Saturday, 1 August 2015

ClinicSpeak: separating the men from the boys or the women from the girls

Will daclizumab prove to be a man or a boy / woman or girl? #ClinicSpeak #MSBlog #MSResearch

"I have made the point many times on this blog that the best human model for studying relapsing MS is natalizumab withdrawal. When natalizumab washes out of your system and immune surveillance restarts the immune system finds what is causing MS and MS flares up with a vengeance. The level of MRI activity, i.e. gadolinium-enhancing activity, associated with post-natalizumab rebound can be so prominent that some of us say the scan looks like a christmas tree, the lights being the active MS lesions."

"Rebound post-natalizumab is one of the observations for the field hypothesis; i.e. there is something in the brain of MSers (the field) that is causing MS and in the absence of an immune system it does no harm. However when you let the immune system in it finds what is there and tries to kill it, this cause direct and indirect damage that results in relapses and primes the nervous system for secondary, or delayed, neurodegeneration in the future (secondary progressive MS)."

"I am therefore thrilled to hear that one Pharma company is using rebound post-natalizumab to see how effective their putative drug is.  If a drug can't prevent rebound then it is not that effective. This is a very high hurdle to pass as most DMTs, or putative DMTs, that have been tried in this setting have failed to prevent rebound. This list includes steroids, glatiramer acetate, interferon-beta and dimethyl fumarate. The drugs that do prevent rebound are fingolimod and rituximab. The rituximab data is not published yet but comes from Sweden. In Sweden, rituximab, despite it being used off-label, is now the standard treatment for MS post-natalizumab. This augurs well for ocrelizumab, which works in the same way rituximab. The jury is still out regarding teriflunomide, but early indicators are that it is also not up to the job. I am reluctant to comment on alemtuzumab, because of the short term dangers associated with an induction therapy in MSers at risk of PML (see earlier posts)."

"Therefore the ability of DMTs to prevent rebound post-natalizumab is the litmus test that has the ability to separate out the men (highly-effective DMTs) from the boys (less effective DMTs). Is this particular Pharma company being brave, bold or stupid? I think they are being very clever; they are simply saying that if our new drug is not good enough to punt with the men then there is little place for it in the market."

"Everyone says that we can't, and we shouldn't, compare the results of clinical trials, but we all do. The purists say that the only way to compare drugs is in head-to-head studies. May be they are correct. But when it comes to relapses another option is to simply ask is drug x good enough to prevent natalizumab rebound? If it prevents natalizumab rebound then it is a highly-effective therapy, if it doesn't it is not a highly-effective therapy. This is why I can't wait to see how daclizumab does in this setting. Based on the phase 3 results I suspect it will be man and not a boy. The mode of action of daclizumab appeals to me and if it can prevent rebound post-natalizumab it may become the drug of choice for natalizumab-switchers. I hope Biogen and Abbvie starts a natalizumab switch study soon to answer this question. Daclizumab is not an immunosuppressive drug; T and B cell function appear normal in MSers on daclizumab and there is no opportunistic infection signal on the drug. Daclizumab does reduce T-reg cell function, which may explain why some MSers get secondary autoimmunity on daclizumab as a side effect. More importantly daclizumab expands a population of natural killer cells (NK cells) that are part of the innate immune system that is designed to fight infections, particularly viral infections. Therefore if someone transitions from natalizumab onto daclizumab, and has early or asymptomatic PML, daclizumab may help the immune system to fight the PML. This is all theoretical, which is why we need a clinical trial."


Gueguen et al.Abnormal inflammatory activity returns after natalizumab cessation in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2014 May.

OBJECTIVE: To characterise recurrence of multiple sclerosis (MS) inflammatory activity during the year following natalizumab (NTZ) cessation.


METHODS: Thirty-two patients with MS were included in a monocentric cohort study. Data were collected prospectively during and after NTZ, with serial clinical and MRI evaluations. The first relapse occurring after interrupting NTZ was the primary outcome measure. The numbers of gadolinium-enhancing lesions before, during and after NTZ treatment, were compared.

RESULTS: During the year following NTZ cessation, the cumulative probability of relapses was estimated at 52.9% and an unusually high MRI inflammation was noticed. It was defined by a number of gadolinium-enhancing lesions >5 and exceeding the gadolinium lesions existing before NTZ initiation. Rebound of MS activity after NTZ cessation was characterised by association of relapses and unusual MRI inflammation. Cumulative probability of rebound was estimated at 39% and mostly occurring between 3 months and 9 months after interrupting NTZ. Risk of rebound appears related with a higher annualised relapse rate and a lower Expanded Disability Status Scale score before NTZ initiation. Rebound was associated with severe recurring relapses in 9% of the patients.

CONCLUSIONS: This study identifies rebound after NTZ cessation as an association of relapses and high MRI activity.

CoI: multiple

21 comments:

  1. Or women from the girls! Given MS is more predominant in females I feel that is a more appropriate idiom;). Apart from my annoying language policing (in jest), this sounds very interesting, but I guess it's still many years away from use?

    ReplyDelete
  2. A very interesting post. My neurologist told me Tecfidera and Gilenya were essentially equivalent to each other in terms of their effectiveness. Are you saying the effect on stopping rebound indicates they are not and that Gilenya is the more effect drug? This is important for me as it would change my decision about which drug to start. Thank you for all the effort you put into this blog, there is no other resource like it on the web.

