Friday, 19 December 2014

ClinicSpeak: improvement in function occurs when you stop inflammation

Do injectable DMTs have a future in the treatment of MS? #MSBlog #MSResearch #ClinicSpeak

Improvement in walking speed on natalizumab #MSBlog #MSResearch #ClinicSpeak

"The study below shows that MSers on natalizumab, a highly-effective DMT, improve; their walking speed gets better. This supports many others studies demonstrating an improvement in function in a proportion of MSers on natalizumab across several neurological subsystems, i.e. vision, bladder, upper-limb function, fatigue, cognitionm etc. Why natalizumab? It is almost certainly because it is a highly-effective DMT and renders the majority of subjects NEDA once they  have been on the drug for more than 12 months. Is this observation specific for natalizumab? No we also see this result with alemtuzumab and BMT (bone marrow transplantation), i.e. other highly-effective treatments. Why does this not occur on lower efficacy drugs? It does, but a much small number have improvements, because the the responders tend to be hidden in a sea of non-responders. If only we could determine responder status prior to starting a DMT it would allow us to optimise the sequencing of DMTs to derive the maximum benefit with the best safety profile for the treated population. I am  surprised that the Pharma companies that produce, and market interferon-beta, blinked. We have known for a decade or more that a type 1 interferon signature in the peripheral blood at baseline predicts a poor response to interferon beta. This finding has been replicated by several groups. Why didn't Pharma validate it in a controlled trial? If they did we interferon-beta may be with us for decades and beyond."

"I was asked by a neurologist in Hyderabad if I saw injectables surviving the onslaught of the oral DMTs. I said yes, firstly they are safe and some of us are now using them in pregnancy; the orals are too new for us to be confident about their safety in pregnancy and at least two are know to be teratogenic (teriflunomide and fingolimod). Secondly, many markets are price sensitive and as the injectables are cheaper than the newer therapies healthcare payers may insist on someone failing on a cheaper drug before they can access a more expensive one; the emergence of biosimilars should bring the costs of injectables even lower and will entrench this requirement in some markets. Thirdly, if we can confirm and validate predictive response markers the injectables will be here for ever. For example, if I can say that the chances of you being rendered NEDA (no evident disease activity) with a normal brain atrophy rate is greater than 80% on interferon-beta, would you choose that compared to an oral without any validated response marker? Finally, if a black swan moment occurs and we find a viral cause of MS and are able to monitor the viral load, interferon-beta may be the platform therapy on to which we graft on other antivirals; an analogy being hepatitis C. Some people laugh when I talk about finding a viral aetiology, but there are many observations in MS that seriously question the autoimmune hypothesis or dogma. I covered a few of  these observations in my recent talk in Canada."

Epub: Voloshyna et al. Natalizumab improves ambulation in relapsing-remitting multiple sclerosis: results from the prospective TIMER study and a retrospective analysis of AFFIRM.Eur J Neurol. 2014 Dec . doi: 10.1111/ene.12618.

BACKGROUND AND PURPOSE: Impaired ambulation is a prominent disabling symptom of multiple sclerosis and can lead to reduced quality of life. Whether natalizumab, a monoclonal antibody shown to reduce disease activity in relapsing-remitting multiple sclerosis, could impact ambulation performance was examined. 

METHODS: A prospective open-label study, TIMER, was conducted in natalizumab-naive MSers (n = 215). The timed 25-foot walk (T25FW) and timed 100-m walk (T100MW) were assessed at baseline and at weeks 24 and 48 of natalizumab therapy, together with Expanded Disability Status Scale scores. The effects of natalizumab on T25FW performance were also examined in a retrospective analysis of natalizumab-treated MSers (n = 627) and placebo control MSers (n = 315) from the AFFIRM study.

RESULTS: In TIMER, a significant increase from baseline in T25FW speed was seen at week 24 (P = 0.0074) and in T100MW speed at weeks 24 and 48 (both P < 0.001). A greater proportion of MSers showed clinically meaningful increases (≥20%) in walking speed on the T100MW (25%) than on the T25FW (13%) at week 48 (P = 0.032). In AFFIRM, natalizumab increased the proportion of patients with ≥20% confirmed improvement in T25FW speed at year 2 by 78% versus placebo (P = 0.0133).

