Haematopoetic Stem Cell Therapy is the best way to deliver NEDA

NEDA status in highly active MS can be more easily obtained with autologous hematopoietic stem cell transplantation than other drugs.Sormani MP, Muraro PA, Saccardi R, Mancardi G. Mult Scler. 2016 Apr 26. pii: 1352458516645670. [Epub ahead of print]

The no evidence of disease activity (NEDA) composite measure has emerged as one attractive new target of therapies in relapsing-remittingmultiple sclerosis (RRMS), consisting of the following features: (1) no relapses, (2) no disability progression, and (3) no magnetic resonance imaging (MRI) activity (new or enlarging T2 lesions or Gd-enhancing lesions). Achievement of NEDA status in patients receiving a disease-modifying therapy (DMT) seems to be an ambitious but ideal goal for therapies in RRMS. Recently, published post hoc analyses of clinical trials reported percentages of RRMS patients maintaining the NEDA status after 2 years of therapy ranging between 13% and 46%. Long-term assessment of NEDA patients in real-life settings showed very low probability to be NEDA in the long run. Against this scenario, immunoablative therapy followed by autologous hematopoietic stem cell transplantation (aHSCT) demonstrated the potential to maintain a much higher proportion of NEDA patients at 2 years (ranging from 78% to 83%) and also at 5 years (ranging from 60% to 68%). This is even more relevant when considering that MS patients who underwent aHSCT are much more active than patients usually enrolled in clinical trials. The emerging evidence of the efficacy of this therapeutic approach in early aggressive and treatment-resistant RRMS calls for the organization of a randomized comparative trial to fully evaluate the risk-benefit profile of aHSCT in patients with highly active MS not responding to DMTs

We have been calling for the desire to achieve NEDA to promote brain health and if you take the ultimate DMT and replace the immune system you get better levels of NEDA than that achieved with any current drug and if you compare this to new data published for beta interferon

Uher T, Havrdova E, Sobisek L, Krasensky J, Vaneckova M, Seidl Z, Tyblova M, Ramasamy D, Zivadinov R, Horakova D. Is no evidence of disease activity an achievable goal in MS patients on intramuscular interferon beta-1a treatment over long-term follow-up?Mult Scler. 2016 May 26. pii: 1352458516650525. [Epub ahead of print]

BACKGROUND:No evidence of disease activity (NEDA) has been proposed as a new treatment goal in multiple sclerosis (MS). NEDA-3 status is defined as the absence of magnetic resonance imaging (MRI; new/enlarging/enhancing lesions and increased whole brain volume loss in NEDA-4) and clinical disease activity.
OBJECTIVES:To investigate the persistence of NEDA status over long-term follow-up in MS patients treated with weekly intramuscular interferon beta-1a.
METHODS:We included 192 patients after the first demyelinating event suggestive of MS, that is, clinically isolated syndrome (CIS) and 162 relapsing-remitting MS (RRMS) patients.
RESULTS: NEDA-3 status was observed in 40.1% of CIS and 20.4% of RRMS patients after 1 year. After 4 years, 10.1% of CIS patients had NEDA-3 status. After 10 years, none of the RRMS patients had NEDA-3 status. Only 4.6% of CIS and 1.0% of RRMS patients maintained NEDA-4 status after 4 years. Loss of NEDA-3 status after the first year was associated with a higher risk of disability progression (hazard ratio (HR) = 2.3-4.0; p = 0.005-0.03) over 6 years.
CONCLUSIONS: Despite intramuscular interferon beta-1a treatment, loss of NEDA status occurred in the vast majority of individuals. Loss of NEDA status during the first year was associated with disability progression over long-term follow-up; however, specificity for individual patient was low.

HSCT is not without risks but the level of NEDA clearly appears better than at least the CRAB drugs. 

Can they recruit to a trial? 

Will this be the death knell of big pharma drugs?. I doubt it, if there are neuros scared to use alemtuzumab, they will be too scared to recommend ablative HSCT.

Wonder how the idea of ZEUS trial is getting on?

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  • Re: "ZEUS Trial". There are two preliminary proposals being assessed by the NIHR (NHS's funding arm) at present. One to compare non-myeloabalative HSCT with best-care at present (alemtuzumab or natalizumab) and a second one comparing the safety of non-myeloablative with myeloablative HSCT in MS.

    We could debate the merits of both these proposals, but let's see if the peer review panel of the NIHR will say. I doubt they will fund both studies. If they do fund one study someone will have to decide which question needs answering first.

    • VS alem/nata seems most useful since then it would be hard to argue it wasn't worth approving if it bests them.

    • Regarding safety for MS, since HSCT is not a new procedure for autoimmune disorders is this necessary?

  • Gavin you need to start leveraging patients who have this done outside of the official UK system. Far more data points, far quicker. A bit of work on the back end but look upon as cost savings for DMDs et al you were giving them before. As this is shown to be an effective treatment with an acceptable (even superior) risk and side effect profile the NHS needs to crack on.

    The savings of using HSCT to the NHS and other welfare budgets could be immense. Cost saving and patient care enhancement all in for. Too golden an opportunity to fumble and dither over.

