03, 2.02 and 1.6, which means that INF actually made things worse.

  • Prof G,

    "sheds a bad light on MS research"

    I stand by my claim. Why do so many MS researchers undertake under-powered studies? Why do they undertake studies and then conclude that larger studies are required?

    I'd guess c.10 MS research studies are published each week = c.500 a year, 5,000 a decade. Yet I can't think of one study which has identified the (i) cause of MS (definitive); (ii) what's causing progression etc etc; (iii) the basic question of whether it's primarily an inflammatiory disease or neuro-degenerative.

    So far this year: CUPID study failed (5 years down the drain), oral Cladribine was pulled; Canadian research suggests beta-interferon has no impact on progression.

    In October there will be another jamoboree (ECTRIMS) in some nice city like Rome, or Lyon, where all the "experts" can get together and award prizes to each other. For what? What's really benefitted MS patients in the last 12 months?

    New way of working needed. Academia isn't delivering (apart from per reviwed articles and PHds for some graduates).

    Research data / publications should be accessible to all. Boot camps needed where 20 top MS researchers e.g. Prof G, Prof Compston…. and work the thing out. I could think of some incentives – $1 for each prof when cure identified, or shoot 1 Prof every month (would incentivise the others to get the job done).

    Even you Prof G, looking at the MS research world from outside, must see that the progress to date has been lamentable.

    This is one of the promises from the NMSS Promise 2010 campaign:

    WWhat if we could actually reverse the damage that MS causes, restoring function to those who have been living with the disease for years?….. The Nervous System Repair and Protection Initiative, funded through the Society’s Promise: 2010 Campaign, is bringing the dream of protecting and repairing brain tissue and restoring function within our grasp."

    What's been delivered on this – I gave $s, but can't see any return. Yet another broken promise.

  • I think the problem ist, that only about 20% of the MS'ers benefit from Interferons.
    And part of these 20% only benefit at a certain level.
    So neither the first nor the second study makes me wonder.
    I would be more interested in studies of the harder stuff like Mitoxantrone, Tysabri, Alemtuzumab…..

  • What if…..

    This is the problem of managing realistic expectations…the media certainly do not help here.

  • Immortal Time bias.

    This is just another opinion saying people are worsened but others say that that idea is "based on an erroneous mix"

  • The canadian study isn't surprising in my opinion, given the fact that several other studies have reached similar conclusions or at least casted doubt upon the "fact" that DMDs do indeed and without question slow MS progession.

    Here there ara a couple of examples:

    http://www.bmj.com/content/339/bmj.b4677.pdf+html

    http://jnnp.bmj.com/content/81/8/907.full.pdf+html

    Apart from that, i think that we have to into consideration not only the "immortal bias" Vasilis was talking about, but also the natural course of the diseas itself, wich some times can improve naturally in an innate way:
    http://www.ncbi.nlm.nih.gov/pubmed/22736751

    Given those facts, and also the philosophycal argument that you cannot predict the behaviour of what you do not understand (and it think it is becoming very clear that MS is a disease that we do not fully comprehend), it's very difficult to asses wether DMDs work or don't work as inhibitors of MS progression.

    Given all the data i've been able to read up to date, my guess is that they do not work in that aspect.

  • Can you please elaborate of Prof Ebers quote – I don't see the logic behind it? I generally am confused when I read that a drug cuts relapses but does little for progression – I thought that avoiding relapses saves nerves/axons/meylin and if your nerves are stable you should not progress/become disabled. So how can one have 'healthy' nerves and progress?


  • He has a little list
    Of sinecured professors who might well be underground
    And who never would be missed

  • In my opinion, Dr. Eber's explanation can be better understood if we asume that there are, at least, two harmful processes going on with MS.
    One being inflamation. This is the primary issue adressed by DMDs.
    The other being neural degeneration and grey matter atrophy, which some think that it happens after inflamation, and some others think it happens before it, actually at the undetected and unseen onset of the disease. This process doesn't seem to be stopped by DMDs, that is why we are all progressing, in my opinion. That is also why i think that you can see people with lots of inflamatory lesions that can still run, and other with less lesions that can't event walk.

    In this blog this perspective was discussec while analyzing Dr. Stys paper titled "will the real multiple sclerosis please stand up?".
    http://multiple-sclerosis-research.blogspot.com.es/2012/07/will-real-ms-please-stand-up.html

  • That is why he also says that DMDs "that relapse rate does not influence progression except early in disease course", because, as we do know, MS tends to be (at least in the remiting recurring type, which is the one that the drugs are useful for) more inflamatory at firts and less as time goes on (we do know that there is a relatively high percentage of people with Remiting recurring MS that converts to Secondary Progressive MS).