CONCLUSIONS: Natalizumab increased walking speed in MSers with relapsing-remitting multiple sclerosis. The T100MW may be more sensitive to changes in ambulation capacity than the T25FW, and both tests appear to detect clinically meaningful improvements in ambulatory function.

CoI: multiple


  1. You also may want to consider what patients are actually saying about the effectiveness of drugs and how satisfied they are with them. Being on Copaxone and stable I would not even consider switching to a "highly effective drug". I think many people would agree:

    In this day and age where contemporary trials are showing annual relapse rates around 0.5, it is getting much harder to justify using new drugs that have potentially serious side effects.

    1. That's fine if your disease is stable much less so if you're not.

    2. Yes - well - my disease is apparently "stable", but there are no relapses, so once again the old SP and PP MSers are left out in the cold.....

    3. It is pretty clear that if it was up to Team G, all MSers would be on Alemtuzumab. I'm glad that the majority of MS doctors have a more rational approach to treatment.

    4. Anon 2:32 you obviously don't read this blog very often and have clearly not read or absorbed the content of this post; it is about Tysabri. I am not sure Team G is promoting alemtuzumab in this post. I have been coming to this site for over a year and I am grateful to have been empowered to make an informed decisions about my MS.

    5. Yes, I realize this post does not discuss Alemtuzumab. My point is Team G pushes the newest "highly effective" drug that has market potential. Alemtuzumab is their latest focus, but Tysabri still has a lot of life left before the patent expires. These drugs have a place but for a minority of MSers that have aggressive disease course and need are willing to take a chance to halt their MS.

      If you have been paying attention to this blog, the Mantra has been that if you have MS you should be on one of these agents.
      Fortunately, the rest of the MS scientific community thinks Team G is on the fringe.

    6. Re: " Team G is on the fringe."

      I prefer the term vanguard to fringe; please focus on end-organ damage, i.e. how much brain atrophy occurs despite NEDA-3 on the less effective drugs. If you want less brain when you get older that is your choice. The new focus is about brain health; maintaining the brain's reserve capacity to allow your brain to age as best it can. It is all about informed choice.

    7. Actually, the respected people don't claim your so called "highly effective" drugs are any better than some of the older agents. The Rocky Mountain MS center rates Tysabri, Alemtuzumab and Copaxone having the same effectivness regarding atrophy:

      The only agent rated better is Rituximab. Why aren't you pushing this drug? I suspect it relates to it being on the edge of comming off patent, so where's the incentive for you.

    8. Anon this blog frequently discusses Rituximab; for example .

  2. Oh Prof G - how true: "If only we could determine responder status prior to starting a DMT it would allow us to optimise the sequencing of DMTs to derive the maximum benefit with the best safety profile". If this was a mandatory element in clinical trials then maybe I wouldn't have spent a wasted year on Interferon Beta-1A (and wouldn't have had to put up with all of the bad stuff it did to me). However, I'm currently on no meds at all except LDN, and feeling an awful lot better than I was. Decisions on meds now deferred until another MRI done early next year - so we'll see what comes out of that......

  3. My balance issues miraculously disappeared after my first tysabri infusion. I wish I could continue taking it, but developed an allergic reaction during the third infusion. Oh well! I am now considering rituxan or lemtrada. Do you know what the chances of developing an allergic reaction to those are for me? I would be thoroughly disappointed if they fail for me. Then I'll just wait for you to prove your virus theory :).

  4. I have never managed to understand how the T25FW could provide meaningful measurements unless your mobility was already bad enough that you needed a walking frame of some kind and could really only shuffle along. 25 feet is such a short distance that any changes measured must be so tiny, unless mobility improvement is dramatic. Use of the T100MW makes much more sense to me, or even 25 or 50 metres seems to be a more "useful" distance over which to take time readings. I know that on a good day I can walk almost normally for around 50 metres (albeit it a bit slowly) before my walking starts to deteriorate. So why is the T25FW used so much as a measure? Seems to me that T100MW would be a far more valid tool, with timings taken at 25, 50, 75, and 100 metres, which would then clearly show a person's level of functioning, plus any deterioration in capacity over distance.


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