Wednesday, 2 April 2014

Will natalizumab slow or flat-line disability progression in SPMS?

Have we found a new phase 2 trial design for progressive MS? #MSBlog #MSResearch #ClinicSpeak


"I have been praising the study since it was presented at ECTRIMS 2012 in Lyon. In this study MSers with SPMS and PPMS were treated with natalizumab and monitored with spinal fluid analyses and MRI. It shows that natalizumab has favourable effects on all metrics studied in a relatively short timeframe of 60 weeks.

This study achieves many things. 

  1. It clearly shows that progressive MS is inflammatory. There is a self-perpetuating myth that progressive MS is not inflammatory but simply neurodegenerative and hence anti-inflammatory therapies are not required, but only neuroprotective therapies. This study should slay that myth. When people with progressive MS die their brains and spinal cord are stuffed full of T-cells, B-cells, plasma cells and activated microglia and macrophages. Therefore if we want to tackle progressive MS we need a potent anti-inflammatory and a second therapy that targets neurodegeneration. This is why I have been promoting the combination therapy strategy for over 10 years and why we are testing this strategy in the PROXIMUS trial. 
  2. Multiple lumbar punctures are possible. Progressive MSers in this study agreed to have two lumbar punctures. A lot of people have been saying that MSers are not prepared to have LPs. This is clearly not true. If the purpose of the study is explained and MSers understand why LPs are necessary they tend to say yes. In addition we have new ways of making LPs safer to do with less complications. I personally think LPs will be come the norm in progressive MS trials. 
  3. Spinal fluid analysis is valuable. This study shows that we can measure markers of inflammation, demyelination and neuroaxonal damage in the spinal fluid and we impact on these favourably with a treatment. This may be a game changer when it comes to doing similar studies in the future. What we (academia and pharma) need is a quick way of doing phase 2 studies in progressive MS. Using serial lumbar punctures is away of doing this. 
  4. Neurofilaments are responsive to treatment in progressive MS. In this study natalizumab reduced, but did not normalise spinal fluid neurofilament levels in progressive MSers. This indicates that more is needed to reduce spinal fluid neurofilament levels. Either further follow-up is required in progressive MS to see the levels become normal or an add-on therapy is needed to protect neurons and axons that are continuing to degenerate or die. I suspect that both are playing a role. Long nerve processes may take many months or even years to degenerate and release their contents; 60 weeks is too short for this process to run its course. In addition, switching off trafficking of inflammatory cells into the central nervous system is not enough to eliminate ongoing damage in progressive MS. Other therapies are need to address  the ongoing damage. 
  5. This study is a proof of principle study and shows that natalizumab may work in progressive MS. This is why Biogen-Idec are doing the ASCEND trial; to test whether or not natalizumab can slow down the rate of disability progression in SPMS. I have concerns that the trial is not long enough and does not take into account the therapeutic lag. Therapeutic lag is an observation that anti-inflammatory treatments in progressive MS only have an impact on disease progression after 2 years of follow-up. I have posted on this before and recommend you read my previous post. I would therefore urge Biogen-Idec to have an extended follow-up of  the study subjects in ASCEND to see what happens in the future. 
  6. Hope. This study gives hope to MSers with both SPMS and PPMS that just may be their disease is modifiable and it has taken a highly-active treatment to have the potency to show an effect. I also don't want to raise false hopes; my expectation is that the ASCEND trial will be positive in that it will slow down the rate of disease progression, but not flatline it or reverse disability. Why do I say this? I think the processes that drive disease progression are not simply inflammatory cells from the periphery, but also process from within the nervous system. In addition, most people with progressive MS have very little reserve capacity and hence don't have the ability for recovery; hence slowing down. We also have lessons from other highly active treatments in progressive MS to reflect on; alemtuzumab, rituximab and mitoxantrone have all been tried in progressive MS. Although these agents switch off relapses and MRI activity they don't stop disease progression. I have little reason to believe natalizumab will be any different. Therefor it is important  to realise that if you have progressive MS and are on one of these drugs that just slows down the rate of disease progression you may think it is not working. 
I would like to congratulate and thank my Danish colleagues for doing such an important study. I hope the above captures my enthusiasm for their work."

Therapeutic Lag Hypothesis

Epub: Romme Christensen et al. Natalizumab in progressive MS: Results of an open-label, phase 2A, proof-of-concept trial. Neurology. 2014 Mar.

OBJECTIVE: Natalizumab inhibits the migration of systemic immune cells to the CNS and may be beneficial in progressive MS. The objective of the study was to examine the effects of natalizumab in progressive MS.