    If at first, MS is more inflamatory and DMDs tend to reduce or prevent inflamation, then the phrase "that relapse rate does not influence progression except early in disease course" makes sense.

    That is, at least, my interpretation.

  • Also, if you read a study in which he participated called "Analysis of clinical outcomes according to original
    treatment groups 16 years after the pivotal
    IFNB-1b trial" (it's posted above) and read the conclusion:

    "Conclusions: The original treatment assignment could not be shown to influence standard assessments of longterm efficacy. On-study behaviour of patients was influenced by factors that could not be controlled with the sacrifice of randomisation and blinding. Mortality was
    higher in patients originally assigned to placebo than those who had received IFNB-1b 50 mg or 250 mg. The dataset provides important resources to explore early predictors of long-term outcome."

    …then what he says makes even more sense as he arrived to a somewhat similar result.

  • Prof Ebers loves to talk the talk and says many provocative things about MS at talks. Then when you ask him to put pen to paper and say things, that pharma do not want to hear he often has sat on the fence. For example his guest post on the blog was nice as humble pie but was that his private view?.

    I will leave it to VV to talk about relapses and progression if he wants to chip-in as I know it is a pet subject. I don't agree with him on point he will make but data is data.

    The problem is the first generation DMT are not that effective, the rest of the confusion follows on from this

    CoI None

  • "… He has a little list of sinecured professors who might well be underground, And who never would be missed."

    I bet this was posted by Prof. Eber's in disguise?

  • "The bottom line is IFNbeta is not a very effective treatment"

    Which means that it was approved based on "exaggerated" efficacy results. Why continue spending so much money and effort (from the patient side) for something "not very effective"?

    When a drug is supposed to help only a minority of patients (in so minimal a way that is literally non-discernible in the long run) , then one has to suspect that the drug does nothing in reality, but those who "benefit" simply do because their MS is such.

    After all, all these double-blinded, placebo controlled studies for INF-b were essentially single-blinded, placebo uncontolled due to characteristic side effects. Let alone that they only measured white matter MRI activity, when it's now clear that profound grey matter activity is there from the beginning, and relapse number in the mysterious and unstandardised way that relapses are defined in each clinical trial.

  • "I'd guess c.10 MS research studies are published each week"

    "More like 100-150 each week. You get more than ten a week posted here".

  • it was approved based on "exaggerated" efficacy results"

    I think this is Rubbish. The results of the phase III studies were clear for anyoe and every one to read.

    If it was so great we would not of had the risk sharing scheme fudge and NICES refusal to back the DMT.

    However at that time you had the option of a marginally effective drug verses no drug at all. At that time you did not know that progresive MSers would not respond to the drug

    Had MSers not bought the drug or wanted it or lobbied to get access to it, it would have gone on the maggot pile and pharama would have not thought that MS was worth investing in.

    I say this because it was the high cost of the interferons that made a change. Companies realised they could make money out of MS after that.

    Had interferons not been approaved there would have been an incentive to get an alternative quicker than waiting until the patents expire.

    Why spend money… this is called choice if you have it that is. There are going to be more and more alternatives for a short while. Why because once one of the newer drugs becomes established it will be difficult to beat it without alot of side effects.

    For all these trials….at least that way people had access to a drug that they were not paying for and being on a trial they did better through the placebo effect even if they did not get drug. This again was a fudge.

    Measuring white mater verses grey matter is all kind of irrelevant as the approaval was based on the clinical profile not the MRI which showed a poor correlate to the clinical effect.

  • I think ms is due to stealth bacteria or bacteria,and viruses as triggers,theres an interesting study on cancer and ebv could viruses infect parts there not meant to then the immune system goes after it

  • Im hoping to get a rather late diagnosis of childhood onset MS its taken a while but feel I have the criteria but what do I know

  • Re: "…. but those who "benefit" simply do because their MS is such."

    Not true; that is why we do randomised placebo-controlled trials. Those who do well, do well compared to those on placebo, it is not simply due to the type of MS they have. If it was so would the MSers in the placebo arm. The problem we have is we can't predict upfront who are going to be responders or non-responders. This may change as there are some promising markers that have been identified that need to be confirmed or validated in larger prospective studies.

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