Friday, 6 November 2015

ResearchSpeak: natalizumab and brain atrophy

Will brain atrophy sort the men out from the boys? Almost surely! #MSResearch #MSBlog #ResearchSpeak

"There is one commentator who keeps saying natalizumab has no effect on brain atrophy; in fact he/she states it has zero effect. This is simply incorrect."

"In the STRATA, or extension study of the pivotal natalizumab trials, about 70% of MSers had brain atrophy rates of -0.4% or lower (slides 4 & 5). This is the unofficial cut-off for 'normalisation'. If you ask me this is pretty impressive data and is congruent with the clinical impact of natalizumab."

"Natalizumab has complex effects on brain atrophy. In year-1 it causes an increase in atrophy rate; we think this is due to the fact that it so effective as an anti-inflammatory that it reduces the swelling of the brain associated with inflammation. We call this effect pseudoatrophy as we don't think the brain atrophy in year-1 is only due to loss of neurones and axons. In year 2 on natalizumab the story is very different, here the atrophy rates are much lower in the order of 0.24% in the pivotal phase 3 or AFFIRM study (slide 1), well within the published 'normal range' (see slides 1-3 below). When you follow MSers up into year 3 the atrophy rates slow even further; the study below from Barcelona shows this very elegantly (slides 6 & 7)."

"Please note that until we follow-up age- and sex-matched normal controls in our phase 3 studies we can't claim brain atrophy rates are normalised. All we can do is compare them to published data sets on normal people."

"It is becoming increasingly clear that brain atrophy occurring now is driven by inflammation in the past. Inflammation doesn't only transect and destroy axons now, it damages other axons that then take months to years to degenerate, which is the pathological substrate for brain atrophy in the future. I have referred to the disconnect between the starting of an anti-inflammatory and its impact on brain atrophy years down the line as 'therapeutic lag'. The latter is not a very good term, but simply tries to capture the disconnect between switching off inflammation and the impact on brain atrophy as a therapeutic marker (see slides 6 & 7)."

"MSers with no inflammation, or Gd-enhancing lesions at baseline, have very little if any pseudoatrophy and much lower brain atrophy rates in years 2 & 3. In comparison, MSers with inflammation, or Gd-enhancing lesions, at baseline have much more prominent pseudoatrophy in year-1 and their brain atrophy rates are greater in year 2 & 3 (slides 6 & 7)."

"Please note pseudoatrophy and therapeutic lag with regard to natalizumab is also observed with other high efficacy therapies, i.e. alemtuzumab and HSCT. The impact of fingolimod is similar, but complicated by an impact of fingolimod on brain volumes very early on. We don't really know what the latter observation means; I suspect the early effect on brain volume changes is due to fingolimod-induced effects on other cell types (glial cells)."

"In conclusion, natalizumab does have an impact on brain atrophy; you simply have to look in the right time window."



Sastre-Garriga et al. Brain atrophy in natalizumab-treated patients: A 3-year follow-up. Mult Scler. 2015 May;21(6):749-56.

BACKGROUND: A pseudoatrophy effect has been held responsible for the lack of net impact of natalizumab on brain volume outcomes in 2-year trials, but no data are available beyond 24 months.

OBJECTIVE: We aimed to investigate brain volume dynamics in natalizumab-treated patients in up to 3 years after therapy initiation with clinical correlations.

METHODS: Patients on natalizumab for at least 3 years were clinically assessed 3-monthly. Magnetic resonance imaging scans were performed at baseline and yearly. Brain volume changes were obtained with SIENA. Multivariate models were used to investigate the association between baseline inflammation and changes in brain volume and disability.

RESULTS: Sixty-two patients with multiple sclerosis were analysed. Mean age and disease duration were 34.7 (SD: 8.3) and 10.4 (SD: 6.6) years. Presence of gadolinium enhancement at baseline was not associated with Expanded Disability Status Scale changes (p=0.468), but was associated with larger brain volume decreases (p=0.005) in the first (p=0.024) and second year (p=0.019) but not in the third year (p=0.863). Brain volume changes at 12 and 36 months were marginally associated with disability status at month 12 (p=0.094) and 36 (p=0.084), respectively.

CONCLUSIONS: Baseline inflammation affects brain volume measures up to 24 months after natalizumab initiation. A marginal association of brainvolume changes with disability is present.

CoI: multiple

16 comments:

  1. Thank you for taking the time to explain this. It is very reassuring to know that natalizumab affects brain atrophy in a positive way.

    ReplyDelete
  2. Actually, there are a lot of people who come to a different conclusion than Team G:

    1. Optimizing therapy early in multiple sclerosis: An evidence-based view

    http://www.sciencedirect.com/science/article/pii/S2211034815001066

    "Natiluzimab: No early and consistent effect on BVL"

    2. Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis

    http://www.cochrane.org/CD011381/MS_immunomodulators-and-immunosuppressants-relapsing-remitting-multiple-sclerosis-network-meta-analysis

    "For preventing relapses, alemtuzumab, natalizumab, and fingolimod are more effective than the other drugs, based on moderate to high quality evidence.