METHODS: In an open-label phase 2A study, 24 progressive MSers were included to receive natalizumab treatment for 60 weeks. Response to natalizumab was assessed in CSF and MRI studies. The primary endpoint was change in CSF osteopontin, a biomarker of intrathecal inflammation, from baseline to week 60.

RESULTS: Seventeen MSers completed the study. No new safety issues were encountered. CSF osteopontin decreased by 65 ng/mL (95% confidence interval 34-96 ng/mL; p = 0.0004) from baseline to week 60 in conjunction with decreases in other CSF biomarkers of inflammation, axonal damage, and demyelination. Magnetization transfer ratio increased in both cortical gray and normal-appearing white matter and correlated with decreases in CSF neurofilament light chain.

CONCLUSIONS: Natalizumab treatment of progressive MS reduces intrathecal inflammation and tissue damage, supporting a beneficial effect of natalizumab treatment in progressive MS and suggesting that systemic inflammation contributes to the pathogenesis. Moreover, the study establishes the feasibility of using CSF biomarkers in proof-of-concept trials, allowing a low number of participants and short study duration.

CoI: multiple, we are a participating site in the ASCEND trial

11 comments:

  1. Thanks for posting this, yes it gives hope. What next?

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  2. Re; "What next?"

    We need to wait for the ASCEND results and lobby for more funding to test additional therapies using CSF biomarkers.

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  3. how is this different from the recent Germanstudy you blogged about? or does it support it? if so,surely its worth a progressive ms person to try getting on to further studies or have it done privately?

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  4. This question is not about natalizumab.
    Do you think some drugs will be more effective if they are injected into the spinal fluid?

    MSers are willing to accept multiple LPs. On the same lines, many will accept any route of drug administration as long as it stops the disease.


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    1. Re: "Do you think some drugs will be more effective if they are injected into the spinal fluid?"

      No not necessarily. The spinal fluid is the outflow path of the brain and hence large drugs can't recirculate.

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  5. Re " alemtuzumab, rituximab and mitoxantrone have all been tried in progressive MS. Although these agents switch off relapses and MRI activity they don't stop disease progression":

    Is it confirmed they do not nothing for progression even if given early enough?
    Could it be because of the therapeutic lag you mention?

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    1. Re: "Is it confirmed they do not nothing for progression even if given early enough?
      Could it be because of the therapeutic lag you mention?"

      I didn't say this. All I said is that they don't flat-line progressive MS, i.e. stabilise it. The question is whether they slow it down and whether or not if wait several years some MSers will develop burnt-out MS from therapeutic lag. The last point is important in relation to how we do future trials.

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  6. Prof G, as encouraging as this is, as a PPMSer it is rather depressing to hear again and again that trials need to be done. The thing is, we don't have the time to wait around for the trials to be done we are deteriorating daily. If you believe in this so strongly can't we be prescribed these off label??
    You also continually mention that you believe in a strong anti-inflammatory coupled with a neuroprotective drug. Is this currenlty how you treat PPMS'ers?

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  7. Modern medicine is evidence based
    .
    If it were a free for all evidence would not be collected propely.

    Then we would not know if it really works or not. If you went on tysabri and it was not flatlining ppms. You would have no idea if it were working or not..

    However doing nothing could say it eould be better to do something maybe a ruk wide egistry to allow pilot data to inform future trials
    However on the plus point if strong anti inflammatories can really stop PPMS as sugested then you may not have long to wait. The gilenya trial will finish soon. I am sure some PPMSers will benefit at the very lease and hopefuly more.

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  8. Mouse, the problem is. There is no great incentive to do these trials, you say so yourself given the lack of patient population or a population that has already progressed beyond the point of any realised effect..
    The horror of my daily reality is that I know I am going to go downhill fast as a newly diagnosed PPMSer. I see these theories and would sign my life away to try. My greatest fear is that Prof G hypothesis may prove correct and I will have to live with myself knowing that I was just diagnosed at the wrong time where treatment was available just not yet.. We have one life, yet are continually denied this hope... I ask what would you do in my situation????

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  9. Good question i have thought of some answers but will not say precisely what i would want to do treatment wise. I guess i would get on my neuros case to be proactive. If you have enhancing lesions there are clear choices if not i have a list of favorites

    if drug works for progressive Ms it is 60% of MSers the first dmt could be costed as an DMT this could be more than a 20 billion dollar market there is incentive.

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