    ReplyDelete
    Replies
    1. Just bear in mind that the long-term effects of Gileyna on the heart are largely unknown. Including the fact that the reduction it creates in your heart's efficiency may well be permanent (I suspect this will be the case).

      I'm not on either of these two drugs, but I'm skeptical about the overtures of cardiac safety claimed by the manufacturer.

      It's tragic that we're so often left to chose between permanent damage to the CNS by this disease, or permanent damage to so many other life-critical organs. The heart, foremost of all.

      Delete
    2. Any effects on the heart seem to be temporary.

      Delete
  3. Very interesting. This blog is very useful.

    ReplyDelete
  4. Prof G,

    The field hypothesis looks spot on. Why can't the target in the brain be identified? Is there much research looking at this?

    ReplyDelete
  5. How do you know that it's not the other way round:

    there is something in the immune system, while the brain is intact, that causes MS

    and when it's removed from the brain due to drugs it ceases activity

    but once the drug is stopped the immune system reappears and causes havoc?

    ReplyDelete
    Replies
    1. If it was the immune system that had the target there is no reason why it would be just in brain that you get lesions. The white cells can go every where butvyou get problems when they recognise their target this i believe is in the brain or spinal cord

      Delete
  6. It appears that about a half of post-Tysabri MSers had a rebound - but why the other half did not have relapses? Does this mean that different mechanisms cause MS in different people - "field hypothesis" for about a half, something else for the other half?

    ReplyDelete
  7. Is there a rebound post-fingolimod or post-rituximab?

    ReplyDelete
    Replies
    1. Without doing some reading, I would preict with fingolimod that this is a potential because it is essentially doing the same as natalizumab one trapping cells in the lymph glands the other trapping cells in the blood. With rituzimab you are depleting B cellsand they will slowly recover, whilst disease may return Iamnot sure it will be a bebound as soon as the drug is gone.

      Yep I'm correct
      Severe disease reactivation in four patients with relapsing-remitting multiple sclerosis after fingolimod cessation.Berger B, Baumgartner A, Rauer S, Mader I, Luetzen N, Farenkopf U, Stich O.J Neuroimmunol. 2015 May 15;282:118-22.

      There are many other reports

      No papers poppe up with rituximab,rebound and MS.

      Delete
    2. Thank you - this is helpful

      Delete
  8. I posted this on a previous post about the rebound effect, but never got a response. I'm still curious to know the answer:

    I've been confused about claims in the literature to have identified a rebound effect. Most papers that report a rebound effect have found it in no more than 20% of patients. Isn't rebound activity, as currently defined, expected in many patients just by chance? The pre-natalizumab baseline is a noisy estimate of how much disease activity these patients are naturally prone to. Some of these patients will be prone to disease activity which is higher than this estimate, and some will be prone to disease activity which is lower. So the observed rebound effect may just be these patients returning to their natural disease course. Not only that, but the patients being put on natalizumab are those with a poor prognosis and severe disease. Won't some proportion of these people be expected to have catastrophic relapses (as have been observed post-natalizumab) by chance? What was the base rate of such relapses in the population before any DMTs became available?

    ReplyDelete
    Replies
    1. Any takers for this question? If you think post-natalizumab rebound is important for understanding the biology of relapsing MS, then there should be easily articulated reasons for thinking that it's a real phenomenon!

      Delete
    2. In terms of rebound and resuming natural course, it is a tricky one.

      In the animals we have seen disease return within a couple of days of stopping drug verses it returning over a few weeks. We took the view this was just disease returning. However some people see this same phenomenon and start shouting rebound rebound....and this had an effect in sodium channel trial. Prof Waxman saw EAE return after stopping drug an this prompted him to terminate his planned trial. It had the knock on effect of also maying the lamotrigine trial have to be extended to see if rebound occurred. It didn't. We don't think sodium channel blockers are that good as immunosuppressives and we would not predict a rebound...however this meant that a potential treatment which is probably beneficial could have been studied 8 years ago.
      It could be available now had this trial gone ahead.

      For the rebound it should probably occur within a short window of the drug washing out of the system and perhaps the disease should be particularly aggressive. This suggests the damaging cells are there and ready to go, once drug is gone. However you may expect disease to reactivate after therapeutic drug is removed..

      Delete
    3. Thanks. The evidence for a real rebound phenomenon seems very thin, unless there's a folklore among clinicians that hasn't yet made it into print.

      Delete
    4. I agree. It does seem very thin, so either it's trying to scare the s**t out of us or it is 'folklore' that hasn't made it into print.

      Delete
    5. when you work with rubbish eae e.g alot of our experience with MOG induced EE and all of a sudden you get disease occuring at the same time and of a high severity you may freak out and shout rebound but this is our normal eae becauze we have quality control in the system and so it would not freak us out.

      Delete
    6. Hey what is this "rubbish EAE" stuff? I don't think it's rubbish, which millions of mice have laid down their lives for and neither do you MD:)

      Delete
    7. A lot of the EAE stuff out there is rubbish though, our own studies excepted of course ;-)

      Delete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.