    For preventing irreversible disability worsening, insufficient evidence is currently available.
    Almost all of the agents included in this review were associated with a higher proportion of participants who withdrew due to any adverse event compared to placebo.
    It is worth noting the following:

    - The benefit of all of these treatments beyond two years is uncertain and this is a very relevant issue for people with a lifelong disease such as multiple sclerosis, who will possibly need long-term treatments.

    - Safety data from these short-term studies are scanty, poorly reported and cannot provide enough evidence for us to obtain a reliable risk profile of the treatments included in this review.

    - Most of the included studies were sponsored by pharmaceutical companies and this is a known potential source of bias."

    3. The SPMS trial for Nataluzimab was a failure. This trial also measured brain atrophy and since nothing has been touted about its effects on this it can be assumed it was a failure for the endpoint also.

    So, I think those who don't have on obvious stake in marketing Tysabri, the evidence is mounting that this is not as "highly effective" as Team G has been touting. It makes you wonder what Team G's true motives are.

    ReplyDelete
    Replies
    1. There are people who think the world is flat. If you think having relapses yo need to have your head looked at literally.
      There could be relapses what is needed in this meta analysis is to ask the question how do people compare if they are on effective treatment early after diagnosis do they do better than the therapy nihalists who do nothing
      If the horse has bolted the horse has bolted and not matter how much meta analysing you do the results wont be as good as you could get by being pro active.

      Delete
    2. Re: "The SPMS trial for Nataluzimab was a failure."

      I have said before it was a failure because of poor trial design. Hidden in the announcement was a positive outcome on upper limb function. I predicted the trial results and in my opinion it is a tragedy this study is negative.

      http://multiple-sclerosis-research.blogspot.com/2014/11/ascend-trial-why-i-think-natalizumab-in.html

      Delete
    3. Re: "Actually, there are a lot of people who come to a different conclusion than Team G."

      It is quite common for people to have different opinions to ourselves. The world of MS would be very boring if we all agreed with each other. The data is what it is; you can interpret it anyway you want. All I am trying to point out is that if you take an average over 2-years in the AFFIRM study there is no impact of natalizumab on brain atrophy. If you analyse year 1 and year 2 separately there are big differences. I prefer to interpret year 1 and year 2 separately, unlike other groups.

      Delete
    4. Re: "It makes you wonder what Team G's true motives are."

      Somebody stated that natalizumab had zero effect on brain atrophy; all I am trying to do is point out that this individual is wrong. Natalizumab does have an impact on brain atrophy, albeit a rather complex effect.

      Delete
    5. I know that I am on Natalizumab, and I got the results of my first annual MRI yesterday. Brain atrophy zero. I know this is not a trial figure.

      Delete
    6. Re: "....it (i.e. ASCEND trial) was a failure because of poor trial design." Firstly, the "lymphocyte centric" theory of MS has shown to be effective in relapses but lacking in progression. http://multiple-sclerosis-research.blogspot.com/2015/10/t-cell-immunotherapy-of-progressive.html Secondly, why would Biogen set themselves up for failure by implementing a flawed trial? Wasting money on poorly designed trials is something corporations do not want to do.
      Re: "If you analyse year 1 and year 2 separately there are big differences. I prefer to interpret year 1 and year 2 separately, unlike other groups." Why would brain atrophy data be positive in year 1 but not year 2? If lymphocytes are driving progression then brain atrophy data should be sustained. The data suggests otherwise.

      Delete
  3. The question that must be asked, as much as an inflammatory dampening response to brain, is whether nat. reduces brain atrophy in progressive MS. We know that there is brain atrophy in progressive MS - so what reduces that? Do we know yet what the atrophy rates from Fingolimod or Ocrelizumab are? http://multiple-sclerosis-research.blogspot.com/2013/10/imaging-brain-damage-in-ppms.html

    ReplyDelete
  4. Even the work by Team G shows that neurodegeneration occurs in the absence of inflammation. So why would they be touting Tysabri as a highly effective therapy even though their own work shows the opposite?

    http://www.ncbi.nlm.nih.gov/pubmed/24364862

    They want you to have the impression that there is no motivation behind what they are marketing, but the science (including their own) is starting to show cracks in their mantra.

    ReplyDelete
    Replies
    1. Re: " neurodegeneration occurs in the absence of inflammation.."