    • there is a register in Australia for this purpose and i understand there is one in the UK. I understand that the uptake of this register is low. In my Australian experience, the register is promoted to people post HSCT by no one and I've been told registration involves numerous forms without a road map. I spoke to MSRA which administers the register about 4 months ago and they assured me simplifying and streamlining access to the register is on their agenda to consider one unspecified day in the future. amongst all that conversation with msra, i never received the registration pack.

  • I have a list of 37 Brits already transplanted overseas. Plus another 31 that are scheduled in the next 6 months. I am in touch with all 68 patients.

    Comparing non-myelo with myelo, infers that an acceptance has already been made, that HSCT is superior to DMDs. Well… better late than never, all you fabulously qualified professionals.

    So here's a novel idea; how about the NIHR, pull their fingers out, and fund HSCT for all MS patients? The amount they would save on DMDs, would be truly phenomenal. Professor John Snowden, presented an HSCT cost benefit at the EBMT Symposium in 2010.

    And here we are SIX YEARS LATER… still begging for funding, when the savings in those six years, could have been massive. I am a Finance Director in the Oil Industry. May I offer you all my services?


    • Make sure they are being followed on the MS register so that knowledge of there progress can benefit all.

  • Here in Brazil in general is only done as a last resort HSTC for MS active and had no efficacy with no DMT here approved for treatment of MS …

    Connheço about 4 people who have non-mieoblativo and who had later rescidivas …
    I was thinking they would have made the transition to SPMS already before the transplant?
    One of them I know that MS became SP after the transplant …

  • When measuring the efficacy of HSCT compared to DMTs there is no mention of Treg response in patients. The use of disability progression, Gd-enhancing lesions and no relapses fails to account for the objective of HSCT which is a return to a normal T-cell population. This should be a required measure for NEDA. http://www.ncbi.nlm.nih.gov/pubmed/23721329

    • Use of HSCT in therapy-refractory RRMS would be to reset the "immunological clock" and restore T-cell tolerance in autoimmune diseases. Restoration of normal, circulating T regs would dampen the pro-inflammatory activity of Th17.

    • Who cares what the Tregs are?! People care about disability, and HSCT halts the underlying disease activity & progression to stabilize (and often reverse) disability. Some people cannot see the forest because the trees are in the way.

    • The fact that anti-CD25 therapy is effective in stopping relapses in MS would seem to argue that T regs are not a main player in MS. Anti-CD25 should deplete T regs and if dogma is correct then you might expect MS to worsen rather then improve, which is what is seen.
      Ask hardcore immunologists about this at a presentation and they shuffle awkwardly, mumble incoherently, shout "There's a squirrel" and run off.

  • If my sister (26) took copax this blog suggest patients need to have highly effective drugs to preserve brain volume. After a steadily progression and MRI changes my sisters neuro switched her treatment to Gilenya. This blog suggest to use BMT. Do not misunderstood me I think you have completely right but neuros don't. My sisters first 100 days with G have been encouraging (her eyes CFF improved from 30/34 to 38/37) and has more energy etc. Calm me down, highly effective drugs are enough to stabilize MS!

    • No we are not suggesting don't take copaxone and do BMT. We can present information and then people can make their mind up. Yes we want you to be NEDA because damage is lost brain, which we do not have the tools to repair. If you are not NEDA I would want your neurologists to help you achieve NEDA. I think if we read the paper the neuros are not suggesting this as a first port of call. As you will see when I post on brain atrophy it is not always clear cut. Each approach has merits some more than others

    • Hit hard early! CRAB drugs do not have any effect on BVL, but highly effective ones do! I think these message very important which is suggested by you. These research prove it clearly. NEDA and CRABs aren't friends. G and Ty partially. Is it enough or not? That's the billion dollars question.

    • MDoc thank you for your answer! First line injections do not have any effect (or maybe minor) on BVL so with these drugs patients do not able to reach NEDA4. When we look fingo or nat we see every 3rd or maybe other patient reach it, and it needs a long time (maybe years) so if MRI is unstable after 6 months with second lines, patients should switch to lemtrada or BMT? Highly active drugs do not bring NEDA4 immediately, and not for everyone…

      Which should be the best startegy?

    • The best strategy is often different for different people

      |fingers crossed your sister does well

    • Thank you MD! She loves G, and find it game changing drug, so G may hit hard but unfortunately not too early (edss 3, after 3,5 yrs)
      All in all the aim is NEDA4, and the billion dollars question which therapy brings it and how soon…

  • Everyone's MS is different Anonymous 5.46pm – that's the thing – we don't always know who's will follow a more progressive path. Good to see new research looking at different areas of treatment.

    • Marc, you should know that stem cell therapy is unproven and not recommended for pwMS…..it is much better to spend hundreds of thousands of dollars on pharmaceuticals per year 🙂 Dr. G posted recently in on the cost of MS drugs in the U.S. It is staggering. Let's hope these types of studies are pursued in MS.

    • Before it is posted the tisch centre is investigating direct injection of stem cell in MS. I would never say never and stems cells have lots of promise but there is a load of hype to that does not live up to the promise.



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