      Only in more advanced disease. There is evidence that inflammation is the primary driver of neurodegeneration. Both acutely (molecular scissors or shredding) and chronically. Axons that survive the initial insult are damaged and programmed to die off over time. If you allow too much damage to occur from inflammation you can't stop this process. This is why it is so important to switch off inflammation and stop the priming of delayed neurodegeneration. There is little doubt that natalizumab is a highly effective treatment in terms of its impact on focal MRI lesions and relapses, which are driven by focal inflammation. This is how the drug got its license. The problem is that if you let too much damage accrue natalizumab cannot fix it. This is what happened in the ASCEND trial too many MSers recruited had lost too much function in their legs and it was lower limb function that was driving two of the outcome measures in the composite outcome measure (EDSS and 25FTW). However, in the upper limbs the one pathway that still had reserve capacity natalizumab had a positive impact.

      In the PPMS ocrelizumab study the median EDSS of the trial participants was less the 5.0. In other words most of the study participants could walk without an aid. That is why this trial was successful. I am sure if natalizumab was trialled in the same group of MSers it would have been positive.

      Hindsight is wonderful; Biogen and the steering committee who designed the trial didn't know what we know now about these factors. They did their best at the time with the knowledge base available to them at the time.

      The important message is for us to learn from the trial.

      Delete
    2. "Even the work by Team G shows that neurodegeneration occurs in the absence of inflammation."

      We have never shown such a thing ....there is inflammation associated with neurodegeneration but it is glial mediated inflammation. There is lymphocytes inflammation assocaited with neurodegeneration too.

      Delete
    3. From the article's conclusion:

      "These findings are consistent with both a partial uncoupling of inflammation and neurodegeneration and that the regenerative response of remyelination is negatively correlated with inflammation."

      Inflamation via. T cell activity is what is being discussed and is what the mechanism of action of Tysabri is involved with. If you are saying Tysabri changes glial cell inflammation please provide your proof to back up this claim. If not, stop confusing the issue.

      Delete
  5. Anonymous 11:07:00 said, "the evidence is mounting that this is not as "highly effective" as Team G has been touting."

    In our experience, the evidence in our household is that it is more effective than they have been touting. Sure, it is only one case but when that one case is in your own household it takes the discussion out of the realm of scientific banter and bullshit and offers a perspective only personal experience affords.

    No new or enhancing lesions, no progression in EDSS since the first infusion in 2002, and I still can't beat that woman at scrabble. Gosh, we have a lot of good days, virtually all of them. There is a unique joy and love of life felt by those who have had a major disease go into remission and which stays there for years. It heightens awareness in some indescribable manner; priorities become more clear.

    I appreciate the lack of scientific data one experience provides. Nevertheless, one experience may provide a crack which helps open the door to understanding this treatment better.

    ReplyDelete
    Replies
    1. I'm glad to hear Tysabri is working for you. Copoxone is working well for me an I think it has helped many people also. The thing about all of the MS drugs is that no one knows the effect any of them has on longterm disability progression as was pointed out in the recently released Cochrane Review.

      However, Team G likes to give the impression that they know what is a "highly effective" therapy and what is not. The truth is they have no basis for their claims.

      I wonder if any of the PML victims also took Team G's opinion to heart also? But I'm sure if this was the case it wouldn't have caused any of the Team G'ers to bat an eye.

      Delete
    2. Likewise, I am glad your treatment is working well for you.

      As for long-term disability progression on Tysabri I can only relate experience in our household and what I have observed in a handful of other patients who were also in the Phase 3 trial from 2002-2005. Each of these who have continued and whom we see regularly have experienced no observable disability. Of course, people dropped out or discontinued treatment so perhaps, we are only looking at responders. Nevertheless, it is pretty impressive to see MSers often coming in for infusions before going to their jobs many years after initiating treatment.

      We all understand and talk about PML risk at the infusion center. It is not something a doctor or patient would omit from consideration. What really, really helps is having information available which informs our discussions. This site has no equal in providing information valuable to doctors and patients, IMO.

      I don't agree that the site is biased. But sometimes I have felt as though it held a less favorable view of Tysabri than was our experience.

      As far as not batting an eye for PML victims... well, no one is that calloused, and certainly no one investing their lives as these folks do.

      Tysabri has a PML risk. Our argument has always been that we recognize that risk and accept it. Why? We've experienced MS without effective treatment. Relapses where a lovely girl must be spoon fed and submit to the humility of someone else (please forgive my vulgarity) wiping her butt gave us the notion an intervention was imperative.

      Tysabri has been that intervention and here, in this household, it has worked better than we could have hoped. For us, no lesions are better than more lesions, no relapses are better than more relapses, and no EDSS progression is better than more progression. Actually, the lovely girl is walking faster than in 2002.

      I'll let the scientists debate definitions and mince semantics over disability progression or lack thereof. However it is defined is secondary to how we experience it. The kiss is what we're after, not the definition of affection.

      Sure, I understand the importance of preciseness; the scientists will work on it, I'm sure. But excuse me, I have a pretty girl to kiss right now.

      Delete

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